Omitting Axillary Dissection in Breast Cancer with Sentinel-Node Metastases.

BACKGROUND: Trials evaluating the omission of completion axillary-lymph-node dissection in patients with clinically node-negative breast cancer and sentinel-lymph-node metastases have been compromised by limited statistical power, uncertain nodal radiotherapy target volumes, and a scarcity of data on relevant clinical subgroups. METHODS: We conducted a noninferiority trial in which patients with clinically node-negative primary T1 to T3 breast cancer (tumor size, T1, ≤20 mm; T2, 21 to 50 mm; and T3, >50 mm in the largest dimension) with one or two sentinel-node macrometastases (metastasis size, >2 mm in the largest dimension) were randomly assigned in a 1:1 ratio to completion axillary-lymph-node dissection or its omission (sentinel-node biopsy only). Adjuvant treatment and radiation therapy were used in accordance with national guidelines. The primary end point was overall survival. We report here the per-protocol and modified intention-to-treat analyses of the prespecified secondary end point of recurrence-free survival. To show noninferiority of sentinel-node biopsy only, the upper boundary of the confidence interval for the hazard ratio for recurrence or death had to be below 1.44. RESULTS: Between January 2015 and December 2021, a total of 2766 patients were enrolled across five countries. The per-protocol population included 2540 patients, of whom 1335 were assigned to undergo sentinel-node biopsy only and 1205 to undergo completion axillary-lymph-node dissection (dissection group). Radiation therapy including nodal target volumes was administered to 1192 of 1326 patients (89.9%) in the sentinel-node biopsy-only group and to 1058 of 1197 (88.4%) in the dissection group. The median follow-up was 46.8 months (range, 1.5 to 94.5). Overall, 191 patients had recurrence or died. The estimated 5-year recurrence-free survival was 89.7% (95% confidence interval [CI], 87.5 to 91.9) in the sentinel-node biopsy-only group and 88.7% (95% CI, 86.3 to 91.1) in the dissection group, with a country-adjusted hazard ratio for recurrence or death of 0.89 (95% CI, 0.66 to 1.19), which was significantly (P<0.001) below the prespecified noninferiority margin. CONCLUSIONS: The omission of completion axillary-lymph-node dissection was noninferior to the more extensive surgery in patients with clinically node-negative breast cancer who had sentinel-node macrometastases, most of whom received nodal radiation therapy. (Funded by the Swedish Research Council and others; SENOMAC ClinicalTrials.gov number, NCT02240472.).

Optimizing Dose and Timing in Magnetic Tracer Techniques for Sentinel Lymph Node Detection in Early Breast Cancers: The Prospective Multicenter SentiDose Trial.

Superparamagnetic iron oxide nanoparticles (SPIO) are non-inferior to radioisotope and blue dye (RI + BD) for sentinel lymph node (SLN) detection. Previously, 2 mL SPIO (Sienna+®) in 3 mL NaCl was used. In this dose-optimizing study, lower doses of a new refined SPIO solution (Magtrace®) (1.5 vs. 1.0 mL) were tested in different timeframes (0-24 h perioperative vs. 1-7 days preoperative) and injections sites (subareolar vs. peritumoral). Two consecutive breast cancer cohorts (n = 328) scheduled for SLN-biopsy were included from 2017 to 2019. All patients received isotope ± blue dye as back-up. SLNs were identified primarily with the SentiMag® probe and thereafter a gamma-probe. The primary endpoint was SLN detection rate with SPIO. Analyses were performed as a one-step individual patient-level meta-analysis using patient-level data from the previously published Nordic Trial (n = 206) as a third, reference cohort. In 534 patients, the SPIO SLN detection rates were similar (97.5% vs. 100% vs. 97.6%, p = 0.11) and non-inferior to the dual technique. Significantly more SLNs were retrieved in the preoperative 1.0 mL cohort compared with 1.5 and the 2.0 mL cohorts (2.18 vs. 1.85 vs. 1.83, p = 0.003). Lower SPIO volumes injected up to 7 days before the operation have comparable efficacy to standard SPIO dose and RI + BD for SLN detection.

Long-Term Prognostication for 20 114 Women With Small and Node-Negative Breast Cancer (T1abN0).

Background: Although small, node-negative breast cancer (ie, T1abN0) constitutes 20% of all newly diagnosed breast cancers, data on prognosis and prognostic factors are limited. Methods: We conducted a population-based cohort study including 20 114 Swedish women treated for T1abN0 breast cancer from 1977 onward. Patient and tumor data were collected from Swedish breast cancer registries. Cohort subjects were followed through linkage to the Cause of Death Register. We calculated the cumulative incidence of breast cancer-specific and overall death and used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: During a median follow-up of 9.1 years (range = 0-38), 915 women died of breast cancer and 5416 of any cause. The 10-, 20-, and 30-year cumulative incidences of breast cancer death were 3.4% (95% CI = 3.1% to 3.7%), 7.6% (95% CI = 7.1% to 8.2%), and 10.5% (95% CI = 9.6% to 11.4%), respectively. The multivariable hazard ratios and 95% confidence intervals of breast cancer death were 0.92 (95% CI = 0.88 to 0.97) for each additional calendar year of diagnosis, 4.38 (95% CI = 2.79 to 6.87) for grade 3 vs grade 1 tumors, 0.43 (95% CI = 0.31 to 0.62) for progesterone receptor-positive vs progesterone receptor-negative disease, and 2.01 (95% CI = 0.99 to 4.07) for HER2-positive vs HER2-negative disease. Women with grade 3 vs grade 1 tumors had a 56% increased risk of death from any cause (HR = 1.56, 95% CI = 1.30 to 1.88). Conclusions: The risk of breast cancer death in T1abN0 disease continues to increase steadily beyond 10 years after diagnosis, has improved over time, and varies substantially by tumor characteristics.

Intrauterine fluid instillation to confirm tubal occlusion after transcervical permanent contraception: A pilot study.

OBJECTIVES: To determine if women with tubal patency experience more fluid loss compared to those with bilateral tubal occlusion following intrauterine instillation of fluid via a balloon catheter. STUDY DESIGN: In this prospective cohort pilot study, we enrolled women with prior Essure® procedures and healthy controls from September 2016 to July 2017. We excluded women using an implant or intrauterine device, or with a prior cesarean delivery or permanent contraception procedures other than Essure®. An infusion pump delivered saline via balloon catheter under continuous pressure monitoring. After one minute, we withdrew the fluid and recorded volumes in and out. Subjects then underwent hysterosalpingogram for evaluation of tubal patency. We conducted crude analyses with t-tests and sensitivity analyses. RESULTS: We recruited 23 participants; ten provided analyzable data in each group. Hysterosalpingogram confirmed patency in all control and occlusion in all post-Essure® subjects in the analysis group. We found the median volume of saline lost among control subjects [7.8 mL (7.4, 8.4)] larger than post-Essure® participants [2.2 mL (2.0, 3.8), p < 0.01]. While 50% of control subjects tolerated the full 10 mL of fluid instillation, none of the post-Essure® subjects tolerated this volume (p = 0.03). A combination of saline loss ≤4 mL and participant intolerance of the full 10 mL volume yielded sensitivity of 0.80 (95% CI: 0.57, 1.00) and specificity of 1.00 for bilateral tubal occlusion. CONCLUSION: Instillation of a fixed volume into the uterus may discriminate between women with tubal patency and occlusion following permanent contraception procedures with high specificity and adequate sensitivity. These findings should be validated in larger, more diverse study populations. IMPLICATIONS: Confirmation of tubal occlusion following permanent contraception with an office-based approach could improve acceptability of transcervical approaches. The recent removal of Essure® from the U.S. market increases the need for novel transcervical procedures and occlusion verification methods.

Differences in intra-tumoral macrophage infiltration and radiotherapy response among intrinsic subtypes in pT1-T2 breast cancers treated with breast-conserving surgery.

Breast cancer (BC) intrinsic subtype classification is based on the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and proliferation marker Ki-67. The expression of these markers depends on both the genetic background of the cancer cells and the surrounding tumor microenvironment. In this study, we explore macrophage traits in cancer cells and intra-tumoral M2-macrophage infiltration (MI) in relation to intrinsic subtypes in non-metastatic invasive BC treated with breast conserving surgery, with and without postoperative radiotherapy (RT). Immunostaining of M2-macrophage-specific antigen CD163 in cancer cells and MI were evaluated, together with ER, PR, HER2, and Ki-67-expression in cancer cells. The tumors were classified into intrinsic subtypes according to the ESMO guidelines. The immunostaining of these markers, MI, and clinical data were analyzed in relation to ipsilateral local recurrence (ILR) as well as recurrence-free (RFS) and disease-free specific (DFS) survival. BC intrinsic subtypes are associated with T-stage, Nottingham Histologic Grade (NHG), and MI. Macrophage phenotype in cancer cells is significantly associated with NHG3-tumors. Significant differences in macrophage infiltration were observed among the intrinsic subtypes of pT1-T2 stage BC. Shorter RFS was observed in luminal B HER2neg tumors after RT, suggesting that this phenotype may be more resistant to irradiation. Ki-67-expression was significantly higher in NHG3 and CD163-positive tumors, as well as those with moderate and high MI. Cancer cell ER expression is inversely related to MI and thus might affect the clinical staging and assessment of BC.

Pressure dynamics in the non-gravid uterus: intrauterine pressure cannot confirm tubal occlusion after non-surgical permanent contraception.

OBJECTIVE: The objective was to determine if intrauterine pressure can distinguish bilateral tubal occlusion (BTO) from unilateral or bilateral tubal patency (TP) in women following a permanent contraception procedure. STUDY DESIGN: We used a small inline pressure sensor to continuously monitor intrauterine pressure during hysterosalpingogram (HSG) in a cross-sectional study that enrolled women having HSGs for any indication. The primary outcome was the peak intrauterine pressure compared between women with BTO and TP as verified by HSG. RESULTS: We enrolled 150 subjects, of which 111 (74.0%) provided usable pressure readings. Of these, 98/111 (88.3%) had TP, and 13 (11.7%) had BTO. There was no difference in peak intrauterine pressure for subjects with TP (mean 293.8±58.7 mmHg) compared to those with BTO (292.7±71.3 mmHg, p=.95). Among parous women, peak intrauterine pressure in subjects with BTO (311.9±78.0 mmHg) was higher but not significantly different from subjects with TP (282.7±49.2 mmHg, p=.20). In linear regression analysis, peak intrauterine pressure was not associated with age, body mass index, gravidity or having at least one prior live birth. CONCLUSIONS: Measurement of peak intrauterine pressure does not distinguish between women with patent and blocked fallopian tubes. This approach would not be clinically useful to verify occlusion following permanent contraception. IMPLICATIONS: Peak intrauterine pressure does not differ between women with patent and occluded fallopian tubes and cannot be used to confirm tubal occlusion after nonsurgical permanent contraception.

Tubal patency during the menstrual cycle and during treatment with hormonal contraceptives: a pilot study in women.

Background Hysterosalpingram (HSG) evaluation of tubal patency is typically performed in the follicular phase, but data to support this timing are lacking. Purpose To determine whether menstrual cycle phase or hormonal treatments affect observation of tubal patency during HSG. Material and Methods Ten participants underwent repeated HSG examinations: during the follicular and luteal phase of a natural menstrual cycle; 30 days following continuous administration of a combined oral contraceptive (COC); and 30 days after an intramuscular injection of depo medroxyprogesterone (DMPA) acetate. Participants with tubal blockade following DMPA had a fifth HSG 30 days following a second course of COCs. The primary outcome was tubal patency. Results All 10 participants demonstrated bilateral tubal patency (BTP) on at least one HSG examination during the study. One participant showed bilateral functional occlusion (FO) during the follicular phase examination, but BTP with the luteal phase, COC cycle, and DMPA exams. One participant with BTP discontinued participation and nine completed the COC HSG exam with BTP in seven, and one each with bilateral or unilateral FO. Seven participants completed the DMPA HSG with BTP in six and unilateral FO in one; BTP was seen in the final HSG after restarting the COC. Conclusion This pilot study supports the luteal phase of natural cycles as the optimum time for evaluation of tubal patency. The occurrence of functional occlusion of the fallopian tube on HSG examination performed during the follicular phase and following contraceptive steroid treatment supports a role of hormonal action on the utero-tubal junction.

Permanent Contraception for Women.

Permanent contraception is a highly desired and commonly used contraceptive option for women around the world who desire never to become pregnant. Current methods of female permanent contraception require surgery. Postpartum tubal ligation and interval surgical tubal ligation are safe and effective, do not interfere with menstrual cycles, and require no ongoing cost or medical checkups. Hysteroscopic tubal occlusion offers a less invasive surgical approach, but requires an imaging study for verification of correct placement. However, not all women have access to a surgeon trained to provide permanent contraception, or they may face other prohibitive logistic or financial burdens. The development of novel permanent contraception methods that are immediately effective and/or nonsurgical could help improve access to and acceptability of permanent contraception. The expansion of permanent contraception options could help women achieve their family planning goals and reduce unintended pregnancies.

Aspiration Abortion With Immediate Intrauterine Device Insertion: Comparing Outcomes of Advanced Practice Clinicians and Physicians.

INTRODUCTION: Immediate postabortion intrauterine device (IUD) insertion is a safe, effective strategy to prevent subsequent unplanned pregnancy. Oregon is one of 5 US states where advanced practice clinicians perform aspiration abortions. This study compares outcomes of first-trimester aspiration abortion with immediate IUD insertion between advanced practice clinicians and physicians. METHODS: We conducted a historical cohort study of first-trimester aspiration abortions with immediate IUD insertion performed at our center from 2009 to 2011. We extracted demographic and clinical data from patient charts. Immediate complications including excessive blood loss, perforation, and reaspirations were recorded at the time of procedure. We used descriptive statistics and multivariable logistic regression to test for differences in outcomes by clinician type. RESULTS: Data were available on 669 of the 1134 combined procedures. Advanced practice clinicians performed 224 of these. There were no significant differences in immediate outcomes. The only immediate complications were reaspirations; 1.8% (4/224) in the advanced practice clinician group, and 2.0% (9/445) in the physician group (P = .83). DISCUSSION: We found no differences in outcomes between provider type for immediate IUD insertion after first-trimester aspiration abortion. This study helps reinforce that advanced practice clinicians can provide immediate postaspiration abortion IUD insertions with similar outcomes to those of physicians. Many countries do not allow advanced practice clinicians to perform this service, but a change in policy could help address family planning provider shortages.

Immediate Intrauterine Device Insertion Following Surgical Abortion.

Placement of an intrauterine device (IUD) immediately after a first or second trimester surgical abortion is safe and convenient and decreases the risk of repeat unintended pregnancy. Immediate postabortion IUD placement is not recommended in the setting of postprocedure hemorrhage, uterine perforation, infection, or hematometra. Otherwise, there are few contraindications to IUD placement following surgical abortion. Sexually transmitted infection screening should follow US Centers for Disease Control and Prevention guidelines. No additional antibiotics are needed beyond those used for the abortion. Placing immediate postabortion IUDs makes highly-effective long-acting reversible contraception more accessible to women.

Update on permanent contraception options for women.

PURPOSE OF REVIEW: Permanent methods are the most commonly used contraceptive options worldwide. Even with the increase in popularity and accessibility of long-acting reversible methods, there remains high demand for permanent options, especially among women in developing countries. RECENT FINDINGS: Traditional methods of permanent contraception, such as postpartum tubal ligation and interval surgical tubal occlusion or electrocautery by mini-laparotomy or laparoscopy are well tolerated and highly effective. Bilateral total salpingectomy for ovarian cancer risk reduction is currently being investigated. Hysteroscopic tubal occlusion reduces or eliminates the need for anesthesia, but requires surgical training and specialized equipment. Alternative permanent contraception methods are being explored including immediately effective hysteroscopic methods, and nonsurgical permanent contraception methods that have the potential to improve access and reduce cost. SUMMARY: Permanent contraception methods are an important part of the contraceptive methods mix designed to meet the needs of women who have completed desired family size or wish never to become pregnant. Current surgical approaches to permanent contraception are well tolerated and highly effective. The development of a highly effective nonsurgical approach could simplify the provision of permanent contraception.

The history and current status of fallopian tube pressures - developing alternate methods for confirmation of tubal occlusion.

Permanent contraception with hysteroscopic tubal ligation is an increasingly popular choice for women around the world. However, inconveniences associated with the required confirmation test for tubal occlusion can be prohibitive. As new methods of permanent contraception are being investigated, ways of making all aspects of the procedure more accessible and comfortable for women should be considered. Means of examining tubal patency in the infertility population, such as tubal perfusion pressures measured at the time of hysterosalpingogram (HSG), provide inspiration for alternative methods of tubal occlusion confirmation after contraception. Evaluation of intrauterine pressures measured by a manometer attached to an intrauterine balloon catheter could serve as a preliminary tool for verification of tubal occlusion; higher pressures would indicate tubal occlusion and lower pressures would indicate the need for confirmatory HSG. The development and validation of this technique is ongoing and could reduce overall costs and patient burdens associated with the current tubal occlusion confirmation procedure.