Preferences on Delivery of Cancer Rehabilitation Services for Cancer-Related Disability Among Older Individuals Surviving Breast Cancer: A Qualitative Study.

Background: Older individuals surviving breast cancer often encounter cancer-related disability as a short-term or long-term effect of cancer and related treatment. Cancer rehabilitation interventions have the potential to prevent, mitigate, or remediate cancer-related disability. However, use of these services remains limited. Understanding the priorities and perspectives of older individuals surviving breast cancer is key to developing effective and implementable cancer rehabilitation interventions. This qualitative descriptive study examined individuals' preferred and valued methods of cancer rehabilitation intervention delivery. Methods: Using a qualitative descriptive design, older individuals surviving breast cancer (n=14) completed a single telephone-based semi-structure interview. Interviews explored survivors' preferences for cancer rehabilitation service delivery. Interview transcriptions were thematically analyzed. Open codes were inductively generated and reviewed for agreement by an independent reviewer. The codes were deductively organized. Differences were resolved through consensus meetings. Results: Findings revealed preferred intervention delivery characteristics for intervention setting, mode of delivery, format, and timing. Participants predominantly preferred interventions delivered in community-based settings, with both in-person and remote components. Participants also appeared to value one-on-one interventions and those delivered post-treatment. Survivors' overarching preferences were based on desire for patient-centric care, one-on-one therapist time, complex medical schedules, and financial concerns. Discussion: Study findings provide guidance on the modification of existing and creation of new cancer rehabilitation interventions addressing cancer-related disability in older individuals surviving breast cancer. Adoption of stakeholder-driven intervention delivery characteristics may improve value and acceptability of interventions. Future intervention research should incorporate and test these characteristics to ensure their effectiveness in real-world settings.

Using Single-Case Experimental Design and Patient-Reported Outcome Measures to Evaluate the Treatment of Cancer-Related Cognitive Impairment in Clinical Practice.

Cancer-related cognitive impairment (CRCI) affects a large proportion of cancer survivors and has significant negative effects on survivor function and quality of life (QOL). Treatments for CRCI are being developed and evaluated. Memory and attention adaptation training (MAAT) is a cognitive-behavioral therapy (CBT) demonstrated to improve CRCI symptoms and QOL in previous research. The aim of this article is to describe a single-case experimental design (SCED) approach to evaluate interventions for CRCI in clinical practice with patient-reported outcome measures (PROs). We illustrate the use of contemporary SCED methods as a means of evaluating MAAT, or any CRCI treatment, once clinically deployed. With the anticipated growth of cancer survivorship and concurrent growth in the number of survivors with CRCI, the treatment implementation and evaluation methods described here can be one way to assess and continually improve CRCI rehabilitative services.

Germline immunomodulatory expression quantitative trait loci (ieQTLs) associated with immune-related toxicity from checkpoint inhibition.

BACKGROUND: Immune checkpoint inhibition (ICI) has improved clinical outcomes for metastatic melanoma patients; however, 65-80% of patients treated with ICI experience immune-related adverse events (irAEs). Given the plausible link of irAEs with underlying host immunity, we explored whether germline genetic variants controlling the expression of 42 immunomodulatory genes were associated with the risk of irAEs in melanoma patients treated with the single-agent anti-CTLA-4 antibody ipilimumab (IPI). METHODS: We identified 42 immunomodulatory expression quantitative trait loci (ieQTLs) most significantly associated with the expression of 382 immune-related genes. These germline variants were genotyped in IPI-treated melanoma patients, collected as part of a multi-institutional collaboration. We tested the association of ieQTLs with irAEs in a discovery cohort of 95 patients, followed by validation in an additional 97 patients. RESULTS: We found that the alternate allele of rs7036417, a variant linked to increased expression of SYK, was strongly associated with an increased risk of grade 3-4 toxicity [odds ratio (OR) = 7.46; 95% confidence interval (CI) = 2.65-21.03; p = 1.43E-04]. This variant was not associated with response (OR = 0.90; 95% CI = 0.37-2.21; p = 0.82). CONCLUSION: We report that rs7036417 is associated with increased risk of severe irAEs, independent of IPI efficacy. SYK plays an important role in B-cell/T-cell expansion, and increased pSYK has been reported in patients with autoimmune disease. The association between rs7036417 and IPI irAEs in our data suggests a role of SYK overexpression in irAE development. These findings support the hypothesis that inherited variation in immune-related pathways modulates ICI toxicity and suggests SYK as a possible future target for therapies to reduce irAEs.

An Analysis of the COVID-19-Induced Flexible Grading Policy at a Public University.

To help students cope with the challenges of the COVID-19 pandemic, higher education institutions offered students flexible grading policies that blended traditional letter grades with alternative grading options such as the pass-fail or credit-no credit options. This study conducted an in-depth analysis of the flexible grading policy at a medium-sized university in the USA. We studied the differential selection of flexible grading options by course characteristics and students' sociodemographics and academic profiles between Spring 2020 and Spring 2021. We also examined the impacts of the policy on sequential courses. Our analysis utilized administrative and transcript data for undergraduate students at the study institution and employed a combination of descriptive statistics and regression models. The analysis revealed that the flexible grading policy was utilized differently depending on course characteristics, with core courses and subjects like mathematics, chemistry, and economics having higher rates of usage. Additionally, sociodemographic and academic profile factors led to varying degrees of utilization, with males, urban students, freshmen, and non-STEM majors using the policy more frequently. Furthermore, the analysis suggested that the policy may have disadvantaged some students as they struggled in subsequent courses after using the pass option. Several implications and directions for future research are discussed.

Digital health and telehealth in cancer care: a scoping review of reviews.

The COVID-19 pandemic necessitated remote cancer care delivery via the internet and telephone, rapidly accelerating an already growing care delivery model and associated research. This scoping review of reviews characterised the peer-reviewed literature reviews on digital health and telehealth interventions in cancer published from database inception up to May 1, 2022, from PubMed, Cumulated Index to Nursing and Allied Health Literature, PsycINFO, Cochrane Reviews, and Web of Science. Eligible reviews conducted a systematic literature search. Data were extracted in duplicate via a pre-defined online survey. Following screening, 134 reviews met the eligibility criteria. 77 of those reviews were published since 2020. 128 reviews summarised interventions intended for patients, 18 addressed family caregivers, and five addressed health-care providers. 56 reviews did not target a specific phase of the cancer continuum, whereas 48 reviews tended to address the active treatment phase. 29 reviews included a meta-analysis, with results showing positive effects on quality of life, psychological outcomes, and screening behaviours. 83 reviews did not report intervention implementation outcomes but when reported, 36 reported acceptability, 32 feasibility, and 29 fidelity outcomes. Several notable gaps were identified in these literature reviews on digital health and telehealth in cancer care. No reviews specifically addressed older adults, bereavement, or sustainability of interventions and only two reviews focused on comparing telehealth to in-person interventions. Addressing these gaps with rigorous systematic reviews might help guide continued innovation in remote cancer care, particularly for older adults and bereaved families, and integrate and sustain these interventions within oncology.

Mutant K-Ras in Pancreatic Cancer: An Insight on the Role of Wild-Type N-Ras and K-Ras-Dependent Cell Cycle Regulation.

The development of K-Ras independence may explain the failure of targeted therapy for pancreatic cancer (PC). In this paper, active N as well as K-Ras was shown in all human cell lines tested. In a cell line dependent on mutant K-Ras, it was shown that depleting K-Ras reduced total Ras activity, while cell lines described as independent had no significant decline in total Ras activity. The knockdown of N-Ras showed it had an important role in controlling the relative level of oxidative metabolism, but only K-Ras depletion caused a decrease in G2 cyclins. Proteasome inhibition reversed this, and other targets of APC/c were also decreased by K-Ras depletion. K-Ras depletion did not cause an increase in ubiquitinated G2 cyclins but instead caused exit from the G2 phase to slow relative to completion of the S-phase, suggesting that the mutant K-Ras may inhibit APC/c prior to anaphase and stabilise G2 cyclins independently of this. We propose that, during tumorigenesis, cancer cells expressing wild-type N-Ras protein are selected because the protein protects cancer cells from the deleterious effects of the cell cycle-independent induction of cyclins by mutant K-Ras. Mutation independence results when N-Ras activity becomes adequate to drive cell division, even in cells where K-Ras is inhibited.

Kinase Insert Domain Receptor Q472H Pathogenic Germline Variant Impacts Melanoma Tumor Growth and Patient Treatment Outcomes.

BACKGROUND: We previously reported a higher incidence of a pathogenic germline variant in the kinase insert domain receptor (KDR) in melanoma patients compared to the general population. Here, we dissect the impact of this genotype on melanoma tumor growth kinetics, tumor phenotype, and response to treatment with immune checkpoint inhibitors (ICIs) or targeted therapy. METHODS: The KDR genotype was determined and the associations between the KDR Q472H variant (KDR-Var), angiogenesis, tumor immunophenotype, and response to MAPK inhibition or ICI treatment were examined. Melanoma B16 cell lines were transfected with KDR-Var or KDR wild type (KDR-WT), and the differences in tumor kinetics were evaluated. We also examined the impact of KDR-Var on the response of melanoma cells to a combination of VEGFR inhibition with MAPKi. RESULTS: We identified the KDR-Var genotype in 81/489 (37%) patients, and it was associated with a more angiogenic (p = 0.003) and immune-suppressive tumor phenotype. KDR-Var was also associated with decreased PFS to MAPKi (p = 0.022) and a trend with worse PFS to anti-PD1 therapy (p = 0.06). KDR-Var B16 murine models had increased average tumor volume (p = 0.0027) and decreased CD45 tumor-infiltrating lymphocytes (p = 0.0282). The anti-VEGFR treatment Lenvatinib reduced the tumor size of KDR-Var murine tumors (p = 0.0159), and KDR-Var cells showed synergistic cytotoxicity to the combination of dabrafenib and lenvatinib. CONCLUSIONS: Our data demonstrate a role of germline KDR-Var in modulating melanoma behavior, including response to treatment. Our data also suggest that anti-angiogenic therapy might be beneficial in patients harboring this genotype, which needs to be tested in clinical trials.

Phase II clinical and immune correlate study of adjuvant nivolumab plus ipilimumab for high-risk resected melanoma.

BACKGROUND: Adjuvant therapy for high-risk resected melanoma with programmed cell-death 1 blockade results in a median relapse-free survival (RFS) of 5 years. The addition of low dose ipilimumab (IPI) to a regimen of adjuvant nivolumab (NIVO) in CheckMate-915 did not result in increased RFS. A pilot phase II adjuvant study of either standard dose or low dose IPI with NIVO was conducted at two centers to evaluate RFS with correlative biomarker studies. METHODS: Patients with resected stages IIIB/IIIC/IV melanoma received either IPI 3 mg/kg and NIVO 1 mg/kg (cohort 4) or IPI 1 mg/kg and NIVO 3 mg/kg (cohorts 5 and 6) induction therapy every 3 weeks for 12 weeks, followed by maintenance NIVO. In an amalgamated subset of patients across cohorts, peripheral T cells at baseline and on-treatment were assessed by flow cytometry and RNA sequencing for exploratory biomarkers. RESULTS: High rates of grade 3-4 adverse events precluded completion of induction therapy in 50%, 35% and 7% of the patients in cohorts 4, 5 and 6, respectively. At a median of 63.9 months of follow-up, 16/56 patients (29%) relapsed. For all patients, at 5 years, RFS was 71% (95% CI: 60 to 84), and overall survival was 94% (95% CI: 88 to 100). Expansion of CD3+CD4+CD38+CD127-GARP- T cells, an on-treatment increase in CD39 expression in CD8+ T cells, and T-cell expression of phosphorylated signal-transducer-and-activator-of-transcription (STAT)2 and STAT5 were associated with relapse. CONCLUSIONS: Adjuvant IPI/NIVO at the induction doses used resulted in promising relapse-free and overall survival, although with a high rate of grade 3-4 adverse events. Biomarker analyses highlight an association of ectoenzyme-expressing T cells and STAT signaling pathways with relapse, warranting future validation. TRIAL REGISTRATION NUMBER: NCT01176474 and NCT02970981.

Self-reported cognitive impairments and quality of life in patients with gastrointestinal stromal tumor: Results of a multinational survey.

BACKGROUND: Cancer-related cognitive impairment (CRCI) has long-term effects on survivor quality of life, but CRCI research on patients with gastrointestinal stromal tumor (GIST) is lacking. The aims of this study were to investigate CRCI and concomitant quality of life among patients with GIST. METHODS: An online survey was used to assess CRCI in adult patients with GIST using the validated Functional Assessment of Cancer Therapy-Cognitive-v.3. Age, education, demographically indexed IQ, general health, and quality of life factors (e.g., fatigue, emotional distress) were also assessed. The online survey was administered through five international GIST and sarcoma support organizations. RESULTS: Over the 3-month recruitment period, the survey was completed by 485 participants: mean age, 57.80 (SD, 11.51), median 5 years after diagnosis. A majority (63.91%) reported experiencing cognitive symptoms with a significant negative quality of life impact. Controlling for age, patients with GIST ≥5 years after diagnosis reported worse cognitive function than those <5 years after diagnosis (p < .05) but did not differ in educational level or IQ. Whereas longer term survivors were more likely to have been treated with tyrosine kinase inhibitor (TKI) therapies, there was no observed association of TKI therapy with self-reported cognitive impairments. CONCLUSIONS: A majority of GIST patients report cognitive symptoms that have a negative impact on quality of life, with longer term survivors (≥5 years) tending to report more cognitive impairments. Given the success of TKI therapy to substantially increase overall survival of patients with GIST, addressing CRCI in clinical practice may improve long-term GIST survivor function and quality of life.

Development of an intervention influencing activity limitations in older breast cancer survivors: A modified Delphi study.

INTRODUCTION: Older breast cancer survivors have difficulty accessing rehabilitation interventions addressing activity limitations. Stakeholder input may improve accessibility of interventions. We sought expert consensus on intervention content and delivery features (e.g., where, mode, duration) to inform development of more accessible interventions for this population. MATERIALS AND METHODS: We conducted a modified Delphi process with patient, clinical, administrative, and research experts. In Round 1, experts evaluated content and delivery features according to domains of feasibility and prioritization. In Round 2, panelists were asked to re-rank or confer agreement of content and delivery features that met Round 1 consensus. Ranking was based on median score. Consensus was defined as a percentage of panelists that ranked an option within one unit of the median. For nominal data, consensus was defined as percent agreement. RESULTS: Panelists (n = 20) prioritized physical activity strategies (Median Rank: 2; Consensus: 85%) and adaptive skills training (3; 65%). Panelists also prioritized delivery through outpatient services (1; 100%), post-treatment (1; 100%), combination mode of delivery (100%), duration of three months or less (100%) and occurring one to two days per week (100%). DISCUSSION: Cancer rehabilitation interventions should be designed with input from stakeholders. The stakeholder intervention priorities identified in this study (e.g., content, setting, and mode) may improve relevance and accessibility of future cancer rehabilitation interventions. Interventions delivered in outpatient clinics and post-treatment using virtual and in-person visits may improve accessibility. Future research should examine the effectiveness and implementation of these intervention characteristics.

A genome-wide association study of germline variation and melanoma prognosis.

Background: The high mortality of cutaneous melanoma (CM) is partly due to unpredictable patterns of disease progression in patients with early-stage lesions. The reliable prediction of advanced disease risk from early-stage CM, is an urgent clinical need, especially given the recent expansion of immune checkpoint inhibitor therapy to the adjuvant setting. In our study, we comprehensively investigated the role of germline variants as CM prognostic markers. Methods: We performed a genome-wide association analysis in two independent cohorts of N=551 (discovery), and N=550 (validation) early-stage immunotherapy-naïve melanoma patients. A multivariable Cox proportional hazard regression model was used to identify associations with overall survival in the discovery group, followed by a validation analysis. Transcriptomic profiling and survival analysis were used to elucidate the biological relevance of candidate genes associated with CM progression. Results: We found two independent associations of germline variants with melanoma prognosis. The alternate alleles of these two SNPs were both associated with an increased risk of death [rs60970102 in MELK: HR=3.14 (2.05-4.81), p=1.48×10-7; and rs77480547 in SH3BP4: HR=3.02 (2.02-4.52), p=7.58×10-8, both in the pooled cohort]. The addition of the combined risk alleles (CRA) of the identified variants into the prognostic model improved the predictive power, as opposed to a model of clinical covariates alone. Conclusions: Our study provides suggestive evidence of novel melanoma germline prognostic markers, implicating two candidate genes: an oncogene MELK and a tumor suppressor SH3BP4, both previously suggested to affect CM progression. Pending further validation, these findings suggest that the genetic factors may improve the prognostic stratification of high-risk early-stage CM patients, and propose putative biological insights for potential therapeutic investigation of these targets to prevent aggressive outcome from early-stage melanoma.

Impact of non-pharmacological interventions on activity limitations and participation restrictions in older breast cancer survivors: A scoping review.

Cancer-related disability is a complex problem for older breast cancer survivors. One aspect of cancer-related disability is a survivor's inability to complete meaningful daily activities and engage in life roles, referred to as activity limitations and participation restrictions respectively. There is a limited understanding of how interventions influence activity limitations and participation restrictions in this population. A scoping review was undertaken to identify and characterize nonpharmacological interventions developed to address activity limitations and participation restrictions. A systematic search of electronic databases (Ovid Medline, Embase, EBSCO CINAHL, and Ovid PsycINFO) was conducted in April 2020 and updated October 2020. Eleven studies met inclusion criteria. Most frequently observed delivery features were in-person and one-on-one format. Six interventions incorporated telehealth delivery components. Interventions were often complex and varied in content. Exercise and behavioral strategies were among the most frequently used active ingredients. Activity limitations and participation restrictions were often secondary outcomes, and measures of these outcomes were varied in content and assessment method. Study samples were not representative of the current population of older adult breast cancer survivors. Future intervention research should clarify intervention delivery, content, and dose, prioritize comprehensive measurement of activity limitations and participation restrictions, as well as recruit and involve representative study samples to enhance generalizability of findings.

Factors influencing utilization of cancer rehabilitation services among older breast cancer survivors in the USA: a qualitative study.

PURPOSE: Many older breast cancer survivors experience long-term disability due to cancer and cancer-related treatments. However, less than 20% of older breast cancer survivors utilize cancer rehabilitation services to address cancer-related disability. Further understanding of survivor experiences may reveal strategies to improve uptake cancer rehabilitation services in the USA. METHODS: Older breast cancer survivors were recruited from university-based registries, previous breast cancer research studies at our institution, community support groups, and geriatric oncology clinics. Participants completed a brief online survey to capture demographic and clinical characteristics. Semi-structured telephone-based interviews were recorded, transcribed, and thematically analyzed. Interviews facilitated conversation about access to rehabilitation and indications for cancer rehabilitation. RESULTS: Participants (n = 14) were, on average, 71 years old, primarily White, and an average of 36.5 months post-diagnosis. Five participants had formally received rehabilitation for a cancer-related concern. Participants described seven factors that influenced utilization of cancer rehabilitation services: (1) emerging awareness of disability; (2) coping styles; (3) comparison of cancer experience with others; (4) provider interaction; (5) perceptions of cancer diagnosis; (6) social support; and (7) cost of rehabilitation. CONCLUSIONS: Older breast cancer survivors consider multiple factors when determining utilization of cancer rehabilitation services. Development of shared decision-making tools addressing the seven described factors may enhance communication and referral to cancer rehabilitation services. Intervention research should adopt frameworks that enhance healthcare accessibility to improve relevance of intervention content and delivery features for older breast cancer survivors.

Health Care Providers' and Professionals' Experiences With Telehealth Oncology Implementation During the COVID-19 Pandemic: A Qualitative Study.

BACKGROUND: Rapid implementation of telehealth for cancer care during COVID-19 required innovative and adaptive solutions among oncology health care providers and professionals (HPPs). OBJECTIVE: The aim of this qualitative study was to explore oncology HPPs' experiences with telehealth implementation during the COVID-19 pandemic. METHODS: This study was conducted at Moffitt Cancer Center (Moffitt), an NCI (National Cancer Institute)-Designated Comprehensive Cancer Center. Prior to COVID-19, Moffitt piloted telehealth visits on a limited basis. After COVID-19, Moffitt rapidly expanded telehealth visits. Telehealth visits included real-time videoconferencing between HPPs and patients and virtual check-ins (ie, brief communication with an HPP by telephone only). We conducted semistructured interviews with 40 oncology HPPs who implemented telehealth during COVID-19. The interviews were recorded, transcribed verbatim, and analyzed for themes using Dedoose software (version 4.12). RESULTS: Approximately half of the 40 participants were physicians (n=22, 55%), and one-quarter of the participants were advanced practice providers (n=10, 25%). Other participants included social workers (n=3, 8%), psychologists (n=2, 5%), dieticians (n=2, 5%), and a pharmacist (n=1, 3%). Five key themes were identified: (1) establishing and maintaining patient-HPP relationships, (2) coordinating care with other HPPs and informal caregivers, (3) adapting in-person assessments for telehealth, (4) developing workflows and allocating resources, and (5) future recommendations. Participants described innovative strategies for implementing telehealth, such as coordinating interdisciplinary visits with multiple HPPs and inviting informal caregivers (eg, spouse) to participate in telehealth visits. Health care workers discussed key challenges, such as workflow integration, lack of physical exam and biometric data, and overcoming the digital divide (eg, telehealth accessibility among patients with communication-related disabilities). Participants recommended policy advocacy to support telehealth (eg, medical licensure policies) and monitoring how telehealth affects patient outcomes and health care delivery. CONCLUSIONS: To support telehealth growth, implementation strategies are needed to ensure that HPPs and patients have the tools necessary to effectively engage in telehealth. At the same time, cancer care organizations will need to engage in advocacy to ensure that policies are supportive of oncology telehealth and develop systems to monitor the impact of telehealth on patient outcomes, health care quality, costs, and equity.

The ecological impacts of multiple environmental stressors on coastal biofilm bacteria.

Ecological communities are increasingly exposed to multiple interacting stressors. For example, warming directly affects the physiology of organisms, eutrophication stimulates the base of the food web, and harvesting larger organisms for human consumption dampens top-down control. These stressors often combine in the natural environment with unpredictable results. Bacterial communities in coastal ecosystems underpin marine food webs and provide many important ecosystem services (e.g. nutrient cycling and carbon fixation). Yet, how microbial communities will respond to a changing climate remains uncertain. Thus, we used marine mesocosms to examine the impacts of warming, nutrient enrichment, and altered top-predator population size structure (common shore crab) on coastal microbial biofilm communities in a crossed experimental design. Warming increased bacterial α-diversity (18% increase in species richness and 67% increase in evenness), but this was countered by a decrease in α-diversity with nutrient enrichment (14% and 21% decrease for species richness and evenness, respectively). Thus, we show some effects of these stressors could cancel each other out under climate change scenarios. Warming and top-predator population size structure both affected bacterial biofilm community composition, with warming increasing the abundance of bacteria capable of increased mineralization of dissolved and particulate organic matter, such as Flavobacteriia, Sphingobacteriia, and Cytophagia. However, the community shifts observed with warming depended on top-predator population size structure, with Sphingobacteriia increasing with smaller crabs and Cytophagia increasing with larger crabs. These changes could alter the balance between mineralization and carbon sequestration in coastal ecosystems, leading to a positive feedback loop between warming and CO2 production. Our results highlight the potential for warming to disrupt microbial communities and biogeochemical cycling in coastal ecosystems, and the importance of studying these effects in combination with other environmental stressors.

Tumor immunogenomic signatures improve a prognostic model of melanoma survival.

BACKGROUND: Tumor mutation burden (TMB) has been associated with melanoma immunotherapy (IT) outcomes, including survival. We explored whether combining TMB with immunogenomic signatures recently identified by The Cancer Genome Atlas (TCGA) can refine melanoma prognostic models of overall survival (OS) in patients not treated by IT. METHODS: Cox proportional-hazards (Cox PH) analysis was performed on 278 metastatic melanomas from TCGA not treated by IT. In a discovery and two validation cohorts Cox PH models assessed the interaction between TMB and 53 melanoma immunogenomic features to refine prediction of melanoma OS. RESULTS: Interferon-γ response (IFNγRes) and macrophage regulation gene signatures (MacReg) combined with TMB significantly associated with OS (p = 8.80E-14). We observed that patients with high TMB, high IFNγRes and high MacReg had significantly better OS compared to high TMB, low IFNγRes and low MacReg (HR = 2.8, p = 3.55E-08). This association was not observed in low TMB patients. CONCLUSIONS: We report a model combining TMB and tumor immune features that significantly improves prediction of melanoma OS, independent of IT. Our analysis revealed that patients with high TMB, high levels of IFNγRes and MacReg had significantly more favorable OS compared to high TMB patients with low IFNγRes and low MacReg. These findings may substantially improve current melanoma prognostic models.