PRKCI promotes immune suppression in ovarian cancer.

A key feature of high-grade serous ovarian carcinoma (HGSOC) is frequent amplification of the 3q26 locus harboring PRKC-ι (PRKCI). Here, we show that PRKCI is also expressed in early fallopian tube lesions, called serous tubal intraepithelial carcinoma. Transgenic mouse studies establish PRKCI as an ovarian cancer-specific oncogene. Mechanistically, we show that the oncogenic activity of PRKCI relates in part to the up-regulation of TNFα to promote an immune-suppressive tumor microenvironment characterized by an abundance of myeloid-derived suppressor cells and inhibition of cytotoxic T-cell infiltration. Furthermore, system-level and functional analyses identify YAP1 as a downstream effector in tumor progression. In human ovarian cancers, high PRKCI expression also correlates with high expression of TNFα and YAP1 and low infiltration of cytotoxic T cells. The PRKCI-YAP1 regulation of the tumor immunity provides a therapeutic strategy for highly lethal ovarian cancer.

Improving the palliative-procedure decision-making process for patients with peritoneal carcinomatosis: A secondary analysis.

BACKGROUND: Peritoneal carcinomatosis (PC) is common in patients with advanced gynecologic and gastrointestinal cancers. Frequently, patients with PC undergo palliative surgery or procedures to manage disease-related complications and side effects. However, there are limited data regarding patients' and family caregivers' decision-making processes about these procedures. Thus, we sought to describe the decision-making experiences of patients with PC who elect to pursue palliative surgical procedures and their family caregivers. METHODS: We conducted a secondary analysis of qualitative data collected during a pilot randomized controlled trial of BOLSTER, a nurse-led telehealth intervention for patients with PC and their caregivers after an acute hospitalization and palliative procedure. Participants in both study arms described their experiences in semi-structured interviews. We re-analyzed coded qualitative data with a focus on understanding decision-making experiences surrounding palliative surgery and procedures using conventional content analysis. RESULTS: Interviews from 32 participants, 23 patients and 9 caregivers, were analyzed. Participants reported their decision-making was complicated by illness uncertainty and a desire for clear, effective communication with surgical and medical oncology teams. Participants requested more information about the impact of palliative procedures on their daily life. Several also noted that, without improved understanding, a misalignment between patient and family caregiver goals and palliative procedures may inadvertently increase suffering. CONCLUSION: Discussions related to patients' goals and preferences can improve the quality of treatment decision-making in patients with PC and their caregivers. Future research should test interventions to improve advanced cancer patients' illness understanding and decision-making surrounding palliative surgery and procedures.

Feasibility and acceptability of a nurse-led telehealth intervention (BOLSTER) to support patients with peritoneal carcinomatosis and their caregivers: A pilot randomized clinical trial.

OBJECTIVE: Patients with advanced gynecologic (GYN) and gastrointestinal (GI) cancers frequently develop peritoneal carcinomatosis (PC), which limits prognosis and diminishes health-related quality of life (HRQoL). Palliative procedures may improve PC symptoms, yet patients and caregivers report feeling unprepared to manage ostomies, catheters, and other complex needs. Our objectives were to (1) assess the feasibility of an efficacy trial of a nurse-led telehealth intervention (BOLSTER) for patients with PC and their caregivers; and (2) assess BOLSTER's acceptability, potential to improve patients' HRQoL and self-efficacy, and potential impact on advance care planning (ACP). METHODS: Pilot feasibility RCT. Recently hospitalized adults with advanced GYN and GI cancers, PC, and a new complex care need and their caregivers were randomized 1:1 to BOLSTER or enhanced discharge planning (EDP). We defined feasibility as a ≥ 50% approach-to-consent ratio and acceptability as ≥70% satisfaction with BOLSTER. We assessed patients' HRQoL and self-efficacy at baseline and six weeks, then compared the proportion experiencing meaningful improvements by arm. ACP documentation was identified using natural language processing. RESULTS: We consented 77% of approached patients. In the BOLSTER arm, 91.0% of patients and 100.0% of caregivers were satisfied. Compared to EDP, more patients receiving BOLSTER experienced improvements in HRQoL (68.4% vs. 40.0%) and self-efficacy for managing symptoms (78.9% vs. 35.0%) and treatment (52.9% vs. 42.9%). The BOLSTER arm had more ACP documentation. CONCLUSIONS: BOLSTER is a feasible and acceptable intervention with the potential to improve patients' HRQoL and promote ACP. An efficacy trial comparing BOLSTER to usual care is underway. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03367247; PI: Wright.

A phase 2 trial exploring the significance of homologous recombination status in patients with platinum sensitive or platinum resistant relapsed ovarian cancer receiving combination cediranib and olaparib.

OBJECTIVE: Combination cediranib/olaparib has reported activity in relapsed ovarian cancer. This phase 2 trial investigated the activity of cediranib/olaparib in relapsed ovarian cancer and its association with homologous recombination deficiency (HRD). METHODS: Seventy patients were enrolled to cohorts of either platinum-sensitive or platinum-resistant ovarian cancer and received olaparib tablets 200 mg twice daily and cediranib tablets 30 mg once daily under a continuous dosing schedule. HRD testing was performed on pre-treatment, on-treatment and archival biopsies by sequencing key homologous recombination repair (HRR) genes and by genomic LOH analysis. The primary objective for the platinum-sensitive cohort was the association of HRD, defined as presence of HRR gene mutation, with progression-free survival (PFS). The primary objective for the platinum-resistant cohort was objective response rate (ORR), with a key secondary endpoint evaluating the association of HRD status with activity. RESULTS: In platinum-sensitive ovarian cancer (N = 35), ORR was 77.1% (95% CI 59.9-89.6%) and median PFS was 16.4 months (95% CI 13.2-18.6). Median PFS in platinum-sensitive HRR-HRD cancers (N = 22) was 16.8 months (95% CI 11.3-18.6), and 16.4 months (95% CI 9.4-NA) in HRR-HR proficient cancers (N = 13; p = 0.57). In platinum-resistant ovarian cancer (N = 35), ORR was 22.9% (95% CI 10.4-40.1%) with median PFS 6.8 months (95% CI 4.2-9.1). Median PFS in platinum-resistant HRR-HRD cancers (N = 7) was 10.5 months (95% CI 3.6-NA) and 5.6 months (95% CI 3.6-7.6) in HRR-HR proficient cancers (N = 18; p = 0.23). CONCLUSIONS: Cediranib/olaparib had clinical activity in both platinum-sensitive and -resistant ovarian cancer. Presence of HRR gene mutations was not associated with cediranib/olaparib activity in either setting.

Uterine serous carcinoma and uterine carcinosarcoma: molecular features, clinical advances, and emerging therapies.

Endometrial cancer, including high-grade subtypes, has a rising incidence and mortality. Uterine serous carcinoma (USC) and uterine carcinosarcoma (UCS) make up a small but increasing proportion of endometrial cancer cases and account for a significant portion of endometrial cancer mortality. Despite being molecularly and clinically distinct, both USC and UCS have a poor prognosis. Thus far, there have been few therapeutic strategies directed at these endometrial cancer subtypes. This review summarizes the genomic and molecular features of USC and UCS, clinical advances in the treatment of primary advanced and recurrent endometrial cancer, and novel molecularly-driven treatment strategies.

Pilot randomized trial of an acceptance-based telehealth intervention for women with ovarian cancer and PARP inhibitor-related fatigue.

OBJECTIVE: Poly(ADP-ribose) polymerase inhibitors (PARPi) have dramatically changed treatment for advanced ovarian cancer, but nearly half of patients experience significant fatigue. We conducted a two-site pilot randomized trial to evaluate the feasibility, acceptability, and preliminary efficacy of a brief, acceptance-based telehealth intervention (REVITALIZE) designed to reduce fatigue interference in patients on PARPi. METHODS: From June 2021 to April 2022, 44 participants were randomized 1:1 to REVITALIZE (6 weekly one-on-one sessions+booster) or enhanced usual care. Feasibility was defined as: ≥50% approach-to-consent among potentially eligible patients and ≥70% completion of 12-week follow-up assessment; acceptance was <20% participants reporting burden and <20% study withdrawal. Fatigue, anxiety, depression, and quality of life were assessed at baseline, 4-, 8- and 12-weeks. RESULTS: Among 44 participants (mean age = 62.5 years, 81.8% stage III/IV disease), the study was feasible (56.4% approach-to-consent ratio, 86.3% completion of 12-week assessment) and acceptable (0% reporting burden, 11.3% study withdrawal). At 12-week follow-up, REVITALIZE significantly reduced fatigue interference (Cohen's d = 0.94, p = .008) and fatigue severity (d = 0.54, p = .049), and improved fatigue levels (d = 0.62, p = .04) relative to enhanced usual care. REVITALIZE also showed promise for improved fatigue self-efficacy, fatigue catastrophizing, anxiety, depression, and quality of life (ds = 0.60-0.86, p ≥ .05). Compared with enhanced usual care, REVITALIZE participants had fewer PARPi dose reductions (6.7% vs. 19.0%), and dose delays (6.7% vs. 23.8%). CONCLUSIONS: Among fatigued adults with ovarian cancer on PARPi, a brief, acceptance-based telehealth intervention was feasible, acceptable, and demonstrated preliminary efficacy in improving fatigue interference, severity, and levels. REVITALIZE is a novel, scalable telehealth intervention worthy of further investigation.

Rational Combinations of PARP Inhibitors with HRD-Inducing Molecularly Targeted Agents.

Cancers with wild-type BRCA, homologous recombination proficiency, or de novo or acquired resistance to PARP inhibition represent a growing population of patients who may benefit from combinatorial PARP inhibitor strategies. We review targeted inhibitors of angiogenesis, epigenetic regulators, and PI3K, MAPK, and other cellular signaling pathways as inducers of homologous recombination deficiency, providing support for the use of PARP inhibitors in contexts not previously considered susceptible to PARP inhibition.

High incidence of poor in-hospital outcomes of term newborns with hypoxic-ischaemic encephalopathy admitted at a regional referral hospital in Dodoma, Tanzania.

AIM: Hypoxic-ischaemic encephalopathy (HIE) is one of the leading causes of neonatal deaths and neurological impairment with the highest impact in resource-limited settings. This study aimed to determine the incidence of poor in-hospital outcomes and related factors among newborns with HIE in Tanzania. METHODS: A prospective observational study in which 170 newborns with HIE (diagnosed using the Thompson clinical score) were followed from 1 September 2020 to 28 February 2021 at the neonatal ward of Dodoma Regional Referral Hospital in Dodoma, central Tanzania, until discharge or death. Clinical parameters were recorded. Multinomial logistic regression analysis was applied to determine factors associated with adverse outcomes. RESULTS: Out of 170 newborns, 44.7% (76/170) had poor outcomes (death 27.1% (46/170); neurological deficits 17.6% (30/170)). Severe HIE (Thompson score > 14) (p < 0.0001), history of aspiration (adjusted odds ratio (AOR) = 3.06, 95% confidence interval (CI) [1.170, 8.014], p = 0.0226) and 5th-min APGAR of <7 (AOR = 2.88, 95% CI [1.133, 7.310], p = 0.0262) were associated with mortality. Severe HIE, delivery at other facilities (AOR = 3.106 CI [1.158, 8.332], p = 0.0244) and abnormal heart rate (<100 or ≥160 beats/min) on admission (AOR = 3.469 [1.200, 10.030], p = 0.0216) predicted neurological impairment at discharge. CONCLUSION: Hypoxic-ischaemic encephalopathy is associated with a high incidence of poor outcomes in resource-limited settings. To improve outcomes newborns with severe HIE, history of aspiration, referred from other facilities, 5th-min APGAR score of <7 and abnormal heart rate need improved quality of neonatal care.

Sesamin: A Promising Therapeutic Agent for Ameliorating Symptoms of Diabetes.

Diabetes is a chronic metabolic disease characterized by improperly regulating proteins, carbohydrates, and lipids due to insulin deficiency or resistance. The increasing prevalence of diabetes poses a tremendous socioeconomic burden worldwide, resulting in the rise of many studies on Chinese herbal medicines to discover the most effective cure for diabetes. Sesame seeds are among these Chinese herbal medicines that were found to contain various pharmacological activities, including antioxidant and anti-inflammatory properties, lowering cholesterol, improving liver function, blood pressure and sugar lowering, regulating lipid synthesis, and anticancer activities. These medicinal benefits are attributed to sesamin, which is the main lignan found in sesame seeds and oil. In this study, Wistar rat models were induced with type 2 diabetes using streptozotocin (STZ) and nicotinamide, and the effect of sesamin on the changes in body weight, blood sugar level, glycosylated hemoglobin (HbA1c), insulin levels, and the states of the pancreas and liver of the rats were evaluated. The results indicate a reduced blood glucose level, HbA1c, TG, and ALT and AST enzymes after sesamin treatment, while increased insulin level, SOD, CAT, and GPx activities were also observed. These findings prove sesamin's efficacy in ameliorating the symptoms of diabetes through its potent pharmacological activities.

Combined PARP and HSP90 inhibition: preclinical and Phase 1 evaluation in patients with advanced solid tumours.

PURPOSE: PARP inhibitor resistance may be overcome by combinatorial strategies with agents that disrupt homologous recombination repair (HRR). Multiple HRR pathway components are HSP90 clients, so that HSP90 inhibition leads to abrogation of HRR and sensitisation to PARP inhibition. We performed in vivo preclinical studies of the HSP90 inhibitor onalespib with olaparib and conducted a Phase 1 combination study. PATIENTS AND METHODS: Tolerability and efficacy studies were performed in patient-derived xenograft(PDX) models of ovarian cancer. Clinical safety, tolerability, steady-state pharmacokinetics and preliminary efficacy of olaparib and onalespib were evaluated using a standard 3 + 3 dose-escalation design. RESULTS: Olaparib/onalespib exhibited anti-tumour activity against BRCA1-mutated PDX models with acquired PARPi resistance and PDX models with RB-pathway alterations(CDKN2A loss and CCNE1 overexpression). Phase 1 evaluation revealed that dose levels up to olaparib 300 mg/onalespib 40 mg and olaparib 200 mg/onalespib 80 mg were safe without dose-limiting toxicities. Coadministration of olaparib and onalespib did not appear to affect the steady-state pharmacokinetics of either agent. There were no objective responses, but disease stabilisation ≥24 weeks was observed in 7/22 (32%) evaluable patients including patients with BRCA-mutated ovarian cancers and acquired PARPi resistance and patients with tumours harbouring RB-pathway alterations. CONCLUSIONS: Combining onalespib and olaparib was feasible and demonstrated preliminary evidence of anti-tumour activity.

Shigella is common in symptomatic and asymptomatic men who have sex with men visiting a sexual health clinic in Amsterdam.

INTRODUCTION: Shigellosis is a reportable infectious disease. It can present as a severe bloody diarrhoea but is often asymptomatic. Shigella can be sexually transmissible. We performed a study among symptomatic and asymptomatic men who have sex with men (MSM) to assess the prevalence of Shigella, Salmonella and Campylobacter. METHODS: From March to June 2020, MSM attending the Amsterdam centre for sexual health were consecutively included. Predefined minimal numbers of inclusion of 150, 100 and 50 were determined, respectively, for MSM who reported no diarrhoea, diarrhoea during last month or diarrhoea on the day of visit to clinic. Anal samples were tested for the presence of Shigella, Salmonella and Campylobacter. During the same period, the frequency of these bacteria was assessed in routinely tested samples requested by general physicians or nursing home physicians. Characteristics of included MSM were compared between the men with different diarrhoea anamnesis, and the prevalence of shigellosis was estimated in each group. RESULTS: We included 212 MSM without diarrhoea, 109 MSM who recently had diarrhoea and 68 MSM who reported diarrhoea on the day of clinic visit. Thirteen (3.3%, 95% CI 1.7% to 5.6%) MSM were infected with Shigella, none with Salmonella and 7 (1.8%, 95% CI 0.7% to 3.7%) with Campylobacter. Shigella prevalence was 2.8% (95% CI 1.0% to 6.1%) in asymptomatic men, 3.7% (95% CI 1.0% to 9.1%) in men who recently had diarrhoea and 4.4% (95% CI 0.9% to 12.4%) in men with current diarrhoea (p=0.799). Shigella was more frequently found in MSM who had used pre-exposure prophylaxis (PrEP) in the preceding 3 months (10/151), compared with those not having used PrEP (2/146) or being HIV positive (1/75) (p=0.038). Shigella was significantly more often detected among MSM compared with routinely obtained faecal samples being 11/770 (1.4%) (p=0.031). CONCLUSION: Shigella infections are relatively common in both symptomatic and asymptomatic MSM. Future studies should focus on the risk of onward transmission via asymptomatic persons. Samenvatting Introductie Shigellose is een meldingsplichtige infectieziekte. Het kan zich presenteren als een ernstige bloederige diarree, maar is vaak asymptomatisch. Shigella kan seksueel overdraagbaar zijn. We hebben een onderzoek uitgevoerd onder symptomatische en asymptomatische mannen die seks hebben met mannen (MSM) om de prevalentie van Shigella, Salmonella en Campylobacter te bepalen. Methoden Van maart tot juni 2020 werden achtereenvolgens MSM van het Amsterdamse centrum voor seksuele gezondheid opgenomen. Vooraf gedefinieerde minimale aantallen van inclusie van respectievelijk 150, 100 en 50 waren bepaald voor MSM die geen diarree, diarree in de afgelopen maand of diarree op de dag van bezoek aan de kliniek meldden. Anale monsters werden getest op de aanwezigheid van Shigella, Salmonella en Campylobacter. In dezelfde periode werd de frequentie van deze bacteriën bepaald in routinematig geteste monsters aangevraagd door huisartsen of verpleeghuisartsen. Kenmerken van geïncludeerde MSM werden vergeleken tussen mannen met verschillende diarree anamnese, en de prevalentie van shigellose werd in elke groep geschat. Resultaten We includeerden 212 MSM zonder diarree, 109 MSM die onlangs diarree hadden en 68 MSM die diarree meldden op de dag van het bezoek aan de kliniek. Dertien (3,3%, 95% CI 1,7-5,6%) MSM waren geïnfecteerd met Shigella, geen enkele met Salmonella, en 7 (1,8%, 95% CI 0,7-3,7%) met Campylobacter. De prevalentie van Shigella was 2,8% (95%CI 1,0-6,1%) bij asymptomatische mannen, 3,7% (95%CI 1,0-9,1%) bij mannen die recent diarree hadden en 4,4% (95%CI 0,9-12,4%) bij mannen met huidige diarree (P=0,799). Shigella werd vaker gevonden bij MSM die in de voorgaande drie maanden (10/151) PrEP hadden gebruikt dan bij mensen die geen PrEP hadden gebruikt (2/146) of hiv-positief waren (1/75) (p=0,038). Shigella werd significant vaker gedetecteerd bij MSM in vergelijking met routinematig verkregen fecale monsters, namelijk 11/770 (1,4%) (p=0,031). Conclusie Shigella infecties komen relatief vaak voor bij zowel symptomatische als asymptomatische MSM. Toekomstige studies moeten zich richten op het risico van verdere overdracht via asymptomatische personen.

Macrolide-Resistant Mycoplasma genitalium Impairs Clinical Improvement of Male Urethritis After Empirical Treatment.

BACKGROUND: Mycoplasma genitalium (MG) is associated with urethritis in men and could play a role in clinical outcome. We examined clinical improvement of symptoms in men receiving empirical treatment for urethritis and correlated the outcome with Neisseria gonorrhoeae (NG), Chlamydia trachomatis (CT), MG, and MG macrolide resistance-associated mutations (MRAM) status. METHODS: At the sexually transmitted infection clinic in Amsterdam, the Netherlands, empirical treatment for gonococcal urethritis is 1 g ceftriaxone and for nongonococcal urethritis 1 g azithromycin. In 2018 to 2019, we tested urine samples of men with urethritis for CT, NG, and MG using transcription-mediated amplification assays. Mycoplasma genitalium-positive samples were tested for MRAM using quantitative polymerase chain reaction. Two weeks after receiving therapy, men were sent a text message inquiring after clinical improvement. RESULTS: We evaluated 2505 cases of urethritis. The positivity rates of NG, CT, and MG were 26% (648 of 2489), 29% (726 of 2489), and 23% (522 of 2288), respectively. In 768 of 2288 of the cases (34%), no causative agent was detected. Most cases were infected with a single pathogen: NG, 417 of 2288 (18%); CT, 486 of 2288 (21%); and MG, 320 of 2288 (14%). The prevalence of MRAM among MG-positives was 74% (327 of 439). For 642 (25.6%) cases, we could evaluate clinical improvement after treatment of whom 127 (20%) indicated no improvement; 9% (15 of 174) in NG cases, 18% (35 of 195) in CT cases, 14% (4 of 28) in MG wild-type cases, and 40% (38 of 94) in MG-MRAM cases. Clinical improvement in MG-MRAM cases was significantly lower compared with all other groups (P < 0.001). CONCLUSIONS: Presence of MG-MRAM is associated with lack of clinical improvement in azithromycin-treated nongonococcal urethritis.

Females undergo selection too.

Extending Campbell's (1999) staying alive theory (SAT) beyond aggression, we reviewed evidence that females are more self-protective than males. Many commentators provided additional supporting data. Sex differences in life-history adaptations, in the optimal relation between survival and reproduction, and in the mechanisms underlying trade-offs involved with self-protection remain important topics with numerous opportunities for improved understanding.

Uterine serous carcinoma: Molecular features, clinical management, and new and future therapies.

Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer. Multimodality treatment with surgery, radiotherapy, and chemotherapy is commonly used, given its propensity for extrauterine spread, distant recurrences, and poor prognosis. However, the use of molecularly-based therapy is expanding. Here, we review key molecular features of USC, discuss current management, and assess the landscape of novel therapies and combinations.

Rationale for combination PARP inhibitor and antiangiogenic treatment in advanced epithelial ovarian cancer: A review.

Inhibitors of poly(ADP-ribose) polymerase (PARP) and angiogenesis have demonstrated single-agent activity in women with advanced ovarian cancer. Recent studies have aimed to establish whether combination therapy can augment the response seen with PARP inhibitors or antiangiogenic agents alone. This review provides an overview of PARP inhibitors and antiangiogenics as monotherapy in women with advanced ovarian cancer, explores potential mechanisms of action of PARP inhibitor and antiangiogenic combination treatments, reviews efficacy and safety data from trials evaluating this combination, and outlines ongoing and future trials evaluating this combination, discussing these in the context of the current and future treatment landscape for women with advanced ovarian cancer. Sentinel studies evaluating PARP inhibitor (n = 8), antiangiogenic (n = 4), and combination (n = 7) therapy were identified in women with newly diagnosed (n = 7) and recurrent (n = 12) ovarian cancer. PARP inhibitors included olaparib (n = 9), niraparib (n = 4), rucaparib (n = 1), and veliparib (n = 1). Antiangiogenic agents included bevacizumab (n = 7) and cediranib (n = 4). PARP inhibitors combined with antiangiogenics demonstrated efficacy based on objective response rates and progression-free survival (PFS) in the relapsed disease setting. Maintenance therapy with the PARP inhibitor, olaparib, plus antiangiogenic therapy offered a significant PFS benefit versus the antiangiogenic alone in women with newly diagnosed advanced ovarian cancer who tested positive for homologous recombination deficiency. Combination therapy was tolerated, with no new safety signals reported compared with monotherapy trials. PARP inhibitors and antiangiogenics have changed the landscape of ovarian cancer treatment. The PARP inhibitor plus antiangiogenic combination is a novel treatment option that appears promising in the first-line advanced and recurrent ovarian cancer settings, although the role of this combination in recurrent disease requires further elucidation. Defining which patients are candidates for monotherapy or combination therapy is critical, taking into consideration safety profiles of therapies alone or in combination, and how these treatments should be sequenced in clinical practice.

Lived experiences of women reporting fatigue during PARP inhibitor maintenance treatment for advanced ovarian cancer: A qualitative study.

OBJECTIVE: Oral PARP inhibitors (PARPi) have dramatically changed the treatment landscape for patients with advanced ovarian cancer. However, a subset of patients discontinue PARPi due to treatment-related fatigue. The current study sought to explore patients' lived experiences with fatigue on PARPi. METHODS: We conducted individual semi-structured interviews with N = 23 women receiving PARPi for advanced ovarian cancer who reported moderate to severe fatigue. Audiotaped interviews were transcribed and we used thematic analysis to code transcripts for emergent themes. RESULTS: Four overarching themes emerged. First, participants described their fatigue as milder than what they experienced on intravenous chemotherapy, but noted it consistently limited their daily activities, including work, and interfered with participation in family and social events. Second, fatigue negatively impacted participants' sense of self and identity. Third, most wanted to continue treatment and believed discontinuing PARPi would lead to a cancer recurrence or death. Finally, many participants reported that their support networks were unaware of their ongoing cancer treatment or the resulting fatigue; a situation that may prove isolating and result in reduced social support. CONCLUSIONS: Our findings underscore patients' persistent experience of fatigue on PARPi, the impact of fatigue on multiple domains of functioning, and a lack of understanding of side effects resulting from oral maintenance treatments among patients' social networks. Our findings highlight the need for interventions to address treatment-related fatigue to limit the negative impacts of fatigue on ovarian cancer patients' well-being.

Phase 1b study of AVB-500 in combination with paclitaxel or pegylated liposomal doxorubicin platinum-resistant recurrent ovarian cancer.

OBJECTIVE: GAS6 and AXL are expressed in high-grade serous ovarian cancer but not in normal ovarian tissue. AVB-500, a novel high affinity Fc-sAXL fusion protein, binds GAS6 preventing AXL signaling. This Phase 1b study (NCT03639246) evaluated safety, efficacy, and exploratory predictive markers of AVB-500 combined with paclitaxel (PAC) or pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant ovarian cancer (PROC), and used a model informed drug development (MIDD) approach for identification of the recommended phase 2 dose (RP2D). METHODS: Eligible patients received AVB-500 at 10, 15, or 20 mg/kg IV q2wk combined with PAC (n = 23) or PLD (n = 30). Patients were treated until progression or unacceptable toxicity. All were followed for survival. RESULTS: No dose limiting toxicities were observed and serum GAS6 was completely suppressed across the three dose levels evaluated. AVB-500 + PAC yielded better clinical activity than AVB-500 + PLD with an ORR of 34.8% (8/23, 2 complete responses) and median DoR, PFS, and OS of 7.0, 3.1, and 10.3 months, respectively. Subgroup analyses showed AVB-500 + PAC patients who had no prior bevacizumab or whose AVB-500 trough levels were >13.8 mg/L exhibited the best clinical response. The ORR and median PFS and OS in patients with these characteristics were ≥50%, ≥7.5 months, and ≥19 months, respectively. Given AVB-500 nor the combination with chemotherapy was expected to cause DLTs, the RP2D of AVB-500 was 15 mg/kg identified using an MIDD approach. CONCLUSION: AVB-500 was well-tolerated in combination with PAC or PLD and contributed to the clinical activity of PAC in PROC patients. Subgroup analyses identified a population of PROC patients who may benefit the most from AVB-500 treatment, which will be further assessed in an ongoing Phase 3 PROC trial.

Stepping into survivorship pilot study: Harnessing mobile health and principles of behavioral economics to increase physical activity in ovarian cancer survivors.

OBJECTIVE: Physical activity improves physical function, quality of life, and mental health, yet fewer than 80% of ovarian cancer survivors meet activity guidelines. This pilot intervention study aimed to increase physical activity in ovarian cancer survivors by leveraging principles of behavioral economics, gamification, and social support. METHODS: This 24-week study (12-week intervention; 12-week follow-up) enrolled women with ovarian cancer after completion of first-line treatment with a self-selected "teammate." Participants used Fitbits to measure daily steps, select an increased step goal, and enroll in a collaborative game, including points and levels for achieving step goals. Primary outcomes were feasibility (defined a priori as ≥60% approach-to-consent ratio and ≥ 70% adherence to Fitbit), acceptability (≤20% of participants reporting burden or regret for participation) and preliminary efficacy (≥70% reporting increased motivation); exploratory outcomes included change in steps. RESULTS: We recruited 24 participants (mean age = 63 years, range = 37-79 years) with a 94% approach-to-consent ratio. All participants completed the intervention with 94% tracker adherence. At 24-week follow-up, 1/24 (≤5%) of participants reported burden; 0/24 (0%) reported regret for study participation; and 22/24 (>90%) agreed/strongly agreed that "the study motivated me to increase activity levels." Participants' mean daily steps were 6210.7 (±3328.1) at baseline and increased to 7643 (± 3610.9) steps (p < 0.001) during the 12-week intervention. CONCLUSIONS: This pilot study demonstrated feasibility, acceptability, and preliminary efficacy, justifying a larger randomized clinical trial to test efficacy at increasing activity levels. Future studies should examine strategies for maintaining increased activity levels in survivors over time.

Clinical use of STOP-BANG and ESS questionnaires in the evaluation of obstructive sleep apnoea-related risk factors for motor vehicle accidents among public transport drivers in Delhi, India.

PURPOSE: To assess the clinical use of Epworth Sleepiness Score (ESS) and STOP-BANG questionnaires in the evaluation of sleep apnoea-related risk factors for motor vehicle accident (MVA) among public transport drivers in Delhi, India. METHODS: The present cross-sectional study is based on data collected between April 2018 and March 2019 from public transport drivers in Delhi. All drivers coming for gas filling to 43 compressed natural gas (CNG) stations in Delhi were included in the study. The evaluation of sleep apnoea-related risk factors for motor vehicle accident was done using ESS and STOP-BANG Score. RESULTS: A total of 4094 drivers participated in this study, and 299 drivers (7%) gave a history of motor vehicle accidents during the preceding 3 years. Drivers with STOP-BANG score ≥ 3 had a higher risk for MVA (OR 1.59; 95% CI 1.26-2.02; p value < 0.0001). Score of ESS ≥ 10 carried a very high risk for MVA (OR 26.95; 95% CI 16.18-44.87; p value < 0.0001). The other risk factor of significance was alcoholism (OR 1.37; 95% CI 1.04-1.80; p value < 0.0248). CONCLUSION: Among public transport drivers in Delhi, daytime sleepiness is the major contributing factor to motor vehicle accidents. ESS and STOP-BANG questionnaires may be good screening tools for the clinical evaluation of OSA. Community-based screening of OSA is required for identification of public transport drivers at high risk of MVA.

Self-protection as an adaptive female strategy.

Many male traits are well explained by sexual selection theory as adaptations to mating competition and mate choice, whereas no unifying theory explains traits expressed more in females. Anne Campbell's "staying alive" theory proposed that human females produce stronger self-protective reactions than males to aggressive threats because self-protection tends to have higher fitness value for females than males. We examined whether Campbell's theory has more general applicability by considering whether human females respond with greater self-protectiveness than males to other threats beyond aggression. We searched the literature for physiological, behavioral, and emotional responses to major physical and social threats, and found consistent support for females' responding with greater self-protectiveness than males. Females mount stronger immune responses to many pathogens; experience a lower threshold to detect, and lesser tolerance of, pain; awaken more frequently at night; express greater concern about physically dangerous stimuli; exert more effort to avoid social conflicts; exhibit a personality style more focused on life's dangers; react to threats with greater fear, disgust, and sadness; and develop more threat-based clinical conditions than males. Our findings suggest that in relation to threat, human females have relatively heightened protective reactions compared to males. The pervasiveness of this result across multiple domains suggests that general mechanisms might exist underlying females' unique adaptations. An understanding of such processes would enhance knowledge of female health and well-being.