Effects of rehabilitation interventions for old adults with long COVID: A systematic review and meta-analysis of randomised controlled trials.

Background: There is limited evidence on the effectiveness of the existing rehabilitation interventions for old adults with long coronavirus disease (COVID), which is of particular concern among old adults. Methods: We systematically searched studies published in PubMed, EMBASE, Web of Science, Scopus, and Cochrane Library databases from their inception to 15 November 2023. Randomised controlled trials (RCTs) compared rehabilitation interventions with other controls in old adults (mean/median age of 60 or older) with long COVID were included. We performed a meta-analysis to compare the effects of the rehabilitation interventions with the common control group. Mean difference (MD) or standardised mean difference (SMD) with its 95% confidence intervals (CI) were used as summary statistics. Moreover, subgroup analyses based on the intervention programmes, the severity of acute infection, and the age of participants were carried out. Results: A total of 11 RCTs involving 832 participants (64.37 ± 7.94 years, 52.2% were men) were included in the analysis. Compared with the control groups, rehabilitation interventions significantly improved 6-minute walking test (6 MWT; MD = 15.77 metres (m), 95% CI = 5.40, 26.13, P < 0.01), 30-second sit-to-stand test (MD = 4.11 number of stands (n), 95% CI = 2.46, 5.76, P < 0.001), all aspects of quality of life, independence in activities of daily living (SMD = 0.31, 95% CI = 0.14, 0.48, P < 0.001), and relieved fatigue (SMD = -0.66, 95% CI = -1.13, -0.19, P < 0.01), depression (SMD = -0.89, 95% CI = -1.76, -0.02, P < 0.05) and anxiety (SMD = -0.81, 95% CI = -1.58, -0.05, P < 0.05). However, the improvement of hand grip strength and pulmonary function was not statistically significant (P > 0.05). Subgroup analyses showed that improvements in 6 MWT, fatigue, anxiety, and depression were more pronounced in old patients who received exercise training, while those who received respiratory rehabilitation had more pronounced improvements in pulmonary function and quality of life. Conclusions: Old adults with long COVID who underwent rehabilitation interventions experienced significant improvement in functional capacity, fatigue, quality of life, independence in activities of daily living, and mental health outcomes compared with usual/standard care. These findings suggest that screening, management, and rehabilitation interventions for long COVID in older adults should be strengthened to improve their complete health status and functional status, thereby reducing the long-term disease burden caused by long COVID and fostering healthy aging during the post-pandemic era.

Overcoming Barriers to Research Competency: a nationwide mixed-method study on residency training in the field of Korean medicine.

Objectives: This study aimed to analyze the educational needs of interns and residents in Korean medicine as the first step in developing an education program to improve their research competencies. Methods: A mixed-method design, incorporating both quantitative and qualitative data collection methods, was used to investigate the educational needs for research competencies among interns and residents working in Korean medicine hospitals nationwide. Data were collected through online surveys and online focus group discussions (FGDs), and processed using descriptive statistical analysis and thematic analysis. The study results were derived by integrating survey data and FGD outcomes. Results: In total, 209 interns and residents participated in the survey, and 11 individuals participated in two rounds of FGDs. The majority of participants felt a lack of systematic education in research and academic writing in postgraduate medical education and highlighted the need for nationally accessible education due to significant disparities in the educational environment across hospitals and specialties. The primary barrier to learning research and academic writing identified by learners was the lack of knowledge, leading to time constraints. Improving learners' research competencies, relationship building, autonomy, and motivation through a support system was deemed crucial. The study also identified diverse learner types and preferred educational topics, indicating a demand for learner-centered education and coaching. Conclusion: This study provides foundational data for designing and developing a program on education on research competencies for interns and residents in Korean medicine and suggests the need for initiatives to strengthen these competencies.

Absolute risk from double nested case-control designs: cause-specific proportional hazards models with and without augmented estimating equations.

We estimate relative hazards and absolute risks (or cumulative incidence or crude risk) under cause-specific proportional hazards models for competing risks from double nested case-control (DNCC) data. In the DNCC design, controls are time-matched not only to cases from the cause of primary interest, but also to cases from competing risks (the phase-two sample). Complete covariate data are available in the phase-two sample, but other cohort members only have information on survival outcomes and some covariates. Design-weighted estimators use inverse sampling probabilities computed from Samuelsen-type calculations for DNCC. To take advantage of additional information available on all cohort members, we augment the estimating equations with a term that is unbiased for zero but improves the efficiency of estimates from the cause-specific proportional hazards model. We establish the asymptotic properties of the proposed estimators, including the estimator of absolute risk, and derive consistent variance estimators. We show that augmented design-weighted estimators are more efficient than design-weighted estimators. Through simulations, we show that the proposed asymptotic methods yield nominal operating characteristics in practical sample sizes. We illustrate the methods using prostate cancer mortality data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Study of the National Cancer Institute.

Final Results From a Phase I Trial and Expansion Cohorts of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced/Metastatic Genitourinary Tumors.

PURPOSE: Cabozantinib and nivolumab (CaboNivo) alone or with ipilimumab (CaboNivoIpi) have shown promising efficacy and safety in patients with metastatic urothelial carcinoma (mUC), metastatic renal cell carcinoma (mRCC), and rare genitourinary (GU) tumors in a dose-escalation phase I study. We report the final data analysis of the safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the phase I patients and seven expansion cohorts. METHODS: This is an investigator-initiated, multicenter, phase I trial. CaboNivo doublet expansion cohorts included (1) mUC, (2) mRCC, and (3) adenocarcinoma of the bladder/urachal; CaboNivoIpi triplet expansion cohorts included (1) mUC, (2) mRCC, (3) penile cancer, and (4) squamous cell carcinoma of the bladder and other rare GU tumors (ClinicalTrials.gov identifier: NCT02496208). RESULTS: The study enrolled 120 patients treated with CaboNivo (n = 64) or CaboNivoIpi (n = 56), with a median follow-up of 49.2 months. In 108 evaluable patients (CaboNivo n = 59; CaboNivoIpi n = 49), the ORR was 38% (complete response rate 11%) and the median duration of response was 20 months. The ORR was 42.4% for mUC, 62.5% for mRCC (n = 16), 85.7% for squamous cell carcinoma of the bladder (n = 7), 44.4% for penile cancer (n = 9), and 50.0% for renal medullary carcinoma (n = 2). Grade ≥ 3 treatment-related adverse events occurred in 84% of CaboNivo patients and 80% of CaboNivoIpi patients. CONCLUSION: CaboNivo and CaboNivoIpi demonstrated clinical activity and safety in patients with multiple GU malignancies, especially clear cell RCC, urothelial carcinoma, and rare GU tumors such as squamous cell carcinoma of the bladder, small cell carcinoma of the bladder, adenocarcinoma of the bladder, renal medullary carcinoma, and penile cancer.

Unraveling motives: identifying the impact of university attendance motives on learning behaviors among dental students.

PURPOSE: Students report various motives for attending university (MAU) grouped under five categories, namely, personal-intellectual development (PER), humanitarian (HUM), careerist-materialist (CAR), expectation-driven (EXP), and uncertain motives. Although the literature demonstrates that these motives exert an influence on learning and achievement, relatively less attention is given to this issue in the context of dental students. This study aimed to examine the relationship among the mindsets, MAU, academic engagement (AE), and DAL of dental students and to test the mediating effect of AE on the relationship between MAU and deep approach to learning (DAL). METHODS: The study recruited 226 dental students at various levels of the curriculum, who responded to four questionnaires for measuring MAU, DAL, mindsets, and AE. The study employed structural equation modeling to analyze the mediation effects of AE on the relationship between MAU and DAL and to determine the influence of mindsets on MAU. RESULTS: This model reveals the significant relationships of a growth mindset with CAR, PER, and HUM. Moreover, the study finds that a fixed mindset was associated with CAR, EXP, and uncertain motives. Furthermore, AE only fully mediated the significant positive relationship between PER and DAL, whereas CAR negatively predicted DAL without a mediator. CONCLUSIONS: These findings suggest that administering the inventories in a dental school setting can facilitate a more comprehensive understanding of students' mindsets toward learning and effective processes related to learning. This understanding can inform instructors' pedagogical practices, enabling them to provide more effective guidance to students navigating the complexities of academic coursework.

MAST4 regulates stem cell maintenance with DLX3 for epithelial development and amelogenesis.

The asymmetric division of stem cells permits the maintenance of the cell population and differentiation for harmonious progress. Developing mouse incisors allows inspection of the role of the stem cell niche to provide specific insights into essential developmental phases. Microtubule-associated serine/threonine kinase family member 4 (Mast4) knockout (KO) mice showed abnormal incisor development with low hardness, as the size of the apical bud was decreased and preameloblasts were shifted to the apical side, resulting in amelogenesis imperfecta. In addition, Mast4 KO incisors showed abnormal enamel maturation, and stem cell maintenance was inhibited as amelogenesis was accelerated with Wnt signal downregulation. Distal-Less Homeobox 3 (DLX3), a critical factor in tooth amelogenesis, is considered to be responsible for the development of amelogenesis imperfecta in humans. MAST4 directly binds to DLX3 and induces phosphorylation at three residues within the nuclear localization site (NLS) that promotes the nuclear translocation of DLX3. MAST4-mediated phosphorylation of DLX3 ultimately controls the transcription of DLX3 target genes, which are carbonic anhydrase and ion transporter genes involved in the pH regulation process during ameloblast maturation. Taken together, our data reveal a novel role for MAST4 as a critical regulator of the entire amelogenesis process through its control of Wnt signaling and DLX3 transcriptional activity.

An update on the status of HSP90 inhibitors in cancer clinical trials.

The evolutionary conserved molecular chaperone heat shock protein 90 (HSP90) plays an indispensable role in tumorigenesis by stabilizing client oncoproteins. Although the functionality of HSP90 is tightly regulated, cancer cells exhibit a unique dependence on this chaperone, leading to its overexpression, which has been associated with poor prognosis in certain malignancies. While various strategies targeting heat shock proteins (HSPs) involved in carcinogenesis have been explored, only inhibition of HSP90 has consistently and effectively resulted in proteasomal degradation of its client proteins. To date, a total of 22 HSP90 inhibitors (HSP90i) have been tested in 186 cancer clinical trials, as reported by clinicaltrials.gov. Among these trials, 60 % have been completed, 10 % are currently active, and 30 % have been suspended, terminated, or withdrawn. HSP90 inhibitors (HSP90i) have been used as single agents or in combination with other drugs for the treatment of various cancer types in clinical trials. Notably, improved clinical outcomes have been observed when HSP90i are used in combination therapies, as they exhibit a synergistic antitumor effect. However, as single agents, HSP90i have shown limited clinical activity due to drug-related toxicity or therapy resistance. Recently, active trials conducted in Japan evaluating TAS-116 (pimitespib) have demonstrated promising results with low toxicity as monotherapy and in combination with the immune checkpoint inhibitor nivolumab. Exploratory biomarker analyses performed in various trials have demonstrated target engagement that suggests the potential for identifying patient populations that may respond favorably to the therapy. In this review, we discuss the advances made in the past 5 years regarding HSP90i and their implications in anticancer therapeutics. Our focus lies in evaluating drug efficacy, prognosis forecast, pharmacodynamic biomarkers, and clinical outcomes reported in published trials. Through this comprehensive review, we aim to shed light on the progress and potential of HSP90i as promising therapeutic agents in cancer treatment.

Tofacitinib to prevent anti-drug antibody formation against LMB-100 immunotoxin in patients with advanced mesothelin-expressing cancers.

Background: LMB-100 is a mesothelin (MSLN)-targeting recombinant immunotoxin (iTox) carrying a Pseudomonas exotoxin A payload that has shown promise against solid tumors, however, efficacy is limited by the development of neutralizing anti-drug antibodies (ADAs). Tofacitinib is an oral Janus Kinase (JAK) inhibitor that prevented ADA formation against iTox in preclinical studies. Methods: A phase 1 trial testing LMB-100 and tofacitinib in patients with MSLN-expressing cancers (pancreatic adenocarcinoma, n=13; cholangiocarcinoma, n=1; appendiceal carcinoma, n=1; cystadenocarcinoma, n=1) was performed to assess safety and to determine if tofacitinib impacted ADA formation. Participants were treated for up to 3 cycles with LMB-100 as a 30-minute infusion on days 4, 6, and 8 at two dose levels (100 and 140 µg/kg) while oral tofacitinib was administered for the first 10 days of the cycle (10 mg BID). Peripheral blood was collected for analysis of ADA levels, serum cytokines and circulating immune subsets. Results: The study was closed early due to occurrence of drug-induced pericarditis in 2 patients. Pericarditis with the combination was not reproducible in a transgenic murine model containing human MSLN. Two of 4 patients receiving all 3 cycles of treatment maintained effective LMB-100 levels, an unusual occurrence. Sustained increases in systemic IL-10 and TNF-α were seen, a phenomenon not observed in prior LMB-100 studies. A decrease in activated T cell subsets and an increase in circulating immunosuppressive myeloid populations occurred. No radiologic decreases in tumor volume were observed. Discussion: Further testing of tofacitinib to prevent ADA formation is recommended in applicable non-malignant disease settings. Clinical trial registration: https://www.clinicaltrials.gov/study/NCT04034238.

Challenges and potential improvements in the Accreditation Standards of the Korean Institute of Medical Education and Evaluation 2019 (ASK2019) derived through meta-evaluation: a cross-sectional study

PURPOSE: This study aimed to identify challenges and potential improvements in Korea's medical education accreditation process according to the Accreditation Standards of the Korean Institute of Medical Education and Evaluation 2019 (ASK2019). Meta-evaluation was conducted to survey the experiences and perceptions of stakeholders, including self-assessment committee members, site visit committee members, administrative staff, and medical school professors. METHODS: A cross-sectional study was conducted using surveys sent to 40 medical schools. The 332 participants included self-assessment committee members, site visit team members, administrative staff, and medical school professors. The t-test, one-way analysis of variance and the chi-square test were used to analyze and compare opinions on medical education accreditation between the categories of participants. RESULTS: Site visit committee members placed greater importance on the necessity of accreditation than faculty members. A shared positive view on accreditation's role in improving educational quality was seen among self-evaluation committee members and professors. Administrative staff highly regarded the Korean Institute of Medical Education and Evaluation's reliability and objectivity, unlike the self-evaluation committee members. Site visit committee members positively perceived the clarity of accreditation standards, differing from self-assessment committee members. Administrative staff were most optimistic about implementing standards. However, the accreditation process encountered challenges, especially in duplicating content and preparing self-evaluation reports. Finally, perceptions regarding the accuracy of final site visit reports varied significantly between the self-evaluation committee members and the site visit committee members. CONCLUSION: This study revealed diverse views on medical education accreditation, highlighting the need for improved communication, expectation alignment, and stakeholder collaboration to refine the accreditation process and quality.

Effect of information provision on parental intention toward COVID-19 vaccination for children: a nationwide survey experiment.

The reluctance of parents to vaccinate their children against COVID-19 was prevalent particularly when uncertainty over vaccination outcomes prevailed. We conducted a nationwide randomized online survey experiment to assess the effect of information provision on parental intention for COVID-19 vaccination before the government started vaccination for children in South Korea. Parents of elementary school children were provided with either no information (Control), information on vaccine profile (vaccine informed group; VI), or COVID-19 (disease informed group; DI). Among 359,110 participants, parental intention for vaccination of children was significantly higher in both VI and DI groups compared with the Control group. In terms of effect size, information on COVID-19 vaccine increased likelihood to vaccinate by 1620 per 100,000 parents and reduced vaccine hesitancy by 1340 per 100,000 parents. Consistently with the positive effect on vaccination intention, both VI and DI interventions increased participants' perceptions on vaccination benefits being higher than its risks and vaccination risks being lower than health risks of COVID-19 infection, and self-reported trust in COVID-19 information. Our results lend strong support to the claim that the provision of targeted, tailored information on COVID-19 vaccine and infection increases parental intention to vaccinate children and reduces vaccine hesitancy.

RAL-1 signaling regulates lipid composition in C. elegans.

Signaling by the Ral small GTPase is poorly understood in vivo . Caenorhabditis elegans animals with constitutively activated RAL-1 or deficient for the inhibitory RalGAP, HGAP-1 /2, display pale intestines. Staining with Oil Red O detected decreased intestinal lipids in the hgap-1 deletion mutant relative to the wild type. Constitutively activated RAL-1 decreased lipid detected by stimulated Raman scattering (SRS) microscopy, a label-free method of detecting lipid by laser excitation and detection. A signaling-deficient missense mutant for RAL-1 also displayed reduced lipid staining via SRS. We conclude that RAL-1 signaling regulates lipid homeostasis, biosynthesis or storage in live animals.

Dental Students' Satisfaction With Web-Based Learning During the Initial Phase of the COVID-19 Pandemic: Mixed Methods Study.

BACKGROUND: The COVID-19 pandemic has precipitated an accelerated shift in education, moving from traditional learning to web-based learning. This transition introduced a notable transactional distance (TD) between the instructors and learners. Although disease control and staff and students' safety are the top priorities during a pandemic, the successful delivery of education is equally crucial. However, the ramifications of this swift transition are particularly critical in the context of dental education. Dental education is inherently practice oriented, necessitating hands-on training and manual skills development, which poses unique challenges to distance learning approaches. OBJECTIVE: This study aims to examine dental students' web-based learning satisfaction and experience of TD, investigate the predictors of web-based learning satisfaction, and explore the perceptions of students about the advantages and disadvantages of web-based learning. METHODS: This study explored the factors associated with web-based learning satisfaction using TD theory during the transition to web-based education. Psychological factors that could influence satisfaction were adapted from the health belief model. We conducted a cross-sectional web-based survey of 345 dental students from 2 institutions in South Korea who were enrolled in the spring semester of 2020. Data were collected between July 8 and September 14, 2020. Qualitative analysis was used to examine responses to open-ended questions concerning perceptions of web-based learning. RESULTS: A multivariate hierarchical linear regression model was used to analyze the effects of student characteristics, TD, and psychological factors (ie, perceived risk of infection and efficacy belief of web-based learning) on web-based learning satisfaction. The average score for web-based learning satisfaction was 3.62 (SD 0.84), just above the midpoint of the possible range (1-5). Self-regulated learning (ß=0.08; P=.046), learner-instructor interaction (ß=0.08; P=.03), and learner-content interaction (ß=0.64; P<.001) were associated with higher levels of satisfaction. Moreover, a significant association was revealed between high efficacy beliefs in web-based learning (ß=0.20; P<.001) and satisfaction. Although the learning structure (synchronous vs asynchronous) did not exhibit a significant association with satisfaction, the qualitative analysis results revealed that each structure possesses distinct strengths and weaknesses. The students in synchronous learning (79/345, 22.9%) recognized heightened autonomy in the "learning environment" (19/79, 24%); however, technical issues (28/79, 35%) and reduced concentration (15/79, 19%) were identified as downsides. Conversely, the students in asynchronous settings (266/345, 77.1%) emphasized unlimited access to learning content (74/266, 27.8%) and the flexibility of "learning in preferred time" (69/266, 25.9%). Nevertheless, challenges, such as self-management difficulties (66/266, 24.8%) and limited interactions (55/266, 20.7%), were evident. CONCLUSIONS: The findings suggest that efforts to minimize TD, facilitating self-regulated learning and interaction among students and instructors, are critical for achieving web-based learning satisfaction. Moreover, establishing a common understanding among students regarding the necessity and efficacy of web-based learning during epidemics could enhance their satisfaction.

The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial.

The multi-cohort phase 2 trial NCT02203513 was designed to evaluate the clinical activity of the CHK1 inhibitor (CHK1i) prexasertib in patients with breast or ovarian cancer. Here we report the activity of CHK1i in platinum-resistant high-grade serous ovarian carcinoma (HGSOC) with measurable and biopsiable disease (cohort 5), or without biopsiable disease (cohort 6). The primary endpoint was objective response rate (ORR). Secondary outcomes were safety and progression-free survival (PFS). 49 heavily pretreated patients were enrolled (24 in cohort 5, 25 in cohort 6). Among the 39 RECISTv1.1-evaluable patients, ORR was 33.3% in cohort 5 and 28.6% in cohort 6. Primary endpoint was not evaluable due to early stop of the trial. The median PFS was 4 months in cohort 5 and 6 months in cohort 6. Toxicity was manageable. Translational research was an exploratory endpoint. Potential biomarkers were investigated using pre-treatment fresh biopsies and serial blood samples. Transcriptomic analysis revealed high levels of DNA replication-related genes (POLA1, POLE, GINS3) associated with lack of clinical benefit [defined post-hoc as PFS < 6 months]. Subsequent preclinical experiments demonstrated significant cytotoxicity of POLA1 silencing in combination with CHK1i in platinum-resistant HGSOC cell line models. Therefore, POLA1 expression may be predictive for CHK1i resistance, and the concurrent POLA1 inhibition may improve the efficacy of CHK1i monotherapy in this hard-to-treat population, deserving further investigation.

Regioselective Arylation of Amidoaryne Precursors via Ag-Mediated Intramolecular Oxy-Argentation.

An unprecedented silver-mediated intramolecular oxy-argentation of 3-amidoaryne precursors that quickly generates a heteroarylsilver species is developed. AgF acts as both a stoichiometric fluoride source and a reagent for the formation of a benzoxazolylsilver intermediate via aryne generation. Pd-catalyzed coupling reactions of (hetero)aryl iodides with a silver species, generated in situ, allow for the synthesis of various C7-arylated benzoxazoles. As a result, an aryl group is selectively introduced into the meta-position of 3-amidobenzyne precursors. Mechanistic studies have indicated the presence of a benzoxazolylsilver intermediate and revealed that the reaction proceeds via an intramolecular oxy-argentation process, which is initiated by a direct fluoride attack on the silyl group.

The Outrage Effect of Personal Stake, Effect on Children, Dread, and Controllability on COVID-19 Risk Perception Moderated by Media Use.

Public response to the COVID-19 pandemic provides a unique opportunity to study how lay people's risk perception involves their emotive responses. We investigated how outrage factors as emotional responses to risk influence levels of risk perception in the context of the pandemic disease. Furthermore, how media use influences the perception of outrage factors is also examined. A nationwide online survey (n = 1,000) was conducted in South Korea. The survey results indicated that pandemic risk perception was connected to the generic intensity of perceived outrage factors as measured by averaging the perception of multiple outrage factors. Individual outrage factors such as personal stake, effect on children, dread, and controllability directly influenced risk perception regarding COVID-19. When the intensity of media use was considered, individuals with heavy media use perceived outrage factors more intensely than those who used media less frequently. Media use also moderated the outrage effect of catastrophic potential and moral nature on the perception of risk associated with the pandemic disease. For heavy media users, the outrage effect of moral nature was increased, while that of catastrophic potential decreased. The implications of the outrage effect on the pandemic disease risk perception are addressed. Finally, we discuss the meaning of heavy media users' varying levels of vulnerability to outrage effect by moral nature and catastrophic potential.

Questionnaire study of application about sentinel lymph node biopsy surgery in locally advanced breast cancer patients who received neoadjuvant chemotherapy.

Background: Nodal staging from sentinel lymph node (SLN) biopsy has become the standard procedure for early-stage breast cancer patients. SLN biopsy implementation after chemotherapy has previously been evaluated. This questionnaire study aimed to investigate the current trend of SLN biopsy after neoadjuvant chemotherapy (NAC) for locally advanced breast cancer. Methods and materials: We conducted a web-based survey among breast surgeons who are members of the Korean Breast Cancer Society. The survey comprised 14 questions about axillary surgery after NAC. Results: Of 135 respondents, 48.1% used a combined method of dye and radioactive isotope (RI). In the absence of SLN metastasis, 67.7% would perform only SLN biopsy, while 3% would perform ALN dissection. In case of SLN metastasis, the proportions of surgeons who would proceed with ALN dissection were 60.2% and 67.2% for less than two and more than three positive SLNs, respectively. Conclusion: The present study confirmed the increasing tendency to adopt SLN biopsy for axillary staging in patients who achieved complete response with initial nodal metastasis. It could be expected that the mapping methods for patients receiving NAC have become diverse, including RI, vital dye, and indocyanine green fluorescence. The implementation of SLN biopsy after NAC will grow in the coming years due to an increasing demand of minimally invasive surgery.

Key Points for Clinicians About the SEER Oral Cancer Survival Calculator.

Importance: In the setting of a new cancer diagnosis, the focus is usually on the cancer as the main threat to survival, but people may have other conditions that pose an equal or greater threat to their life than their cancer: a competing risk of death. This is especially true for patients who have cancer of the oral cavity, because prolonged exposure to alcohol and tobacco are risk factors for cancer in this location but also can result in medical conditions with the potential to shorten life expectancy, competing as a cause of death that may intervene in conjunction with or before the cancer. Observations: A calculator designed for public use has been released that allows patients age 20 to 86 years who have a newly diagnosed oral cancer to obtain estimates of their health status-adjusted age, life expectancy in the absence of the cancer, and probability of surviving, dying of the cancer, or dying of other causes within 1 to 10 years after diagnosis. The models in the calculator showed that patients with oral cavity cancer had a higher than average risk of death from other causes than the matched US population, and this risk increases by stage. Conclusions and Relevance: The Surveillance, Epidemiology and End Results Program Oral Cancer Survival Calculator supports a holistic approach to the life of the patient, and the risk of death of other causes is treated equally to consideration of the probability of death of the cancer. This tool may be usefully paired with the other available prognostic calculators for oral cancer and is an example of the possibilities now available with registry linkages to partially overlapping or independent data sets and statistical techniques that allow the use of 2 time scales in 1 analysis.

A New Personalized Oral Cancer Survival Calculator to Estimate Risk of Death From Both Oral Cancer and Other Causes.

Importance: Standard cancer prognosis models typically do not include much specificity in characterizing competing illnesses or general health status when providing prognosis estimates, limiting their utility for individuals, who must consider their cancer in the context of their overall health. This is especially true for patients with oral cancer, who frequently have competing illnesses. Objective: To describe a statistical framework and accompanying new publicly available calculator that provides personalized estimates of the probability of a patient surviving or dying from cancer or other causes, using oral cancer as the first data set. Design, Setting, and Participants: The models used data from the Surveillance, Epidemiology, and End Results (SEER) 18 registry (2000 to 2011), SEER-Medicare linked files, and the National Health Interview Survey (NHIS) (1986 to 2009). Statistical methods developed to calculate natural life expectancy in the absence of the cancer, cancer-specific survival, and other-cause survival were applied to oral cancer data and internally validated with 10-fold cross-validation. Eligible participants were aged between 20 and 94 years with oral squamous cell carcinoma. Exposures: Histologically confirmed oral cancer, general health status, smoking, and selected serious comorbid conditions. Main Outcomes and Measures: Probabilities of surviving or dying from the cancer or from other causes, and life expectancy in the absence of the cancer. Results: A total of 22 392 patients with oral squamous cell carcinoma (13 544 male [60.5%]; 1476 Asian and Pacific Islander [6.7%]; 1792 Black [8.0%], 1589 Hispanic [7.2%], 17 300 White [78.1%]) and 402 626 NHIS interviewees were included in this calculator designed for public use for patients ages 20 to 86 years with newly diagnosed oral cancer to obtain estimates of health status-adjusted age, life expectancy in the absence of the cancer, and the probability of surviving, dying from the cancer, or dying from other causes within 1 to 10 years after diagnosis. The models in the calculator estimated that patients with oral cancer have a higher risk of death from other causes than their matched US population, and that this risk increases by stage. Conclusions and relevance: The models developed for the calculator demonstrate that survival estimates that exclude the effects of coexisting conditions can lead to underestimates or overestimates of survival. This new calculator approach will be broadly applicable for developing future prognostic models of cancer and noncancer aspects of a person's health in other cancers; as registries develop more linkages, available covariates will become broader, strengthening future tools.

A Single-Arm, Open-Label Phase II Study of ONC201 in Recurrent/Refractory Metastatic Breast Cancer and Advanced Endometrial Carcinoma.

BACKGROUND: ONC201 is a small molecule that can cause nonapoptotic cell death through loss of mitochondrial function. Results from the phase I/II trials of ONC201 in patients with refractory solid tumors demonstrated tumor responses and prolonged stable disease in some patients. METHODS: This single-arm, open-label, phase II clinical trial evaluated the efficacy of ONC201 at the recommended phase II dose (RP2D) in patients with recurrent or refractory metastatic breast or endometrial cancer. Fresh tissue biopsies and blood were collected at baseline and at cycle 2 day 2 for correlative studies. RESULTS: Twenty-two patients were enrolled; 10 patients with endometrial cancer, 7 patients with hormone receptor-positive breast cancer, and 5 patients with triple-negative breast cancer. The overall response rate was 0%, and the clinical benefit rate, defined by complete response (CR) + partial response (PR) + stable disease (SD), was 27% (n = 3/11). All patients experienced an adverse event (AE), which was primarily low grade. Grade 3 AEs occurred in 4 patients; no grade 4 AEs occurred. Tumor biopsies did not show that ONC201 consistently induced mitochondrial damage or alterations in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the TRAIL death receptors. ONC201 treatment caused alterations in peripheral immune cell subsets. CONCLUSION: ONC201 monotherapy did not induce objective responses in recurrent or refractory metastatic breast or endometrial cancer at the RP2D dose of 625 mg weekly but had an acceptable safety profile (ClinicalTrials.gov Identifier: NCT03394027).

Targeting Replication Stress and Chemotherapy Resistance with a Combination of Sacituzumab Govitecan and Berzosertib: A Phase I Clinical Trial.

PURPOSE: Despite promising preclinical studies, toxicities have precluded combinations of chemotherapy and DNA damage response (DDR) inhibitors. We hypothesized that tumor-targeted chemotherapy delivery might enable clinical translation of such combinations. PATIENTS AND METHODS: In a phase I trial, we combined sacituzumab govitecan, antibody-drug conjugate (ADC) that delivers topoisomerase-1 inhibitor SN-38 to tumors expressing Trop-2, with ataxia telangiectasia and Rad3-related (ATR) inhibitor berzosertib. Twelve patients were enrolled across three dose levels. RESULTS: Treatment was well tolerated, with improved safety over conventional chemotherapy-based combinations, allowing escalation to the highest dose. No dose-limiting toxicities or clinically relevant ≥grade 4 adverse events occurred. Tumor regressions were observed in 2 patients with neuroendocrine prostate cancer, and a patient with small cell lung cancer transformed from EGFR-mutant non-small cell lung cancer. CONCLUSIONS: ADC-based delivery of cytotoxic payloads represents a new paradigm to increase efficacy of DDR inhibitors. See related commentary by Berg and Choudhury, p. 3557.