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Abstract Background Mesenchymal stromal cell (MSC) therapy holds great potential yet efficacy and safety concerns with cell therapy persist. The beneficial effects of MSCs are often attributed to their secretome that includes extracellular vesicles (EVs). EVs carry biologically active molecules, protected by a lipid bilayer. However, several barriers hinder large-scale MSC EV production. A serum-free culturing approach is preferred for producing clinical-grade MSC-derived EVs but this can affect both yield and purity. Consequently, new strategies have been explored, including genetically engineering MSCs to alter EV compositions to enhance potency, increase circulation time or mediate targeting. However, efficient transfection of MSCs is challenging. Typical sources of MSC include adipose tissue and bone marrow, which both require invasive extraction procedures. Here, we investigate the use of urine-derived stem cells (USCs) as a non-invasive and inexhaustible source of MSCs for EV production. Methods We isolated, expanded, and characterized urine-derived stem cells (USCs) harvested from eight healthy donors at three different time points during the day. We evaluated the number of clones per urination, proliferation capacity and conducted flow cytometry to establish expression of surface markers. EVs were produced in chemically defined media and characterized. PEI/DNA transfection was used to genetically engineer USCs using transposon technology. Results There were no differences between time points for clone number, doubling time or viability. USCs showed immunophenotypic characteristics of MSCs, such as expression of CD73, CD90 and CD105, with no difference at the assessed time points, however, male donors had reduced CD73 + cells. Expanded USCs were incubated without growth factors or serum for 72 h without a loss in viability and EVs were isolated. USCs were transfected with high efficiency and after 10 days of selection, pure engineered cell cultures were established. Conclusions Isolation and expansion of MSCs from urine is non-invasive, robust, and without apparent sex-related differences. The sampling time point did not affect any measured markers or USC isolation potential. USCs offer an attractive production platform for EVs, both native and engineered.

Abstract Background E. coli O83 (Colinfant Newborn) is a Gram-negative (G-) probiotic bacterium used in the clinic. When administered orally, it reduces allergic sensitisation but not allergic asthma. Intranasal administration offers a non-invasive and convenient delivery method. This route bypasses the gastrointestinal tract and provides direct access to the airways, which are the target of asthma prevention. G- bacteria such as E. coli O83 release outer membrane vesicles (OMVs) to communicate with the environment. Here we investigate whether intranasally administered E. coli O83 OMVs (EcO83-OMVs) can reduce allergic airway inflammation in mice. Methods EcO83-OMVs were isolated by ultracentrifugation and characterised their number, morphology (shape and size), composition (proteins and lipopolysaccharide; LPS), recognition by innate receptors (using transfected HEK293 cells) and immunomodulatory potential (in naïve splenocytes and bone marrow-derived dendritic cells; BMDCs). Their allergy-preventive effect was investigated in a mouse model of ovalbumin-induced allergic airway inflammation. Results EcO83-OMVs are spherical nanoparticles with a size of about 110 nm. They contain LPS and protein cargo. We identified a total of 1120 proteins, 136 of which were enriched in OMVs compared to parent bacteria. Proteins from the flagellum dominated. OMVs activated the pattern recognition receptors TLR2/4/5 as well as NOD1 and NOD2. EcO83-OMVs induced the production of pro- and anti-inflammatory cytokines in splenocytes and BMDCs. Intranasal administration of EcO83-OMVs inhibited airway hyperresponsiveness, and decreased airway eosinophilia, Th2 cytokine production and mucus secretion. Conclusions We demonstrate for the first time that intranasally administered OMVs from probiotic G- bacteria have an anti-allergic effect. Our study highlights the advantages of OMVs as a safe platform for the prophylactic treatment of allergy. Graphical Abstract Video Abstract

Objectives Many adolescents and young adults with emerging mood disorders do not achieve substantial improvements in education, employment, or social function after receiving standard youth mental health care. We have developed a new model of care referred to as ‘highly personalised and measurement-based care’ (HP&MBC). HP&MBC involves repeated assessment of multidimensional domains of morbidity to enable continuous and personalised clinical decision-making. Although measurement-based care is common in medical disease management, it is not a standard practice in mental health. This clinical effectiveness trial tests whether HP&MBC, supported by continuous digital feedback, delivers better functional improvements than standard care and digital support.Method and analysis This controlled implementation trial is a PROBE study (Prospective, Randomised, Open, Blinded End-point) that comprises a multisite 24-month, assessor-blinded, follow-up study of 1500 individuals aged 15–25 years who present for mental health treatment. Eligible participants will be individually randomised (1:1) to 12 months of HP&MBC or standardised clinical care. The primary outcome measure is social and occupational functioning 12 months after trial entry, assessed by the Social and Occupational Functioning Assessment Scale. Clinical and social outcomes for all participants will be monitored for a further 12 months after cessation of active care.Ethics and dissemination This clinical trial has been reviewed and approved by the Human Research Ethics Committee of the Sydney Local Health District (HREC Approval Number: X22-0042 & 2022/ETH00725, Protocol ID: BMC-YMH-003-2018, protocol version: V.3, 03/08/2022). Research findings will be disseminated through peer-reviewed journals, presentations at scientific conferences, and to user and advocacy groups. Participant data will be deidentified.Trial registration number ACTRN12622000882729.

Concentrations of SARS-CoV-2 RNA in wastewater settled solids from publicly owned treatment works (POTWs) historically correlated strongly with laboratory confirmed incident COVID-19 case data. With the increased availability of at-home antigen tests since late 2021 and early 2022, laboratory test availability and test seeking behavior has decreased. In the United States, the results from at-home antigen tests are not typically reportable to public health agencies and thus are not counted in case reports. As a result, the number of reported laboratory-confirmed incident COVID-19 cases has decreased dramatically, even during times of increased test positivity rates and wastewater concentrations of SARS-CoV-2 RNA. Herein, we tested whether the correlative relationship between wastewater concentrations of SARS-CoV-2 RNA and reported laboratory-confirmed COVID-19 incidence rate has changed since 1 May 2022, a point in time immediately before the onset of the BA.2/BA.5 surge, the first surge to begin after at-home antigen test availability was high in the region. We used daily data from three POTWs in the Greater San Francisco Bay Area of California, USA for the analysis. We found that although there is a significant positive association between wastewater measurements and incident rate data collected after 1 May 2022, the parameters describing the relationship are different than those describing the relationship between the data collected prior to 1 May 2022. If laboratory test seeking or availability continues to change, the relationship between wastewater and reported case data will continue to change. Our results suggest, assuming SARS-CoV-2 RNA shedding remains relatively stable among those infected with the virus as different variants emerge, that wastewater concentrations of SARS-CoV-2 RNA can be used to estimate COVID-19 cases as they would have been during the time when laboratory testing availability and test seeking behavior were at a high (here, before 1 May 2022) using the historical relationship between SARS-CoV-2 RNA and COVID-19 case data.

SARS-CoV-2 variants of concern are less susceptible to therapeutic neutralizing antibodies, given mutations in the surface glycoprotein S. Here, Case et al. show that therapeutic antibodies S309 and AZD7442 reduce lung infection with SARSCoV-2 Omicron lineages in humanized mouse model despite the loss of neutralizing potency in vitro.

Abstract Over the last decade, research interest in defining how extracellular vesicles (EVs) shape cross‐species communication has grown rapidly. Parasitic helminths, worm species found in the phyla Nematoda and Platyhelminthes, are well‐recognised manipulators of host immune function and physiology. Emerging evidence supports a role for helminth‐derived EVs in these processes and highlights EVs as an important participant in cross‐phylum communication. While the mammalian EV field is guided by a community‐agreed framework for studying EVs derived from model organisms or cell systems [e.g., Minimal Information for Studies of Extracellular Vesicles (MISEV)], the helminth community requires a supplementary set of principles due to the additional challenges that accompany working with such divergent organisms. These challenges include, but are not limited to, generating sufficient quantities of EVs for descriptive or functional studies, defining pan‐helminth EV markers, genetically modifying these organisms, and identifying rigorous methodologies for in vitro and in vivo studies. Here, we outline best practices for those investigating the biology of helminth‐derived EVs to complement the MISEV guidelines. We summarise community‐agreed standards for studying EVs derived from this broad set of non‐model organisms, raise awareness of issues associated with helminth EVs and provide future perspectives for how progress in the field will be achieved.

BackgroundInfections with Ascaris lumbricoides and Trichuris trichiura remain significant contributors to the global burden of neglected tropical diseases. Infection may in particular affect child development as they are more likely to be infected with T. trichiura and/or A. lumbricoides and to carry higher worm burdens than adults. Whilst the impact of heavy infections are clear, the effects of moderate infection intensities on the growth and development of children remain elusive. Field studies are confounded by a lack of knowledge of infection history, nutritional status, presence of co-infections and levels of exposure to infective eggs. Therefore, animal models are required. Given the physiological similarities between humans and pigs but also between the helminths that infect them; A. suum and T. suis, growing pigs provide an excellent model to investigate the direct effects of Ascaris spp. and Trichuris spp. on weight gain.Methods and resultsWe employed a trickle infection protocol to mimic natural co-infection to assess the effect of infection intensity, determined by worm count (A. suum) or eggs per gram of faeces (A. suum and T. suis), on weight gain in a large pig population (n = 195) with variable genetic susceptibility. Pig body weights were assessed over 14 weeks. Using a post-hoc statistical approach, we found a negative association between weight gain and T. suis infection. For A. suum, this association was not significant after adjusting for other covariates in a multivariable analysis. Estimates from generalized linear mixed effects models indicated that a 1 kg increase in weight gain was associated with 4.4% (p = 0.00217) decrease in T. suis EPG and a 2.8% (p = 0.02297) or 2.2% (p = 0.0488) decrease in A. suum EPG or burden, respectively.ConclusionsOverall this study has demonstrated a negative association between STH and weight gain in growing pigs but also that T. suis infection may be more detrimental that A. suum on growth.

BackgroundPredicting patient's Length of Stay (LOS) before total joint replacement (TJR) surgery is vital for hospitals to optimally manage costs and resources. Many hospitals including in rural areas use publicly available models such as National Surgical Quality Improvement Program (NSQIP) calculator which, unfortunately, performs suboptimally when predicting LOS for TJR procedures.ObjectiveThe objective of this research was to develop a Machine Learning (ML) model to predict LOS for TJR procedures performed at a Perioperative Surgical Home implemented rural community hospital for better accuracy and interpretation than the NSQIP calculator.MethodsA total of 158 TJR patients were collected and analyzed from a rural community hospital located in Montana. A random forest (RF) model was used to predict patient's LOS. For interpretation, permuted feature importance and partial dependence plot methods were used to identify the important variables and their relationship with the LOS.ResultsThe root mean square error for the RF model (0.7) was lower than the NSQIP calculator (1.21). The five most important variables for predicting LOS were BMI, Duke Activity Status-Index, diabetes, patient's household income, and patient's age.ConclusionThis pilot study is the first of its kind to develop an ML model to predict LOS for TJR procedures that were performed at a small-scale rural community hospital. This pilot study contributes an approach for rural hospitals, making them more independent by developing their own predictions instead of relying on public models.

ABSTRACT A number of recent retrospective studies have demonstrated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA concentrations in wastewater are associated with coronavirus disease 2019 (COVID-19) cases in the corresponding sewersheds. Implementing high-resolution, prospective efforts across multiple plants depends on sensitive measurements that are representative of COVID-19 cases, scalable for high-throughput analysis, and comparable across laboratories. We conducted a prospective study across eight publicly owned treatment works (POTWs). A focus on SARS-CoV-2 RNA in solids enabled us to scale up our measurements with a commercial lab partner. Samples were collected daily, and results were posted to a website within 24 h. SARS-CoV-2 RNA in daily samples correlated with the incidence of COVID-19 cases in the sewersheds; a 1 log10 increase in SARS-CoV-2 RNA in settled solids corresponds to a 0.58 log10 (4×) increase in sewershed incidence rate. SARS-CoV-2 RNA signals measured with the commercial laboratory partner were comparable across plants and comparable to measurements conducted in a university laboratory when normalized by pepper mild mottle virus (PMMoV) RNA. Results suggest that SARS-CoV-2 RNA should be detectable in settled solids for COVID-19 incidence rates of >1/100,000 (range, 0.8 to 2.3 cases per 100,000). These sensitive, representative, scalable, and comparable methods will be valuable for future efforts to scale up wastewater-based epidemiology. IMPORTANCE Access to reliable, rapid monitoring data is critical to guide response to an infectious disease outbreak. For pathogens that are shed in feces or urine, monitoring wastewater can provide a cost-effective snapshot of transmission in an entire community via a single sample. In order for a method to be useful for ongoing COVID-19 monitoring, it should be sensitive for detection of low concentrations of SARS-CoV-2, representative of incidence rates in the community, scalable to generate data quickly, and comparable across laboratories. This paper presents a method utilizing wastewater solids to meet these goals, producing measurements of SARS-CoV-2 RNA strongly associated with COVID-19 cases in the sewershed of a publicly owned treatment work. Results, provided within 24 h, can be used to detect incidence rates as low as approximately 1/100,000 cases and can be normalized for comparison across locations generating data using different methods.

OBJECTIVE: To estimate the effect of preoperative diagnostic hysteroscopy on peritoneal cytology in patients with endometrial cancer. METHODS: A total of 256 charts were reviewed. Two cohorts were established based on diagnosis by hysteroscopy or blind endometrial sampling via either endometrial biopsy or dilatation and curettage (D&C). Malignant or suspicious peritoneal cytology was the primary outcome. Cohorts were compared using logistic regression to correct for potential confounders of stage and grade. RESULTS: A total of 204 cases were diagnosed by endometrial biopsy or D&C, whereas 52 were identified by hysteroscopy. In the endometrial biopsy or D&C arm, 14 of 204 (6.9%) patients had malignant or suspicious cytology compared with 7 of 52 (13.5%) patients in the hysteroscopy arm (P = .15). After logistic regression controlling for stage and grade, the odds ratio for positive cytology after hysteroscopy was 3.88 (95% confidence interval 1.11,13.6; P = .03). Four of the 52 (7.7%) cases diagnosed by hysteroscopy were stage IIIA due to cytology alone compared with 3 of the 204 (1.4%) cases diagnosed by endometrial biopsy or D&C (P = .03). CONCLUSION: Hysteroscopy appears to be associated with an increased rate of malignant cytology after controlling for confounders of stage and grade. Further, there appears to be an association between hysteroscopy and upstaging patients due to cytology alone. LEVEL OF EVIDENCE: II-2. [ABSTRACT FROM AUTHOR]

Background: Agomelatine is a melatonin agonist and 5HT antagonist developed for the treatment of major depressive disorder which also has some effects on the circadian system. Since circadian dysfunctions are thought to play a role in the pathophysiology of depression, some of the mechanism of action of this drug may relate to improvements in circadian rhythms.Objective: This proof of concept open-label study sought to determine if improvements in depressive symptoms following an adjunctive multimodal intervention including agomelatine intake are associated with the magnitude of circadian realignment. This was investigated in young people with depression, a subgroup known to have high rates of delayed circadian rhythms.Methods: Young people with depression received a psychoeducation session about sleep and circadian rhythms, were asked to progressively phase advance their wake up time, and completed an 8 weeks course of agomelatine (25–50 mg). Participants underwent semi-structured psychological assessments, ambulatory sleep-wake monitoring and measurement of melatonin circadian phase before and after the intervention.Results: Twenty-four young adults with depression (17–28 years old; 58% females) completed the study. After the intervention, depressive symptoms were significantly reduced [t(23) = 6.9, p < 0.001] and, on average, the timing of dim light melatonin onset (DLMO) shifted 3.6 h earlier [t(18) = 4.4, p < 0.001]. On average, sleep onset was phase shifted 28 min earlier [t(19) = 2.1, p = 0.047] and total sleep time increased by 24 min [t(19) = –2.6, p = 0.018]. There was no significant change in wake-up times. A strong correlation (r = 0.69, p = 0.001) was found between the relative improvements in depression severity and the degree of phase shift in DLMO.Conclusion: Although this needs to be replicated in larger randomized controlled trials, these findings suggest that the degree of antidepressant response to a multimodal intervention including psychoeducation and agomelatine intake may be associated with the degree of change in evening melatonin release in young people with depression. This offers promising avenues for targeted treatment based on the prior identification of objective individual characteristics.

Background: Exosomes have been implicated in tumour progression and metastatic spread. Little is known of the effect of mechanical and innate immune interactions of malignant cell-derived exosomes on endothelial integrity, which may relate to increased extravasation of circulating tumour cells and, therefore, increased metastatic spread. Methods: Exosomes isolated from non-malignant immortalized HCV-29 and isogenic malignant non-metastatic T24 and malignant metastatic FL3 bladder cells were characterized by nanoparticle tracking analysis and quantitative nanomechanical mapping atomic force microscopy (QNM AFM) to determine size and nanomechanical properties. Effect of HCV-29, T24 and FL3 exosomes on human umbilical vein endothelial cell (HUVEC) monolayer integrity was determined by transendothelial electrical resistance (TEER) measurements and transport was determined by flow cytometry. Complement activation studies in human serum of malignant and non-malignant cell-derived exosomes were performed. Results: FL3, T24 and HCV-29 cells produced exosomes at similar concentration per cell (6.64, 6.61 and 6.46×104 exosomes per cell for FL3, T24 and HCV-29 cells, respectively) and of similar size (120.2 nm for FL3, 127.6 nm for T24 and 117.9 nm for HCV-29, respectively). T24 and FL3 cell-derived exosomes exhibited a markedly reduced stiffness, 95 MPa and 280 MPa, respectively, compared with 1,527 MPa with non-malignant HCV-29 cell-derived exosomes determined by QNM AFM. FL3 and T24 exosomes induced endothelial disruption as measured by a decrease in TEER in HUVEC monolayers, whereas no effect was observed for HCV-29 derived exosomes. FL3 and T24 exosomes traffic more readily (11.6 and 21.4% of applied exosomes, respectively) across HUVEC monolayers than HCV-29 derived exosomes (7.2% of applied exosomes). Malignant cell-derived exosomes activated complement through calcium-sensitive pathways in a concentration-dependent manner. Conclusions: Malignant (metastatic and non-metastatic) cell line exosomes display a markedly reduced stiffness and adhesion but an increased complement activation compared to non-malignant cell line exosomes, which may explain the observed increased endothelial monolayer disruption and transendothelial transport of these vesicles.

In the last two decades, extracellular vesicles (EVs) from the three domains of life, Archaea, Bacteria and Eukaryotes, have gained increasing scientific attention. As such, the role of EVs in host-pathogen communication and immune modulation are being intensely investigated. Pivotal to EV research is the determination of how and where EVs are taken up by recipient cells and organs in vivo, which requires suitable tracking strategies including labelling. Labelling of EVs is often performed post-isolation which increases risks of non-specific labelling and the introduction of labelling artefacts. Here we exploited the inability of helminths to de novo synthesise fatty acids to enable labelling of EVs by whole organism uptake of fluorescent lipid analogues and the subsequent incorporation in EVs. We showed uptake of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(lissamine rhodamine B sulfonyl) (DOPE-Rho) in Anisakis spp. and Trichuris suis larvae. EVs isolated from the supernatant of Anisakis spp. labelled with DOPE-Rho were characterised to assess the effects of labelling on size, structure and fluorescence of EVs. Fluorescent EVs were successfully taken up by the human macrophage cell line THP-1. This study, therefore, presents a novel staining method that can be utilized by the EV field in parasitology and potentially across multiple species.

Background: Cells release a mixture of extracellular vesicles, amongst these exosomes, that differ in size, density and composition. The standard isolation method for exosomes is centrifugation of fluid samples, typically at 100,000×g or above. Knowledge of the effect of discrete ultracentrifugation speeds on the purification from different cell types, however, is limited. Methods: We examined the effect of applying differential centrifugation g-forces ranging from 33,000×g to 200,000×g on exosome yield and purity, using 2 unrelated human cell lines, embryonic kidney HEK293 cells and bladder carcinoma FL3 cells. The fractions were evaluated by nanoparticle tracking analysis (NTA), total protein quantification and immunoblotting for CD81, TSG101, syntenin, VDAC1 and calreticulin. Results: NTA revealed the lowest background particle count in Dulbecco's Modified Eagle's Medium media devoid of phenol red and cleared by 200,000×g overnight centrifugation. The centrifugation tube fill level impacted the sedimentation efficacy. Comparative analysis by NTA, protein quantification, and detection of exosomal and contamination markers identified differences in vesicle size, concentration and composition of the obtained fractions. In addition, HEK293 and FL3 vesicles displayed marked differences in sedimentation characteristics. Exosomes were pelleted already at 33,000×g, a g-force which also removed most contaminating microsomes. Optimal vesicle-to-protein yield was obtained at 67,000×g for HEK293 cells but 100,000×g for FL3 cells. Relative expression of exosomal markers (TSG101, CD81, syntenin) suggested presence of exosome subpopulations with variable sedimentation characteristics. Conclusions: Specific g-force/k factor usage during differential centrifugation greatly influences the purity and yield of exosomes. The vesicle sedimentation profile differed between the 2 cell lines.

Although early-stage affective disorders are associated with both cognitive dysfunction and sleep-wake disruptions, relationships between these factors have not been specifically examined in young adults. Sleep and circadian rhythm disturbances in those with affective disorders are considerably heterogeneous, and may not relate to cognitive dysfunction in a simple linear fashion. This study aimed to characterise profiles of sleep and circadian disturbance in young people with affective disorders and examine associations between these profiles and cognitive performance. Actigraphy monitoring was completed in 152 young people (16-30 years; 66% female) with primary diagnoses of affective disorders, and 69 healthy controls (18-30 years; 57% female). Patients also underwent detailed neuropsychological assessment. Actigraphy data were processed to estimate both sleep and circadian parameters. Overall neuropsychological performance in patients was poor on tasks relating to mental flexibility and visual memory. Two hierarchical cluster analyses identified three distinct patient groups based on sleep variables and three based on circadian variables. Sleep clusters included a 'long sleep' cluster, a 'disrupted sleep' cluster, and a 'delayed and disrupted sleep' cluster. Circadian clusters included a 'strong circadian' cluster, a 'weak circadian' cluster, and a 'delayed circadian' cluster. Medication use differed between clusters. The 'long sleep' cluster displayed significantly worse visual memory performance compared to the 'disrupted sleep' cluster. No other cognitive functions differed between clusters. These results highlight the heterogeneity of sleep and circadian profiles in young people with affective disorders, and provide preliminary evidence in support of a relationship between sleep and visual memory, which may be mediated by use of antipsychotic medication. These findings have implications for the personalisation of treatments and improvement of functioning in young adults early in the course of affective illness.

Considering the marked changes in sleep and circadian rhythms across the lifespan, age may contribute to the heterogeneity in sleep-wake profiles linked to mood disorders. This study aimed to investigate the contributions of age and depression severity to sleep-wake disturbances. The Hamilton Depression Rating Scale (HDRS) was administered to assess current symptoms severity in 238 persons with a history of a mood disorder between 12 and 90 years of age (y.o.). Actigraphy was recorded over five to 22 days. Regression analyses and analyses of variance [age (12-19 y.o., 20-39 y.o., 40-59 y.o., and ≥ 60 y.o.) by depression severity (HDRS< and ≥ 8)] were conducted. The 12-19 y.o. and 20-39 y.o. groups had a delayed sleep schedule and acrophase compared to all other groups. The ≥ 60 y.o. group had a lower rhythmicity and amplitude (p ≤ .006) than the 12-19 y.o. group (p ≤ .046). Participants with a HDRS ≥ 8 spent longer time in bed, had later sleep offset times and had lower circadian rhythmicity than those with a HDRS

OBJECTIVE: To determine the effect of patient clinical factors on the utilization of hysterectomy and alternatives of hysterectomy. STUDY DESIGN: The database of Empire Blue Cross Blue Shield was abstracted for all claims relating to a hysterectomy procedure or a hysterectomy-associated diagnosis during the 48 consecutive months of May 2001-April 2005. Two hundred ninety-five thousand one hundred forty-eight claim lines were abstracted and analyzed by CPT and diagnostic grouping codes. RESULTS: One thousand nine hundred seventy-two hysterectomies were performed during the time analyzed, and 5,077 hysterectomy alternatives. The mean age of all patients encountered was 39.1 years. Patients undergoing a hysterectomy alternative or hysterectomy had mean ages of 46.0 and 49.7 years, respectively. Abnormal bleeding was associated with the most encounters, while leiomyomata was associated with the most hysterectomies performed. CONCLUSION: Patients who undergo hysterectomy are, on average, older than those undergoing office management or hysterectomy alternatives. Procedures are most commonly associated with diagnosis of bleeding, leiomyomata, or cancer. Bleeding typically results in a hysterectomy alternative, while leiomyomata has the highest association with hysterectomy. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The purpose of this study was to determine the effect of physician gender and specialty on the utilization of hysterectomy and alternatives to hysterectomy. STUDY DESIGN: The database of Empire Blue Cross Blue Shield was abstracted for all claims relating to a hysterectomy procedure or a hysterectomy-associated diagnosis during the 48 consecutive months May 2001-April 2005. Two hundred ninety-five thousand, one hundred forty-eight claim lines were abstracted and analyzed by CPT and diagnostic grouping codes. RESULTS: One thousand nine hundred seventy-two hysterectomies were performed during the time analyzed, as well as 5077 hysterectomy alternatives. These 7049 procedures represented 2.4% of all coded physician encounters. Male physicians utilize hysterectomy and hysterectomy alternatives at the same rate as female physicians. Physicians who practice gynecology-only or gynecologic oncology utilize laparoscopically assisted vaginal hysterectomy more often than their counterparts who practice obstetrics as well as gynecology. CONCLUSION: Gender does not influence the rate of hysterectomy for similar clinical diagnoses. Subspecialty physicians utilize laparoscopic assisted vaginal hysterectomies more frequently than general obstetricians and gynecologists. [ABSTRACT FROM AUTHOR]

Background: The phase III PRIMA/ENGOT-OV26/GOG-3012 trial met its primary endpoint. Niraparib first-line maintenance significantly prolonged progression-free survival (PFS) among patients with newly diagnosed advanced ovarian cancer that responded to first-line platinum-based chemotherapy, regardless of homologous recombination deficiency (HRD) status. Final overall survival (OS) results are reported., Patients and Methods: Patients were randomized 2:1 to niraparib or placebo, stratified by response to first-line treatment, receipt of neoadjuvant chemotherapy, and tumor HRD status. After reaching 60% target maturity, OS was evaluated via a stratified log-rank test using randomization stratification factors and summarized using Kaplan-Meier methodology. OS testing was hierarchical [overall population first, then the homologous recombination-deficient (HRd) population]. Other secondary outcomes and long-term safety were assessed; an updated, ad hoc analysis of investigator-assessed PFS was also conducted (cut-off date, 8 April 2024)., Results: The median follow-up was 73.9 months. In the overall population, the OS hazard ratio was 1.01 [95% confidence interval (CI) 0.84-1.23; P = 0.8834] for niraparib (n = 487) versus placebo (n = 246). In the HRd (n = 373) and homologous recombination-proficient (n = 249) populations, the OS hazard ratios were 0.95 (95% CI 0.70-1.29) and 0.93 (95% CI 0.69-1.26), respectively. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 11.7% and 15.8% of niraparib patients and 37.8% and 48.4% of placebo patients in the overall and HRd populations, respectively. The 5-year PFS rate numerically favored niraparib in the overall (niraparib, 22%; placebo, 12%) and HRd populations (niraparib, 35%; placebo, 16%). Myelodysplastic syndromes/acute myeloid leukemia incidence was <2.5% (niraparib, 2.3%; placebo, 1.6%). No new safety signals were observed., Conclusions: In patients with newly diagnosed advanced ovarian cancer at high risk of recurrence, there was no difference in OS between treatment arms. In the HRd population, patients alive at 5 years were two times as likely to be progression free with niraparib treatment than placebo. Long-term safety remained consistent with the established niraparib safety profile., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: This phase 1b study (ClinicalTrials.gov identifier NCT03695380) evaluated regimens combining PARP and MEK inhibition, with or without PD-L1 inhibition, for BRCA wild-type, platinum-sensitive, recurrent ovarian cancer (PSROC)., Methods: Patients with PSROC who had received one or two prior treatment lines were treated with 28-day cycles of cobimetinib 60 mg daily (days 1-21) plus niraparib 200 mg daily (days 1-28) with or without atezolizumab 840 mg (days 1 and 15). Stage 1 assessed safety before expansion to stage 2, which randomized patients who had BRCA wild-type PSROC to receive either doublet or triplet therapy, stratified by genome-wide loss of heterozygosity status (<16% vs. ≥16%; FoundationOne CDx assay) and platinum-free interval (≥6 to <12 vs. ≥12 months). Coprimary end points were safety and the investigator-determined objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Potential associations between genetic parameters and efficacy were explored, and biomarker profiles of super-responders (complete response or those with progression-free survival [PFS] >15 months) and progressors (disease progression as the best response) were characterized., Results: The ORR in patients who had BRCA wild-type PSROC was 35% (95% confidence interval, 20%-53%) with the doublet regimen (n = 37) and 27% (95% confidence interval, 14%-44%) with the triplet regimen (n = 37), and the median PFS was 6.0 and 7.4 months, respectively. Post-hoc analyses indicated more favorable ORR and PFS in the homologous recombination-deficiency-signature (HRDsig)-positive subgroup than in the HRDsig-negative subgroup. Tolerability was consistent with the known profiles of individual agents. NF1 and MKNK1 mutations were associated with sustained benefit from the doublet and triplet regimens, respectively., Conclusions: Chemotherapy-free doublet and triplet therapy demonstrated encouraging activity, including among patients who had BRCA wild-type, HRDsig-positive or HRDsig-negative PSROC harboring NF1 or MKNK1 mutations., (© 2024 F. Hoffmann‐La Roche. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

The objective of this study was to determine if quantifying the microsatellite instability (MSI) phenotype could serve as a biomarker for clinical and immunologic features of deficient mismatch repair (dMMR) endometrial cancer (EC). Patients with EC undergoing hysterectomy whose tumors demonstrated dMMR were included. Immunohistochemistry (IHC) of mismatch repair proteins and polymerase chain reaction analysis of NR27, BAT25, BAT26, NR24, and NR21 microsatellite loci were performed on each case. The MSI phenotype was quantified by subtracting the number of nucleotides of each microsatellite in tumor tissue from the corresponding microsatellite in paired normal tissue and summing the absolute differences. This was termed marker sum (MS) and is a novel quantification. Tumor-infiltrating lymphocytes (TILs) were identified by IHC for CD3, CD4, and CD8 and quantified with digital image analysis. Tumor infiltration of lymphocytes and clinical characteristics were stratified by MS. Four hundred fifty-nine consecutive patients with dMMR EC were analyzed. MS ranged from 1 to 32. Post hoc, 2 cohorts were defined using receiver operating characteristic curves (MS less than 13 and MS greater than 12). With the exception of tumor grade, all clinical and pathologic features, all tumor characteristics, and the numbers of TILs were similar between cohorts. The MSI phenotype is highly variable in dMMR EC, and no correlation between the immune profile and the severity of the MSI phenotype was observed., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Brachytherapy irradiation carries risks of both bleeding and venous thromboembolism (VTE). No screening or management recommendations for VTE in this setting have been developed. Our study aims to understand the incidence of VTE, compile published anticoagulation guidelines, and call for future guidelines to address thromboprophylaxis in this population., Methods and Materials: A retrospective, single institution study of patients undergoing brachytherapy irradiation between 2012 and 2022 was undertaken. We analyzed 2 cohorts: 87 patients undergoing brachytherapy with an inpatient admission, and 66 patients assessed for risk of VTE or bleeding after discharge from an inpatient admission for brachytherapy. Caprini risk scores were calculated for each patient, and statistical analyses were performed., Results: Eighty-seven patients were included, and 25% had a VTE diagnosis. Forty-seven (54%) of patients included underwent brachytherapy as definitive treatment of cervical cancer, and 16 (18%) received brachytherapy irradiation to treat recurrent endometrial cancer. In the cohort of 66 patients assessed for risk of VTE or bleeding after brachytherapy discharge, 23 (34.8%) were discharged with thromboprophylaxis, and 43 (65.2%) were discharged without thromboprophylaxis. None of the patients discharged on thromboprophylaxis were diagnosed with a VTE within 90 days of discharge after brachytherapy, whereas 3 of 43 (7%) discharged without thromboprophylaxis were diagnosed with a VTE, OR and 95% CI: 0.25 (0.01-5.29), p = 0.37. Of the 23 patients discharged on thromboprophylaxis, 1 was readmitted for bleeding OR and 95% CI: 5.8 (0.22-155.18), p = 0.29. The median Caprini score was 11., Conclusions: VTE is a common occurrence in patients undergoing brachytherapy. Patients undergoing brachytherapy irradiation who require inpatient admission represent a unique population, and specialty organizations should develop consensus recommendations to address these clinical challenges., (Copyright © 2023 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To inform continued development of the novel immune agent GEN-1, we compared ovarian cancer patients' end points from a neoadjuvant single-arm phase IB study with those of similar historic clinical trial (HCT) patients who received standard neoadjuvant chemotherapy., Methods: Applying OVATION-1 trial (ClinicalTrials.gov identifier: NCT02480374) inclusion and exclusion criteria to Medidata HCT data, we identified historical trial patients for comparison. Integrating patient-level Medidata historic trial data (N = 41) from distinct neoadjuvant ovarian phase I-III trials with patient-level OVATION-1 data (N = 18), we selected Medidata patients with similar baseline characteristics as OVATION-1 patients using propensity score methods to create an external control arm (ECA)., Results: Fifteen OVATION-1 patients (15 of 18, 83%) were matched to 15 (37%, 15 of 41) Medidata historical trial control patients. Matching attenuated preexisting differences in attributes between the groups. The median progression-free survival time was not reached by the OVATION-1 group and was 15.8 months (interquartile range, 11.40 months to nonestimable) for the ECA. The hazard of progression was 0.53 (95% CI, 0.16 to 1.73), favoring GEN-1 patients. Compared with ECA patients, OVATION-1 patients had more nausea, fatigue, chills, and infusion-related reactions., Conclusion: Comparing results of a single-arm early-phase trial to those of a rigorously matched HCT ECA yielded insights regarding comparative efficacy prior to a randomized controlled trial. The effect size estimate itself informed both the decision to continue development and the randomized phase II trial (ClinicalTrials.gov identifier: NCT03393884) sample size. The work illustrates the potential of HCT data to inform drug development.

Objective: To evaluate the association between surgical timing and postoperative residual disease status on the efficacy of niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer at high risk of recurrence., Methods: Post hoc analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) study of niraparib in patients with newly diagnosed primary advanced ovarian, primary peritoneal, or fallopian tube cancer with a complete/partial response to first-line platinum-based chemotherapy. Progression-free survival (PFS) was assessed by surgical status (primary debulking surgery [PDS] vs neoadjuvant chemotherapy/interval debulking surgery [NACT/IDS]) and postoperative residual disease status (no visible residual disease [NVRD] vs visible residual disease [VRD]) in the intent-to-treat population., Results: In PRIMA (N = 733), 236 (32.2%) patients underwent PDS, and 481 (65.6%) received NACT/IDS before enrollment. Median PFS (niraparib vs placebo) and hazard ratios (95% CI) for progression were similar in PDS (13.7 vs 8.2 months; HR, 0.67 [0.47-0.96]) and NACT/IDS (14.2 vs 8.2 months; HR, 0.57 [0.44-0.73]) subgroups. In patients who received NACT/IDS and had NVRD (n = 304), the hazard ratio (95% CI) for progression was 0.65 (0.46-0.91). In patients with VRD following PDS (n = 183) or NACT/IDS (n = 149), the hazard ratios (95% CI) for progression were 0.58 (0.39-0.86) and 0.41 (0.27-0.62), respectively. PFS was not evaluable for patients with PDS and NVRD because of sample size (n = 37)., Conclusions: In this post hoc analysis, niraparib efficacy was similar across PDS and NACT/IDS subgroups. Patients who had NACT/IDS and VRD had the highest reduction in the risk of progression with niraparib maintenance., Competing Interests: Declaration of Competing Interest REO reports participating in advisory boards with Bayer, Fresenius Kabi, GlaxoSmithKline, Immunogen, Regeneron, and Seattle Genetics; personal fees from GOG Foundation; and service as a noncompensated steering committee member for the PRIMA (niraparib) and DUO-O (olaparib) studies; institutional research support grants from AstraZeneca/Merck, Atara Biotherapeutics/Bayer, Genentech, Genmab, GlaxoSmithKline, Gynecologic Oncology Group Foundation, Juno Therapeutics, Kite/Gilead, Ludwig Institute for Cancer Research, Regeneron, Sellas Life Sciences, Stem CentRx, Syndax, TapImmune Inc., and TCR2 Therapeutics. JAPF reports personal fees from Abilify Pharma, Amgen, AstraZeneca, Clinigen, Clovis, GlaxoSmithKline, and Roche; and institutional grants from GlaxoSmithKline. BJM reports consulting fees from Agenus, Akeso Bio, Amgen, Aravive, Bayer, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Iovance, Karyopharm, Macrogenics, Mersana, Myriad, Novartis, Novocure, Regeneron, Sorrento, Pfizer, Puma, US Oncology Research, and VBL; speaker's bureau honoraria from AstraZeneca, Clovis, Eisai, Merck, Roche/Genentech, TESARO/GSK; and is an investigator for US Oncology Research. IT reports personal fees from Celgene and Roche Pharma AG; institutional grants from Roche; and travel support from Roche. RGM reports personal fees from Abcodia Inc., Fujirebio Diagnostics Inc., and Humphries Pharmaceutical; and institutional grants from Angle Plc. MSS reports personal fees from AstraZeneca, Clovis Oncology, GlaxoSmithKline, Merck, and Pacira Pharmaceuticals Inc.; and institutional grants from GlaxoSmithKline. DO reports personal fees from Agenus, Eisai, GlaxoSmithKline, and Immunogen; consultant/advisory board for Abbvie, Ambry, Amgen, Array Biopharma, Clovis, EMD Serono, Ergomed, Janssen/J&J, INC Research Inc., inVentiv Health Clinical, Iovance Biotherapeutics Inc., Myriad Genetics, Novacure, Regeneron, Tarveda, and VentiRx; steering committee for Genentech/Roche and Merck; institutional funding from Ajinomoto Inc., Bristol Myers Squibb, Cerulean Pharma, GOG Foundation, Ludwig Cancer Research, New Mexico Cancer Care Alliance, PRA International, Stemcentrx Inc., Serono Inc., Tracon Pharmaceuticals, and Yale University. BMS reports consulting/advisory fees from Abbvie, AstraZeneca, Clovis, Eisai, Genentech, GlaxoSmithKline, GOG Foundation, Merck, and Myriad. FS reports personal fees from AstraZeneca, Clovis, GlaxoSmithKline, MSD, PharmaMar, and Roche; and travel support from AstraZeneca, GlaxoSmithKline, MSD, PharmaMar, and Roche. AK reports personal fees from AstraZeneca and GlaxoSmithKline. AGM reports consulting or advisory roles at Amgen, AstraZeneca, Clovis, Genmab, GlaxoSmithKline, Merck & Co., Mersana, Immunogen, Roche, Sotio, and Takeda; speaker's bureau compensation from AstraZeneca, Clovis, GlaxoSmithKline, Merck & Co., and Roche; institutional research funding from Roche and GlaxoSmithKline; and travel support from AstraZeneca, GlaxoSmithKline, and Roche. CM, CV, JF, FF, WHB, SH, AD, KB, PMC, GA, and TL have nothing to disclose. IAM and DG are employees of GlaxoSmithKline. YL was an employee at GlaxoSmithKline at the time of the analysis; currently an employee of Adagio Therapeutics Inc., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Ovarian cancer is the most lethal gynecological malignancy among women worldwide and is characterized by aggressiveness, cancer stemness, and frequent relapse due to resistance to platinum-based therapy. Ovarian cancer cells metastasize through ascites fluid as 3D spheroids which are more resistant to apoptosis and chemotherapeutic agents. However, the precise mechanism as an oncogenic addiction that makes 3D spheroids resistant to apoptosis and chemotherapeutic agents is not understood. To study the signaling addiction mechanism that occurs during cancer progression in patients, we developed an endometrioid subtype ovarian cancer cell line named 'MCW-OV-SL-3' from the ovary of a 70-year-old patient with stage 1A endometrioid adenocarcinoma of the ovary. We found that the cell line MCW-OV-SL-3 exhibits interstitial duplication of 1q (q21-q42), where this duplication resulted in high expression of the PIK3C2B gene and aberrant activation of PI3K-AKT-ERK signaling. Using short tandem repeat (STR) analysis, we demonstrated that the cell line exhibits a unique genetic identity compared to existing ovarian cancer cell lines. Notably, the MCW-OV-SL-3 cell line was able to form 3D spheroids spontaneously, which is an inherent property of tumor cells when plated on cell culture dishes. Importantly, the tumor spheroids derived from the MCW-OV-SL-3 cell line expressed high levels of c-Kit, PROM1, ZEB1, SNAI, VIM, and Twist1 compared to 2D monolayer cells. We also observed that the hyperactivation of ERK and PI3K/AKT signaling in these cancer cells resulted in resistance to cisplatin. In summary, the MCW-OV-SL3 endometrioid cell line is an excellent model to study the mechanism of cancer stemness and chemoresistance in endometrioid ovarian cancer.

Background: There is a high unmet need for treatment regimens that increase the chance of long-term remission and possibly cure for women with newly diagnosed advanced ovarian cancer. In the primary analysis of SOLO1/GOG 3004, the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib significantly improved progression-free survival versus placebo in patients with a BRCA mutation; median progression-free survival was not reached. Here, we report an updated, post-hoc analysis of progression-free survival from SOLO1, after 5 years of follow-up., Methods: SOLO1 was a randomised, double-blind, placebo-controlled, phase 3 trial, done across 118 centres in 15 countries, that enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1 and with BRCA-mutated, newly diagnosed, advanced, high-grade serous or endometrioid ovarian cancer with a complete or partial clinical response after platinum-based chemotherapy. Patients were randomly assigned (2:1) via a web-based or interactive voice-response system to receive olaparib (300 mg twice daily) or placebo tablets orally as maintenance monotherapy for up to 2 years; randomisation was by blocks and was stratified according to clinical response after platinum-based chemotherapy. Patients, treatment providers, and data assessors were masked to group assignment. The primary endpoint was investigator-assessed progression-free survival. Efficacy is reported in the intention-to-treat population and safety in patients who received at least one dose of treatment. The data cutoff for this updated, post-hoc analysis was March 5, 2020. This trial is registered with ClinicalTrials.gov (NCT01844986) and is ongoing but closed to new participants., Findings: Between Sept 3, 2013, and March 6, 2015, 260 patients were randomly assigned to olaparib and 131 to placebo. The median treatment duration was 24·6 months (IQR 11·2-24·9) in the olaparib group and 13·9 months (8·0-24·8) in the placebo group; median follow-up was 4·8 years (2·8-5·3) in the olaparib group and 5·0 years (2·6-5·3) in the placebo group. In this post-hoc analysis, median progression-free survival was 56·0 months (95% CI 41·9-not reached) with olaparib versus 13·8 months (11·1-18·2) with placebo (hazard ratio 0·33 [95% CI 0·25-0·43]). The most common grade 3-4 adverse events were anaemia (57 [22%] of 260 patients receiving olaparib vs two [2%] of 130 receiving placebo) and neutropenia (22 [8%] vs six [5%]), and serious adverse events occurred in 55 (21%) of 260 patients in the olaparib group and 17 (13%) of 130 in the placebo group. No treatment-related adverse events that occurred during study treatment or up to 30 days after discontinuation were reported as leading to death. No additional cases of myelodysplastic syndrome or acute myeloid leukaemia were reported since the primary data cutoff, including after the 30-day safety follow-up period., Interpretation: For patients with newly diagnosed advanced ovarian cancer and a BRCA mutation, after, to our knowledge, the longest follow-up for any randomised controlled trial of a PARP inhibitor in this setting, the benefit derived from 2 years' maintenance therapy with olaparib was sustained beyond the end of treatment, extending median progression-free survival past 4·5 years. These results support the use of maintenance olaparib as a standard of care in this setting., Funding: AstraZeneca; Merck Sharpe & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA., Competing Interests: Declaration of interests SB reports clinical trial support paid to her institution from AstraZeneca for this study; grants to her institution from AstraZeneca, GlaxoSmithKline and Tesaro; personal consulting fees from Amgen, AstraZeneca, Genmab, GlaxoSmithKline, Immunogen, Mersana, Merck Sharpe & Dohme, Merck Serono, Oncxerna, Pfizer, and Roche; personal fees from Amgen, AstraZeneca, Clovis Oncology, GlaxoSmithKline, Pfizer, Takeda, and Tesaro; support for attending a meeting or travel from Nucana; unpaid participation on a Epsilogen advisory board; and an unpaid role as director of membership for the European Society of Medical Oncology. KNM reports clinical trial support paid to her institution for this study; contracts from Genentech/Roche, Lilly Pharmaceuticals, and PTC Therapeutics for ovarian cancer investigator-initiated trials; consulting fees from IMab; payment to her institution for educational content in gynaecological cancers from Onc Live, Physician Education Resource (PER), PRIME Oncology, and Research to Practice; payment to her institution for advisory boards for use of assets in gynaecological cancers from Alkemeres, Aravive, Blueprint Pharmaceuticals, Eisai, Genentech/Roche, Immunogen, Mersana, Mereo, and VBL Therapeutics; participation on a data safety monitoring board for Incyte; and payments to her institution for being an associate director of GOG partners and committee chair for NRG Ovarian Cancer. NC reports grants from AstraZeneca, PharmaMar, and Roche; personal consulting fees from AstraZeneca, BIOCAD, Clovis Oncology, Eisai, GlaxoSmithKline, Immunogen, Merck Sharp & Dohme, Mersana, Oncxerna, Pfizer, PharmaMar, Roche, and Tesaro; and personal fees from AstraZeneca, Clovis Oncology, Eisai, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, and Tesaro. GS reports grants and research support from Merck Sharpe & Dohme Italia; consulting fees from Johnson & Johnson and Tesaro Bio Italy; and speakers bureau fees and honoraria from Clovis Oncology Italy. AOa reports grants paid to her institution from AbbVie Deutschland, Abililty Pharmaceuticals, Advaxis, Aeterna Zentaris, Amgen, Aprea Therapeutics, Bristol Myers Squibb, Clovis Oncology, Eisai, F Hoffmann-La Roche, Immunogen, Merck Sharp & Dohme de España, Millennium Pharmaceuticals, Pharmamar, Regeneron Pharmaceuticals, and Tesaro; personal fees from AstraZeneca, Clovis Oncology, Deciphera Pharmarceutia, Genmab, GlaxoSmithKline, Immunogen, Mersana Therapeutic, PharmaMar, Roche, Sutro, and Tesaro; and support for attending meetings or travel, or both from AstraZeneca, Pharmamar, and Roche. MF reports personal advisory board and lecture fees, support to travel to a meeting and a grant to his institution from AstraZeneca; personal advisory board fees and a grant to his institution from Novartis; personal advisory board fees from GlaxoSmithKline, Lilly, Merck Sharpe & Dohme, and Takeda; personal lecture fees from Act Genomics and GlaxoSmithKline; research support to his institution from BeiGene; consulting for AbbVie (not renumerated); and participation on the Australasian Gastro-Intestinal Trials Group Independent Data Monitoring and Safety Committee. AF reports support for attending a medical congress from AstraZeneca. ALe reports grants from AstraZeneca and Sanofi; consulting fees from Seattle Genetics; honoraria or reimbursement and advisory board fees from AstraZeneca; advisory board fees or continuing medical education from Ability Pharma, Biocad, Clovis Oncology, GlaxoSmithKline, Medscape, Merck Serono, Merck Sharpe & Dohme, TouchCongress, and Zentalis; and support for attending meetings or travel, or both, from AstraZeneca, Clovis Oncology, GlaxoSmithKline, and Roche; and participation on a data safety monitoring board or advisory board for ARIEL4 and TROPHIMMUNE. GSS reports institutional research support from AstraZeneca and Merck for this study; institutional research support from Novartis and Roche; and consulting fees paid to his institution from Biovica and Seagen. CG reports clinical trial funding for this study to his institution from AstraZeneca; clinical research grants to his institution from Aprea, AstraZeneca, BergenBio, Clovis, GlaxoSmithKline, Medannexin, Merck Sharpe & Dohme, Novartis, Nucana, and Tesaro; personal consulting fees from AstraZeneca, GlaxoSmithKline, Merck Sharpe & Dohme, and Tesaro; honoraria for lectures or presentations from AstraZeneca, Chugai, Clovis Oncology, GlaxoSmithKline, Merck Sharpe & Dohme, Nucana, Roche, Takeda, and Tesaro; honoraria for lectures, presentations, or preparing educational materials from Cor2Ed; advisory board attendance for AstraZeneca, Chugai, GlaxoSmithKline, Merck Sharpe & Dohme, Nucana, Roche, and Tesaro; and being a committee member on the Scottish Medicines Consortium. AOz reports a grant from AstraZeneca to his institution outside the submitted work. AG-M reports clinical trial funding from GlaxoSmithKline and Roche; consulting fees from Alkermes, Amgen, AstraZeneca, Clovis, Genmab, GlaxoSmithKline, Immunogen, Mersana, Merck Sharpe & Dohme, Oncoinvent, Pharmamar, Roche, Sotio, and Takeda; personal fees from AstraZeneca, Clovis, GlaxoSmithKline, Merck Sharpe & Dohme, and Roche; support for attending meetings or travel, or both, from AstraZeneca, GlaxoSmithKline, Merck Sharpe & Dohme, Pharmamar, and Roche; and being the current chairman of GEICO and the chairman of ENGOT from 2018 to 2020. CA reports receiving advisory board fees from AbbVie, AstraZeneca/Merck, Eisai/Merck, Mersana Therapeutics, Repare Therapeutics, and Roche/Genentech; participation on an advisory board for Blueprint Medicine; participation on the board of directors for GOG Foundation and NRG Oncology; clinical trial funding to her institution from AstraZeneca for this study; and clinical trial funding to her institution from AbbVie, AstraZeneca, Clovis, and Genentech. ESL reports full-time employment with AstraZeneca during the conduct of the study and AstraZeneca stock ownership. EH reports full-time employment with AstraZeneca, contracted by PHASTAR, during the conduct of the study. B-GK, ALi, WHB, and PDS declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: In a prospective study of platinum-resistant ovarian cancer patients, we examined whether the Disease-related Symptoms-Physical (DRS--P) scale of the NCCN/FACT-Ovarian Cancer Symptom Index-18 (NFOSI-18) is responsive to clinical change in patients estimated by their provider to survive at least six months., Methods: The NFOSI-18, and other FACT measures, was collected at study entry and 3 and 6 months post-enrollment. Measures were compared for those who died or dropped off study prior to 3 months or prior to 6 months (assumed as health deterioration over time), or those who stayed on study through 6 months (presumed as stable disease over time). Statistical analyses included a fitted linear mixed model for estimating the group differences over time, Cox regression to assess the probability of survival with patient-reported outcomes, and effect size., Results: DRS-P scores of patients who completed only one assessment were significantly lower compared to patients who were able to complete two assessments [5.9 points lower (2.0-9.8); p < 0.01], or three assessments [8.1 points lower (4.8-11.5); p < 0.01]. Measures of abdominal discomfort, functional well-being, emotional well-being, and quality of life were also significant, but treatment side effects were not. Further, in every scale except for neurotoxicity, higher (better) baseline scores were associated with a decreased likelihood of death, after adjusting for age, performance and disease status., Conclusion: The NFOSI-18 DRS-P scale is responsive to clinical change. It has potential as an indicator of changing health status with ovarian cancer disease progression, distinct from treatment side effects., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Although patients with advanced ovarian cancer may respond initially to treatment, disease relapse is common, and nearly 50% of patients do not survive beyond five years, indicating an urgent need for improved therapies. To identify new therapeutic targets, we performed single-cell and nuclear RNA-seq data set analyses on 17 human ovarian cancer specimens, revealing the oncostatin M receptor (OSMR) as highly expressed in ovarian cancer cells. Conversely, oncostatin M (OSM), the ligand of OSMR, was highly expressed by tumor-associated macrophages and promoted proliferation and metastasis in cancer cells. Ovarian cancer cell lines and additional patient samples also exhibited elevated levels of OSMR when compared with other cell types in the tumor microenvironment or to normal ovarian tissue samples. OSMR was found to be important for ovarian cancer cell proliferation and migration. Binding of OSM to OSMR caused OSMR-IL6ST dimerization, which is required to produce oncogenic signaling cues for prolonged STAT3 activation. Human monoclonal antibody clones B14 and B21 directed to the extracellular domain of OSMR abrogated OSM-induced OSMR-IL6ST heterodimerization, promoted the internalization and degradation of OSMR, and effectively blocked OSMR-mediated signaling in vitro . Importantly, these antibody clones inhibited the growth of ovarian cancer cells in vitro and in vivo by suppressing oncogenic signaling through OSMR and STAT3 activation. Collectively, this study provides a proof of principle that anti-OSMR antibody can mediate disruption of OSM-induced OSMR-IL6ST dimerization and oncogenic signaling, thus documenting the preclinical therapeutic efficacy of human OSMR antagonist antibodies for immunotherapy in ovarian cancer. SIGNIFICANCE: This study uncovers a role for OSMR in promoting ovarian cancer cell proliferation and metastasis by activating STAT3 signaling and demonstrates the preclinical efficacy of antibody-based OSMR targeting for ovarian cancer treatment., (©2021 American Association for Cancer Research.)

Purpose: GEN-1 (phIL-12-005/PPC), an IL12 plasmid formulated with polyethyleneglycol-polyethyleneimine cholesterol lipopolymer, has preclinical activity when combined with platinum-taxane intravenous chemotherapy and administered intraperitoneally in epithelial ovarian cancer (EOC) models. OVATION I was a multicenter, nonrandomized, open-label phase IB trial to evaluate the safety, preliminary antitumor activity, and immunologic response to GEN-1 in combination with neoadjuvant chemotherapy (NACT) carboplatin-paclitaxel in patients with advanced EOC., Patients and Methods: A total of 18 patients with newly diagnosed stage IIIC and IV EOC were enrolled. A standard 3+3 dose-escalation design tested four GEN-1 doses (36, 47, 61, 79 mg/m 2 ) to determine the maximum tolerated dose and dose-limiting toxicities (DLTs). GEN-1 was administered in eight weekly intraperitoneal infusions starting at cycle 1 week 2 in combination with three 21-day cycles of NACT carboplatin AUC 6 and weekly paclitaxel 80 mg/m 2 ., Results: The most common treatment-emergent adverse events at least possibly related were nausea, fatigue, abdominal pain/cramping, anorexia, diarrhea, and vomiting. Eight patients experience grade 4 neutropenia attributed to NACT. No DLTs occurred. A total of 14 patients were evaluable for response and 12 (85.7%) had radiological response (two complete response and 10 partial response) prior to debulking; nine were R0 at debulking and one patient had complete pathologic response. IL12 and its downstream cytokine, IFNγ, increased in peritoneal washings but not as much in blood. Increased levels of myeloid dendritic cells and T-effector memory cells in peritoneal fluid, plus elevated CD8 + T cells and reduced immunosuppression within the tumor microenvironment were found. A median time to treatment failure of 18.4 months (95% confidence interval, 9.2-24.5) was observed in the intention-to-treat population., Conclusions: Adding GEN-1 to standard NACT is safe, appears active, and has an impact on the tumor microenvironment., (©2021 The Authors; Published by the American Association for Cancer Research.)

Objectives: In the phase III SOLO1 trial (NCT01844986), maintenance olaparib provided a substantial progression-free survival benefit in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation who were in response after platinum-based chemotherapy. We analyzed the timing, duration and grade of the most common hematologic and non-hematologic adverse events in SOLO1., Methods: Eligible patients were randomized to olaparib tablets 300 mg twice daily (N = 260) or placebo (N = 131), with a 2-year treatment cap in most patients. Safety outcomes were analyzed in detail in randomized patients who received at least one dose of study drug (olaparib, n = 260; placebo, n = 130)., Results: Median time to first onset of the most common hematologic (anemia, neutropenia, thrombocytopenia) and non-hematologic (nausea, fatigue/asthenia, vomiting) adverse events was <3 months in olaparib-treated patients. The first event of anemia, neutropenia, thrombocytopenia, nausea and vomiting lasted a median of <2 months and the first event of fatigue/asthenia lasted a median of 3.48 months in the olaparib group. These adverse events were manageable with supportive treatment and/or olaparib dose modification in most patients, with few patients requiring discontinuation of olaparib. Of 162 patients still receiving olaparib at month 24, 64.2% were receiving the recommended starting dose of olaparib 300 mg twice daily., Conclusions: Maintenance olaparib had a predictable and manageable adverse event profile in the newly diagnosed setting with no new safety signals identified. Adverse events usually occurred early, were largely manageable and led to discontinuation in a minority of patients., Competing Interests: Declaration of competing interest NC reports personal fees from AstraZeneca during the conduct of the study; and personal fees from MSD, Roche, Tesaro, GSK, Clovis Oncology, PharmaMar, Pfizer, Amgen, Novartis, Biocad and Immunogen outside the submitted work. KM reports personal fees from Astra-Zeneca, AbbVie, Aravive, Eisai, GSK/Tesaro, Genentech/Roche, Immunogen, Merck, Myriad, Mersana, VBL Therapeutics, Vavotar and Tarveda, outside the submitted work. AOaknin reports personal fees, other and grants from PharmaMar and Clovis Oncology, personal fees and other from Roche and AstraZeneca, personal fees and grants from Tesaro and Immunogen, personal fees from Genmab, and grants from AbbVie Deutchland, Ability Pharmaceuticals, Advaxis, Æterna Zentaris, Amgen SA, Aprea Therapeutics AB, Eisai, F. Hoffmann-La Roche, Regeneron, Merck Sharp & Dohme de España SA, Millennium Pharmaceuticals and Bristol Myers Squibb, outside the submitted work. MF reports grants, personal fees and other from AstraZeneca, grants and personal fees from Novartis, personal fees from Takeda, GSK, Lilly and MSD, and other from AbbVie, outside the submitted work. AF reports personal fees and other from AstraZeneca, MSD and GSK outside the submitted work. ALeary reports grants and personal fees from AstraZeneca, Clovis Oncology, MSD, Tesaro, GSK and Ability, personal fees from Biocad and Zentalis, and grants from Iovance, Agenus, Sanofi, Inivata and Roche, outside the submitted work. GSS reports institutional reimbursement for patient accrual and medical writing assistance from AstraZeneca during the conduct of the study, and institutional research support from Merck, Novartis and Roche outside the submitted work. CG reports grants from AstraZeneca during the conduct of the study; grants and personal fees from AstraZeneca, Clovis Oncology, Tesaro, Nucana and Sierra Oncology, grants from Aprea and Novartis, and personal fees from Roche, Foundation One, Chugai, MSD and Cor2Ed, outside the submitted work; and patents for molecular diagnostic tests for cancer. SB reports grants and personal fees from AstraZeneca and Tesaro, personal fees from Clovis Oncology, GSK, MSD, Pfizer, Mersana, Merck Serono, Roche, Seattle Genetics, Genmab, Amgen and Immunogen, and other from Nucana, outside the submitted work. AOza reports being a principal investigator of investigator-initiated studies with AstraZeneca, that his institution has received grant funding from AstraZeneca, and being a steering committee member (noncompensated) for trials with AstraZeneca, Clovis Oncology, Tesaro and Merck. AGM reports personal fees from Amgen, AstraZeneca, Clovis Oncology, Genmab, Immunogen, MSD, Novartis, Oncoinvent, Pfizer/Merck, PharmaMar, Roche and Sotio and grants and personal fees from GSK-Tesaro, outside the submitted work. CA reports personal fees from AstraZeneca/Merck, Tesaro, Immunogen, Eisai/Merck, Mersana Therapeutics and Roche, grants from Genentech, and grants and personal fees from AstraZeneca, Clovis Oncology and AbbVie, outside the submitted work. CM reports grants from Syros, Deciphera, AstraZeneca, Astellas Pharma, Tesaro/GSK, Seattle Genetics and Regeneron outside the submitted work. JL reports personal fees from AstraZeneca, Clovis Oncology, Genentech, Regeneron and Tesaro/GSK, and other from Merck, outside the submitted work; and funding to her institution as Principal Investigator on trials from 2X Oncology, Aravive, Arch Oncology, AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, CytomX Therapeutics, GlaxoSmithKline, Regeneron, Surface Oncology, Tesaro and Vigeo Therapeutics. ESL and RB report full-time employment with AstraZeneca during the conduct of the study and AstraZeneca stock ownership. PDS reports personal fees from AstraZeneca outside the submitted work. All other authors (GS, ALisyanskaya, WB and JWK) declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In the phase 3 SOLO1 trial, maintenance olaparib provided a significant progression-free survival benefit versus placebo in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation in response after platinum-based chemotherapy. We analysed health-related quality of life (HRQOL) and patient-centred outcomes in SOLO1, and the effect of radiological disease progression on health status., Methods: SOLO1 is a randomised, double-blind, international trial done in 118 centres and 15 countries. Eligible patients were aged 18 years or older; had an Eastern Cooperative Oncology Group performance status score of 0-1; had newly diagnosed, advanced, high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian tube cancer with a BRCA mutation; and were in clinical complete or partial response to platinum-based chemotherapy. Patients were randomly assigned (2:1) to either 300 mg olaparib tablets or placebo twice per day using an interactive voice and web response system and were treated for up to 2 years. Treatment assignment was masked for patients and for clinicians giving the interventions, and those collecting and analysing the data. Randomisation was stratified by response to platinum-based chemotherapy (clinical complete or partial response). HRQOL was a secondary endpoint and the prespecified primary HRQOL endpoint was the change from baseline in the Functional Assessment of Cancer Therapy-Ovarian Cancer Trial Outcome Index (TOI) score for the first 24 months. TOI scores range from 0 to 100 (higher scores indicated better HRQOL), with a clinically meaningful difference defined as a difference of at least 10 points. Prespecified exploratory endpoints were quality-adjusted progression-free survival and time without significant symptoms of toxicity (TWiST). HRQOL endpoints were analysed in all randomly assigned patients. The trial is ongoing but closed to new participants. This trial is registered with ClinicalTrials.gov, NCT01844986., Findings: Between Sept 3, 2013, and March 6, 2015, 1084 patients were enrolled. 693 patients were ineligible, leaving 391 eligible patients who were randomly assigned to olaparib (n=260) or placebo (n=131; one placebo patient withdrew before receiving any study treatment), with a median duration of follow-up of 40·7 months (IQR 34·9-42·9) for olaparib and 41·2 months (32·2-41·6) for placebo. There was no clinically meaningful change in TOI score at 24 months within or between the olaparib and placebo groups (adjusted mean change in score from baseline over 24 months was 0·30 points [95% CI -0·72 to 1·32] in the olaparib group vs 3·30 points [1·84 to 4·76] in the placebo group; between-group difference of -3·00, 95% CI -4·78 to -1·22; p=0·0010). Mean quality-adjusted progression-free survival (olaparib 29·75 months [95% CI 28·20-31·63] vs placebo 17·58 [15·05-20·18]; difference 12·17 months [95% CI 9·07-15·11], p<0·0001) and the mean duration of TWiST (olaparib 33·15 months [95% CI 30·82-35·49] vs placebo 20·24 months [17·36-23·11]; difference 12·92 months [95% CI 9·30-16·54]; p<0·0001) were significantly longer with olaparib than with placebo., Interpretation: The substantial progression-free survival benefit provided by maintenance olaparib in the newly diagnosed setting was achieved with no detrimental effect on patients' HRQOL and was supported by clinically meaningful quality-adjusted progression-free survival and TWiST benefits with maintenance olaparib versus placebo., Funding: AstraZeneca and Merck Sharp & Dohme., Competing Interests: Declaration of interests MF reports institutional research support, personal fees, consulting fees, and travel support from AstraZeneca; institutional research support and personal fees from Novartis; institutional research support from Beigene; personal fees from Takeda, GlaxoSmithKline, Lilly and Merck Sharp & Dohme, and being on a trial management committee for AbbVie, outside the submitted work. KNM reports personal fees from AstraZeneca, AbbVie, Aravive, Eisai, GlaxoSmithKline, Tesaro, Genentech/Roche, Immunogen, Merck, Myriad, Mersana, VBL Therapeutics, Vavotar, and Tarveda, outside the submitted work. NC reports personal fees from AstraZeneca during the conduct of the study; and personal fees from Merck Sharp & Dohme, Roche, Tesaro, GlaxoSmithKline, Clovis Oncology, PharmaMar, Pfizer, Amgen, Novartis, Biocad, and Immunogen, outside the submitted work. AOa reports personal fees, travel and accommodation support, and grants from PharmaMar and Clovis Oncology; personal fees, and travel and accomodation support from Roche and AstraZeneca; personal fees and grants from Tesaro and Immunogen; personal fees from Genmab; and grants from AbbVie Deutchland, Ability Pharmaceuticals, Advaxis, Aeterna Zentaris, Amgen, Aprea Therapeutics, Eisai, F Hoffmann-La Roche, Regeneron, Merck Sharp & Dohme de España, Millennium Pharmaceuticals, and Bristol Myers Squibb, outside the submitted work. GSS reports institutional reimbursement for patient accrual and medical writing assistance from AstraZeneca, during the conduct of the study; and institutional research support from Merck, Novartis, and Roche, outside the submitted work. CG reports grants from AstraZeneca during the conduct of the study; grants and personal fees from AstraZeneca, Clovis Oncology, GlaxoSmithKline, Tesaro, Nucana, and Sierra Oncology; grants from Aprea and Novartis; personal fees from Roche, Foundation One, Chugai, Merck Sharp & Dohme, and Cor2Ed, outside the submitted work; and patents for molecular diagnostic tests for cancer. SB reports grants and personal fees from AstraZeneca and Tesaro; personal fees from Clovis Oncology, GlaxoSmithKline, Merck Sharp & Dohme, Pfizer, Mersana, Merck Serono, Roche, Seattle Genetics, Genmab, Amgen, and Immunogen; and travel support from Nucana, outside the submitted work. AOz reports being a principal investigator of investigator-initiated studies with AstraZeneca, that his institution has received grant funding from AstraZeneca, and being a steering committee member (non-compensated) for AstraZeneca, Clovis Oncology, and GlaxoSmithKline. AG-M reports personal fees from Amgen, AstraZeneca, Clovis Oncology, Genmab, Immunogen, Merck Sharp & Dohme, Novartis, Oncoinvent, Pfizer/Merck, PharmaMar, Roche, and Sotio; and grants and personal fees from GlaxoSmithKline, and Tesaro, outside the submitted work. CA reports personal fees from AstraZeneca/Merck, Tesaro, Immunogen, Eisai/Merck, Mersana Therapeutics, and Roche/Genentech; grants from Genentech; and grants and personal fees from AstraZeneca, Clovis Oncology, and AbbVie, outside the submitted work. JL reports personal fees from AstraZeneca, Clovis Oncology, Genentech, Regeneron, Tesaro, and GlaxoSmithKline; and advisory board fees from Merck, outside the submitted work; and funding to her institution as principal investigator on trials from 2X Oncology, Aravive, Arch Oncology, AstraZeneca, Bristol Myers Squibb, Clovis Oncology, CytomX Therapeutics, GlaxoSmithKline, Regeneron, Surface Oncology, Tesaro, and Vigeo Therapeutics. CM reports grants from Syros, Deciphera, AstraZeneca, Astellas Pharma, Tesaro, GlaxoSmithKline, Seattle Genetics, Regeneron, and Moderna, outside the submitted work. FS reports personal fees and non-financial support from Roche, AstraZeneca, Tesaro, Merck Sharp & Dohme, and PharmaMar; and personal fees from GlaxoSmithKline and Clovis Oncology, outside the submitted work. ESL, RH, and EF report full-time employment with AstraZeneca during the conduct of the study and AstraZeneca stock ownership. EP reports employment with Parexel, which has received consultancy fees from AstraZeneca, during the conduct of the study. PDS reports personal fees from AstraZeneca, GlaxoSmithKline, Tesaro, and AbbVie, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: In SOLO1, maintenance olaparib (300 mg twice daily) significantly improved progression-free survival (PFS) for patients with newly diagnosed BRCA1 - and/or BRCA2 -mutated advanced ovarian cancer compared with placebo (hazard ratio [HR], 0.30; 95% CI, 0.23 to 0.41; median not reached v 13.8 months). We investigated PFS in SOLO1 for subgroups of patients based on preselected baseline factors., Patients and Methods: Investigator-assessed PFS subgroup analyses of SOLO1 included clinical response after platinum-based chemotherapy (complete [CR] or partial response [PR]), surgery type (upfront or interval surgery), disease status after surgery (residual or no gross residual disease), and BRCA mutation status ( BRCA1 or BRCA2 ). Additionally, we evaluated PFS in patients with stage III disease who underwent upfront surgery and had no gross residual disease. We also report objective response rate., Results: The risk of disease progression or death was reduced with olaparib compared with placebo by 69% (HR, 0.31; 95% CI, 0.21 to 0.46) and 63% (HR, 0.37; 95% CI, 0.24 to 0.58) in patients undergoing upfront or interval surgery; 56% (HR, 0.44; 95% CI, 0.25 to 0.77) and 67% (HR, 0.33; 95% CI, 0.23 to 0.46) in patients with residual or no residual disease after surgery; 66% (HR, 0.34; 95% CI, 0.24 to 0.47) and 69% in women with clinical CR or PR at baseline (HR, 0.31; 95% CI, 0.18 to 0.52); and 59% (HR, 0.41; 95% CI, 0.30 to 0.56) and 80% (HR 0.20; 95% CI, 0.10 to 0.37) in patients with a BRCA1 or BRCA2 mutation, respectively., Conclusion: Patients with newly diagnosed advanced ovarian cancer achieve substantial benefit from maintenance olaparib treatment regardless of baseline surgery outcome, response to chemotherapy, or BRCA mutation type.

Background: Niraparib, an inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP), has been associated with significantly increased progression-free survival among patients with recurrent ovarian cancer after platinum-based chemotherapy, regardless of the presence or absence of BRCA mutations. The efficacy of niraparib in patients with newly diagnosed advanced ovarian cancer after a response to first-line platinum-based chemotherapy is unknown., Methods: In this randomized, double-blind, phase 3 trial, we randomly assigned patients with newly diagnosed advanced ovarian cancer in a 2:1 ratio to receive niraparib or placebo once daily after a response to platinum-based chemotherapy. The primary end point was progression-free survival in patients who had tumors with homologous-recombination deficiency and in those in the overall population, as determined on hierarchical testing. A prespecified interim analysis for overall survival was conducted at the time of the primary analysis of progression-free survival., Results: Of the 733 patients who underwent randomization, 373 (50.9%) had tumors with homologous-recombination deficiency. Among the patients in this category, the median progression-free survival was significantly longer in the niraparib group than in the placebo group (21.9 months vs. 10.4 months; hazard ratio for disease progression or death, 0.43; 95% confidence interval [CI], 0.31 to 0.59; P<0.001). In the overall population, the corresponding progression-free survival was 13.8 months and 8.2 months (hazard ratio, 0.62; 95% CI, 0.50 to 0.76; P<0.001). At the 24-month interim analysis, the rate of overall survival was 84% in the niraparib group and 77% in the placebo group (hazard ratio, 0.70; 95% CI, 0.44 to 1.11). The most common adverse events of grade 3 or higher were anemia (in 31.0% of the patients), thrombocytopenia (in 28.7%), and neutropenia (in 12.8%). No treatment-related deaths occurred., Conclusions: Among patients with newly diagnosed advanced ovarian cancer who had a response to platinum-based chemotherapy, those who received niraparib had significantly longer progression-free survival than those who received placebo, regardless of the presence or absence of homologous-recombination deficiency. (Funded by GlaxoSmithKline; PRIMA/ENGOT-OV26/GOG-3012 ClinicalTrials.gov number, NCT02655016.)., (Copyright © 2019 Massachusetts Medical Society.)

Objective: To identify factors that affect successful adaptation of sentinel lymph node mapping and those that lead to unintended adipose-only sentinel lymph node identification., Methods: Surgical and pathological data were prospectively collected on patients with endometrial cancer who underwent sentinel lymph node mapping with indocyanine green with or without pelvic and/or para-aortic lymph node dissection between November 2013 and April 2017. All mapping cases were performed with the robotic system. Adipose-only specimens were defined as a sentinel lymph node without a pathologically identified lymph node after ultrastaging., Results: A total of 202 patients were included: 83% had endometrioid pathology, 12% serous, 3% carcinosarcoma, and 2% clear cell, with mixed pathology noted in 2%. The bilateral sentinel lymph node detection rate was 66%, and the rate of mapping at least a unilateral sentinel lymph node was 86%. Neither the bilateral nor the unilateral sentinel lymph node mapping rate changed with increased surgeon experience. The rate of adipose-only sentinel lymph node identification was more frequent when comparing the first 10 cases (37%), cases 11 - 30 (28%), and > 30 cases (9%) (P = 0.006). Body mass index > 30 kg/m 2 , uterine fibroids, The International Federation of Gynecology and Obstetrics (FIGO) grade, and histology were not found to have a statistically significant impact on either sentinel lymph node identification or adipose-only sentinel lymph node identification. Adipose-only sentinel lymph nodes were more likely with increased time from cervical injection to identification of the sentinel lymph node in the right hemipelvis. The median range was 28 min (14-73) for true sentinel lymph node identification vs 33 min (23-74) for adipose-only sentinel lymph node identification (P = 0.02)., Conclusion: Patient and surgeon factors did not impact the identification of sentinel lymph nodes over time. Adipose-only sentinel lymph nodes were more frequently identified in the initial cases and represent a potential complication to adapting sentinel lymph node biopsy without lymphadenectomy. The increase in adipose-only sentinel lymph node identification that was associated with time from cervical injection may represent delayed or disrupted uptake of indocyanine green., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The goals of treating recurrent platinum-resistant ovarian cancer are palliative, aimed at reducing symptoms and improving progression free survival. A prospective trial was conducted to determine the prevalence and severity of symptoms, and associated care needs., Methods: Eligible women included those with persistent or recurrent platinum-resistant ovarian cancer with an estimated life expectancy of at least 6 months. The Needs at the End-of-Life Screening Tool (NEST), FACIT-Fatigue (FACIT-F), NCCN-FACT Ovarian Symptom Index [NFOSI-18]; Disease Related Symptoms (DRS), Treatment Side Effects (TSE), and Function/Well Being (F/WB) were collected at study entry, 3 and 6 months., Results: We enrolled 102 evaluable patients. Initiation of Do Not Resuscitate (DNR) discussions increased over time from 28% at study entry to 37% at 6 months. At study entry, the most common disease-related symptoms were fatigue (92%), worry (89%), and trouble sleeping (76%); 73% reported being "bothered by treatment side effects", which included nausea (41%) and hair loss (51%) neither of which changed over time. The most common NEST unmet needs were in the symptom dimension. The social dimension was associated with F/WB (p = 0.002) and FACIT-F (p = 0.006); symptoms were associated with DRS (p = 0.04), TSE (p = 0.03), and FACIT-F (p = 0.04); existential was not associated with any of the patient-reported symptoms; therapeutic was associated with F/WB (p = 0.02)., Conclusions: In patients nearing the end of life, there are significant associations between disease and treatment related symptoms and unmet patient needs, which do not change substantially over time. Careful exploration of specific end-of-life care needs can improve patient-centered care and QOL., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: The study's purpose was to assess safety and efficacy of escalating doses of weekly GEN-1 with pegylated liposomal doxorubicin (PLD) in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancers (EOC)., Methods: Patients had persistent or recurrent platinum-resistant EOC. The trial was a standard 3+3 phase I dose escalation design with patients receiving intravenous PLD 40mg/m 2 (dose level 1 and 2) or 50mg/m 2 (dose level 3) every 28days and intraperitoneal GEN-1 at 24mg/m 2 (dose level 1) or 36mg/m 2 (dose level 2 and 3) on days 1, 8, 15, and 22 of a 28day cycle. Cycles were repeated every 28days until disease progression. Patients were monitored for toxicity, clinical efficacy, and evidence of systemic and intraperitoneal immunologic effect., Results: Sixteen evaluable patients received a median of 4cycles (range 1-8). No dose limiting toxicities were found. The adverse side effects were 4 grade 3 anemia, 2 grade 3 abdominal pain, 7 grade 3 neutropenia, and 2 grade 4 neutropenia. A clinical benefit of 57.1% (PR=21.4%; SD=35.7%) was found in the 14 patients with measurable disease. The highest number of partial responses (28.6%) and stable disease (57.1%) were found at dose level 3. The maximum tolerated dose was not reached. Increases in IL-12, IFN-γ, and TNF-α levels were found in peritoneal fluid following GEN-1 treatment., Conclusions: GEN-1 in combination with PLD has encouraging clinical benefit and biological activity in recurrent or persistent EOC and warrants further investigation with escalating doses of GEN-1., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Despite improvements in operative management and therapies, overall survival rates in advanced ovarian cancer have remained largely unchanged over the past three decades. Although it is possible to identify high-risk patients following surgery, the knowledge does not provide information about the genomic aberrations conferring risk, or the implications for treatment. To address these challenges, we developed an integrative pathway-index model and applied it to messenger RNA expression from 458 patients with serous ovarian carcinoma from the Cancer Genome Atlas project. The biomarker derived from this approach, IPI59, contains 59 genes from six pathways. As we demonstrate using independent datasets from six studies, IPI59 is strongly associated with overall and progression-free survival, and also identifies high-risk patients who may benefit from enhanced adjuvant therapy.

Purpose: A simple measure to predict chemotherapy tolerance in elderly patients would be useful. We prospectively tested the association of baseline Instrumental Activities of Daily Living (IADL) score with ability to complete 4 cycles of first line chemotherapy without dose reductions or >7days delay in elderly ovarian cancer patients., Patients and Methods: Patients' age ≥70 along with their physicians chose between two regimens: CP (Carboplatin AUC 5, Paclitaxel 135mg/m 2 ) or C (Carboplatin AUC 5), both given every 3weeks either after primary surgery or as neoadjuvant chemotherapy (NACT) with IADL and quality of life assessments performed at baseline, pre-cycle 3, and post-cycle 4., Results: Two-hundred-twelve women were enrolled, 152 selecting CP and 60 selecting C. Those who selected CP had higher baseline IADL scores (p<0.001). After adjusting for age and PS, baseline IADL was independently associated with the choice of regimen (p=0.035). The baseline IADL score was not found to be associated with completion of 4 cycles of chemotherapy without dose reduction or delays (p=0.21), but was associated with completion of 4 cycles of chemotherapy regardless of dose reduction and delay (p=0.008) and toxicity, with the odds ratio (OR) of grade 3+ toxicity decreasing 17% (OR: 0.83; 95%CI: 0.72-0.96; p=0.013) for each additional activity in which the patient was independent. After adjustment for chemotherapy regimen, IADL was also associated with overall survival (p=0.019) for patients receiving CP., Conclusion: Patients with a higher baseline IADL score (more independent) were more likely to complete 4 cycles of chemotherapy and less likely to experience grade 3 or higher toxicity., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background and Methods: To evaluate surgical and pathologic outcomes of robotic assisted versus open hysterectomy for women with at least class II (BMI >35) and class III (BMI >40) obesity with endometrial cancer. Women with endometrial cancer and class II obesity, treated with open or robotic hysterectomy between 3/2005 and 3/2013 were eligible for inclusion in this retrospective cohort. Patients with class III obesity were reviewed both within the cohort of class II and as a separate subset. Data were collected on demographics, operative statistics, pathology, post-operative complications, and oncologic outcomes. Tests of significance used Chi-square, Fisher's exact test, t-test, and Wilcoxon rank-sum., Results: One hundred and thirty-six women with BMI >35 who underwent hysterectomy (56 robotic and 80 abdominal) were included. Patients undergoing robotic hysterectomies had fewer post-operative complications, shorter hospital stays, and lower blood loss compared to the abdominal group. A subset (83 of 136) with class III obesity had similar findings. Operative times, lymph node dissection rates, and lymph node yield (both pelvic and para-aortic) were similar between open and robotic surgery in both obesity classes. Oncologic outcomes and use of adjuvant treatment was not compromised., Conclusions: Robotic hysterectomy is a safe and effective option for morbidly obese women with endometrial cancer. J. Surg. Oncol. 2016;114:884-887. © 2016 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)