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Background: This study aimed to evaluate the vaccine effectiveness (VE) of mRNA-1273.815, a 2023-2024 Omicron XBB.1.5-containing mRNA COVID-19 vaccine, at preventing COVID-19-related hospitalizations and any medically attended COVID-19 in adults., Methods: In a linked electronic health record-claims dataset, we identified US adults (≥18 years) who received the mRNA-1273.815 vaccine (exposed cohort) between 12 September and 15 December 2023, matched 1:1 to individuals who did not receive a 2023-2024 updated COVID-19 vaccine (unexposed cohort). Cohorts were balanced using inverse probability of treatment weighting on demographics, vaccination and infection history, and underlying medical conditions. Study cohorts were followed until 31 December 2023 for COVID-19-related hospitalizations and medically attended COVID-19. Cox regression was used to estimate hazard ratios and VE. Subgroup analyses were performed for adults ≥50 years, adults ≥65 years, and individuals with underlying medical conditions., Results: Overall, 859 335 matched pairs of mRNA-1273.815 recipients and unexposed adults were identified. The mean (standard deviation) age was 63 (16) years. More than 60% of individuals in both cohorts had an underlying medical condition. Among the overall adult population, VE was 60.2% (95% confidence interval, 53.4-66.0) against COVID-19-related hospitalization and 33.1% (30.2-35.9) against medically attended COVID-19 over a median follow-up of 63 (interquartile range: 44-78) days. VE estimates by age and underlying medical conditions were similar., Conclusions: These results demonstrate the significant protection provided by mRNA-1273.815 against COVID-19-related hospitalizations and any medically attended COVID-19 in adults, regardless of vaccination history, and support Centers for Disease Control and Prevention recommendations to stay up-to-date with COVID-19 vaccination to prevent COVID-19-related outcomes, including hospitalizations., Competing Interests: Potential conflicts of interest. A.B.A., D.M., H.K., J.A.M., M.A.M., and T.L. are employees of and shareholders in Moderna Inc. A.B., J.P.W.-J., N.Z., I.H.W., and M.B. are employees of Veradigm, which was contracted by Moderna and received fees for data management and statistical analyses. V.H.N. is an employee of VHN Consulting, which was contracted by Moderna to help conduct this analysis., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel, engineered cytokine that selectively binds to the intermediate-affinity interleukin-2 receptor, preferentially activating CD8 + T cells and natural killer cells, with minimal expansion of regulatory T cells, thereby mitigating the risk of toxicities associated with high-affinity interleukin-2 receptor activation. Clinical outcomes with nemvaleukin are unknown. ARTISTRY-1 investigated the safety, recommended phase 2 dose (RP2D), and antitumor activity of nemvaleukin in patients with advanced solid tumors., Methods: This was a three-part, open-label, phase 1/2 study: part A, dose-escalation monotherapy, part B, dose-expansion monotherapy, and part C, combination therapy with pembrolizumab. The study was conducted at 32 sites in 7 countries. Adult patients with advanced solid tumors were enrolled and received intravenous nemvaleukin once daily on days 1-5 (21-day cycle) at 0.1-10 µg/kg/day (part A), or at the RP2D (part B), or with pembrolizumab (part C). Primary endpoints were RP2D selection and dose-limiting toxicities (part A), and overall response rate (ORR) and safety (parts B and C)., Results: From July 2016 to March 2023, 243 patients were enrolled and treated (46, 74, and 166 in parts A, B, and C, respectively). The maximum tolerated dose was not reached. RP2D was determined as 6 µg/kg/day. ORR with nemvaleukin monotherapy was 10% (7/68; 95% CI 4 to 20), with seven partial responses (melanoma, n=4; renal cell carcinoma, n=3). Robust CD8 + T and natural killer cell expansion, and minimal regulatory T cell expansion were observed following nemvaleukin treatment. ORR with nemvaleukin plus pembrolizumab was 13% (19/144; 95% CI 8 to 20), with 5 complete and 14 partial responses; 6 responses were in PD-(L)1 inhibitor-approved and five in PD-(L)1 inhibitor-unapproved tumor types. Three responses were in patients with platinum-resistant ovarian cancer. The most common grade 3-4 treatment-related adverse events (TRAEs) in parts B and C, respectively, were neutropenia (49%, 21%) and anemia (10%, 11%); 4% of patients in each part discontinued due to TRAEs., Conclusions: Nemvaleukin was well tolerated and demonstrated promising antitumor activity across heavily pretreated advanced solid tumors. Phase 2/3 studies of nemvaleukin are ongoing., Trial Registration Number: NCT02799095., Competing Interests: Competing interests: UNV declares research support from Bristol Myers Squibb and Merck; consulting fees from Alkermes, Novartis, Bristol Myers Squibb, Exelixis, Bayer, Gilead, Seattle Genetics, Pfizer, and Aveo; speaker honoraria fees from Exelixis, Bayer, and Pfizer. JM declares advisory board attendance and honoraria from Exelixis. IW declares participation in advisory board for GOG Partners; Travel/Honoraria fees from Regeneron and IIT Collaborative funding from Chimerix for trial purposes only. SDR declares stock ownership at Pfizer, Amgen, and Johnson & Johnson. CJH declares grants from Merck; consulting fees from Merck, Eisai, and Seagen; honoraria fees from Eisai, Seagen, and Astellas; and advisory board attendance for CRISPR and Seagen. AChauhan declares grants from Bristol Myers Squibb, Clovis, Tersera, and ECS Progastrin; consulting fees from Tersera, Novartis, Lexicon, Ipsen, Curium, and Seneca Therapeutics; and honoraria from Tersera, Novartis, Lexicon, and Ipsen. AS declares funding to the institution from Alkermes. KDL declares funding to the institution from Alkermes and Merck; and employment with Regeneron. DSB declares independent research grant (payments made to institution) from AstraZeneca; consulting fees from or advisory board attendance for Bristol Myers Squibb, Mirati Therapeutics, Novartis, Eli Lilly, Amgen, Merck, Novocure, Regeneron, Syneos Health, Tempus and Daiichi-Sankyo; honoraria fees from AstraZeneca; advisory board attendance or travel fees from Bristol Myers Squibb, Novocure, AstraZeneca, Mirati Therapeutics and Regeneron; leadership as panel member for non-small cell lung cancer, thymic malignancies and pleural and peritoneal mesothelioma for National Comprehensive Cancer Network (NCCN). OD and MSE declare no conflicts of interest. DFM declares consulting fees from or advisory board attendance for Roche/Genentech BioOncology, Guidepoint, Bristol Myers Squibb, Merck, Exelixis, Pfizer, Lovance, Werewolf Therapeutics, and Svnthekine; leadership at Beth Israel, Dana-Farber Harvard Cancer Center; committee service at Beth Israel, Dana-Farber Harvard Cancer Center; grant review for FDA, Dana-Farber Harvard Cancer Center, National Cancer Institute; and funding from Prometheus Laboratories, X4 Pharmaceuticals, Alkermes, NIH, and Dept of Defense. JFS declares consulting fees from Synlogic (institution) and Binhui Biopharmaceuticals (institution); leadership at Dialectic Therapeutics; stock ownership at AbbVie, Abbot, Bristol Myers Squibb, Intuitive Surgical, Johnson & Johnson, Merck, and Regeneron. QSC declares grants from AstraZeneca; consulting fees from AbbVie, Amgen, AnHeart, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daichii Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novartis, Ocellaris, Pfizer, Roche, and Takeda; honoraria from AbbVie, Amgen, AnHeart, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daichii Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novartis, Ocellaris, Pfizer, Roche, and Takeda; serving on data and safety monitoring board for Merck KgaA; and unpaid and medical advocacy leadership for Lung Cancer Canada. LG declares consulting fees from or advisory board attendance for Merck and GlaxoSmithKline; honoraria fees from Merck, AstraZeneca, Eisai, GlaxoSmithKline, Eisai-Merck, Novocure, and GOG; institutional research funding from Merck Sharp & Dohme, IMV, AstraZeneca, ImmunoGen, Tesaro/GlaxoSmithKline, Karyopharm Therapeutics, Alkermes, OncoQuest, Novocure, Esperas Pharma, Mersana, Roche, and K-Group Beta Inc. AChaudhry declares receiving grants or clinical trial contracts from Arcus, Boehringer Ingelheim, AbbVie, Exelixis, Medilink, Gilead, Seagen, BeiGene, Roche, Tvardi, Amgen, Bristol Myers Squibb, Henlius, Merck, Mersana, Eli Lilly, Zia Pharmaceuticals, and AstraZeneca. EC declares employment at START, HM Hospitales Group; leadership at START, PharmaMar, EORTC, Sanofi, BeiGene, Novartis, and Merus NV; stock and other ownership interests at START and Oncoart Associated; honoraria fees from HM Hospitales Group; consulting or advisory role at Nanobiotix, Janssen-Cilag, Roche/Genentech, TargImmune Therapeutics, Servier, Bristol Myers Squibb, Amunix, Adcendo, Anaveon, AstraZeneca/MedImmune, Chugai Pharma, MonTa, MSD Oncology, Nouscom, Novartis, OncoDNA, T-Knife, Elevation Oncology, PharmaMar, Ellipses Pharma, Syneos Health, Genmab, and Diaccurate; research funding to the company from START; other relationships as president and founder of Foundation INTHEOS (Investigational Therapeutics in Oncological Sciences), not-for-profit foundation PharmaMar, and not-for-profit CRIS Cancer Foundation. RD declares previous employment at and stock ownership in Mural Oncology. VB declares institutional research funding from Sanofi, Seattle Genetics, Loxo, Novartis, CytomX Therapeutics, Puma Biotechnology, Kura, Tesaro, Roche/Genentech, Bristol Myers Squibb, Menarini, Synthon, Janssen Oncology, Merck, Lilly, Merus, Pfizer, Bayer, Incyte, AbbVie, Zenith Epigenetics, Genmab, AstraZeneca, Adaptimmune, Alkermes, Amgen, Array BioPharma, Boehringer Ingelheim, BioNTech AG, and Boston Biomedical; consulting fees from OncoArt, and Guidepoint Global; honoraria fees from Loxo, Ideaya Biosciences, Puma Biotechnology, Amunix, Guidepoint Global, and EMD Serono; speakers’ bureau fees from Solti, Lilly, and Tactics; advisory board attendance or travel fees from START and Bayer; leadership at Next Oncology (Institution); stock ownership at 1TRIALSP; and employment at Quironsalud, Next Oncology. VV declares serving as a consultant or in an advisory role for Bristol Myers Squibb, Merck, AstraZeneca, Regeneron, G1 Therapeutics, Amgen, GSK, and Novocure., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/objectives: This retrospective cohort study evaluated the relative vaccine effectiveness (rVE) of two bivalent (original/Omicron BA.4/BA.5) vaccines mRNA-1273.222 versus the BNT162b2 Bivalent in preventing COVID-19-related outcomes in adults with underlying medical conditions associated with increased risk for severe COVID-19., Methods: In a linked electronic health record/claims dataset, US adults (≥18 years) with ≥1 underlying medical condition of interest who received either the bivalent vaccine between 31 August 2022 and 28 February 2023 were identified. The inverse probability of treatment weighting was used to adjust for cohort differences. Cohorts were followed up for COVID-19-related hospitalizations and outpatient encounters until 31 May 2023. Hazard ratios and rVEs were estimated using Cox regression. Subgroup analyses were performed on individuals with pre-specified comorbid conditions., Results: 757,572 mRNA-1273.222 and 1,204,975 BNT162b2 Bivalent recipients were identified. The adjusted rVE over a median follow-up of 198 days was 10.9% (6.2%-15.2%) against COVID-19-related hospitalization and 3.2% (1.7%-4.7%) against COVID-19-related outpatient encounters. rVE estimates for COVID-19 hospitalizations among subgroups with comorbid conditions were as follows: diabetes 15.1% (8.7%-21.0%), cerebro- and cardiovascular disease 14.7% (9.0%-20.1%), chronic lung disease 11.9% (5.1%-18.2%), immunocompromised 15.0% (7.2%-22.2%), chronic kidney disease 8.4% (0.5%-15.7%)., Conclusions: Overall, among adults with underlying medical conditions, mRNA-1273.222 was more effective than BNT162b2 Bivalent, especially in preventing COVID-19-related hospitalizations.

Background: Ezabenlimab (BI 754091) is a humanised monoclonal antibody targeting programmed cell death protein-1. We report results from open-label, dose-escalation/expansion, Phase I trials that evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics and antitumour activity of ezabenlimab at the recommended Phase II dose in patients with selected advanced solid tumours., Study Design: Study 1381.1 (NCT02952248) was conducted in Canada, the United Kingdom and the United States. Study 1381.4 (NCT03433898) was conducted in Japan. Study 1381.3 (NCT03780725) was conducted in the Netherlands. The primary endpoints were: number of patients experiencing dose-limiting toxicities (DLTs) in the first cycle (dose escalation parts), number of patients with DLTs during the entire treatment period and objective response (dose expansion part of Study 1381.1)., Results: Overall, 117 patients received ezabenlimab intravenously every 3 weeks (80 mg, n = 3; 240 mg, n = 111; 400 mg, n = 3). No DLTs were observed and the MTD was not reached. Fifty-eight patients (52.3%) had grade ≥ 3 adverse events, most commonly anaemia (10.8%) and fatigue (2.7%). In 111 assessed patients treated with ezabenlimab 240 mg, disease control rate was 56.8% and objective response rate was 16.2%. Three patients had complete response; at data cut-off (November 2021) one remained in response and was still receiving ongoing treatment (duration of response [DoR]: 906 days). Partial responses occurred across several tumour types; DoR ranged from 67 to 757 days., Conclusions: Ezabenlimab was well tolerated and associated with durable antitumour activity in multiple solid tumours, comparable to other immune checkpoint inhibitors in similar patient populations and treatment settings., (© 2024. The Author(s).)

The emergence of Omicron variants coincided with declining vaccine-induced protection against SARS-CoV-2. Two bivalent mRNA vaccines, mRNA-1273.222 (Moderna) and BNT162b2 Bivalent (Pfizer-BioNTech), were developed to provide greater protection against the predominate circulating variants by including mRNA that encodes both the ancestral (original) strain and BA.4/BA.5. We estimated their relative vaccine effectiveness (rVE) in preventing COVID-19-related outcomes in the US using a nationwide dataset linking primary care electronic health records and pharmacy/medical claims data. The study population (aged ≥18 years) received either vaccine between 31 August 2022 and 28 February 2023. We used propensity score weighting to adjust for baseline differences between groups. We estimated the rVE against COVID-19-related hospitalizations (primary outcome) and outpatient visits (secondary) for 1,034,538 mRNA-1273.222 and 1,670,666 BNT162b2 Bivalent vaccine recipients, with an adjusted rVE of 9.8% (95% confidence interval: 2.6-16.4%) and 5.1% (95% CI: 3.2-6.9%), respectively, for mRNA-1273.222 versus BNT162b2 Bivalent. The incremental relative effectiveness was greater among adults ≥ 65; the rVE against COVID-19-related hospitalizations and outpatient visits in these patients was 13.5% (95% CI: 5.5-20.8%) and 10.7% (8.2-13.1%), respectively. Overall, we found greater effectiveness of mRNA-1273.222 compared with the BNT162b2 Bivalent vaccine in preventing COVID-19-related hospitalizations and outpatient visits, with increased benefits in older adults.

Background and Aims: This study aimed to estimate the extent of US health care resource use (HRU) and direct cost burden of cyclic vomiting syndrome (CVS)., Methods: We selected patients in the MarketScan Commercial and Medicare Supplemental databases with ≥1 inpatient (IP) or ≥2 outpatient (OP) claims for CVS between October 1, 2015 and June 30, 2019, and continuous insurance enrollment for ≥12 months before (baseline) and ≥3 months after first CVS diagnosis (index). Using propensity scores based on baseline characteristics, each patient with CVS was matched to ∼3 non-CVS controls. We annualized HRU and costs to accommodate varying follow-up periods. Multivariable regressions further balanced CVS and non-CVS groups, and differences in HRU and costs between the matched cohorts were compared to quantify the direct cost burden of CVS., Results: Patients with CVS incurred significantly higher average annualized HRU, with the largest differences in emergency room (1.9 vs 0.4) visits and hospital IP (0.9 vs 0.1) stays ( P < .001). Patients with CVS had significantly higher annual total health care costs ($57,140 vs $14,912), with IP spending as the primary driver ($28,522 vs $3250) of the cost difference (all P < .001). After multivariable regression adjustments, total health care costs remained 4.1 times higher for patients with CVS relative to non-CVS controls, with IP costs 12.3 times higher, emergency room costs 5.8 times higher, OP visit costs 2.9 times higher, and OP pharmacy costs 1.5 times higher (all P < .001)., Conclusion: Newly diagnosed patients with CVS have greater health care utilization and higher costs than matched non-CVS counterparts, suggesting substantial economic burden of CVS on the US health care system., (© 2022 The Authors.)

Objectives: To evaluate risk of a second cancer and associated survival times in United States women with diagnosis of cancer., Methods: The Surveillance Epidemiology and End Results (SEER) database was queried for 2 cohorts of women aged 18 - 89 with either an index gynecologic or non-gynecologic cancer diagnosed between 1992 - 2017. Index cases were followed to determine if a second primary cancer was subsequently diagnosed; defined according to SEER multiple primary and histology coding rules. Standard Incident Ratios (SIR) and latency intervals between index diagnosis and second primary diagnosis were evaluated. Among those who developed a second primary cancer, median survival times from diagnosis of second primary cancer were also calculated., Results: Between 1992 - 2017, 227,313 US women were diagnosed with an index gynecological cancer and 1,483,016 were diagnosed with an index non-gynecologic cancer. Among patients with index gynecologic cancer, 7.78% developed a non-gynecologic subsequent primary cancer. The risk of developing any non-gynecologic cancer following an index gynecologic cancer was higher than the risk in the general population (SIR 1.05, 95% CI 1.04 - 1.07). Organs especially at risk were Thyroid (SIR 1.45), Colon and Rectum (SIR 1.23), and Urinary System (SIR 1.33). Among women diagnosed with an index non-gynecologic cancer, 0.99% were diagnosed with a subsequent gynecologic cancer. The risk of developing a gynecologic cancer following a non-gynecologic cancer was also elevated compared to the average risk of the general population (SIR 1.05, 1.03 - 1.07), with uterine cancer having the highest SIR of 1.13., Conclusion: The risk of a developing a second primary cancer and the corresponding survival time is based on the order and site of the index and subsequent cancer. Surveillance guidelines should be examined further to optimize survivorship programs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Corey, Ruterbusch, Shore, Ayoola-Adeola, Baracy, Vezina and Winer.)

Early stage cancer detection technologies can provide functional information and potentially decrease the mortality rate caused by cervical cancer. In our previous work, a miniaturized ultrasound and photoacoustic endoscopic system has been developed to image the cervical tissue through the cervical canal to fulfills the need for a safe, low-cost, and high-resolution functional diagnostic system. However, the miniaturized size of endoscope and American National Standards Institute safety limits cause constraints of using high-intensity illumination during imaging. In addition, the strong light scattering of tissues limits the light penetration depth. Fortunately, the cervix anatomy allows for the delivery of additional light from the ectocervix by using an external illumination system. Here we propose a dual, co-planar illumination system, which can provide adequate illumination to the cervical tissue via combined internal and external light delivery strategies. Therefore, an increase in the area of light-tissue interaction allows us to raise the laser light energy while keeping fluence under safety limits. Thus, a reliable PA imaging can be obtained for the whole cervical tissue thickness. The system performance was tested using a Monte Carlo simulation, and laser-light fluence was calculated and compared at different depths within a simulated cervical-tissue model. The results indicated a higher and more uniform fluence in the Monte Carlo simulations. In addition, the photoacoustic imaging of the proposed system was evaluated by two cervical tissue-mimicking phantoms with human blood and graphite rods as inclusions inside it. In accordance with the simulations, the phantom study revealed a more reliable photoacoustic signal for the entire depth of the phantoms with an improved contrast to noise ratio and signal to noise ratio, and a higher coverage ratio of the imaging field of view. In summary, the dual-mode illumination system can provide more realistic information of inclusions within the tissue while considering safety limits, which can lead to more accuracy in biomarker detection for cervical cancer diagnostics.

Glycogen synthase kinase-3β (GSK-3β), a serine/threonine kinase, has been implicated in the pathogenesis of many cancers, with involvement in cell-cycle regulation, apoptosis, and immune response. Small-molecule GSK-3β inhibitors are currently undergoing clinical investigation. Tumor sequencing has revealed genomic alterations in GSK-3β , yet an assessment of the genomic landscape in malignancies is lacking. This study assessed >100,000 tumors from two databases to analyze GSK-3β alterations. GSK-3β expression and immune cell infiltrate data were analyzed across cancer types, and programmed death-ligand 1 (PD-L1) expression was compared between GSK-3β -mutated and wild-type tumors. GSK-3β was mutated at a rate of 1%. The majority of mutated residues were in the kinase domain, with frequent mutations occurring in a GSK-3β substrate binding pocket. Uterine endometrioid carcinoma was the most commonly mutated (4%) tumor, and copy-number variations were most commonly observed in squamous histologies. Significant differences across cancer types for GSK-3β -mutated tumors were observed for B cells ( P = 0.018), monocytes ( P = 0.002), dendritic cells ( P = 0.005), neutrophils ( P = 0.0003), and endothelial cells ( P = 0.014). GSK-3β mRNA expression was highest in melanoma. The frequency of PD-L1 expression was higher among GSK-3β -mutated tumors compared with wild type in colorectal cancer ( P = 0.03), endometrial cancer ( P = 0.05), melanoma ( P = 0.02), ovarian carcinoma ( P = 0.0001), and uterine sarcoma ( P = 0.002). Overall, GSK-3β molecular alterations were detected in approximately 1% of solid tumors, tumors with GSK-3β mutations displayed a microenvironment with increased infiltration of B cells, and GSK-3β mutations were associated with increased PD-L1 expression in selected histologies. These results advance the understanding of GSK-3β complex signaling network interfacing with key pathways involved in carcinogenesis and immune response., (©2020 American Association for Cancer Research.)

Objectives: To investigate corticosteroid and opioid use among patients with SLE and to examine the impact of belimumab initiation on the use of other SLE therapies., Methods: We identified adult patients with SLE (International Classification of Diseases, 9th Revision/10th Revision 710.0 and M32) between 1 January 2012 and 31 May 2018 (earliest SLE diagnosis=index date) within MarketScan administrative claims data. Patients were followed from index date for a minimum of 12 months and until the earlier of disenrolment in their health plan or study end (31 May 2018). Corticosteroid utilisation, corticosteroid dose (in prednisone equivalents) and opioid utilisation (overall, by strength (weak, strong) and by duration (chronic use defined as >90 days of cumulative drug supply)) were measured during follow-up. Oral corticosteroid and opioid use were compared in the 6 months before and after initiation of belimumab., Results: There were 49 413 patients with SLE eligible for analysis (mean (SD) age: 50.1 (14.0) years, 90.2% female). Of these, 68.5% received corticosteroids, and the average number of prescriptions was 4.59 (4.11) over the first 12 months of follow-up. Among patients with oral corticosteroids, average daily dose was 19.4 (14.2) mg and 59.6% had an average daily dose of ≥15 mg. Half (52.6%) had at least one opioid prescription and of these, 34.6% had chronic use over the first 12 months of follow-up. Among patients initiating belimumab during follow-up (n=1710), oral corticosteroid use decreased by 9.1% (p=0.001), and average daily dose decreased from 14.5 (18.4) mg to 11.9 (18.0) mg (p<0.001) in the 6 months after initiation compared with the 6 months prior. Initiation of belimumab had no impact on prevalence of opioid use., Conclusions: A high proportion of patients with SLE are treated with corticosteroids to control SLE and opioid therapy to manage chronic pain. While there was no change in opioid use, oral corticosteroid use and dose intensity decreased following initiation of belimumab., Competing Interests: Competing interests: JAB, JW, KG and NB are employees of Eli Lilly and Company. NP, IW and CRL are employed by IBM Watson Health which received funding from Eli Lilly and Company to conduct this study. KHC is a paid consultant of Eli Lilly and Company., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Novelty and Impact Statement: Our findings suggest that soluble folate receptor (sFR) could be used in both the initial diagnosis and surveillance of patients with ovarian cancer. Our cohort constitutes one of the largest comparison groups for sFR analyzed so far. We have defined the background level of sFR using healthy volunteers. This is also the first study to prospectively follow patients in the surveillance setting to concurrently identify differential changes in tumor markers CA-125 and sFR., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: Bilateral tubal ligation (BTL) is a common form of birth control in the United States. There are limited, contradictory data examining BTL and the risk of endometrial cancer and none examining type I and type II cancers separately. We investigated the association between BTL and endometrial cancer risk using the Women's Health Initiative (WHI) Observational and Dietary Modification Studies., Methods: Demographic information and history of BTL were obtained from the baseline questionnaires from 76,483 WHI participants in the Observational and Dietary Modification Studies. Univariable and multivariable models were used to examine the association of BTL with type I and type II endometrial cancers., Results: A total of 1137 women were diagnosed with incident endometrial cancer (972 type I and 128 type II) during a mean follow-up of 11.3 years. Overall, 14,499 (19%) women had undergone BTL. There were no statistically significant associations noted between BTL and age at BTL for type I or type II cancers., Conclusions: We examined the largest patient cohort to date in an effort to determine the impact of BTL on endometrial cancer risk. In the WHI trial, we observed no overall effect of BTL on the risk of type I or type II endometrial cancer, suggesting that patients undergoing this popular birth control method likely do not have an associated change in their baseline risk for endometrial cancer.

Hemangiopericytomas are vascular tumors with a susceptibility to arise anywhere in the human body. We present a case of a 68-year-old female with primary omental hemangiopericytoma and a two-time recurrence managed with surgery and close follow-up. The first recurrence was at 52 months and the second at 37 months following the prior presentation. No adjuvant chemotherapy or radiation therapy was administered. Given the widespread nature of the cell of origin, routine follow-up postoperatively with interval imaging in order to detect recurrences is imperative. Pathologic tumor characteristics may determine potential for recurrence and may also assist in determining whether adjuvant treatment modalities should be included in the management plan. Review of the English literature reveals a total of 24 cases of omental hemangiopericytomas inclusive of the current report.

Objective: There is an increased risk of developing ovarian cancer (OC) in patients with endometriosis. Hence, development of new biomarkers may provide a positive clinical outcome for early detection. MicroRNAs (miRNAs) are small non-coding RNAs that play an important role in biological and pathological process and are currently used as diagnostic and prognostic markers in various cancers. In the current study, we assessed the differential expression of miRNAs from 19 paired ovarian cancer and its associated endometriosis tissue samples. In addition we also analyzed the downstream targets of those miRNAs., Methods: Nineteen paired cases of ovarian cancer and endometriosis foci were identified by a gynecologic pathologist and macro-dissected. The total RNAs were extracted and subjected to comprehensive miRNA profiling from the pooled samples of these two different entities using microarray analysis. Later, the abnormal expressions of few selected miRNAs were validated in individual cases by quantitative real-time PCR (qRT-PCR). Ingenuity pathway analysis revealed target mRNAs which were validated by qRT-PCR., Results: The miRNA profiling identified deregulation of greater than 1156 miRNAs in OC, of which the top seven were further validated by qRT-PCR. The expression of miR-1 , miR-133a , and miR-451 were reduced significantly (p<0.0001) in the OC patients compared to its associated endometriosis. In contrast, the expression of miR-141 , miR-200a , miR-200c , and miR-3613 were elevated significantly (p<0.05) in most of the OC patients. Furthermore, among the downstream mRNAs of these miRNAs, the level of PTEN expression was significantly (p<0.05) reduced in OC compared to endometriosis while no significant difference was observed in NF-κB expression., Conclusion: The expression of miRNAs and mRNAs in OC were significantly different compared to its concurrent endometriosis. These differential expressed miRNAs may serve as potential diagnostic and prognostic biomarkers for OC associated with endometriosis.

Objective: We aimed to compare the differences in demographic features, clinicopathologic features, and survival in patients with vulvar/vaginal melanoma versus cutaneous melanoma with a special emphasis on race., Materials and Methods: Data were obtained from the Surveillance Epidemiology and End Results database from 1973 to 2008. Kaplan-Meier curves and Cox multivariate model were used for statistical analysis., Results: Seven hundred sixty-two patients with vulvar/vaginal melanoma and 55,485 patients with cutaneous melanoma patients were included in the study. Twenty-eight patients of the vulvar/vaginal group and 334 patients of the cutaneous group were black (3.6% vs 0.6%, respectively). The median age at the time of diagnosis was 68 years in the vulvar/vaginal group and 52 years in the cutaneous group (P < 0.0001). Three hundred fifty patients (45.9%) in the vulvar/vaginal and 46,499 patients (83.8%) in the cutaneous group presented with localized disease (P < 0.0001), whereas 64 patients (8.4%) in the vulvar/vaginal group and 1520 patients (2.7%) in cutaneous group presented with advanced disease (P = 0.0081). The median survival of the black patients was 16 months in the vulvar/vaginal group and 124 months in the cutaneous melanoma group (P < 0.0001). The median survival in the nonblack population was 39 months in the vulvar/vaginal group compared to 319 months in the cutaneous melanoma group (P <0.0001). In multivariate analysis performed for patients between 1988 and 2008, age, stage, and positive lymph nodes were negative independent prognostic factors for survival in vulvar/vaginal melanoma; whereas age, race, stage, radiation therapy, and lymph node positivity were negative prognostic factors in cutaneous melanoma., Conclusion: These findings emphasize that cutaneous and vulvar/vaginal melanomas have different clinicopathologic features and survival patterns.

Recent studies indicate that ovarian cancer may be highly responsive to antivascular therapeutics. We have developed an antivascular tumor therapeutic using the F3 peptide to target cisplatin-loaded nanoparticles (F3-Cis-Np) to tumor vessels. We show that although F3-Cis-Np bind with high specificity to both human ovarian tumor cells and tumor endothelial cells in vitro, they only show cytotoxic activity against the tumor endothelial cells. In vivo these nanoparticles bind primarily to tumor endothelial cells. Therapeutic studies in both flank and orthotopic i.p. murine ovarian tumor models, as well as human tumor xenograft models, show rapid tumor regression with treatment. Treatment was associated with significant vascular necrosis consistent with an antivascular effect. Furthermore, treatment was active in both platinum-sensitive and platinum-resistant cell lines. Importantly, we show that F3-Cis-Np bind to human tumor endothelial cells in vitro and to human tumor vessels in vivo. Therapy targeting human vasculature in vivo with F3-Cis-Np led to near complete loss of all human tumor vessels in a murine model of human tumor vasculature. Our studies indicate that F3-targeted vascular therapeutics may be an effective treatment modality in human ovarian cancer., (©2010 AACR.)

Pseudomyxoma peritonei (PMP) is a rare tumor syndrome that can be diagnosed in association with mucinous ovarian tumors of low malignant potential. Surgical debulking is the primary treatment modality as chemotherapy has generally proven ineffective in this slowly progressive tumor. When patients with PMP are not surgical candidates, there is no effective treatment, and patients will die of progressive disease. We report two patients with PMP with associated mucinous ovarian tumor of low malignant potential treated with Bevacizumab therapy. Both patients demonstrated disease response to single agent Bevacizumab therapy. One patient had a prolonged response while on therapy, remained stable for 6 months when treatment was held, and then after progressing responded to a second course of therapy. We discuss here (1) the clinical features which may predict a better response to Bevacizumab therapy, and (2) evidence for the use of chemotherapy for inoperable PMP. These cases suggest that Bevacizumab may represent a rare effective therapy for patients with inoperable PMP with ovarian involvement and should be considered for clinical trials in this patient population.

Wnt ligands have pleiotropic and context-specific roles in embryogenesis and adult tissues. Among other effects, certain Wnts stabilize the beta-catenin protein, leading to the ability of beta-catenin to activate T-cell factor (TCF)-mediated transcription. Mutations resulting in constitutive beta-catenin stabilization underlie development of several human cancers. Genetic studies in Drosophila highlighted the split ends (spen) gene as a positive regulator of Wnt-dependent signaling. We have assessed the role of SHARP, a human homologue of spen, in Wnt/beta-catenin/TCF function in mammalian cells. We found that SHARP gene and protein expression is elevated in human colon and ovarian endometrioid adenocarcinomas and mouse colon adenomas and carcinomas carrying gene defects leading to beta-catenin dysregulation. When ectopically expressed, the silencing mediator for retinoid and thyroid receptors/histone deacetylase 1-associated repressor protein (SHARP) protein potently enhanced beta-catenin/TCF transcription of a model reporter gene and cellular target genes. Inhibition of endogenous SHARP function via RNA inhibitory (RNAi) approaches antagonized beta-catenin/TCF-mediated activation of target genes. The effect of SHARP on beta-catenin/TCF-regulated genes was mediated via a functional interaction between SHARP and TCF. beta-Catenin-dependent neoplastic transformation of RK3E cells was enhanced by ectopic expression of SHARP, and RNAi-mediated inhibition of endogenous SHARP in colon cancer cells inhibited their transformed growth. In toto, our findings implicate SHARP as an important positive regulator of Wnt signaling in cancers with beta-catenin dysregulation.

In many eukaryotes, expression of nuclear-encoded mRNA can be strongly inhibited by the presence of a double-stranded RNA (dsRNA) corresponding to exon sequences in the mRNA (refs 1,2). The use of this "RNA interference" (RNAi) in mammalian studies had lagged well behind its utility in lower animals because uninterrupted RNA duplexes longer than 30 base pairs trigger generalized cellular responses through activation of dsRNA-dependent protein kinases. Recently it was demonstrated that RNAi can be made to work in cultured human cells by introducing shorter, synthetic duplex RNAs (approximately 20 base pairs) through liposome transfection. We have explored several strategies for expressing similar short interfering RNA (siRNA) duplexes within cells from recombinant DNA constructs, because this might allow long-term target-gene suppression in cells, and potentially in whole organisms. Effective suppression of target gene product levels is achieved by using a human U6 small nuclear RNA (snRNA) promoter to drive nuclear expression of a single RNA transcript. The siRNA-like parts of the transcript consists of a 19 base pair siRNA stem with the two strands joined by a tightly structured loop and a U1-4 3' overhang at the end of the antisense strand. The simplicity of the U6 expression cassette and its widespread transcription in human cell types suggest that this mode of siRNA delivery could be useful for suppressing expression of a wide range of genes.

In many cancers, inactivation of the adenomatous polyposis coli (APC) or Axin tumor suppressor proteins or activating mutations in beta-catenin lead to elevated beta-catenin levels, enhanced binding of beta-catenin to T cell factor (TCF) proteins, and increased expression of TCF-regulated genes. We found that the gene for the basic helix-loop-helix transcription factor ITF-2 (immunoglobulin transcription factor-2) was activated in rat E1A-immortalized RK3E cells following neoplastic transformation by beta-catenin or ligand-induced activation of a beta-catenin-estrogen receptor fusion protein. Human cancers with beta-catenin regulatory defects had elevated ITF-2 expression, and ITF-2 was repressed by restoring wild-type APC function or inhibiting TCF activity. Of note, ITF-2 promoted neoplastic transformation of RK3E cells. We propose that ITF-2 is a TCF-regulated gene, which functions in concert with other TCF target genes to promote growth and/or survival of cancer cells with defects in beta-catenin regulation.