Tumor-reactive T cell clonotype dynamics underlying clinical response to TIL therapy in melanoma.

Adoptive cell therapy (ACT) using in vitro expanded tumor-infiltrating lymphocytes (TILs) has inconsistent clinical responses. To better understand determinants of therapeutic success, we tracked TIL clonotypes from baseline tumors to ACT products and post-ACT blood and tumor samples in melanoma patients using single-cell RNA and T cell receptor (TCR) sequencing. Patients with clinical responses had baseline tumors enriched in tumor-reactive TILs, and these were more effectively mobilized upon in vitro expansion, yielding products enriched in tumor-specific CD8+ cells that preferentially infiltrated tumors post-ACT. Conversely, lack of clinical responses was associated with tumors devoid of tumor-reactive resident clonotypes and with cell products mostly composed of blood-borne clonotypes that persisted in blood but not in tumors post-ACT. Upon expansion, tumor-specific TILs lost tumor-associated transcriptional signatures, including exhaustion, and responders exhibited an intermediate exhausted effector state after TIL engraftment in the tumor, suggesting functional reinvigoration. Our findings provide insight into the nature and dynamics of tumor-specific clonotypes associated with clinical response to TIL-ACT, with implications for treatment optimization.

Fear of cancer recurrence in breast cancer survivors carrying a BRCA1 or 2 genetic mutation : a cross-sectional study.

BACKGROUND: Fear of cancer recurrence (FCR) affects virtually all patients who have been treated for cancer, to varying degrees. Breast cancer survivors who carry a BRCA1 or BRCA2 gene mutation are at high risk of cancer recurrence. No study has yet assessed FCR specifically in this population. OBJECTIVES: This cross-sectional study, conducted in women who were treated for breast cancer and carrying a BRCA1/2 mutation, aimed to: (1) assess the mean level of FCR and estimate the proportion of patients with clinical levels of FCR; (2) examine the relationships between FCR and selected psychological variables (e.g., avoidance, intolerance to uncertainty) and quality of life; (3) explore whether FCR levels vary as a function of the past preventive treatment received; and (4) to assess the associations between FCR and the presence of decisional conflict or regret regarding the various preventive options. METHOD: Participants were recruited through an e-mail sent to an oncogenetic network mailing list (Réseau ROSE). Participants were asked to complete a battery of questionnaires online assessing FCR and other psychological and quality of life variables. RESULTS: A total of 89 women completed the survey. Most participants had undergone a preventive mastectomy (62.9%) and a preventive salpingo-oophorectomy (75.3%) at the time of the study. The mean Fear of Cancer Recurrence Inventory-severity score was 16.8, which exceeds the clinical cut-off score of 13, and 70.8% of the participants showed a clinical level of FCR. FCR was significantly associated with higher levels of anxiety and depression, and higher avoidance and intolerance of uncertainty, but not with quality of life. No significant difference was observed on the total FCR score between women who had received preventive surgery (mastectomy and/or salpingo-oophorectomy) and those considering it, and those not considering it. The association was significant between higher FRC scores and greater decisional conflicts and regrets about choosing to undergo preventive surgery. CONCLUSION: These data suggest that FCR is a significant problem for breast cancer survivors carrying a BRCA1/2 genetic mutation, even after undergoing a prophylactic surgery. This highlights the importance of providing these women with specific psychological intervention focusing on FCR.

Health Care Provider Willingness to Recommend Self-collected Tests for Human Papillomavirus: A Mixed Methods Examination of Associated Factors.

INTRODUCTION: Cervical cancer disproportionately affects those who are underscreened. Human papillomavirus self-collection is a promising tool to expand screening. OBJECTIVE: Study objectives were to examine 1) factors (provider characteristics and practice type) associated with and 2) attitudes (perceived benefits and concerns) toward using human papillomavirus self-collection for cervical cancer screening in clinical practice. METHODS: This study had a mixed method design; prior to regulatory approval of self-collection, we conducted a national survey and interviews of health care providers who perform cervical cancer screening. Quantitative measures included provider and practice characteristics, willingness to recommend, and preferences related to self-collection. Qualitative interviews further elucidated provider perspectives. RESULTS: A total of 1,251 providers completed surveys, and 56 completed interviews. Among survey respondents, 33.4% reported they were likely to offer self-collection, 28.6% were unsure, and 38.0% reported they were unlikely. Most would offer self-collection either in the clinic or at home per patient preference. Male participants, advanced practice providers, internal and family physicians, and those practicing in academic medical center, hospital, or community health settings were more likely than female participants, obstetrician-gynecologist physicians, and those in private practice to indicate they were likely to offer self-collection. Concerns expressed in both surveys and interviews included the adequacy of sample collection and the ability to follow up. Respondents felt that self-collection would be particularly beneficial for those who did not have access to clinician-collected screening, as well as for patients who may have difficulty with pelvic examinations for any reason. CONCLUSION: Providers considered human papillomavirus self-collection to be a way to expand access for patients with health care barriers and pelvic examination difficulties. They had concerns related to sample adequacy and follow-up after abnormal results.

The Emerging Landscape of Social Media Influencers in Public Health Collaborations: A Scoping Review.

Social media content creators or "influencers" are an increasingly influential voice in the public discourse generally, including global perceptions and practices related to health. In response, public health entities are increasingly embracing social media influencers (SMIs) as potential health promotion collaborators. Despite burgeoning interest in the potential of these partnerships, research evaluating this strategy remains limited. To address this gap, we conducted a scoping review to characterize and describe the current landscape of health promotion collaborations with SMIs with a focus on current practices. A search of six electronic databases (PubMed, SCOPUS, Communication & Mass Media Complete, CINAHL Plus, Web of Science, and APA PsycINFO) revealed wide-ranging and inconsistent approaches to these partnerships, including their optimal practices, data reported, and their evaluation criteria. Among the 658 articles initially identified, 15 publications met our inclusion criteria, spanning 7 countries, 8 social media platforms, 11 distinct health topics, and 21 different outcome measures. Basic information necessary for comparing across interventions was often lacking. We noted a lack of consensus on what constitutes an SMI with 53% of included studies lacking any definition or criteria. Although SMIs offer substantial promise as an emerging opportunity for health promotion, particularly for populations that may be otherwise difficult to identify or reach, this review highlights how the current lack of standardized methodologies and metrics prevents meaningful comparisons between collaborations and evaluations of their effectiveness. Based on these findings, we propose four key criteria to aid practitioners in the implementation and evaluation of SMI collaborations.

Identification of clinically relevant T cell receptors for personalized T cell therapy using combinatorial algorithms.

A central challenge in developing personalized cancer cell immunotherapy is the identification of tumor-reactive T cell receptors (TCRs). By exploiting the distinct transcriptomic profile of tumor-reactive T cells relative to bystander cells, we build and benchmark TRTpred, an antigen-agnostic in silico predictor of tumor-reactive TCRs. We integrate TRTpred with an avidity predictor to derive a combinatorial algorithm of clinically relevant TCRs for personalized T cell therapy and benchmark it in patient-derived xenografts.

The Relationship Between Restrictive Regulation of Midwives, Practice Environment, and Professional Burnout: A 7-State Mixed-Methods Comparison of Autonomous and Restrictive State Regulation.

PURPOSE: The purpose of the study was to investigate the relationship between state regulation of the midwifery workforce, practice environment, and burnout. BACKGROUND: Burnout threatens the US midwifery workforce, with over 40% of certified nurse-midwives meeting criteria. Burnout can lead to poorer physical and mental health and withdrawal from the workforce. Burnout in midwives has been associated with lack of control and autonomy. In the United States, midwives' autonomy is restricted through state-level regulation that limits scope of practice and professional independence. METHODS: A mixed-methods study was conducted using an explanatory sequential approach. Quantitative and qualitative data were collected by online surveys and analyzed in a 2-stage process, followed by data integration. RESULTS: State regulation was not found to be independently associated with burnout (n = 248; P = .250); however, mediation analysis showed a significant association between state regulation, practice environment, and burnout. Qualitative analysis mirrored the importance of practice environment and expanded on its features. CONCLUSION: For midwives, unrestrictive practice regulation may not translate to burnout prevention without supportive practice environments. IMPLICATIONS FOR PRACTICE AND RESEARCH: Interventions should focus on promoting job flexibility, realistic demands, and professional values. While midwives' commitment to patients and the profession can help bolster the workforce, it can also amplify negative experiences of the practice environment.

Attitudes toward the American Cancer Society's 2020 cervical cancer screening guidelines: A qualitative study of a national sample of US clinicians.

BACKGROUND: The 2020 American Cancer Society (ACS) guidelines are the most recent national guidelines for cervical cancer screening. These guidelines propose two major changes from current practice: initiating screening at age 25 years and using primary human papillomavirus (HPV) testing. Adoption of guidelines often occurs slowly, and therefore understanding clinician attitudes is important to facilitate practice change. METHODS: Interviews with a national sample of clinicians who perform cervical cancer screening in a variety of settings explored attitudes toward the two major changes from the 2020 ACS cervical cancer screening guidelines. Clinicians participated in 30- to 60-min interviews exploring their attitudes toward various aspects of cervical cancer screening. Qualitative analysis was performed. RESULTS: Seventy clinicians participated from across the United States. Few respondents were initiating screening at age 25 years, and none were using primary HPV testing. However, over half would be willing to adopt these practices if supported by scientific evidence and recommended by professional medical organizations. Barriers to adoption included the lack of endorsement by professional societies, lack of laboratory availability and insurance coverage, limited autonomy within large health care systems, and concerns related to missed disease. CONCLUSIONS: Few clinicians have adopted screening initiation or primary HPV testing, as recommended by the 2020 ACS guidelines, but over half were open to adopting these changes. Implementation may be facilitated via professional organization endorsement, clinician education, and laboratory, health care system, and insurance support. PLAIN LANGUAGE SUMMARY: In 2020, the American Cancer Society (ACS) released updated guidelines for cervical cancer screening. The main changes to current practices were to initiate screening at age 25 years instead of age 21 years and to screen using primary human papillomavirus (HPV) testing rather than cytology alone or in combination with HPV testing. We performed in-depth interviews with 70 obstetrics and gynecology, family medicine, and internal medicine physicians and advanced practice providers about their attitudes toward these guidelines. Few clinicians are following the 2020 ACS guidelines, but over half were open to changing practice if the changes were supported by evidence and recommended by professional medical organizations. Barriers to adoption included the lack of endorsement by professional medical organizations, logistical issues, and concerns about missed disease.

Factors Associated With Guideline-concordant and Excessive Cervical Cancer Screening: A Mixed Methods Study.

INTRODUCTION: National guidelines recommend cervical cancer screening with Papanicolaou (Pap) testing at 3-year intervals or with human papillomavirus (HPV) testing alone or HPV/Pap cotesting at 5-year intervals for average-risk individuals aged 30-65 years. METHODS: We explored factors associated with clinician-reported guideline-concordant screening, as well as facilitators and barriers to appropriate cervical cancer screening. RESULTS: A national sample of clinicians (N = 1,251) completed surveys; a subset (n = 55) completed interviews. Most (94%) reported that they screened average-risk patients aged 30-65 years with cotesting. Nearly all clinicians who were categorized as nonadherent to national guidelines were overscreening (98%). Guideline concordant screening was reported by 47% and 82% of those using cotesting and HPV testing, respectively (5-year intervals), and by 62% of those using Pap testing only (3-year intervals). Concordant screening was reported more often by clinicians who were aged <40 years, non-Hispanic, and practicing in the West or Midwest, and less often by obstetrician-gynecologists and private practice physicians. Concordant screening was facilitated by beliefs that updated guidelines were evidence-based and reduced harms, health care system dissemination of guidelines, and electronic medical record prompts. Barriers to concordant screening included using outdated guidelines, relying on personal judgment, concern about missing cancers, inappropriate patient risk assessment, and lack of support for guideline adoption through health care systems or electronic medical records. CONCLUSIONS: Most clinicians screened with Pap/HPV cotesting and approximately one-half endorsed a 5-year screening interval. Clinician knowledge gaps include understanding the evidence underlying 5-year intervals and appropriate risk assessment to determine which patients should be screened more frequently. Education and tracking systems can promote guideline-concordant screening.

Impact of the COVID-19 pandemic on social media utilization, influences related to parental vaccine decision making, and opinions on trustworthy social media vaccination campaigns: A qualitative analysis.

There is a continued need for research to better understand the influence social media has on parental vaccination attitudes and behaviors, especially research capturing the effects of the COVID-19 pandemic. The goal of this study was to explore parents' perspectives related to the impact the pandemic had on 1) social media engagement, 2) vaccine messaging on social media, and 3) factors to guide future intervention development. Between February and March 2022, 6 online, synchronous, text-based focus groups were conducted with parents of adolescents aged 11 to 17 years. Participants who all utilized social media were recruited from across the United States. Qualitative data were analyzed using content analysis. A total of 64 parents participated. Average age was 47 years, and participants were predominantly White (71.9%), female (84.3%), and engaged with social media multiple times per day (51.6%). Participants (95.3%) viewed obtaining all recommended vaccines as important or very important; however, overall vaccination rates for their adolescents were varied (50% ≥1 dose HPV; 59.4% MenACWY; 78.1% Tdap; 65.6% Flu; 81.3% COVID-19). Three themes emerged highlighting the pandemic's impact on parent's (1) general patterns of social media use, (2) engagement about vaccines on social media and off-line behaviors related to vaccination, and (3) perspectives for developing a credible and trustworthy social media intervention about vaccination. Participants reported fatigue from contentious vaccine-related content on social media and desired future messaging to be from recognizable health institutions/associations with links to reputable resources. Plus, providers should continue to provide strong vaccine recommendations in clinic.

Leveraging a Peer-to-Peer Approach to Mitigate Vaccine Misinformation and Improve Vaccine Communication During a Pandemic: Experiences From the Development of a Massive Open Online Course.

The COVID-19 pandemic has not only led to massive global mortality and morbidity, but it has also fueled an infodemic of false and misleading information about COVID-19 and vaccines. The spread of misinformation and disinformation on vaccine safety and efficacy has contributed to vaccine hesitancy and distrust of public health institutions and has undermined the public health response to the COVID-19 pandemic. Because communication plays a monumental role in pandemic preparedness, a promising approach to countering the COVID-19 infodemic is empowering peers to serve as trusted messengers to provide accurate information using evidence-based communication approaches. With this in mind, we developed a massive open online course (MOOC) to provide the general public with the knowledge, skills, and resources to effectively navigate potentially contentious vaccine conversations with their peers, with a specific focus on parents. Within the first year of the course launch, 29,000 people had enrolled. Learners appreciated the information related to vaccine development, communication tips and techniques, and identifying and responding to vaccine misinformation. Over 1,000 learners who completed the course participated in an online evaluation survey. To address public distrust in healthcare providers, government, and science, our survey results indicate that peer-to-peer approaches to addressing vaccine hesitancy can empower community members to educate others and promote vaccine acceptance at scale.

Comparing Web-Based and Blended Training for Coping With Challenges of Flexible Work Designs: Randomized Controlled Trial.

BACKGROUND: Workers with flexible work designs (FWDs) face specific challenges, such as difficulties in detaching from work, setting boundaries between work and private life, and recovering from work. OBJECTIVE: This study evaluated the effectiveness of an intervention in improving the recovery, work-life balance, and well-being of workers with FWDs compared with a waitlist control group. It also compares the effectiveness of a web-based training format and blended training format. METHODS: In the web-based training format, participants individually completed 6 web-based modules and daily tasks over 6 weeks, learning self-regulation strategies to meet the particular challenges of FWDs. In the blended training format, participants attended 3 group sessions in addition to completing the 6 web-based modules. In a randomized controlled trial, participants were assigned to a web-based intervention group (196/575, 34.1%), blended intervention group (198/575, 34.4%), or waitlist control group (181/575, 31.5%). Study participants self-assessed their levels of primary outcomes (psychological detachment, satisfaction with work-life balance, and well-being) before the intervention, after the intervention, at a 4-week follow-up, and at a 6-month follow-up. The final sample included 373 participants (web-based intervention group: n=107, 28.7%; blended intervention group: n=129, 34.6%; and control group: n=137, 36.7%). Compliance was assessed as a secondary outcome. RESULTS: The results of multilevel analyses were in line with our hypothesis that both training formats would improve psychological detachment, satisfaction with work-life balance, and well-being. We expected blended training to reinforce these effects, but blended training participants did not profit more from the intervention than web-based training participants. However, they reported to have had more social exchange, and blended training participants were more likely to adhere to the training. CONCLUSIONS: Both web-based and blended training are effective tools for improving the recovery, work-life balance, and well-being of workers with FWDs. Group sessions can increase the likelihood of participants actively participating in web-based modules and exercises. TRIAL REGISTRATION: German Clinical Trials Register DRKS00032721; https://drks.de/search/en/trial/DRKS00032721.

A phase 1 trial of adoptive transfer of vaccine-primed autologous circulating T cells in ovarian cancer.

We have previously shown that vaccination with tumor-pulsed dendritic cells amplifies neoantigen recognition in ovarian cancer. Here, in a phase 1 clinical study ( NCT01312376 /UPCC26810) including 19 patients, we show that such responses are further reinvigorated by subsequent adoptive transfer of vaccine-primed, ex vivo-expanded autologous peripheral blood T cells. The treatment is safe, and epitope spreading with novel neopeptide reactivities was observed after cell infusion in patients who experienced clinical benefit, suggesting reinvigoration of tumor-sculpting immunity.

Examining the perceived impact of the COVID-19 pandemic on cervical cancer screening practices among clinicians practicing in Federally Qualified Health Centers: A mixed methods study.

Background: The COVID-19 pandemic led to reductions in cervical cancer screening and colposcopy. Therefore, in this mixed methods study we explored perceived pandemic-related practice changes to cervical cancer screenings in federally qualified health centers (FQHCs). Methods: Between October 2021 and June 2022, we conducted a national web survey of clinicians (physicians and advanced practice providers) who performed cervical cancer screening in FQHCs in the United States during the post-acute phase of the COVID-19 pandemic, along with a sub-set of qualitative interviews via video conference, to examine perceived changes in cervical cancer screening practices during the pandemic. Results: A total of 148 clinicians completed surveys; a subset (n=13) completed qualitative interviews. Most (86%) reported reduced cervical cancer screening early in the pandemic, and 28% reported continued reduction in services at the time of survey completion (October 2021- July 2022). Nearly half (45%) reported staff shortages impacting their ability to screen or track patients. Compared to clinicians in Obstetrics/Gynecology/Women's health, those in family medicine and other specialties more often reported reduced screening compared to pre-pandemic. Most (92%) felt that screening using HPV self-sampling would be very or somewhat helpful to address screening backlogs. Qualitative interviews highlighted the impacts of staff shortages and strategies for improvement. Conclusions: Findings highlight that in late 2021 and early 2022, many clinicians in FQHCs reported reduced cervical cancer screening and of pandemic-related staffing shortages impacting screening and follow-up. If not addressed, reduced screenings among underserved populations could worsen cervical cancer disparities in the future. Funding: This study was funded by the American Cancer Society, who had no role in the study's design, conduct, or reporting.

Examining the association of clinician characteristics with perceived changes in cervical cancer screening and colposcopy practice during the COVID-19 pandemic: a mixed methods assessment.

Background: The COVID-19 pandemic led to reductions in cervical cancer screening and colposcopy. Therefore, in this mixed method study we explored perceived pandemic-related practice changes to cervical cancer screenings and colposcopies. Methods: In 2021, a national sample of 1251 clinicians completed surveys, including 675 clinicians who performed colposcopy; a subset (n=55) of clinicians completed qualitative interviews. Results: Nearly half of all clinicians reported they were currently performing fewer cervical cancer screenings (47%) and colposcopies (44% of those who perform the procedure) than before the pandemic. About one-fifth (18.6%) of colposcopists reported performing fewer LEEPs than prior to the pandemic. Binomial regression analyses indicated that older, as well as internal medicine and family medicine clinicians (compared to OB-GYNs), and those practicing in community health centers (compared to private practice) had higher odds of reporting reduced screening. Among colposcopists, internal medicine physicians and those practicing in community health centers had higher odds of reporting reduced colposcopies. Qualitative interviews highlighted pandemic-related care disruptions and lack of tracking systems to identify overdue screenings. Conclusions: Reductions in cervical cancer screening and colposcopy among nearly half of clinicians more than 1 year into the pandemic raise concerns that inadequate screening and follow-up will lead to future increases in preventable cancers. Funding: This study was funded by the American Cancer Society, who had no role in the study's design, conduct, or reporting.

Neoantigen-specific CD8 T cells with high structural avidity preferentially reside in and eliminate tumors.

The success of cancer immunotherapy depends in part on the strength of antigen recognition by T cells. Here, we characterize the T cell receptor (TCR) functional (antigen sensitivity) and structural (monomeric pMHC-TCR off-rates) avidities of 371 CD8 T cell clones specific for neoantigens, tumor-associated antigens (TAAs) or viral antigens isolated from tumors or blood of patients and healthy donors. T cells from tumors exhibit stronger functional and structural avidity than their blood counterparts. Relative to TAA, neoantigen-specific T cells are of higher structural avidity and, consistently, are preferentially detected in tumors. Effective tumor infiltration in mice models is associated with high structural avidity and CXCR3 expression. Based on TCR biophysicochemical properties, we derive and apply an in silico model predicting TCR structural avidity and validate the enrichment in high avidity T cells in patients' tumors. These observations indicate a direct relationship between neoantigen recognition, T cell functionality and tumor infiltration. These results delineate a rational approach to identify potent T cells for personalized cancer immunotherapy.

TCR sequencing and cloning methods for repertoire analysis and isolation of tumor-reactive TCRs.

T cell receptor (TCR) technologies, including repertoire analyses and T cell engineering, are increasingly important in the clinical management of cellular immunity in cancer, transplantation, and other immune diseases. However, sensitive and reliable methods for repertoire analyses and TCR cloning are still lacking. Here, we report on SEQTR, a high-throughput approach to analyze human and mouse repertoires that is more sensitive, reproducible, and accurate as compared with commonly used assays, and thus more reliably captures the complexity of blood and tumor TCR repertoires. We also present a TCR cloning strategy to specifically amplify TCRs from T cell populations. Positioned downstream of single-cell or bulk TCR sequencing, it allows time- and cost-effective discovery, cloning, screening, and engineering of tumor-specific TCRs. Together, these methods will accelerate TCR repertoire analyses in discovery, translational, and clinical settings and permit fast TCR engineering for cellular therapies.