Maveropepimut-S, a DPX-Based Immune-Educating Therapy, Shows Promising and Durable Clinical Benefit in Patients with Recurrent Ovarian Cancer, a Phase II Trial.

PURPOSE: Patients with platinum-resistant ovarian cancer respond poorly to existing therapies. Hence there is a need for more effective treatments. PATIENTS AND METHODS: The DeCidE1 trial is a multicenter, randomized, open-label, single-arm phase II study to evaluate the safety and effectiveness of maveropepimut-S with cyclophosphamide in patients with recurrent ovarian cancer. Median follow-up for evaluable subjects was 4.4 months. Data were collected from March 2019 to June 2021. Subjects received two injections of 0.25 mL maveropepimut-S 3 weeks apart, followed by one 0.1-mL doses, every 8 weeks up to progression. Oral cyclophosphamide, 50 mg twice daily, was administered in repeating weekly on and off cycles. RESULTS: Twenty-two patients were enrolled. Median age was 58 years (38-78 years). Among the evaluable population, the objective response rate (ORR) was 21% [90% confidence interval (CI), 7.5%-41.9%], with a disease control rate (DCR) of 63% (90% CI, 41.8%-81.3%), including 4 (21%) patients with partial responses, 8 (42%) stable disease, and 7 (37%) progressive disease. The ORRs were consistent across subgroups based on platinum sensitivity, and DCR was higher in the platinum-resistant subpopulation. Four SD patients maintained clinical benefit up to 25 months. Most treatment-related adverse events (TRAE) were grade 1 and 2 (87% of unique events). Most common AEs were injection site reactions. Eight subjects reported grade 3 and no grade 4 AEs. Survivin-specific T-cell responses were observed in treated patients with clinical benefit. CONCLUSIONS: Maveropepimut-S with intermittent low-dose cyclophosphamide is well-tolerated, with clinical benefit for patients with recurrent ovarian cancer. Observed responses are irrespective of the platinum status.

Menopausal symptom management in women with cardiovascular disease or vascular risk factors.

Women with preexisting cardiovascular disease (CVD) or vascular risk factors commonly experience bothersome symptoms of menopause, including vasomotor symptoms (VMS) and genitourinary syndrome of menopause (GSM). Due to confusion surrounding the safety of menopausal hormone therapy (HT) in symptomatic women with CVD, evidence-based guidelines should be followed regarding identifying candidates for treatment and HT decision making. This review summarizes best practices in the evaluation and treatment of VMS and GSM in women with preexisting CVD, based on international expert consensus guidelines and/or expert opinion when data are scarce. For women with preexisting CVD or vascular risk factors who are candidates for HT, guidelines often address the appropriate formulation, dose, and route of delivery. For women who are not candidates for HT, non-hormonal options are reviewed, and their safety and efficacy in treating VMS and GSM are discussed. Due to increased knowledge of the role that pregnancy-related complications play in maternal risk for future CVD, these conditions are considered when addressing the use of systemic HT. Women at increased risk for future CVD without the use of HT, such as women with premature or early menopause, are also discussed, as well as the safely profile of HT in these special populations. With worldwide rates of CVD increasing among women in midlife, it is important for clinicians to have clear guidelines for identifying candidates for hormonal and nonhormonal treatments for symptom management to safeguard the health and quality of life of these patients through the menopause transition and post-menopause.

Clinical impact of 2020 American Heart Association statement on menopause and cardiovascular disease risk.

The American Heart Association published a 2020 scientific statement on cardiovascular disease risk for women transitioning through or experiencing menopause. The report reflects scientific evidence on menopause and cardiovascular risks, and this article reviews the statement with a focus on what is new and what is clinically important for healthcare providers treating this patient population.

Reverse Translating Molecular Determinants of Anti-Programmed Death 1 Immunotherapy Response in Mouse Syngeneic Tumor Models.

Targeting the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway with immunotherapy has revolutionized the treatment of many cancers. Somatic tumor mutational burden (TMB) and T-cell-inflamed gene expression profile (GEP) are clinically validated pan-tumor genomic biomarkers that can predict responsiveness to anti-PD-1/PD-L1 monotherapy in many tumor types. We analyzed the association between these biomarkers and the efficacy of PD-1 inhibitor in 11 commonly used preclinical syngeneic tumor mouse models using murinized rat anti-mouse PD-1 DX400 antibody muDX400, a surrogate for pembrolizumab. Response to muDX400 treatment was broadly classified into three categories: highly responsive, partially responsive, and intrinsically resistant to therapy. Molecular and cellular profiling validated differences in immune cell infiltration and activation in the tumor microenvironment of muDX400-responsive tumors. Baseline and on-treatment genomic analysis showed an association between TMB, murine T-cell-inflamed gene expression profile (murine-GEP), and response to muDX400 treatment. We extended our analysis to investigate a canonical set of cancer and immune biology-related gene signatures, including signatures of angiogenesis, myeloid-derived suppressor cells, and stromal/epithelial-to-mesenchymal transition/TGFß biology previously shown to be inversely associated with the clinical efficacy of immune checkpoint blockade. Finally, we evaluated the association between murine-GEP and preclinical efficacy with standard-of-care chemotherapy or antiangiogenic agents that previously demonstrated promising clinical activity, in combination with muDX400. Our profiling studies begin to elucidate the underlying biological mechanisms of response and resistance to PD-1/PD-L1 blockade represented by these models, thereby providing insight into which models are most appropriate for the evaluation of orthogonal combination strategies.

Parents' Perspectives on Safe Storage of Firearms.

Firearms contribute substantially to leading causes of death among US children ages 10-19 (suicide and homicide). Safe storage of guns is important but poorly adopted. This study sought to understand knowledge, attitudes, beliefs, and firearm storage practices among parents living in households with firearms. Focus groups (FG) were conducted with gun-owning parents/guardians in three US states with high firearm ownership. Participants also completed an anonymous survey which included demographic characteristics, previous gun education, purpose of gun ownership, and storage practices. Eight FG were conducted with 57 parents. 74% of participants stored at least one firearm unlocked, with many loaded. Overall risk perception for firearm injury was low. Many participants believed modeling responsible use within the family would demystify the presence of a firearm and decrease accidental shootings. There was strong perception that safe storage interferes with personal protection needs, especially for handguns. Trigger locks were considered a nuisance and rarely used. Parents were confident in their youth's ability to handle guns safely and did not believe that safe storage would deter suicide. Preferred messengers for safe storage education were military or law enforcement rather than physicians. Participants advocated for safe storage education paired with hands-on use education. Gun-owning parents supported safety education and endorsed education from nonmedical sources. Education about suicide prevention may improve adoption of safe storage by parents. These results will inform the development of a firearm safe storage campaign with improved acceptability for communities with high firearms use and ownership.

Paternal perception of infant sleep risks and safety.

BACKGROUND: Sudden Unexpected Infant Death (SUID) results in 3400 sleep-related deaths yearly in the United States, yet caregivers' compliance with safe sleep recommendations remains less than optimal. Paternal caregiver's attitudes toward infant safe sleep messages are largely unaddressed, despite established differences between female and male caregiver perceptions. This study aimed to explore the determinants of safe sleep practices among male caregivers. METHODS: Focus groups were conducted in Arkansas with male caregivers of infants ages 2-12 months to discuss infant sleep routines, parental roles, sources for safe sleep information, and messaging suggestions for safe sleep promotion. The Health Belief Model of behavior change framed a moderator guide. Transcript-based analysis was used, and data were managed using HyperRESEARCH (version 2.8.3). The transcribed data were coded to identify significant themes. RESULTS: Ten focus groups were conducted with 46 participants. Inconsistent adherence to safe sleep practices was reported. Participants were more likely to describe safe location (57% of participants) and supine position behaviors (42%) than an uncluttered bed environment (26%). Caregivers acknowledged the importance of recommended safe sleep behavior, but admitted to unsafe practices, such as co-sleeping and unsafe daytime sleep. Lack of perceived risk, comfort, and/or resources, and disagreement among family members about safety practices were identified as barriers. Participants voiced concerns that current advertising portrays males as incompetent caregivers. Suggestions included portraying positive images of fathers and male caregivers acting to promote safety and the incorporation of statistics about the hazards of unsafe sleep to better engage fathers. Potential distribution venues included sporting events, home improvement and/or automotive stores, and social media from trusted sites (e.g. hospitals or medical professionals). CONCLUSIONS: Male caregivers demonstrate some knowledge base about infant sleep safety, but are not fully practicing all aspects of safe sleep. Targeted messaging towards male caregivers that includes factual information and statistics along with representing males in a positive light is desired.

The Use of ACOG Guidelines: Perceived Contraindications to IUD and Implant Use Among Family Planning Providers.

Objectives The uptake and actual use of the current guidelines from the American College of Obstetrics and Gynecology (ACOG) is unknown. Methods Family planning providers across Colorado and Iowa were surveyed as part of statewide initiatives to reduce unintended pregnancy in 2010 and 2012, both before and after the release of the guidelines. These initiatives focused on the promotion of intrauterine devices (IUDs) and implants. These surveys included questions on providers' views regarding the suitability and safety of the copper T IUD, hormonal IUD, and single rod implant for various subgroups of clients. The results are contrasted with guidelines provided in July of 2011 by ACOG. This strategy provides both baseline and follow-up models about the methods promoted in these guidelines. Results Findings show that there is some improvement in beliefs that IUDs are suitable and safe for women who are post-partum, post-abortion, have had an ectopic pregnancy, are nulliparous, teenagers, or have a history of STIs. However, these clinicians' views are not entirely in alignment with ACOG recommendations in their beliefs that these methods should not be used immediately post-partum or post-abortion. Notable percentages of these clinicians were hesitant to recommend these effective methods for other groups of patients, approved for use by ACOG. Conclusions While the cost of these methods is a barrier to adoption, these data suggest that there are continuing provider barriers to their use as well. The paper concludes with suggestions for further training for family planning providers.

ERAAs for menopause treatment: Welcome the 'designer estrogens'.

Estrogen receptor agonist-antagonists (ERAAs) selectively inhibit or stimulate estrogen-like action in targeted tissues. This review summarizes how ERAAs can be used in combination with an estrogen or alone to treat menopausal symptoms (vasomotor symptoms, genitourinary syndrome of menopause), breast cancer or the risk of breast cancer, osteopenia, osteoporosis, and other female midlife concerns.

Characterization of immune regulatory molecules B7-H4 and PD-L1 in low and high grade endometrial tumors.

BACKGROUND: The objective of this investigation was to characterize the expression landscape of immune regulatory molecules programmed death-ligand-1 (PD-L1, B7-H1) and B7-H4 in a cohort of endometrial tumors across the spectrum of grade and histology. MATERIALS AND METHODS: With institutional review board approval, 70 endometrial tumors from patients with known clinical outcomes were identified representing a spectrum of grade and histology. Immunohistochemistry (IHC) was performed for PD-L1 and B7-H4 and scored. Microsatellite instability (MSI) status was assessed for endometrioid tumors using the institutional IHC assay for expression of the mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2. RNA sequencing data from the Cancer Genome Atlas was queried for expression levels of CD274 (PD-L1 protein) and VTCN1 (B7-H4) across molecular subtypes of endometrial carcinoma and were correlated with a T cell infiltration index. RESULTS: We identified 40 low grade endometrioid tumors and a cohort of 30 high grade tumors. PD-L1 expression was observed in both high and low grade endometrial tumors (56% vs 35%, p=0.07). In the low grade tumors, PD-L1 expression was associated with MSI status (p<0.01). The high grade cohort had similar rates of PD-L1 expression compared to low grade MSI tumor (56% and 62% respectively), and both were distinct from low grade MSS tumors (22%, p<0.05). High (3+) B7-H4 positive cells were observed in both high and low grade carcinomas (33% and 31% respectively). RNA profiling data from confirmed highest CD274 expression in POLE and MSI tumors that was linearly correlated with T cell infiltration, while VTCN1 expression appeared consistent across molecular subtypes. CONCLUSIONS: While PD-L1 expression correlated with MSI and high grade tumors, B7-H4 expression was independent of grade, histology and immune cell infiltration. The development and testing of multi-agent therapeutics targeting PD-L1 and B7-H4 may be a novel strategy for endometrial tumors.

Phase I Trial of the Human Double Minute 2 Inhibitor MK-8242 in Patients With Advanced Solid Tumors.

Purpose To evaluate MK-8242 in patients with wild-type TP53 advanced solid tumors. Patients and Methods MK-8242 was administered orally twice a day on days 1 to 7 in 21-day cycles. The recommended phase II dose (RP2D) was determined on the basis of safety, tolerability, pharmacokinetics (PK), and by mRNA expression of the p53 target gene pleckstrin homology-like domain, family A, member 3 ( PHLDA3). Other objectives were to characterize the PK/pharmacodynamic (PD) relationship, correlate biomarkers with response, and assess tumor response. Results Forty-seven patients received MK-8242 across eight doses that ranged from 60 to 500 mg. Initially, six patients developed dose-limiting toxicities (DLTs): grade (G) 2 nausea at 120 mg; G3 fatigue at 250 mg; G2 nausea and G4 thrombocytopenia at 350 mg; and G3 vomiting and G3 diarrhea at 500 mg. DLT criteria were revised to permit management of GI toxicities. Dosing was resumed at 400 mg, and four additional DLTs were observed: G4 neutropenia and G4 thrombocytopenia at 400 mg and G4 thrombocytopenia (two patients) at 500 mg. Other drug-related G3 and G4 events included anemia, leukopenia, pancytopenia, nausea, hyperbilirubinemia, hypophosphatemia, and anorexia. On the basis of safety, tolerability, PK, and PD, the RP2D was established at 400 mg (15 evaluable patients experienced two DLTs). PK for 400 mg (day 7) showed Cmax 3.07 µM, Tmax 3.0 hours, t1/2 (half-life) 6.6 hours, CL/F (apparent clearance) 28.9 L/h, and Vd/F (apparent volume) 274 L. Blood PHLDA3 mRNA expression correlated with drug exposure ( R2 = 0.68; P < .001). In 41 patients with postbaseline scans, three patients with liposarcoma achieved a partial response (at 250, 400, and 500 mg), 31 showed stable disease, and eight had progressive disease. In total, 27 patients with liposarcoma had a median progression-free survival of 237 days. Conclusion At the RP2D of 400 mg twice a day, MK-8242 activated the p53 pathway with an acceptable safety and tolerability profile. The observed clinical activity (partial response and prolonged progression-free survival) provides an impetus for further study of HDM2 inhibitors in liposarcoma.

Medical management of urinary incontinence in women.

Urinary incontinence is common, underreported, and undertreated. Primary care physicians should be comfortable discussing urinary incontinence with their female patients and managing it with conservative treatment.

MCL1 and BCL-xL levels in solid tumors are predictive of dinaciclib-induced apoptosis.

Dinaciclib is a potent CDK1, 2, 5 and 9 inhibitor being developed for the treatment of cancer. Additional understanding of antitumor mechanisms and identification of predictive biomarkers are important for its clinical development. Here we demonstrate that while dinaciclib can effectively block cell cycle progression, in vitro and in vivo studies, coupled with mouse and human pharmacokinetics, support a model whereby induction of apoptosis is a main mechanism of dinaciclib's antitumor effect and relevant to the clinical duration of exposure. This was further underscored by kinetics of dinaciclib-induced downregulation of the antiapoptotic BCL2 family member MCL1 and correlation of sensitivity with the MCL1-to-BCL-xL mRNA ratio or MCL1 amplification in solid tumor models in vitro and in vivo. This MCL1-dependent apoptotic mechanism was additionally supported by synergy with the BCL2, BCL-xL and BCL-w inhibitor navitoclax (ABT-263). These results provide the rationale for investigating MCL1 and BCL-xL as predictive biomarkers for dinaciclib antitumor response and testing combinations with BCL2 family member inhibitors.

Impact of years of clinical experience on perceived contraindications and barriers to the use of LARC: a survey of family planning providers.

BACKGROUND: Despite their efficacy in preventing unintended pregnancies, intrauterine devices (IUDs) are still relatively underutilized by American women. Although cost of these methods is clearly a barrier to use, IUDs have had a long and sometimes controversial history, and earlier versions were removed from the market. METHODS: This study explores the degree to which the length of licensure for providers is related to their attitudes toward or fears about these methods. Data come from a 2012 survey of 114 clinicians in Colorado and Iowa, collected as part of two, statewide initiatives to reduce unintended pregnancy. Providers were asked about service barriers to prescribing these methods and for which patients they perceived them to be suitable and safe. RESULTS: The most experienced clinicians were the least concerned about uterine perforation and history of the Dalkon Shield, but were more likely to fear a lawsuit over complications. More experienced clinicians were also less approving of Copper T IUDs for all 11 subgroups of women, including nulliparous women and those with histories of sexually transmitted infections. They were also less approving of hormonal IUDs for 10 groups of women, including those with histories of ectopic pregnancies. However, clinicians with the most recent licensure were more conservative in their approval of single rod implants than were the providers with the most years since licensure. CONCLUSIONS: This paper explores potential reasons for these findings and suggests trainings to recognize and overcome these barriers so as to promote consistent and accurate practice across clinicians, regardless of years of experience.

Evaluating TBK1 as a therapeutic target in cancers with activated IRF3.

UNLABELLED: TBK1 (TANK-binding kinase 1) is a noncanonical IκB protein kinase that phosphorylates and activates downstream targets such as IRF3 and c-Rel and, mediates NF-κB activation in cancer. Previous reports demonstrated synthetic lethality of TBK1 with mutant KRAS in non-small cell lung cancer (NSCLC); thus, TBK1 could be a novel target for treatment of KRAS-mutant NSCLC. Here, the effect of TBK1 on proliferation in a panel of cancer cells by both genetic and pharmacologic approaches was evaluated. In KRAS-mutant cancer cells, reduction of TBK1 activity by knockdown or treatment with TBK1 inhibitors did not correlate with reduced proliferation in a two-dimensional viability assay. Verification of target engagement via reduced phosphorylation of S386 of IRF3 (pIRF3(S386)) was difficult to assess in NSCLC cells due to low protein expression. However, several cell lines were identified with high pIRF3(S386) levels after screening a large panel of cell lines, many of which also harbor KRAS mutations. Specifically, a large subset of KRAS-mutant pancreatic cancer cell lines was uncovered with high constitutive pIRF3(S386) levels, which correlated with high levels of phosphorylated S172 of TBK1 (pTBK1(S172)). Finally, TBK1 inhibitors dose-dependently inhibited pIRF3(S386) in these cell lines, but this did not correlate with inhibition of cell growth. Taken together, these data demonstrate that the regulation of pathways important for cell proliferation in some NSCLC, pancreatic, and colorectal cell lines is not solely dependent on TBK1 activity. IMPLICATIONS: TBK1 has therapeutic potential under certain contexts and phosphorylation of its downstream target IRF3 is a biomarker of TBK1 activity.

Preclinical evaluation of the WEE1 inhibitor MK-1775 as single-agent anticancer therapy.

Inhibition of the DNA damage checkpoint kinase WEE1 potentiates genotoxic chemotherapies by abrogating cell-cycle arrest and proper DNA repair. However, WEE1 is also essential for unperturbed cell division in the absence of extrinsic insult. Here, we investigate the anticancer potential of a WEE1 inhibitor, independent of chemotherapy, and explore a possible cellular context underlying sensitivity to WEE1 inhibition. We show that MK-1775, a potent and selective ATP-competitive inhibitor of WEE1, is cytotoxic across a broad panel of tumor cell lines and induces DNA double-strand breaks. MK-1775-induced DNA damage occurs without added chemotherapy or radiation in S-phase cells and relies on active DNA replication. At tolerated doses, MK-1775 treatment leads to xenograft tumor growth inhibition or regression. To begin addressing potential response markers for MK-1775 monotherapy, we focused on PKMYT1, a kinase functionally related to WEE1. Knockdown of PKMYT1 lowers the EC(50) of MK-1775 by five-fold but has no effect on the cell-based response to other cytotoxic drugs. In addition, knockdown of PKMYT1 increases markers of DNA damage, γH2AX and pCHK1(S345), induced by MK-1775. In a post hoc analysis of 305 cell lines treated with MK-1775, we found that expression of PKMYT1 was below average in 73% of the 33 most sensitive cell lines. Our findings provide rationale for WEE1 inhibition as a potent anticancer therapy independent of a genotoxic partner and suggest that low PKMYT1 expression could serve as an enrichment biomarker for MK-1775 sensitivity.

Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth.

Metformin, the first-line drug for treating diabetes, inhibits cellular transformation and selectively kills cancer stem cells in breast cancer cell lines. In a Src-inducible model of cellular transformation, metformin inhibits the earliest known step in the process, activation of the inflammatory transcription factor NF-κB. Metformin strongly delays cellular transformation in a manner similar to that occurring upon a weaker inflammatory stimulus. Conversely, inhibition of transformation does not occur if metformin is added after the initial inflammatory stimulus. The antitransformation effect of metformin can be bypassed by overexpression of Lin28B or IL1ß, downstream targets of NF-κB. Metformin preferentially inhibits nuclear translocation of NF-κB and phosphorylation of STAT3 in cancer stem cells compared with non-stem cancer cells in the same population. The ability of metformin to block tumor growth and prolong remission in xenografts in combination with doxorubicin is associated with decreased function of the inflammatory feedback loop. Lastly, metformin-based combinatorial therapy is effective in xenografts involving inflammatory prostate and melanoma cell lines, whereas it is ineffective in noninflammatory cell lines from these lineages. Taken together, our observations suggest that metformin inhibits a signal transduction pathway that results in an inflammatory response. As metformin alters energy metabolism in diabetics, we speculate that metformin may block a metabolic stress response that stimulates the inflammatory pathway associated with a wide variety of cancers.

Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types.

Metformin, the first-line drug for treating diabetes, selectively kills the chemotherapy resistant subpopulation of cancer stem cells (CSC) in genetically distinct types of breast cancer cell lines. In mouse xenografts, injection of metformin and the chemotherapeutic drug doxorubicin near the tumor is more effective than either drug alone in blocking tumor growth and preventing relapse. Here, we show that metformin is equally effective when given orally together with paclitaxel, carboplatin, and doxorubicin, indicating that metformin works together with a variety of standard chemotherapeutic agents. In addition, metformin has comparable effects on tumor regression and preventing relapse when combined with a four-fold reduced dose of doxorubicin that is not effective as a monotherapy. Finally, the combination of metformin and doxorubicin prevents relapse in xenografts generated with prostate and lung cancer cell lines. These observations provide further evidence for the CSC hypothesis for cancer relapse, an experimental rationale for using metformin as part of combinatorial therapy in a variety of clinical settings, and for reducing the chemotherapy dose in cancer patients.