Molecular classification of metastatic and recurrent endometrial endometrioid carcinoma: prognostic relevance among low- and high-stage tumours.

AIMS: Molecular classification according to The Cancer Genome Atlas (TCGA) improves endometrial endometrioid carcinoma (EEC) prognostication and has specific treatment implications; however, original data were skewed towards low-grade and low-stage tumours. Herein, we molecularly classify EECs metastatic at the time of diagnosis or with subsequently documented recurrent/metastatic disease to examine correlation with clinical outcomes. METHODS: TCGA categories include POLE-mutated, microsatellite instability (MSI), p53 abnormal (p53 abnl) and no specific molecular profile (NSMP). POLE targeted sequencing at exons 9, 11, 13 and 14 and immunohistochemistry (IHC) for PMS2, MSH6 and p53 were performed to establish molecular classification. RESULTS: The distribution in our cohort of 141 EECs was similar to that generally reported in EEC, with nine POLE-mutated (6%), 45 MSI (32%), 16 p53 abnl (11%) and 71 NSMP (50%), with similar distributions between low- and high-stage cohorts. We demonstrate that when stratified by molecular subtype, disease-specific survival from the time of high-stage (stages III-IV) presentation or time of recurrence in low-stage (stages I-II) disease among metastatic and/or recurrent EEC is strongly associated with TCGA classification (high-stage P = 0.02, low-stage P = 0.017). Discordant molecular classification between primary and metastatic/recurrent tumours occurred in four of 105 (3.8%) patients, two related to PMS2/MSH6 IHC and two related to p53 IHC. CONCLUSIONS: We demonstrate that molecular classification is prognostically relevant not only at the time of diagnosis, but also at the time of recurrence and in the metastatic setting. Rare subclonal alterations occur and suggest a role for confirming TCGA classification in recurrent/metastatic tumours.

Trends in ovarian, fallopian tube, and primary peritoneal cancer incidence, mortality, and survival: A 15-year population-based analysis.

OBJECTIVE: To characterize trends in ovarian, fallopian tube, and primary peritoneal cancer incidence and incidence-based mortality based on histology and site of origin. METHODS: We obtained age-adjusted incidence and incidence-based mortality for patients with ovarian, fallopian tube, and primary peritoneal cancer from 2000 to 2019 from the US SEER 17 database. Joinpoint 4.9.1.0 was used to characterize log-linear time trends. RESULTS: The incidence and incidence-based mortality of all cancers trended down during the study period. The incidence of epithelial cancers decreased from 2004 to 2019 (AAPC -1.2%, p < 0.001), including that of high-grade (2006-2019: APC -1.2%, p < 0.05) and low-grade (2003-2019: APC -2.4%, p < 0.05) epithelial cancers. There was no change in incidence or incidence-based mortality for ovarian stromal and germ cell cancers. CONCLUSION: There has been a decrease in the incidence and incidence-based mortality of ovarian, fallopian tube, and primary peritoneal cancer, primarily due to reductions in advanced stage epithelial cancers originating in the ovary, fallopian tube, or peritoneum.

Inhalable paclitaxel nanoagglomerate dry powders for lung cancer chemotherapy: Design of experiments-guided development, characterization and in vitro evaluation.

Conventional intravenous chemotherapy for lung cancer frequently results in inefficient drug penetration into primary lung tumors and severe systemic toxicities. This study reports the development of inhalable paclitaxel (PTX) nanoagglomerate dry powders (PTX-NADP) for enhanced pulmonary delivery of PTX chemotherapy to lung tumors using full factorial Design of Experiments. PTX nanoparticles were fabricated by flash nanoprecipitation with the aid of N-polyvinylpyrrolidone (PVP) and curcumin (CUR) as stabilizer and co-stabilizer respectively, and subsequently agglomerated into inhalable dry powders via co-spray drying with methylcellulose. The optimized PTX-NADP formulation exhibited acceptable aqueous redispersibility (redispersibility index = 1.17 ± 0.02) into âˆ¼ 150 nm nanoparticles and superb in vitro aerosol performance [mass median aerodynamic diameter (MMAD) = 1.69 ± 0.05 µm and fine particle fraction (FPF) of 70.89 ± 1.72 %] when dispersed from a Breezhaler® at 90 L/min. Notably, adequate aerosolization (MMAD < 3.5 µm and FPF > 40 %) of the optimized formulation was maintained when dispersed at reduced inspiratory flow rates of 30 - 60 L/min. Redispersed PTX nanoparticles from PTX-NADP demonstrated enhanced in vitro antitumor efficacy and cellular uptake in A549 lung adenocarcinoma cells without compromising tolerability of BEAS-2B normal lung epithelial cells towards PTX chemotherapy. These findings highlight the potential of inhaled PTX-NADP therapy to improve therapeutic outcomes for lung cancer patients with varying levels of pulmonary function impairment.

Development of favipiravir dry powders for intranasal delivery: An integrated cocrystal and particle engineering approach via spray freeze drying.

The therapeutic potential of pharmaceutical cocrystals in intranasal applications remains largely unexplored despite progressive advancements in cocrystal research. We present the application of spray freeze drying (SFD) in successful fabrication of a favipiravir-pyridinecarboxamide cocrystal nasal powder formulation for potential treatment of broad-spectrum antiviral infections. Preliminary screening via mechanochemistry revealed that favipiravir (FAV) can cocrystallize with isonicotinamide (INA), but not nicotinamide (NCT) and picolinamide (PIC) notwithstanding their structural similarity. The cocrystal formation was characterized by differential scanning calorimetry, Fourier-transform infrared spectroscopy, and unit cell determination through Rietveld refinement of powder X-ray analysis. FAV-INA crystalized in a monoclinic space group P21/c with a unit cell volume of 1223.54(3) Å3, accommodating one FAV molecule and one INA molecule in the asymmetric unit. The cocrystal was further reproduced as intranasal dry powders by SFD, of which the morphology, particle size, in vitro drug release, and nasal deposition were assessed. The non-porous flake shaped FAV-INA powders exhibited a mean particle size of 19.79 ± 2.61 µm, rendering its suitability for intranasal delivery. Compared with raw FAV, FAV-INA displayed a 3-fold higher cumulative fraction of drug permeated in Franz diffusion cells at 45 min (p = 0.001). Dose fraction of FAV-INA deposited in the nasal fraction of a customized 3D-printed nasal cast reached over 80 %, whereas the fine particle fraction remained below 6 % at a flow rate of 15 L/min, suggesting high nasal deposition whilst minimal lung deposition. FAV-INA was safe in RPMI 2650 nasal and SH-SY5Y neuroblastoma cells without any in vitro cytotoxicity observed. This study demonstrated that combining the merits of cocrystallization and particle engineering via SFD can propel the development of advanced dry powder formulations for intranasal drug delivery.

Integrated continuous manufacturing of inhalable remdesivir nanoagglomerate dry powders: Design, optimization and therapeutic potential for respiratory viral infections.

While inhalable nanoparticle-based dry powders have demonstrated promising potential as next-generation respiratory medicines, erratic particle redispersibility and poor manufacturing reproducibility remain major hurdles hindering their translation from bench to bedside. We developed a one-step continuous process for fabricating inhalable remdesivir (RDV) nanoagglomerate dry powder formulations by integrating flash nanoprecipitation and spray drying. The nanosuspension formulation was optimized using a three-factor Box-Behnken design with a z-average particle size of 233.3 ± 2.3 nm and < 20% size change within six hours. The optimized inhalable nanoagglomerate dry powder formulation produced by spray drying showed adequate aqueous redispersibility (Sf/Si = 1.20 ± 0.01) and in vitro aerosol performance (mass median aerodynamic diameter of 3.80 ± 0.58 µm and fine particle fraction of 39.85 ± 10.16%). In A549 cells, RDV nanoparticles redispersed from the inhalable nanoagglomerate powders displayed enhanced and accelerated RDV cell uptake and negligible cytotoxicity at therapeutic RDV concentrations. No statistically significant differences were observed in the critical quality attributes of the inhalable nanoagglomerate powders produced from the continuous manufacturing and standalone batch modes. This work demonstrates the feasibility of large-scale continuous manufacturing of inhalable nanoagglomerate dry powder formulations, which pave the way for their clinical translation.

Role of Particle Size in Translational Research of Nanomedicines for Successful Drug Delivery: Discrepancies and Inadequacies.

Despite significant research progress in substantiating the therapeutic merits of nanomedicines and the emergence of sophisticated nanotechnologies, the translation of this knowledge into new therapeutic modalities has been sluggish, indicating the need for a more comprehensive understanding of how the unique physicochemical properties of nanoparticles affect their clinical applications. Particle size is a critical quality attribute that impacts the bio-fate of nanoparticles, yet precise knowledge of its effect remains elusive with discrepancies among literature reports. This review aims to address this scientific knowledge gap from a drug development perspective by highlighting potential inadequacies during the evaluation of particle size effects. We begin with a discussion on the major issues in particle size characterization along with the corresponding remedies. The influence of confounding factors on biological effects of particle size, including colloidal stability, polydispersity, and in vitro drug release, are addressed for establishing stronger in vitro-in vivo correlation. Particle size design and tailoring approaches for successful nanoparticulate drug delivery beyond parenteral administration are also illustrated. We believe a holistic understanding of the effect of particle size on bio-fate, combined with consistent nanoparticle manufacturing platforms and tailored characterization techniques, would expedite the translation of nanomedicines into clinical practice.

Inhalable Nanoparticle-based Dry Powder Formulations for Respiratory Diseases: Challenges and Strategies for Translational Research.

The emergence of novel respiratory infections (e.g., COVID-19) and expeditious development of nanoparticle-based COVID-19 vaccines have recently reignited considerable interest in designing inhalable nanoparticle-based drug delivery systems as next-generation respiratory therapeutics. Among various available devices in aerosol delivery, dry powder inhalers (DPIs) are preferable for delivery of nanoparticles due to their simplicity of use, high portability, and superior long-term stability. Despite research efforts devoted to developing inhaled nanoparticle-based DPI formulations, no such formulations have been approved to date, implying a research gap between bench and bedside. This review aims to address this gap by highlighting important yet often overlooked issues during pre-clinical development. We start with an overview and update on formulation and particle engineering strategies for fabricating inhalable nanoparticle-based dry powder formulations. An important but neglected aspect in in vitro characterization methodologies for linking the powder performance with their bio-fate is then discussed. Finally, the major challenges and strategies in their clinical translation are highlighted. We anticipate that focused research onto the existing knowledge gaps presented in this review would accelerate clinical applications of inhalable nanoparticle-based dry powders from a far-fetched fantasy to a reality.

Monocytes: A Promising New TRAIL in Ovarian Cancer Cell Therapy.

Adoptive cell transfer of IFN-activated monocytes administered intraperitoneally to patients with platinum-resistant ovarian cancer demonstrated antitumor effects and acceptable tolerability. The exposure of monocytes to IFNα and IFNγ upregulated TRAIL, which triggered caspase 8 and direct cell-to-cell contact-dependent apoptosis of ovarian cancer cells. See related article by Green et al., p. 349.

Epigenome-Wide Study Identifies Epigenetic Outliers in Normal Mucosa of Patients with Colorectal Cancer.

Nongenetic predisposition to colorectal cancer continues to be difficult to measure precisely, hampering efforts in targeted prevention and screening. Epigenetic changes in the normal mucosa of patients with colorectal cancer can serve as a tool in predicting colorectal cancer outcomes. We identified epigenetic changes affecting the normal mucosa of patients with colorectal cancer. DNA methylation profiling on normal colon mucosa from 77 patients with colorectal cancer and 68 controls identified a distinct subgroup of normally-appearing mucosa with markedly disrupted DNA methylation at a large number of CpGs, termed as "Outlier Methylation Phenotype" (OMP) and are present in 15 of 77 patients with cancer versus 0 of 68 controls (P < 0.001). Similar findings were also seen in publicly available datasets. Comparison of normal colon mucosa transcription profiles of patients with OMP cancer with those of patients with non-OMP cancer indicates genes whose promoters are hypermethylated in the OMP patients are also transcriptionally downregulated, and that many of the genes most affected are involved in interactions between epithelial cells, the mucus layer, and the microbiome. Analysis of 16S rRNA profiles suggests that normal colon mucosa of OMPs are enriched in bacterial genera associated with colorectal cancer risk, advanced tumor stage, chronic intestinal inflammation, malignant transformation, nosocomial infections, and KRAS mutations. In conclusion, our study identifies an epigenetically distinct OMP group in the normal mucosa of patients with colorectal cancer that is characterized by a disrupted methylome, altered gene expression, and microbial dysbiosis. Prospective studies are needed to determine whether OMP could serve as a biomarker for an elevated epigenetic risk for colorectal cancer development. PREVENTION RELEVANCE: Our study identifies an epigenetically distinct OMP group in the normal mucosa of patients with colorectal cancer that is characterized by a disrupted methylome, altered gene expression, and microbial dysbiosis. Identification of OMPs in healthy controls and patients with colorectal cancer will lead to prevention and better prognosis, respectively.

Technetium Tc 99m tilmanocept fails to detect sentinel lymph nodes in endometrial cancer.

Background: Technetium Tc 99m tilmanocept is a synthetic radiotracer specifically designed for sentinel lymph node (SLN) mapping that has been FDA-approved in breast cancer, melanoma, and head and neck cancer. No published studies exist for the use of this radiotracer in endometrial cancer. Objective: The primary objective was to determine the detection rate of bilateral SLNs in endometrial cancer with the concurrent use of technetium Tc 99m tilmanocept and ICG. Methods: An open-label, single cohort, prospective feasibility study was conducted with participants receiving preoperative cervical injections of technetium Tc 99m tilmanocept followed by subsequent imaging and SPECT/CT. Intraoperative ICG injections were administered for all patients with near-infrared imaging used to visualize lymphatic vessels and nodes. A laparoscopic gamma counter was used to detect radioactive SLN intraoperatively. Results: All six evaluated patients had FIGO grade 1 or 2 endometrioid histology. Stage IA/IB were in 33% and 66% of patients, respectively. Tilmanocept did not map any SLN in the first six patients but instead showed retention of the tracer in the cervical stroma, leading to study discontinuation for futility. ICG mapped bilateral SLN in all patients with the most common location being the external iliac region, followed by the obturator and common iliac areas. All patients had CD206 positive staining throughout the full wall thickness of ectocervix, transformation zone, endocervix, and lymphatic vessels. No patients experienced adverse events. Conclusion: Technetium Tc 99m tilmanocept did not detect SLN in early stage endometrial cancers and is unlikely to improve bilateral detection rate compared to ICG alone. ICG remains a standard technique for SLN detection in low stage, low grade endometrial cancer.

Atypical Functional Connectivity During Unfamiliar Music Listening in Children With Autism.

Background: Atypical processing of unfamiliar, but less so familiar, stimuli has been described in Autism Spectrum Disorder (ASD), in particular in relation to face processing. We examined the construct of familiarity in ASD using familiar and unfamiliar songs, to investigate the link between familiarity and autism symptoms, such as repetitive behavior. Methods: Forty-eight children, 24 with ASD (21 males, mean age = 9.96 years ± 1.54) and 24 typically developing (TD) controls (21 males, mean age = 10.17 ± 1.90) completed a music familiarity task using individually identified familiar compared to unfamiliar songs, while magnetoencephalography (MEG) was recorded. Each song was presented for 30 s. We used both amplitude envelope correlation (AEC) and the weighted phase lag index (wPLI) to assess functional connectivity between specific regions of interest (ROI) and non-ROI parcels, as well as at the whole brain level, to understand what is preserved and what is impaired in familiar music listening in this population. Results: Increased wPLI synchronization for familiar vs. unfamiliar music was found for typically developing children in the gamma frequency. There were no significant differences within the ASD group for this comparison. During the processing of unfamiliar music, we demonstrated left lateralized increased theta and beta band connectivity in children with ASD compared to controls. An interaction effect found greater alpha band connectivity in the TD group compared to ASD to unfamiliar music only, anchored in the left insula. Conclusion: Our results revealed atypical processing of unfamiliar songs in children with ASD, consistent with previous studies in other modalities reporting that processing novelty is a challenge for ASD. Relatively typical processing of familiar stimuli may represent a strength and may be of interest to strength-based intervention planning.

Abdominopelvic FLASH Irradiation Improves PD-1 Immune Checkpoint Inhibition in Preclinical Models of Ovarian Cancer.

Treatment of advanced ovarian cancer using PD-1/PD-L1 immune checkpoint blockade shows promise; however, current clinical trials are limited by modest response rates. Radiotherapy has been shown to synergize with PD-1/PD-L1 blockade in some cancers but has not been utilized in advanced ovarian cancer due to toxicity associated with conventional abdominopelvic irradiation. Ultrahigh-dose rate (FLASH) irradiation has emerged as a strategy to reduce radiation-induced toxicity, however, the immunomodulatory properties of FLASH irradiation remain unknown. Here, we demonstrate that single high-dose abdominopelvic FLASH irradiation promoted intestinal regeneration and maintained tumor control in a preclinical mouse model of ovarian cancer. Reduced tumor burden in conventional and FLASH-treated mice was associated with an early decrease in intratumoral regulatory T cells and a late increase in cytolytic CD8+ T cells. Compared with conventional irradiation, FLASH irradiation increased intratumoral T-cell infiltration at early timepoints. Moreover, FLASH irradiation maintained the ability to increase intratumoral CD8+ T-cell infiltration and enhance the efficacy of αPD-1 therapy in preclinical models of ovarian cancer. These data highlight the potential for FLASH irradiation to improve the therapeutic efficacy of checkpoint inhibition in the treatment of ovarian cancer.

Role of sentinel lymph node biopsy for gynecologic cancers.

PURPOSE OF REVIEW: To provide an overview of the current knowledge and recent advances of sentinel lymph node (SLN) assessment in uterine, cervical, vulvar, and ovarian cancers. RECENT FINDINGS: In endometrial cancer, SLN evaluation has become increasingly utilized as part of the treatment of early-stage disease, with data showing improved detection of pelvic lymph node metastasis. In cervical cancer, SLN biopsy has also gained increasing traction with studies demonstrating the feasibility and accuracy of SLN detection. Evaluation with frozen section, however, remains limited in the detection of metastases. The prognostic significance of positive SLN in vulvar cancer is currently being investigated, with preliminary data showing lower recurrence rates in patients receiving adjuvant radiation. SUMMARY: SLN evaluation remains standard of care to detect lymph node metastasis in early-staged endometrial cancer. In cervical cancer, SLN biopsy has been shown to be reliable, while decreasing morbidity without impacting disease-free survival in select patients. The technique and high sensitivity of SLN biopsy in vulvar cancer has been demonstrated in large prospective trials. There are no randomized controlled trials in ovarian cancer that evaluate the role of SLN biopsy on treatment and outcome; current SLN evaluation remains investigational.

Differential Diagnosis of a Unique Vulvar Mass in an Adolescent.

BACKGROUND: Vulvar masses in adolescents have a broad differential diagnosis, yet few reports exist detailing masses of mammary origin. CASE: A nulliparous, healthy 16-year-old adolescent presented with a longstanding, ulcerated, 17-cm vulvar mass of unknown origin and pronounced inguinal lymphadenopathy. The patient underwent a left radical partial vulvectomy, with pathology revealing terminal duct lobular units consistent with polymastia. CONCLUSION: Differential diagnosis of a vulvar mass in an adolescent should include polymastia.

Abdominal FLASH irradiation reduces radiation-induced gastrointestinal toxicity for the treatment of ovarian cancer in mice.

Radiation therapy is the most effective cytotoxic therapy for localized tumors. However, normal tissue toxicity limits the radiation dose and the curative potential of radiation therapy when treating larger target volumes. In particular, the highly radiosensitive intestine limits the use of radiation for patients with intra-abdominal tumors. In metastatic ovarian cancer, total abdominal irradiation (TAI) was used as an effective postsurgical adjuvant therapy in the management of abdominal metastases. However, TAI fell out of favor due to high toxicity of the intestine. Here we utilized an innovative preclinical irradiation platform to compare the safety and efficacy of TAI ultra-high dose rate FLASH irradiation to conventional dose rate (CONV) irradiation in mice. We demonstrate that single high dose TAI-FLASH produced less mortality from gastrointestinal syndrome, spared gut function and epithelial integrity, and spared cell death in crypt base columnar cells compared to TAI-CONV irradiation. Importantly, TAI-FLASH and TAI-CONV irradiation had similar efficacy in reducing tumor burden while improving intestinal function in a preclinical model of ovarian cancer metastasis. These findings suggest that FLASH irradiation may be an effective strategy to enhance the therapeutic index of abdominal radiotherapy, with potential application to metastatic ovarian cancer.

Development of Therapeutic Vaccines for Ovarian Cancer.

Ovarian cancer remains the deadliest of all gynecologic malignancies. Our expanding knowledge of ovarian cancer immunology has allowed the development of therapies that generate systemic anti-tumor immune responses. Current immunotherapeutic strategies include immune checkpoint blockade, cellular therapies, and cancer vaccines. Vaccine-based therapies are designed to induce both adaptive and innate immune responses directed against ovarian cancer associated antigens. Tumor-specific effector cells, in particular cytotoxic T cells, are activated to recognize and eliminate ovarian cancer cells. Vaccines for ovarian cancer have been studied in various clinical trials over the last three decades. Despite evidence of vaccine-induced humoral and cellular immune responses, the majority of vaccines have not shown significant anti-tumor efficacy. Recently, improved vaccine development using dendritic cells or synthetic platforms for antigen presentation have shown promising clinical benefits in patients with ovarian cancer. In this review, we provide an overview of therapeutic vaccine development in ovarian cancer, discuss proposed mechanisms of action, and summarize the current clinical experience.

Uterine clear cell carcinoma risk in White versus non-White US subpopulations: does race matter?

OBJECTIVE: To determine incidence rates of uterine clear cell carcinoma among non-White US subpopulations. METHODS: Data from the United States Cancer Statistics and National Cancer Database from 2004 to 2016 were analyzed using descriptive statistics. RESULTS: A total of 488,811 women were diagnosed with uterine cancer from 2004-2016. Of these, 73.3% were endometrioid, 6.6% were serous, 5.3% were carcinosarcoma, 1.4% were clear cell, and 13.4% were other. Blacks had the highest incidence rate of uterine clear cell compared with Whites, Asian/Pacific Islanders, and American Indian/Alaska Natives (0.59 vs. 0.31, 0.29, and 0.24, respectively). Overall mean age at diagnosis was 68.6 years, with the youngest age in Asian/Pacific Islanders compared to Whites, Blacks, and American Indian/Alaska Natives (65.9 vs. 68.7, 68.6, and 66.3 years, respectively). Analysis of the Asian subpopulation revealed significantly younger age at diagnosis in Vietnamese women (55.8 years) compared with 72.4 years in Japanese, 68.6 years in Pacific Islander, 66.6 years in Indian/Pakistani, 65.9 years in Filipino, 65.8 years in Chinese, 65.2 years in Korean, and 63.7 years in other Asians. CONCLUSIONS: Black women are two times more likely to be diagnosed with uterine clear cell carcinoma compared with other races. Asians present at younger ages, with Vietnamese women most likely to be diagnosed at the youngest age.

Trends and survival outcomes of robotic, laparoscopic, and open surgery for stage II uterine cancer.

INTRODUCTION: A recent randomized clinical trial showed that minimally invasive surgery led to poorer survival compared with open surgery in early stage cervical cancer. We determined the trends in adoption of minimally invasive surgery and 5-year overall survival outcomes after open, laparoscopic-assisted, and robotic-assisted hysterectomy for stage II uterine cancer with cervical stromal involvement. METHODS: Data for patients with stage II uterine cancer were acquired from the National Cancer Database from 2010 to 2015. χ2 testing, Kaplan-Meier methods, and Cox models were used for statistical analyses. RESULTS: Of 2949 patients, 44.3% underwent open hysterectomy, 13.9% underwent laparoscopic hysterectomy, and 41.8% underwent robotic hysterectomy. The proportion of robotic cases increased from 26.8% in 2010 to 48.3% in 2015 (annual percent change 10.1%), with a decrease in open hysterectomy from 63.3% to 34.3% (annual percent change -12.5%). The overall 5-year survival was 77.6% in robotic, 76.8% in laparoscopic, and 72.5% in open hysterectomy (p=0.045); however, after adjusting for known prognostic factors, robotic (HR 1.00, 95% CI 0.82 to 1.21; p=0.97) and laparoscopic hysterectomy (HR 1.09, 95% CI 0.83 to 1.44; p=0.54) did not portend for improved survival compared with open hysterectomy. Black women (HR 1.59, 95% CI 1.25 to 2.02; p<0.001) and individuals with co-morbidities (HR 1.45, 95% CI 1.21 to 1.75, p<0.001) had worse adjusted survival and the highest rates of open hysterectomy. CONCLUSION: The use of minimally invasive surgery for stage II uterine cancer has increased over time, with comparable adjusted 5-year survival after robotic or laparoscopic hysterectomy compared with open hysterectomy. Black women and those with co-morbidities had lowest rates of minimally invasive surgery and the poorest adjusted survival.

Breast cancer risk after hysterectomy with and without salpingo-oophorectomy for benign indications.

BACKGROUND: Breast cancer risk has been extensively studied in women with genetic predisposition, that is, mutations in breast cancer genes 1 and 2. Although there are guidelines for performing bilateral salpingo-oophorectomies in individuals with specific genetic risks, oophorectomies are also performed in many women considered to be at average risk of developing breast cancer. The risk of breast cancer in women with average risk who undergo hysterectomy with bilateral salpingo-oophorectomy for benign indications is less clear. OBJECTIVE: This study aimed to estimate breast cancer risk after hysterectomy with and without concomitant bilateral salpingo-oophorectomy for benign indications. STUDY DESIGN: From 2001 to 2015, women aged 18 years and older from Kaiser Permanente Northern California who underwent hysterectomy alone and hysterectomy with bilateral salpingo-oophorectomy were identified using the International Classification of Diseases, Ninth Revision, procedure and Current Procedural Terminology codes. Women with a breast cancer gene mutation and previous history of breast cancer or gynecologic cancer were excluded. Descriptive and bivariate analyses were used to describe and compare demographic and clinical characteristics. Breast cancer incidence rates were calculated per 100,000 person-years. Survival analysis and Cox proportional hazard models were conducted to compare the risk of developing breast cancer. RESULTS: Of 49,215 women who underwent hysterectomy, 19,826 had hysterectomy with bilateral salpingo-oophorectomy. Whites, Hispanics, blacks, Asians, and other or unknown comprised 51.2%, 20.3%, 12.7%, 10.4%, and 5.3% of the study population, respectively. The average age of women with hysterectomy alone was 45.5 years compared with 50.8 years for those who had hysterectomy with bilateral salpingo-oophorectomy. During the study period, 915 women received a diagnosis of breast cancer. Age-specific breast cancer incidence rates were higher in women older than 60 years with oophorectomy than hysterectomy alone (471.2 [95% confidence interval, 386.2-556.2] vs 463.0 [95% confidence interval, 349.6-576.5], respectively). After controlling for age, race, income, and Charlson Comorbidity Index, women with bilateral salpingo-oophorectomy had a 14% lower risk of breast cancer than women with hysterectomy alone (hazard ratio, 0.86; 95% confidence interval, 0.75-0.98). All-cause mortality was higher with oophorectomy than hysterectomy alone (64.4% vs 35.6%, P<.0001, respectively). CONCLUSION: Women with concurrent bilateral salpingo-oophorectomy for benign indications had a lower risk of breast cancer than those who had hysterectomy alone. However, all-cause mortality was higher in women with oophorectomy. Perimenopausal patients undergoing hysterectomy for benign indications should be counseled on the risks and benefits of oophorectomy at the time of surgery.