Stage Endometrial Cancer Research Articles

Progestin-based pharmacotherapy in fertility preservation in early endometrial cancer

Endometrial cancer is a common tumor of the female reproductive system. In recent years, as the age of onset of the disease has gradually become younger, this has caused distress to some young patients with reproductive needs, and the active search for methods of preserving reproductive function has gradually attracted attention. In this paper, we will systematize the current status of progestin-based pharmacotherapy in combination with other drug therapies in the conservative management of early-stage endometrial cancer. With the expectation of providing a reference for the treatment of early stage endometrial cancer patients in China and for the in-depth development of related research in this field.

Safety and feasibility of same-day discharge in robotic hysterectomy and staging for endometrial cancer: A multicenter review

Safety and feasibility of same-day discharge in robotic hysterectomy and staging for endometrial cancer: A multicenter review

Understanding new endometrial cancer staging; How old becomes new

Understanding new endometrial cancer staging; How old becomes new

Survival analysis of a prospective intraoperative algorithm to guide surgical staging in early-stage endometrial cancer

Survival analysis of a prospective intraoperative algorithm to guide surgical staging in early-stage endometrial cancer

Challenges in implementation of molecular classification in early stage endometrial cancer-An NRG Oncology cooperative group mixed-methods study.

Professional guidelines recommend molecular profiling for mismatch repair (MMR), p53, and polymerase epsilon (POLE) status in endometrial cancer (EC). However, adoption in the United States has not been documented, and barriers to the implementation of testing have not been described. In this mixed-methods study, implementation science frameworks were used to develop a quantitative survey. Gynecologic oncologists, medical oncologists, radiation oncologists, and pathologists affiliated with NRG Oncology programs were contacted through snowball sampling and were surveyed during 2022-2023. A subset of respondents was interviewed. Statistical and thematic analyses were performed. At least 403 NRG Oncology-affiliated providers were contacted for the survey, and 107 (26.6%) responded. Greater than 90% of respondents perceived POLE, MMR, and p53 status as important for clinical care. MMR and p53 tests were perceived as easy to obtain, but only 24.2% of respondents reported that POLE testing was moderately or very easy to obtain. Respondents from academic sites reported better access to molecular classification and perceived greater importance of molecular classification compared with respondents from community sites. In thematic analysis of 13 qualitative interviews, cost concerns were reported as large barriers to testing. Interviewees reported a desire for prospective data to guide treatment selection based on classification results. Although integrating molecular classification into standard pathologic reporting is recommended, and clinicians perceive molecular profiling in early stage EC as important, survey respondents noted significant implementation barriers. Implementation challenges that differ between community oncology and academic practice settings were identified. Strategies to improve equitable access to molecular classification of early stage EC are needed.

Accuracy of intraoperative frozen section in surgical staging of endometrial cancer

ObjectiveThis study evaluates the role of frozen section (FS) in determining the extent of disease during surgery. Materials and methodsThis study retrospectively analyzed a cohort of patients diagnosed with endometrioid-type endometrial cancer between 2019 and 2022 who underwent surgical intervention. The frozen section (FS) results were compared with the final pathology reports, focusing on tumor grade, depth of myometrial invasion, cervical involvement, and tumor diameter. ResultsThe final analysis included 187 patients. The predictive accuracy of FS in determining PS results was 85.6 % for endometrioid histology, 95.7 % for grade 3 tumors, 90.2 % for depth of myometrial invasion, 89.7 % for cervical involvement, and 95.9 % for tumor diameter. Notably, 9.8 % of cases initially classified as grade 1 intraoperatively were upgraded with the final pathology. Similarly, 6.3 % of grade II cases were upgraded, while 60.4 % were downgraded. ConclusionOur study highlights the effectiveness of FS as a dependable tool for assessing endometrial carcinomas and guiding surgical staging decisions. By utilizing FS, the risk of unnecessary surgeries and associated morbidity in patients can be reduced.

The Impact of Positive Peritoneal Cytology on the Survival of Endometrial Cancer Patients

Background: Since the revision of the FIGO staging of endometrial cancer in 2009, patients with positive peritoneal cytology are no longer upstaged to stage IIIA. However, several studies demonstrated poorer outcomes in patients with positive washings. We conducted a survival analysis with the aim of evaluating the impact of positive peritoneal cytology on the survival of EC patients. Methods: We performed a retrospective analysis of prospectively collected data on patients with endometrial cancer operated in our institution between 2008 and 2014. We analysed the impact of positive peritoneal cytology and other established prognostic factors on survival. Results: A total of 227 patients with a median follow-up of 6.9 years were included in the study. A total of 12.8% had positive peritoneal cytology. Positive peritoneal cytology was significantly associated with worse overall survival (HR 1.82; 95% CI 1.02–3.26; p 0.043) but not with worse recurrence-free survival (HR 1.64; 95% CI 0.92–2.93; p 0.091) in univariate analyses. In addition, tumour stage, histologic subtype, lymphovascular space invasion, grade, and the depth of myometrial invasion were all significant prognostic factors for overall survival in univariate analyses. In multivariate survival analysis, only the histologic subtype, tumour stage, and myometrial invasion remained in the model at the last step. Conclusions: Positive peritoneal cytology was associated with worse overall survival in our series of endometrial cancer patients. However, other traditional prognostic factors had a more important prognostic role for survival in a multivariate model.

Combined robotic surgery for concomitant treatment of endometrial cancer and obesity.

Endometrial Cancer (EC) is strongly linked to obesity. Bariatric surgery is recognized as a long-term solution for weight loss in severely obese patients. This pilot study investigates the feasibility, intraoperative and 30-day morbidity outcomes of integrating gynecological surgical staging and bariatric robotic surgery in class II and III obese patients affected by early EC or Endometrial Intraepithelial Neoplasia (EIN). Patients aged over 18years old with early EC or EIN and class II and III obesity (Body mass index (BMI) ≥ 35kg/m2) who are surgical and anesthesiologic candidates. Standard robotic surgery for early EC staging performed alone (THBSO group) or in conjunction with sleeve gastrectomy (THBSO + SG group) for obesity management was proposed. Of the 13 patients who met the inclusion criteria, 5 (38.46%) opted for combined surgery. The groups showed a significant difference in preoperative BMI (49.68kg/m2 vs. 40.24kg/m2 p = 0.017 with and without SG), preoperative weight (143.92kg vs. 105.62kg p = 0.004 with and without SG), preoperative (p = 0.01) and postoperative (p = 0.005) aspartate transaminase (AST). The THBSO + SG group had higher anesthesia induction end-tidal carbon dioxide (ETCO2) (p = 0.05), final Partial pressure of carbon dioxide (PaCO2) (p = 0.044), anesthesia induction lactate (p = 0.001) and final lactate (p = 0.011) without a significant difference in final pH (p = 0.31). Operative time was longer in the THBSO + SG group (p < 0.001), but this did not result in longer ICU (p = 0.351), total hospital stays (p = 0.208), nor increased blood loss and transfusion. The simultaneous combined approach had an 80% success rate. At 6months, the THBSO + SG group achieved significantly greater weight loss than the THBSO group (ΔBMI -11.81kg/m2 vs -1.72kg/m2, p = 0.003, with and without SG). Integrating robotic EC staging with SG in obese women with early EC increased the operative time without increasing intraoperative risks, early and 30days post-surgery complication and offering a promising approach to simultaneously treating both conditions.

VNOTES scarless and painless endometrial cancer staging surgery.

Sentinel lymph node dissection is performed in endometrial cancer surgery instead of staging surgery, particularly when the disease is advanced and confined to the uterus. The aim of this study is to share our sentinel lymph node detection rates via the vaginal natural orifice transluminal endoscopic surgery method with the literature and to demonstrate a safer and more comfortable surgical treatment process. The analysis includes the patients who underwent surgery sentinel lymph node dissection for endometrial cancer utilizing indociyanin green in our center between January 2022 and June 2024. In all, of 24 endometrial cancer patients underwent surgery sentinel lymph node dissection, nonendometrioid (serous) pathology was observed in only 1 (4%) patient, our other patients (96%) had endometrioid adenocarcinoma pathology. The rates of our sentinel lymph node dissection bilateral and symmetric are 96% (23/24), 94% (22/24), and 79% (19/24), respectively. We would like to emphasize that we successfully used vaginal natural orifice transluminal endoscopic surgery approach on four of our patients who were unsuitable for laparoscopic and robotic surgery due to pain scores of 2 at the 12th hour after surgery and low lung capacity. Vaginal natural orifice transluminal endoscopic surgery and sentinel lymph node dissection will be considered as surgical options in other gynecological cancers due to the comfort it brings to the patient in endometrial cancer.

Adjuvant Brachytherapy for Early Stage Endometrial Cancer: Clinical Outcomes and Dosimetric Comparisons of Ovoid and Cylinder Applicators

Adjuvant Brachytherapy for Early Stage Endometrial Cancer: Clinical Outcomes and Dosimetric Comparisons of Ovoid and Cylinder Applicators

SENECA study: staging endometrial cancer based on molecular classification

ObjectiveManagement of endometrial cancer is advancing, with accurate staging crucial for guiding treatment decisions. Understanding sentinel lymph node (SLN) involvement rates across molecular subgroups is essential. To evaluate SLN involvement...

Staging for endometrial carcinoma FIGO 2023 and its relevance for clinical practice.

International Federation of Gynaecology and Obstetrics (Fédération Internationale de Gynécologie et d'Obstétrique - FIGO) introduced a new staging system for endometrial carcinoma - FIGO 2023 - in June 2023. The new staging system differs significantly from previous versions. The new system represents a significant departure from the traditional staging systems for other gynaecological cancers, as the definition of individual stages includes not only the traditional anatomical extent of the tumour, but also the molecular profile of the tumour and other histopathological parameters - histological type of tumour, tumour grade and the presence of substantial lymphovascular invasion. The new system defines stages I and II in a completely different way and expands the definition of stages III and IV, allowing for different types of tumour spread outside the uterus. The introduction of molecular testing is the main change in the new staging system. When certain molecular markers are detected, stage I or II is completely changed. By including these non-anatomical parameters, the FIGO 2023 staging system improves the accuracy of a patient's prognosis at a specific stage with better options for individualized treatment, including the use of immunotherapy. Another goal was to synchronise staging as much as possible with the recommendations of three professional societies: the European Society of Gynaecological Oncology (ESGO), the European Society for Radiotherapy and Oncology (ESTRO) and the European Society of Pathology (ESP). The staging system for carcinosarcoma remains identical to the staging system for endometrial cancer. This article presents an overview of the new FIGO 2023 endometrial cancer staging system and discusses its advantages and disadvantages for clinical practice.

Prognostic significance of lymphovascular space invasion in early-stage low-grade endometrioid endometrial cancer: a fifteen-year retrospective Chinese cohort study

ObjectiveIn 2016, the ESMO-ESGO-ESTRO consensus included LVSI (Lymph-vascular space invasion, LVSI) status as a risk stratification factor for stage I endometrioid endometrial cancer (EEC) patients and as one of the indications for adjuvant therapy. Furthermore, LVSI is included in the new FIGO staging of endometrial cancer (EC) in 2023. However, the data contribution of the Chinese population in this regard is limited. The present study aimed to further comfirm the influence of LVSI on the prognosis of early-stage low-grade EEC in a fifteen-year retrospective Chinese cohort study.MethodsThis retrospective analysis cohort included 702 EEC patients who underwent TAH/BSO surgery, total abdominal hysterectomy, bilateral salpingooophorectomy in Peking University People’s Hospital from 2006 to 2020. Patients were stratified based on LVSI expression status as: LVSI negative group and LVSI positive group. Clinical outcome measures related to LVSI, assessed with a univariate and multivariate Cox proportional hazards regression model.Results702 EEC patients with stage I and grade 1–2 were analyzed. 58 patients (8.3%) were LVSI-positive and 14 patients (2.0%) was relapse. Recurrence rates in LVSI-negative and LVSI-positive were 1.6% and 6.9%, respectively. 5-year disease-free survival (DFS) rate in LVSI-negative and LVSI-positive were 98.4% and 93.1%, respectively. These rates for 5-year overall (OS) survival in LVSI-negative were 98.9% while it was 94.8% in LVSI-positive. Multivariate analysis showed that LVSI is an independent risk factor for 5-year DFS (HR = 4.60, p = 0.010). LVSI has a similar result for 5-year OS(HR = 4.39, p = 0.028).ConclusionsLVSI is an independent predictor of relapse and poor prognosis in early-stage low-grade endometrioid endometrial cancer in the Chinese cohort.

Endometrial cancer recurrence after the use of a uterine manipulator during laparoscopic surgery

ObjectiveMinimally invasive surgery (MIS) is the standard approach for the staging and treatment of early-stage endometrial cancer (EC) and often includes use of a uterine manipulator. Uterine perforation is a known risk in this setting, and the impact of perforation and tumor spillage on cancer recurrence is largely unknown. The aim of this study was to assess the association between uterine perforation and/or tumor spillage at the time of MIS for low-grade, early-stage EC on disease recurrence. MethodsA retrospective single-center cohort study was conducted including patients who underwent MIS for management of low-grade and early-stage EC with use of a uterine manipulator. Rates of disease recurrence were compared between patients with and without documented uterine perforation and/or tumor spillage at the time of surgery. Statistical significance was defined as p < 0.05. Results408 patients with low-grade and early-stage EC were identified from the tumor registry and included in the study. Uterine perforation and/or tumor spillage was documented in 5.9 % (24/408) of cases. Recurrent disease was noted in 8.1 % (33/408) of the entire cohort. Most patients had isolated local recurrence (23/33; 69.7 %), while 9.1 % (3/33) had distant recurrence and 21.2 % (7/33) had both local and distant recurrence. There was no association between uterine perforation and/or tumor spillage and recurrence rates (p = 0.67). The trend in disease free survival was shorter among patients with these complications. ConclusionsOur analysis did not demonstrate a statistically significant difference in disease recurrence rates among patients with early-stage, low-grade EC based on uterine perforation and/or tumor spillage at the time of surgery.

The prognostic role of mitosis index, stage and grade of endometrial cancer in Dr. Soetomo General Academic Hospital Surabaya, Indonesia, in 2018-2020

HIGHLIGHTS 1. Mitotic index and grade are prognostic factors for endometrial cancer, but both are independent.2. Stage and mitotic index associated with cell proliferation affect the prognosis of endometrial cancer. ABSTRACT Objective: This study aimed to analyze the correlation between the mitotic index and the stage and grade of endometrial cancer. Materials and Methods: We collected pathology reports of endometrial cancer from the Pathology Laboratory at Dr. Soetomo General Hospital in Surabaya, Indonesia, covering cases diagnosed between 2018 and 2020. A total of 106 cases of endometrial cancer were included in this study. For each case, detailed records of the cancer stage, grade, and mitotic index were recorded. The mitotic index, an indicator of cell proliferation, was quantified, and its correlation with cancer stage and grade was assessed. To determine the strength and direction of these relationships, we performed a Spearman rank correlation statistical analysis for non-parametric data. Results: Our findings indicated a significant positive correlation between the mitotic index and the stage of endometrial cancer. An increase in the mitotic index, reflecting a higher proliferation rate of cancer cells, was associated with a more advanced cancer stage, suggesting that the mitotic index could potentially serve as a prognostic marker for assessing tumor progression in endometrial cancer. However, our analysis revealed no significant correlation between the mitotic index and the histological grade of endometrial cancer, implying that the grade, which typically reflects the differentiation status and morphological characteristics of the tumor cells, is independent of the proliferation rate as measured by the mitotic index. Conclusion: The mitotic index is positively correlated with the stage of endometrial cancer but does not show a correlation with the histological grade. These findings highlight the potential use of the mitotic index in staging endometrial cancer.

Is fluorometric sentinel lymph node biopsy in endometrial cancer necessary?

In this study, we collected perioperative and postoperative follow-up data from patients with endometrial cancer (EC) at different stages to evaluate the role of sentinel lymph node biopsy (SLNB) in endometrial cancer surgery. A total of 186 endometrial cancer patients undergoing radical hysterectomy from January 2018 to April 2022 were retrospectively analyzed. Patients were classified into four groups. Group A comprised patients diagnosed with stage IA grade 1 and 2 endometrioid EC who underwent SLNB. Group B comprised patients with stage IA grade 1 and 2 endometrioid EC who did not undergo SLNB. Group C comprised patients with higher-grade endometrioid EC, wherein systematic lymph node dissection was performed based on SLNB results. Group D comprised patients with higher-grade endometrioid EC who did not undergo SLNB and instead underwent direct systematic lymph node dissection. Clinical, pathological data, and follow-up information for all patients were collected. In Group A and B, SLNB was performed on 36 out of 67 patients with IA stage 1 and 2 endometrial cancer, yielding a SLN positivity rate of 5.6%. There were no significant differences observed between the two groups regarding perioperative outcomes and postoperative follow-up. Conversely, among 119 patients with higher-grade endometrial cancer, 52 underwent SLNB, with 20 patients exhibiting SLN positivity, resulting in a SLN positivity rate of 38.4%. However, the decision to undergo SLNB did not yield significant differences in perioperative outcomes and postoperative follow-up among these patients. For stage IA grade 1 and 2 endometrioid EC, the incidence of lymph node positivity is low, omitting SLNB in this subpopulation is a feasible option. In other stages of endometrioid EC, there is no significant difference in perioperative and postoperative follow-up data between patients undergoing routine systematic lymphadenectomy and those undergoing systematic lymphadenectomy based on SLNB results. Therefore, if SLNB is not available, the standard procedure of PLND remains an option to obtain information about lymph node status, despite the surgical complications associated with this procedure.

ENDOLUNG trial. A phase 1/2 study of the Akt/mTOR inhibitor and autophagy inducer Ibrilatazar (ABTL0812) in combination with paclitaxel/carboplatin in patients with advanced/recurrent endometrial cancer

BackgroundCarboplatin and paclitaxel (CP) have been the standard of care for advanced/recurrent endometrial cancer (EC) for many years. However, this chemotherapy combination shows limited efficacy and recurrences often occur in less than 12 months. ABTL0812 is a novel drug that selectively kill cancer cells by cytotoxic autophagy and has shown anticancer efficacy in preclinical models of EC in combination with CP.MethodsENDOLUNG was an open-label, phase 1/2 clinical trial designed to determine the safety and efficacy of Ibrilatazar (ABTL0812) with CP in patients with advanced/recurrent EC and non-irradiable stage III and IV squamous non-small cell lung cancer (sq-NSCLC). The phase 1 part consisted of a 3 + 3 de-escalation design followed by an expansion cohort with 12 patients. The primary endpoint was safety. ABTL0812 starting dose was 1300 mg tid combined with carboplatin at area under the curve (AUC) 5 and paclitaxel at 175 mg/m2 both administered every 21 days for up to 8 cycles. The phase 2 part included a total of 51 patients. The primary endpoint was overall response rate (ORR) and the secondary endpoints included duration of response (DOR), progression-free survival (PFS) and overall survival (OS).ResultsDuring the phase 1 only one dose limiting toxicity (DLT), a grade 4 neutropenia, was observed in 1 out of 6 patients, thus no de-escalation was applied. One additional DLT, a grade 3 febrile neutropenia, was observed in the expansion cohort, thus the recommended phase 2 dose (RP2D) for ABTL0812 was established at 1300 mg tid. Most frequent hematological adverse events (AE) of the combination were neutropenia (52.9%), anemia (37.3%) and thrombocytopenia (19.6%). Nausea (66.7%), asthenia (66.7%), diarrhea (54.9%) and vomiting (54.9%) were the most frequent non-hematological adverse events (AEs). The combination of ABTL0812 plus CP showed an ORR of 65.8% (13.2% complete response and 52.6% partial response) with a median DOR of 7.4 months (95% CI: 6.3–10.8 months). Median PFS was 9.8 months (95% CI: 6.6–10.6) and median OS 23.6 months (95% CI 6.4-ND). Pharmacokinetic parameters were compatible with target engagement observed in preclinical studies, and blood pharmacodynamic biomarkers indicated sustained target regulation during, at least, 28 days after starting the treatment.ConclusionsThis study suggests that the combination of ABTL0812 with CP is safe and feasible with an encouraging activity in patients with advanced/recurrent EC. Our data warrant further confirmation in prospective randomized trials.Trial registrationEU Clinical Trial Register, EudraCT number 2016-001352-21 and National Clinical Trials Number, NCT03366480. Registration on 19 September 2016.

Use of indocyanine green dye for sentinel lymph node mapping in patients with endometrial cancer and a history of iodinated contrast allergy

ObjectivesSentinel lymph node (SLN) mapping is a surgical technique with high accuracy in detecting metastases while limiting morbidity associated with full lymphadenectomy in endometrial cancer. Cervical injection of indocyanine green (ICG) dye is associated with very high SLN detection rates; however, iodinated contrast allergy has traditionally been viewed as a contraindication to ICG use. The objective of this study was to describe the use of ICG in a population of patients with iodinated contrast allergies undergoing surgical staging for endometrial cancer. MethodsIRB approval was obtained. All patients with clinically early-stage endometrial cancer who underwent minimally invasive surgical staging with SLN mapping with ICG at a single academic institution from 1/1/2017 to 12/31/2020 were identified retrospectively. Patients with reported iodinated contrast allergies prior to surgery were identified. Data were collected through electronic medical record review and compared using descriptive statistics. Results820 patients who underwent minimally invasive surgical staging with SLN mapping with ICG were identified, and 25 had documented iodinated contrast allergies. Documented reactions included rash/hives (n = 10, 40 %), anaphylaxis (n = 6, 24 %), shortness of breath (n = 5, 20 %), diarrhea (n = 1, 4 %), and not specified (n = 3, 12 %). A majority (24/25, 96 %) received 4 mg intravenous dexamethasone during induction of general anesthesia as per the institutional enhanced recovery after surgery (ERAS) protocol. No patients experienced allergic reactions or other adverse events after ICG injection. ConclusionsNo patients in this cohort demonstrated an adverse reaction after ICG injection for SLN mapping. This study supports the reasonable safety of ICG in patients with contrast allergies, particularly when routine ERAS protocols containing dexamethasone are utilized.

Advanced endometrial cancer—The next generation of treatment: A society of gynecologic oncology journal club clinical commentary

In February of 2024, the Society of Gynecologic Oncology (SGO) hosted a journal club focused on new treatment options for the management of advanced and metastatic endometrial cancer. This clinical commentary is intended to provide a summary report of that presentation. The session described the importance of molecular characterization shown in the work of The Cancer Genome Atlas (TCGA). The updated 2023 FIGO staging of endometrial cancer was reviewed. The panel then described the role of upfront immunotherapy for the treatment of advanced or recurrent endometrial cancer as demonstrated in four recent trials (RUBY, NRG-GY018, AtTEnd, and DUO-E studies). The DUO-E study uniquely examined the combination immunotherapy with a PARP inhibitor. The trials had unique differences in inclusion criteria, primary outcomes, and length of maintenance therapy, but all boasted similarly promising results particularly in mismatch repair deficient (dMMR) endometrial cancer. This era of rapid innovation in advanced and recurrent endometrial cancer will hopefully enhance individualized treatment approaches and improved outcomes for patients with endometrial cancer.

Insights into inflammation and implications for the pathogenesis and long-term outcomes of endometrial cancer: genome-wide surveys and a clinical cohort study

BackgroundDespite evidence showing a connection between inflammation and endometrial cancer (EC) risk, the surveys on genetic correlation and cohort studies investigating the impact on long-term outcomes have yet to be refined. We aimed to address the impact of inflammation factors on the pathogenesis, progression and consequences of EC.MethodsFor the genetic correlation analyses, a two-sample of Mendelian randomization (MR) study was applied to investigate inflammation-related single-nucleotide polymorphisms involved with endometrial cancer from GWAS databases. The observational retrospective study included consecutive patients diagnosed with EC (stage I to IV) with surgeries between January 2010 and October 2020 at the Cancer Hospital of Shantou University Medical College.ResultsThe 2-sample MR surveys indicated no causal relationship between inflammatory cytokines and endometrial cancer. 780 cases (median age, 55.0 years ) diagnosed with EC were included in the cohort and followed up for an average of 6.8 years. Increased inflammatory parameters at baseline were associated with a higher FIGO stage and invasive EC risk (odds ratios [OR] 1.01 to 4.20). Multivariate-cox regression suggested that multiple inflammatory indicators were significantly associated with overall survival (OS) and progression-free survival (PFS) (P < 0.05). Nomogram models based on inflammatory risk and clinical factors were developed for OS and PFS with C-index of 0.811 and 0.789, respectively. LASSO regression for the validation supported the predictive efficacy of inflammatory and clinical factors on the long-term outcomes of EC.ConclusionsDespite the fact that the genetic surveys did not show a detrimental impact of inflammatory cytokines on the endometrial cancer risk, our cohort study suggested that inflammatory level was associated with the progression and long-term outcomes of EC. This evidence may contribute to new strategies targeted at decreasing inflammation levels during EC therapy.