A Systematic Review of the Psychosocial Impact of Endometriosis before and after Treatment.

While endometriosis is a common gynecologic disease associated with infertility, the psychosocial impact of endometriosis has not been evaluated against various quality of life (QoL) instruments and compared with other chronic illnesses. We rigorously analyzed the psychosocial burden of endometriosis in adult women and compared standardized and validated QoL scores of women with and without endometriosis, before and following treatment, and against other chronic illnesses. We searched PubMed, PsychINFO Embase, and Cochrane Reviews and ClinicalTrials.gov from January 1990 to December 2022 for publications using a detailed list of search terms related to QoL, endometriosis, and questionnaires. Only English-language publications that evaluated the association between Endometriosis and QoL using standardized and validated questionnaires measured at baseline and following treatment were considered. Four reviewers first performed a title and abstract screening followed by full text-review to finalize included articles. QoL scores of women with endometriosis were measured at baseline and analyzed against women without endometriosis and women with endometriosis who had undergone treatment. Additionally, baseline endometriosis scores were assessed against the published QoL scores of populations with other chronic conditions. Assessment of risk of bias was performed in accordance with Cochrane and Newcastle-Ottawa Scale guidelines. A total of 30 articles were included in this review: 4 randomized trials and 26 observational studies. The diagnosis and experience of women with symptomatic endometriosis had an equal or worse QoL score than that of other chronic conditions including heart disease, diabetes, and breast cancer when compared using the 36-Item Short Form Survey and World Health Organization Quality of Life questionnaires. Evidence showed association between low QoL and infertility, sexual dysfunction, mental health struggles, physical pain, poor sleep and fatigue. QoL scores were lower at baseline compared to following treatment in the majority of these domains. Endometriosis is associated with significant psychosocial burden and impaired QoL scores across baseline measurements in comparison to controls and other chronic illnesses. Medical and surgical interventions significantly decreased experienced burdens and improved QoL of women with endometriosis.

High grade adverse event reporting and enrolment in gynecologic oncology clinical trials.

OBJECTIVE: The primary objective is to assess factors associated with treatment related high grade (CTCAE grade ≥ 3) adverse event (AE) reporting among participants in gynecologic oncology clinical trials. METHODS: All AEs recorded in the Princess Margaret Clinical Trial adverse event database between 01/2016 and 12/2018 were evaluated. Gynecologic oncology clinical trials assessing systemic therapy were included. Inferential statistics on risk factors of related grade ≥ 3 adverse event reporting and GEE logistic models with Odds Ratios (OR) were performed. Multivariable analysis adjusting for age, clinical trial phase, sponsor, and therapy type. RESULTS: The gynecology cancer clinical trials accrued 317 unique patients (359 nested on trials) in 42 systemic therapy trials. In the period, 17,175 related AEs were reported in the gynecological cancer trials, 7.4% were grade ≥ 3. On multivariable analysis, no odds differences of grade ≥ 3 related AEs were detected according to study phase. Patients in immunotherapy clinical trials had lower odds of related grade ≥ 3 AEs than patients on targeted or other therapy (adjusted OR [aOR] 0.43; 95% CI 0.24-0.75). There was greater odds of related grade ≥ 3 AEs in clinical trials assessing combination vs single therapeutics (aOR 2.26, 95% CI 1.34-3.80). Patients aged ≥65 (aOR 1.77; 95% CI 1.08-2.89) had greater odds of related grade ≥ 3 AEs than patients aged 50 to 65 years. When compared to other disease sites, the odds of having a grade  ≥ 3 related AE reported in gynecology clinical trials was no different. CONCLUSIONS: In this cohort, factors influencing the odds of related grade ≥ 3 AE reporting in gynecologic trials included type of therapy and age. The study phase did not correlate with odds of high-grade AE reporting.

Identifying Healthcare Professionals With Lower Human Papillomavirus (HPV) Vaccine Recommendation Quality: A Systematic Review.

PURPOSE: Strengthening healthcare professionals' (HCPs) communication is an evidence-based approach to increasing human papillomavirus (HPV) vaccine uptake among adolescents. To better target future interventions, we sought to synthesize evidence on HCP subgroups who most need to improve their HPV vaccine recommendation quality. METHODS: We searched five databases for quantitative studies published from 2012 to 2022 on HPV vaccine recommendation quality, including recommendation consistency and strength, for United States adolescents. Two coders independently abstracted data from each eligible study, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We summarized variation in recommendation quality by clinical and HCP characteristics. RESULTS: The 28 eligible studies indicated that relatively low proportions of HCPs used higher-quality recommendation practices (median: 61% across 30 measures) and that recommendation quality varied across HCP subgroups. The most consistent findings were that more pediatric HCPs used higher-quality recommendations than family medicine HCPs (8 of 11 studies, 2-60 percentage point difference) and that HPV-related knowledge was associated with higher recommendation quality (four of seven studies). Most studies observed no differences in recommendation quality by clinical role (e.g., provider vs. nurse) or HCP demographics (e.g., gender, age, race/ethnicity). DISCUSSION: Studies suggest a substantial need to improve HCPs' recommendation quality, with opportunities for targeting future interventions.

Late Cardiac Toxic Effects Associated With Treatment Protocols for Hodgkin Lymphoma in Children.

Importance: Contemporary North American trials for children with Hodgkin lymphoma (HL) have decreased radiation therapy (RT) use and increased pharmacologic cardioprotection but also increased the cumulative doxorubicin dose, making overall treatment consequences for late cardiac toxic effects uncertain. Objective: To estimate the risk of cardiac toxic effects associated with treatments used in modern pediatric HL clinical trials. Design, Setting, and Participants: For this cohort study, Fine and Gray models were fitted using survivors in the Childhood Cancer Survivor Study who were diagnosed with HL between January 1, 1970, and December 31, 1999, and were followed for a median of 23.5 (range, 5.0-46.3) years. These models were applied to the exposures in the study population to estimate the 30-year cumulative incidence of cardiac disease. The study population comprised patients with intermediate-risk or high-risk HL treated in 4 consecutive Children's Oncology Group clinical trials from September 2002 to October 2022: AHOD0031, AHOD0831, AHOD1331, and S1826. Data analysis was performed from April 2020 to February 2023. Exposures: All patients received chemotherapy including doxorubicin, and some patients received mediastinal RT, dexrazoxane, or mediastinal RT and dexrazoxane. Main Outcomes and Measures: Estimated 30-year cumulative incidence of grade 3 to 5 cardiac disease. Results: The study cohort comprised 2563 patients, with a median age at diagnosis of 15 (range, 1-22) years. More than half of the patients were male (1357 [52.9%]). All 2563 patients received doxorubicin, 1362 patients (53.1%) received mediastinal RT, and 307 patients (12.0%) received dexrazoxane. Radiation therapy use and the median mean heart dose among patients receiving RT decreased, whereas the planned cumulative dose of doxorubicin and use of dexrazoxane cardioprotection increased. For patients treated at age 15 years, the estimated 30-year cumulative incidence of severe or fatal cardiac disease was 9.6% (95% CI, 4.2%-16.4%) in the AHOD0031 standard treatment group (enrolled 2002-2009), 8.6% (95% CI, 3.8%-14.9%) in the AHOD0831 trial (enrolled 2009-2012), 8.2% (95% CI, 3.6%-14.3%) in the AHOD1331 trial (enrolled 2015-2019), and 6.2% (95% CI, 2.7%-10.9%) in the S1826 trial (enrolled 2019-2022), whereas the expected rate in an untreated population was 5.0% (95% CI, 2.1%-9.3%). Despite the estimated reduction in late cardiac morbidity, the frequency of recommended echocardiographic screening among survivors will increase based on current guidelines. Conclusions and Relevance: In this cohort study of sequential HL trials, reductions in the proportion of children receiving mediastinal RT and increases in dexrazoxane use were estimated to offset the increased doxorubicin dose and produce a net reduction in late cardiac disease. Further studies on dexrazoxane are warranted to confirm whether its role in reducing cardiac toxic effects is maintained long term. These findings suggest that survivorship follow-up guidelines should be refined to align with the risks associated with treatment.

Neglect, online invasive exploitation, and childhood sexual abuse in Hong Kong: Breaking the links.

BACKGROUND: Childhood sexual abuse (CSA) is a form of maltreatment that involves a child in sexual activity that she or he cannot fully comprehend or is unable to give informed consent to. The empirical link between child neglect and contact child sexual abuse is well established but little research examines mediators that explain this link. OBJECTIVE: This study tests online risk behaviors and unwanted sexual experiences online as sequential mediators of the neglect - CSA relationship. PARTICIPANT AND SETTING: The study uses a representative cross-sectional sample of 1097 Hong Kong adolescents. METHODS: Preacher and Hayes' (2008) non-parametric bootstrap approach was used to test three mediation hypotheses. RESULTS: Baseline logistic regression models showed neglected children had 11.2 times higher odds of reporting contact CSA (p < .001). Similarly, neglect was associated with 3.5 times higher odds of more online risk behavior (p < .001), which in turn was associated with 2.7 times higher odds of more online invasive exploitation (p < .001). Online invasive exploitation was associated with 2.7 times higher odds of reporting offline contact CSA (p < .001). The study found online risk behaviors to be a significant mediator of the relationship between neglect and online invasive exploitation (unwanted online sexual experiences). Online invasive exploitation, in turn, mediated the relationship between online risk behaviors and offline contact CSA. CONCLUSION: The findings highlight the importance of intervening against neglect as it appears to play a vital role in the etiology of contact CSA in Hong Kong.

Machine learning in the evaluation of voice and swallowing in the head and neck cancer patient.

PURPOSE OF REVIEW: The purpose of this review is to present recent advances and limitations in machine learning applied to the evaluation of speech, voice, and swallowing in head and neck cancer. RECENT FINDINGS: Novel machine learning models incorporating diverse data modalities with improved discriminatory capabilities have been developed for predicting toxicities following head and neck cancer therapy, including dysphagia, dysphonia, xerostomia, and weight loss as well as guiding treatment planning. Machine learning has been applied to the care of posttreatment voice and swallowing dysfunction by offering objective and standardized assessments and aiding innovative technologies for functional restoration. Voice and speech are also being utilized in machine learning algorithms to screen laryngeal cancer. SUMMARY: Machine learning has the potential to help optimize, assess, predict, and rehabilitate voice and swallowing function in head and neck cancer patients as well as aid in cancer screening. However, existing studies are limited by the lack of sufficient external validation and generalizability, insufficient transparency and reproducibility, and no clear superior predictive modeling strategies. Algorithms and applications will need to be trained on large multiinstitutional data sets, incorporate sociodemographic data to reduce bias, and achieve validation through clinical trials for optimal performance and utility.

Impact of visit characteristics on intention to recommend HPV vaccine: An experiment with US health care professionals.

OBJECTIVE: Presumptive recommendations that assume parents want to vaccinate can increase human papillomavirus (HPV) vaccine uptake. We sought to examine how visit characteristics affect health care professionals' (HCPs) intention to use this evidence-based recommendation style. METHODS: In 2022, we conducted an online experiment with 2527 HCPs who had a role in adolescent vaccination in the United States. Participants read 1 of 8 randomly assigned vignettes about a well-child visit. Using a 2 × 2 × 2 between-subjects factorial design, the vignettes varied the following visit characteristics: patient age (9 vs. 12-year-old), prior parental vaccine refusal (yes vs. no), and time pressure on the HCP (low vs. high). HCPs reported on their intention to use a presumptive HPV vaccine recommendation, as well as on related attitudes, subjective norms, and self-efficacy. Analyses used 3-way analysis of variance and parallel mediation. RESULTS: Participants were pediatricians (26%), family/general medicine physicians (22%), advanced practitioners (24%), and nursing staff (28%). Overall, about two-thirds of HCPs (64%) intended to use a presumptive recommendation. Intentions were higher for older children (b = 0.23) and parents without prior vaccine refusal (b = 0.39, both p < 0.001). Time pressure had no main effect or interactions. HCPs' attitudes and self-efficacy partially mediated effects of patient age and prior vaccine refusal (range of b = 0.04-0.28, all p < 0.05). CONCLUSION: To better support visits with younger children and parents who have refused vaccines, HCPs may need more training for making presumptive recommendations for HPV vaccine. Reinforcing positive attitudes and self-efficacy can help HCPs adopt this evidence-based recommendation style.

TORCH Infections.

Perinatal and neonatal infections are a significant cause of morbidity and mortality. As such, early recognition and workup when there is clinical concern is essential to supporting affected neonates. This article aims to focus specifically on the effects of toxoplasmosis, rubella, cytomegalovirus, herpes, and other agents (TORCH) infections, discussing epidemiology, diagnostics, and treatment if available. [Pediatr Ann. 2023;52(11):e400-e406.].

Parathyroidectomy outcomes for Asians in the United States: Implications for resident surgical education.

Introduction: Outcomes for Asian patients in the United States are often overlooked in the surgical literature. Surgical education includes little emphasis on reporting outcomes for Asian patients in the United States. Our null hypothesis (H0) is that there is no difference in surgical complications following parathyroid surgery between Asians and all other ethnicities in the United States. Our alternate hypothesis (H1) is that Asians have more incidences of certain complications (possibly due to culture and language barriers). Methods: Data from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) was queried for parathyroidectomy and patient race. Complications within 30 days of surgery were extracted. Results: Among, White, Black, Asian, Pacific Islanders, Native Americans, and Hispanic patients of the United States the Asians (p = 0.018) and Blacks (p = 0.003) had increased operative time for parathyroid surgery compared to other groups. Hispanics had the most surgical complications (p = 0.025). Blacks had statistically significant longer hospital stay (p < 0.0001). Discussion/conclusion: United States Asian patient data is not typically analyzed separately for complications. We found that in the United States Asians have increased operative time for parathyroidectomy. Future studies of healthcare inequities should include analysis of data for Asian surgical data in the United States as this may help prevent future surgical complications.

The New Zealand eating behavior questionnaire - Validation study for a novel assessment tool to describe actionable eating behavior traits.

Individualised management of obesity remains challenging and, to date, most treatment is based on clinical judgement. This study aimed to develop and validate a novel questionnaire-based tool to identify three pre-defined eating behavior (EB) traits, emotional eating, reduced satiety (constant hunger) and reduced satiation (feasters) that may predict selective medication response given their targeted actions. We recruited 977 individuals from a tertiary academic diabetes clinic to participate in this two-phase validation study. Participants self-reported weight management activities and were asked to self-assess their EB characteristics. The initial questionnaire included 42 visual analogue scale questions. In Phase I, 729 participants completed the questionnaire, including Maori (11.8%) and Pacific peoples (19.3%). After random division of the study sample, Exploratory Factor Analysis (EFA) confirmed a three-factor model as the best fit. Stepwise removal of items with inadequate factor loading retained 27 of 42 items, which accounted for 96% of the variance. Confirmatory Factor Analysis (CFA), performed on the second half of the sample, demonstrated good model fit with the final 27-item questionnaire. Internal consistency was high for factor (α = 0.82-0.95) and demographic subgroups, and similar to those obtained in the EFA. Test-retest reliability in a subset of 399 participants who repeated the questionnaire after a four-week interval (Phase II) showed moderate to good reliability. Participants classified into one of three EB types based on the highest median score among the factors. Test-retest reliability was robust for emotional eaters (71.25%) and constant hunger (68.9%). The correlation between aggregate EB score (sum of three EB scores) and BMI was significant (Spearman rho = 0.314, P = .0005). The questionnaire reliably identified three distinct EB traits, which may be informative for precision medicine applications for obesity management.

Nutritional Considerations for the First Year of Life.

Feeding during the first year of life is a dynamic process with unique questions, concerns, and milestones emerging at every step. This article will review a small selection of specific questions and concerns related to feeding in the first 12 months of infancy. The aim of this article is to inform and support pediatric providers and parents during this crucial developmental period. [Pediatr Ann. 2023;52(9):e316-e321.].

Childhood emotional abuse and alcohol use disorders in a national Nepali women sample: The mediating role of borderline personality traits.

While many studies have found an association between childhood emotional abuse and alcohol use disorders (AUD) during adulthood, underlying psychological mechanisms linking the two remain inadequately understood. Drawing on the developmental psychopathology perspective, this study examined the relationship between childhood emotional abuse and AUD during adulthood with a national sample of women in Nepal (N = 1,100, M age = 37.73), focusing on the mediating role of borderline personality traits. Mediation analyses were performed using the Karlson-Holm-Breen (KHB) method and bootstrapping confidence intervals. Results indicated that Nepali women's borderline personality traits significantly mediated the relationship between childhood emotional abuse and AUD. Hence, emotional abuse in childhood increases the risk for AUD during adulthood for Nepali women by increasing the risk of borderline personality traits. Findings underscore the necessity of continued emphasis on developing and implementing early interventions for childhood emotional abuse and therapeutic interventions for borderline personality traits in reducing AUD among vulnerable women in Nepal.

Clinical empathy as perceived by patients with chronic illness in Canada: a qualitative focus group study.

BACKGROUND: Although clinical empathy - the ability of a physician to understand a patient's illness experience, communicate this understanding and act collaboratively to create a treatment plan - provides substantial benefits to both physicians and patients, medical students typically experience a decline in empathy during training. The primary objective of this study was to generate a model of clinical empathy grounded in the perspectives of people with chronic illness living in Canada, to promote empathy-focused curricular development in Canadian medical education. METHODS: We conducted a qualitative focus group study using a constructivist grounded theory approach. We recruited adults (age ≥ 18 yr) with chronic illness who had recently seen a physician in Canada from virtual support groups. Six semistructured virtual focus groups with 3-5 participants each were scheduled between June and September 2021. We coded the transcripts using the constant comparative method, allowing for the construction of an overarching theory. RESULTS: Twenty patients (17 women and 3 men) participated in the focus groups; 1 group had 2 participants because 1 participant failed to appear. The majority of participants (14 [70%]) had at least a college degree. The mean rating for overall satisfaction with the Canadian health care system was 5.4/10.0 (median 5.0). The emergent theory showed that the perceived presence of physician empathy engendered positive internal processing by patients, leading to increased health care efficacy and enhanced mental health outcomes. Negative patient processing in response to the perceived absence of empathy led to reduced quality of health care delivery (e.g., ineffective referrals and more appointments), increased use of health care resources, disruptions in patients' personal lives, and negative physical and mental health outcomes. INTERPRETATION: Clinical empathy can have life-altering impacts on patients, and its absence may increase resource use. As empathy involves understanding patients' lived experiences, any valid intervention to improve clinical empathy must be informed by patient perspectives.

Diagnostic Specificity and Association With Cognition of Molecular Alterations in Prefrontal Somatostatin Neurons in Schizophrenia.

Importance: Individuals with schizophrenia (SZ) exhibit pronounced deficits in somatostatin (SST) messenger RNA (mRNA) levels in the dorsolateral prefrontal cortex (DLPFC). Molecularly distinct subtypes of SST neurons, located in the superficial and deep zones of the DLPFC, are thought to contribute to different functional processes of this region; understanding the specificity of SST alterations in SZ across these zones could inform the functional consequences of those alterations, including cognitive impairments characteristic of SZ. Objective: To quantify mRNA levels of SST and related neuropeptides in the DLPFC in individuals with SZ, bipolar disorder (BPD), or major depressive disorder (MDD) and unaffected comparison individuals. Design, Setting, and Participants: This case-control study, conducted from January 20, 2020, to March 30, 2022, used postmortem brain tissue specimens previously obtained from individuals with SZ, MDD, or BPD and unaffected individuals from a community population through 2 medical examiners' offices. Demographic, clinical, and educational information was ascertained through psychological autopsies. Exposures: Diagnosis of SZ, BPD, or MDD. Main Outcome and Measures: The main outcome was levels of SST and related neuropeptide mRNA in 2 DLPFC zones, examined using laser microdissection and quantitative polymerase chain reaction or fluorescent in situ hybridization (FISH). Findings were compared using educational attainment as a proxy measure of premorbid cognition. Results: A total of 200 postmortem brain specimens were studied, including 65 from unaffected comparison individuals (42 [65%] male; mean [SD] age, 49.2 [14.1] years); 54 from individuals with SZ (37 [69%] male; mean [SD] age, 47.5 [13.3] years); 42 from individuals with MDD (24 [57%] male; mean [SD] age, 45.6 [12.1] years); and 39 from individuals with BPD (23 [59%] male; mean (SD) age, 46.2 [12.5] years). Compared with unaffected individuals, levels of SST mRNA were lower in both superficial (Cohen d, 0.68; 95% CI, 0.23-1.13; P = .004) and deep (Cohen d, 0.60; 95% CI, 0.16-1.04; P = .02) DLPFC zones in individuals with SZ; findings were confirmed using FISH. Levels of SST were lower only in the superficial zone in the group with MDD (Cohen d, 0.58; 95% CI, 0.14-1.02; P = .12), but the difference was not significant; SST levels were not lower in either zone in the BPD group. Levels of neuropeptide Y and tachykinin 1 showed similar patterns. Neuropeptide alterations in the superficial, but not deep, zone were associated with lower educational attainment only in the group with SZ (superficial: adjusted odds ratio, 1.71 [95% CI, 1.11-2.69]; P = .02; deep: adjusted odds ratio, 1.08 [95% CI, 0.64-1.84]; P = .77). Conclusions and Relevance: The findings revealed diagnosis-specific patterns of molecular alterations in SST neurons in the DLPFC, suggesting that distinct disease processes are reflected in the differential vulnerability of SST neurons in individuals with SZ, MDD, and BPD. In SZ, alterations specifically in the superficial zone may be associated with cognitive dysfunction.

The Feasibility of Quality Assurance in the TOPGEAR International Phase 3 Clinical Trial of Neoadjuvant Chemoradiation Therapy for Gastric Cancer (an Intergroup Trial of the AGITG/TROG/NHMRC CTC/EORTC/CCTG).

PURPOSE: The TOPGEAR phase 3 trial hypothesized that adding preoperative chemoradiation therapy (CRT) to perioperative chemotherapy will improve survival in patients with gastric cancer. Owing to the complexity of gastric irradiation, a comprehensive radiation therapy quality assurance (RTQA) program was implemented. Our objective is to describe the RTQA methods and outcomes. METHODS AND MATERIALS: RTQA was undertaken in real time before treatment for the first 5 patients randomized to CRT from each center. Once acceptable quality was achieved, RTQA was completed for one-third of subsequent cases. RTQA consisted of evaluating (1) clinical target volume and organ-at-risk contouring and (2) radiation therapy planning parameters. Protocol violations between high- (20+ patients enrolled) and low-volume centers were compared using the Fisher exact test. RESULTS: TOPGEAR enrolled 574 patients, of whom 286 were randomized to receive preoperative CRT and 203 (71%) were included for RTQA. Of these, 67 (33%) and 136 (67%) patients were from high- and low-volume centers, respectively. The initial RTQA pass rate was 72%. In total, 28% of cases required resubmission. In total, 200 of 203 cases (99%) passed RTQA before treatment. Cases from low-volume centers required resubmission more often (44/136 [33%] vs 13/67 [18%]; P = .078). There was no change in the proportion of cases requiring resubmission over time. Most cases requiring resubmission had multiple protocol violations. At least 1 aspect of the clinical target volume had to be adjusted in all cases. Inadequate coverage of the duodenum was most common (53% major violation, 25% minor violation). For the remaining cases, the resubmission process was triggered secondary to poor contour/plan quality. CONCLUSIONS: In a large multicenter trial, RTQA is feasible and effective in achieving high-quality treatment plans. Ongoing education should be performed to ensure consistent quality during the entire study period.

Taking Care of Preterm Infants: Outpatient Considerations.

In recent decades, the number of pre-term infants born each year has been on the rise as mortality rates decline with improvements in technology and medical care. As a result, many preterm infants are successfully discharged from the neonatal intensive care unit (NICU). However, with prematurity comes the increased risk of ongoing health and development needs. Special attention must be given to certain chronic conditions by the outpatient provider, including growth and nutrition; gastroesophageal reflux; immunizations; vision and hearing impairments; chronic lung diseases, including bronchopulmonary dysplasia and pulmonary hypertension; and neurodevelopmental outcomes. This article will detail some of these topics to better inform the primary care provider of appropriate strategies to manage these chronic conditions and sequalae on NICU discharge. [Pediatr Ann. 2023;52(6):e200-e205.].

Differences between HbA1c and glucose-related variables in predicting weight loss and glycaemic changes in individuals with overweight and hyperglycaemia - The PREVIEW trial.

AIMS: To examine the differences between HbA1c and glucose related variables in predicting weight loss and glycaemic changes following 8 weeks of low energy diet (LED) in individuals with overweight and hyperglycaemia. RESEARCH DESIGN AND METHODS: 2178 individuals with ADA-defined pre-diabetes - impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) - who started an 8 week LED weight loss diet, were included in this analysis. Participants were enrolled in the PREVIEW (PREVention of diabetes through lifestyle interventions and population studies In Europe and around the World) clinical trial. Multivariable linear mixed effects regression models and generalised additive mixed effect logistic models were used. RESULTS: Only 1 in 3 participants (33%) had HbA1c levels defined as pre-diabetes. Neither baseline HbA1c, IFG or IGT were associated with body weight change at 8 weeks. Higher baseline body weight, baseline fasting insulin and weight loss predicted normalisation of fasting plasma glucose (FPG), whilst higher baseline fasting insulin, C-reactive protein (hsCRP) and older age predicted normalisation of HbA1c. Additionally, male sex and higher baseline BMI, body fat and energy intake were positively associated with weight loss, whereas greater age and higher HDL-cholesterol predicted less weight loss. CONCLUSIONS: Whilst neither HbA1c nor fasting glucose predicts short-term weight loss success, both may impact the metabolic response to rapid weight loss. We propose a role of inflammation versus total body adiposity since these variables are independent predictors of the normalisation of HbA1c and fasting glucose, respectively.

DKK1 is a predictive biomarker for response to DKN-01: Results of a phase 2 basket study in women with recurrent endometrial carcinoma.

PURPOSE: Dickkopf-1 (DKK1) is a Wnt signaling modulator promoting tumor growth, metastasis, angiogenesis, and immunosuppression by regulating innate immunity. DKK1 is over-expressed in gynecologic cancers and is associated with shortened survival. DKN-01 is a humanized monoclonal antibody with DKK1 neutralizing activity that may provide clinical benefit to patients whose tumors have overexpression of DKK1 or Wnt genetic alterations. METHODS: We conducted an open-label, Phase 2 basket study with 2-stage design in patients with endometrial carcinoma (EC) and platinum-resistant/refractory epithelial ovarian cancer. DKN-01 was administered either as monotherapy or in combination with weekly paclitaxel at investigator's discretion. All patients underwent NGS testing prior to enrollment; tumor tissue was also tested for DKK1 expression by RNAscope pre-treatment and after cycle 1 if available. At least 50% of patients were required to have a Wnt signaling alteration either directly or tangentially. This publication reports results from the EC population overall and by DKK1-expression. RESULTS: DKN-01 monotherapy and in combination with paclitaxel was more effective in patients with high DKK1-expressing tumors compared to low-expressing tumors. DKN-01 monotherapy demonstrated an objective response rate [ORR] of 25.0% vs. 0%; disease control rate [DCR] of 62.5% vs. 6.7%; median progression-free survival [PFS] was 4.3 vs. 1.8 months, and overall survival [OS] was 11.0 vs. 8.2 months in DKK1-high vs DKK1-low patients. Similarly, DKN-01 in combination with paclitaxel demonstrated greater clinical activity in patients with DKK1-high tumors compared to DKK1-low tumors: DCR was 55% vs. 44%; median PFS was 5.4 vs. 1.8 months; and OS was 19.1 vs. 10.1 months. Wnt activating mutations correlated with higher DKK1 expression. DKN-01 was well tolerated as a monotherapy and in combination with paclitaxel. CONCLUSIONS: Collectively, data demonstrates promising clinical activity of a well-tolerated drug, DKN-01, in EC patients with high tumoral DKK1 expression which frequently corresponded to the presence of a Wnt activating mutation. Future development will focus on using DKN-01 in DKK1-high EC patients in combination with immunotherapy.