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Objectives: Cancer diagnosis comes as a shock to many patients, and many of them feel unprepared to handle the complexity of the life-changing event, understand technicalities of the diagnostic reports, and fully engage with the clinical team regarding the personalized clinical decision-making., Materials and Methods: We develop Oncointerpreter.ai an interactive resource to offer personalized summarization of clinical cancer genomic and pathological data, and frame questions or address queries about therapeutic opportunities in near-real time via a graphical interface. It is built on the Mistral-7B and Llama-2 7B large language models trained on a local database trained using a large, curated corpus., Results: We showcase its utility with case studies, where Oncointerpreter.ai extracted key clinical and molecular attributes from deidentified pathology and clinical genomics reports, summarized their contextual significance and answered queries on pertinent treatment options. Oncointerpreter also provided personalized summary of currently active clinical trials that match the patients' disease status, their selection criteria, and geographic locations. Benchmarking and comparative assessment indicated that the model responses were generally consistent, and hallucination, ie, factually incorrect or nonsensical response was rare; treatment- and outcome related queries led to context-aware responses, and response time correlated with verbosity., Discussion: The choice of model and domain-specific training also affected the response quality., Conclusion: Oncointerpreter.ai can aid the existing clinical care with interactive, individualized summarization of diagnostics data to promote informed dialogs with the patients with new cancer diagnoses., Availability: https://github.com/Siris2314/Oncointerpreter., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Venous thromboembolism (VTE) is a well-recognized complication in pediatric cancer patients. We aimed to determine the frequency of central venous catheter (CVC) removal and survival impact of children with cancer who develop VTE. After ethics approval, a retrospective population-based study of cancer patients less than 21 years between 2005 and 2020, in the Maritime Provinces Nova Scotia, New Brunswick, and Prince Edward Island was conducted. Clinical data was collected from hospital charts and online medical records. Data on demographics, cancer diagnosis and treatment, diagnosis of VTE, use of CVC, were assessed. Kaplan-Meier survival curves were computed and compared among study groups. This study included 770 patients with a male to female ratio of 1.1:1. There were 49 patients with symptomatic VTE, 49 patients with clinically unsuspected VTE, and 671 patients with no VTE. There were 15 (1.9%) non-CVC-symptomatic (ncsVTE), 34 (4.4%) CVC-symptomatic (csVTE), 40 (5.2%) non-CVC-clinically unsuspected (ncuVTE), 9 (1.2%) CVC-clinically unsuspected (cVTE), and 671 (87%) no VTE patients. The mean number of CVCs required during treatment was significantly higher among patients with VTE (p < 0.001). Both symptomatic and clinically unsuspected VTE required significantly more CVCs compared to no VTE patients (p < 0.001 and p = 0.049 respectively). Kaplan-Meier survival curves showed ncsVTE patients' survival was significantly reduced compared to all other patients (p < 0.001). This study demonstrates that pediatric oncology patients with ncsVTE have significantly lower survival. This suggests that ncsVTE may be a biomarker for increased disease burden. This study also demonstrated that clinically unsuspected VTE had significantly more CVCs placed during treatment compared to patients without a VTE, indicating the need for better screening., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose We aimed to document the acceptability (enrollment rate) and feasibility (phone call delivery rate) of implementing a behavioral PA intervention over 12 weeks, in addition to documenting its effects on patient-reported outcomes and physical functioning. This study also describes the costs of carrying out a behavioral PA intervention. A total of 40 participants were randomized in a 1:1 ratio. The tailored behavioral PA intervention was developed based on the most recent PA guidelines in pediatric oncology and on the COM-B framework to enact PA behavior changes. The prescription (frequency, intensity, time and type (FITT)) was adjusted each week during the weekly support calls. The control group did not receive the intervention. 26 males and 14 females (13.6 years old on average and 2.9 years post-cancer treatment on average) participated in our study. The acceptability rate was 90.9% and the feasibility rate was > 85%. We found that 85% improved PA frequency, 80% improved PA intensity, 100% improved PA time, and 50.0% achieved the recommended PA guidelines. No adverse events were reported over the duration of the intervention. Physical function improved with longer 6-minute walk distances in the intervention group (465.8 ± 74.5 m) than in the control group (398.7 ± 92.9 m) (p = 0.016). PROs scores for all participants were within the limits of the normal range. The estimated cost per participant of carrying out this intervention was USD $126.57. Our 12-week behavioral PA intervention, based on the COM-B framework, was found to be acceptable, feasible and safe in childhood cancer survivors. This study is an important step in the right direction to make exercise standard practice in pediatric oncology., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Cancer drug development remains a critical but challenging process that affects millions of patients and their families. Using biomedical informatics and artificial intelligence (AI) approaches, we assessed the regulatory and translational research landscape defining successful first-in-class drugs for patients with cancer., Methods: This is a retrospective observational study of all novel first-in-class drugs approved by the US Food and Drug Administration (FDA) from 2018 to 2022, stratified by cancer versus noncancer drugs. A biomedical informatics pipeline leveraging interoperability standards and ChatGPT performed integration and analysis of public databases provided by the FDA, National Institutes of Health, and WHO., Results: Between 2018 and 2022, the FDA approved a total of 247 novel drugs, of which 107 (43.3%) were first-in-class drugs involving a new biologic target. Of these first-in-class drugs, 30 (28%) treatments were indicated for patients with cancer, including 19 (63.3%) for solid tumors and the remaining 11 (36.7%) for hematologic cancers. A median of 68 publications of basic, clinical, and other relevant translational science preceded successful FDA approval of first-in-class cancer drugs, with oncology-related treatments involving fewer median years of target-based research than therapies not related to cancer (33 v 43 years; P < .05). Overall, 94.4% of first-in-class drugs had at least 25 years of target-related research papers, while 85.5% of first-in-class drugs had at least 10 years of translational research publications., Conclusion: Novel first-in-class cancer treatments are defined by diverse clinical indications, personalized molecular targets, dependence on expedited regulatory pathways, and translational research metrics reflecting this complex landscape. Biomedical informatics and AI provide scalable, data-driven ways to assess and even address important challenges in the drug development pipeline.

Inconsistencies in the definition of clinically unsuspected venous thromboembolism (VTE) in pediatric patients recently led to the recommendation of standardizing this terminology. Clinically unsuspected VTE (cuVTE) is defined as the presence of VTE on diagnostic imaging performed for indications unrelated to VTE in a patient without symptoms or clinical history of VTE. The prevalence of cuVTE in pediatric cancer patients is unclear. Therefore, the main objective of our study was to determine the prevalence of cuVTE in pediatric cancer patients. All patients 0-18 years old, treated at the IWK in Halifax, Nova Scotia, from August 2005 through December 2019 with a known cancer diagnosis and at least one imaging study were eligible (n = 743). All radiology reports available for these patients were reviewed (n = 18,120). The VTE event was labeled a priori as cuVTE event for radiology reports that included descriptive texts indicating a diagnosis of thrombosis including thrombus, central venous catheter-related, thrombosed aneurysm, tumor thrombosis, non-occlusive thrombus, intraluminal filling defect, or small fragment clot for patients without documentation of clinical history and or signs of VTE. A total of 18,120 radiology reports were included in the review. The prevalence of cuVTE was 5.5% (41/743). Echocardiography and computed tomography had the highest rate of cuVTE detection, and the most common terminologies used to diagnose cuVTE were thrombus and non-occlusive thrombus. The diagnosis of cuVTE was not associated with age, sex, and type of cancer. Future efforts should focus on streamlining radiology reports to characterize thrombi. The clinical significance of these cuVTE findings and their application to management, post-thrombotic syndrome, and survival compared to cases with symptomatic VTE and patients without VTE should be further studied., (© 2024 Wiley Periodicals LLC.)

Objectives: Managing cancer symptoms while patients receive systemic treatment remains a challenge in oncology. The use of complementary and alternative medicine (CAM) approaches like virtual reality (VR) and neurofeedback (NF) in tandem with systemic treatment might reduce symptom burden for patients. The combination of VR + NF as a CAM intervention approach is novel and understudied, particularly as it relates to supportive cancer care. The purpose of this study is to summarize our VR + NF study protocol and share preliminary results regarding study retention (across 2 treatment sessions) and preliminary impact of VR or VR + NF on patient-reported outcomes such as anxiety and pain., Methods: We utilized a parallel arm trial design to compare preliminary impact of VR only and VR + NF on cancer symptoms among patients who are actively receiving cancer treatment., Results: Sixty-seven percent ( n = 20) of participants returned to participate in a second VR session, and the rates of return were the same between the VR groups. Patients in the VR + NF group showed improvements in anxiety after both sessions, while patients in the VR only group showed significant improvements in pain and depression after both sessions. Patients in the VR + NF group showed improved pain after session 1., Significance of Results: This study demonstrates that patients can be retained over multiple treatment sessions and that VR and NF remain promising treatment approaches with regard to impact on patient-reported outcomes like anxiety and pain.

The clinical importance of assessing and combining data on TP53 mutations and isoforms is discussed in this article. It gives a succinct overview of the structural makeup and key biological roles of the isoforms. It then provides a comprehensive summary of the roles that p53 isoforms play in cancer development, therapy response and resistance. The review provides a summary of studies demonstrating the role of p53 isoforms as potential prognostic indicators. It further provides evidence on how the presence of TP53 mutations may affect one or more of these activities and the association of p53 isoforms with clinicopathological data in various tumour types. The review gives insight into the present diagnostic hurdles for identifying TP53 isoforms and makes recommendations to improve their evaluation. In conclusion, this review offers suggestions for enhancing the identification and integration of TP53 isoforms in conjunction with mutation data within the clinical context., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Emerging technologies focused on the detection and quantification of circulating tumor DNA (ctDNA) in blood show extensive potential for managing patient treatment decisions, informing risk of recurrence, and predicting response to therapy. Currently available tissue-informed approaches are often limited by the need for additional sequencing of normal tissue or peripheral mononuclear cells to identify non-tumor-derived alterations while tissue-naïve approaches are often limited in sensitivity. Here we present the analytical validation for a novel ctDNA monitoring assay, FoundationOne®Tracker. The assay utilizes somatic alterations from comprehensive genomic profiling (CGP) of tumor tissue. A novel algorithm identifies monitorable alterations with a high probability of being somatic and computationally filters non-tumor-derived alterations such as germline or clonal hematopoiesis variants without the need for sequencing of additional samples. Monitorable alterations identified from tissue CGP are then quantified in blood using a multiplex polymerase chain reaction assay based on the validated SignateraTM assay. The analytical specificity of the plasma workflow is shown to be 99.6% at the sample level. Analytical sensitivity is shown to be >97.3% at ≥5 mean tumor molecules per mL of plasma (MTM/mL) when tested with the most conservative configuration using only two monitorable alterations. The assay also demonstrates high analytical accuracy when compared to liquid biopsy-based CGP as well as high qualitative (measured 100% PPA) and quantitative precision (<11.2% coefficient of variation)., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Stock and Employment from Foundation Medicine, Inc: D.R.Z., A.F., Y.H., C.G., M.C., C.X., D.J., B.W., P.P., W.C., P.H., J.H., L.D., A.Y. Stock and Employment from Natera: E.R., J.S., A.K., W.G., G.B., C.H., R.R., L.R., D.H., D.S., V.P., M.D., S.F. Stock and Employment from F. Hoffmann-La Roche: C.C., N.D., V.D., P.G., S.M. Honararia- Astellas, Pfizer, Seagen, BMS, Roche, Astra-Zeneca, MSD, Natera, Merck Serono, Johnson and Johnson - T.P. This does not alter our adherence to PLOS ONE policies on sharing data and materials, (Copyright: © 2024 Zollinger et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Importance: Complex cancer procedures are now performed in the ambulatory surgery setting. Remote symptom monitoring (RSM) with electronic patient-reported outcomes (ePROs) can identify patients at risk for acute hospital encounters. Defining normal recovery is needed to set patient expectations and optimize clinical team responses to manage evolving problems in real time., Objective: To describe the patterns of postoperative recovery among patients undergoing ambulatory cancer surgery with RSM using an ePRO platform-the Recovery Tracker., Design, Setting, and Participants: In this retrospective cohort study, patients who underwent 1 of 5 of the most common procedures (prostatectomy, nephrectomy, mastectomy, hysterectomy, or thyroidectomy) at the Josie Robertson Surgery Center at Memorial Sloan Kettering Cancer Center from September 2016 to June 2022. Patients completed the Recovery Tracker, a brief ePRO platform assessing symptoms for 10 days after surgery. Data were analyzed from September 2022 to May 2023., Main Outcomes and Measures: Symptom severity and interference were estimated by postoperative day and procedure., Results: A total of 12 433 patients were assigned 110 936 surveys. Of these patients, 7874 (63%) were female, and the median (IQR) age at surgery was 57 (47-65) years. The survey response rate was 87% (10 814 patients responding to at least 1 of 10 daily surveys). Among patients who submitted at least 1 survey, the median (IQR) number of surveys submitted was 7 (4-8), and each assessment took a median (IQR) of 1.7 (1.2-2.5) minutes to complete. Symptom burden was modest in this population, with the highest severity on postoperative days 1 to 3. Pain was moderate initially and steadily improved. Fatigue was reported by 6120 patients (57%) but was rarely severe. Maximum pain and fatigue responses (very severe) were reported by 324 of 10 814 patients (3%) and 106 of 10 814 patients (1%), respectively. The maximum pain severity (severe or very severe) was highest after nephrectomy (92 of 332 [28%]), followed by mastectomy with reconstruction (817 of 3322 [25%]) and prostatectomy (744 of 3543 [21%]). Nausea (occasionally, frequently, or almost constantly) was common and experienced on multiple days by 1485 of 9300 patients (16%), but vomiting was less common (139 of 10 812 [1%]). Temperature higher than 38 °C was reported by 740 of 10 812 (7%). Severe or very severe shortness of breath was reported by 125 of 10 813 (1%)., Conclusions and Relevance: Defining detailed postoperative symptom burden through this analysis provides valuable data to inform further implementation and maintenance of RSM programs in surgical oncology patients. These data can enhance patient education, set expectations, and support research to allow iterative improvement of clinical care based on the patient-reported experience after discharge.

Exercise oncology clinical trials contribute to the advancement of our scientific knowledge and to the safety and care of patients diagnosed with cancer. Nevertheless, regulatory reviewers and committees may not be familiar with the well-documented long-term health benefits and safety of the regular practice of physical activity. Moreover, they may not see how the benefits outweigh the risks in the context where patients diagnosed with cancer are typically seen as vulnerable. Therefore, we would like to provide a purpose-built overview of exercise oncology clinical trials for members involved in institutional review committees, including the Scientific Review Committee (SRC), the Institutional Review Board (IRB), and the Data Safety Monitoring Committee (DSMC) to facilitate a greater understanding of the safety and benefits of physical activity during cancer treatments. Communication is key to improve the success of exercise oncology clinical trials, which are vital for patients diagnosed with cancer., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Advanced age is the largest risk factor for many diseases and several types of cancer, including colorectal cancer (CRC). Senescent cells are known to accumulate with age in various tissues, where they can modulate the surrounding tissue microenvironment through their senescence associated secretory phenotype (SASP). Recently, we showed that there is an increased number of senescent cells in the colons of CRC patients and demonstrated that senescent fibroblasts and their SASP create microniches in the colon that are conducive to CRC onset and progression. However, the composition of the SASP is heterogenous and cell-specific, and the precise senescence profile of colon fibroblasts has not been well-defined. To generate a SASP atlas of human colon fibroblasts, we induced senescence in primary human colon fibroblasts using various in vitro methods and assessed the resulting transcriptome. Using RNASequencing and further validation by quantitative RT-PCR and Luminex assays, we define and validate a 'core senescent profile' that might play a significant role in shaping the colon microenvironment. We also performed KEGG analysis and GO analyses to identify key pathways and biological processes that are differentially regulated in colon fibroblast senescence. These studies provide insights into potential driver proteins involved in senescence-associated diseases, like CRC, which may lead to therapies to improve overall health in the elderly and to prevent CRC.

PRODUCTS with janus kinase (JAK) inhibition have been shown to promote hair regrowth in patients with alopecia areata (AA). To guide drug-approval and treatment decisions, it is important to understand patients' willingness to accept the potential risks of JAK inhibition in exchange for potential benefits. We quantified the treatment preferences of adult (≥18 years) and adolescent patients (12-17 years) with AA in the US and Europe to determine the trade-offs they are willing to make between benefits and risks. Preferences for oral AA treatment attributes were elicited using a discrete choice experiment consisting of 12 tasks in which patients chose between two hypothetical treatment alternatives and no treatment. Benefits included the probability of 80%-100% scalp hair regrowth (Severity of Alopecia Tool score ≤ 20) and achieving moderate-to-normal eyebrow and eyelash hair. Treatment-related risks included 3-year probabilities of serious infection, cancer, and blood clots. Preference estimates were used to calculate the maximum level of each risk that patients were willing to accept for increases in treatment benefits. The most important attribute to both adults (n = 201) and adolescents (n = 120) was a 50% probability of achieving hair regrowth on most or all the scalp; however, adolescents placed greater relative importance on this attribute than did adults. Adults were averse to the risks of serious infection, cancer, and blood clots, whereas adolescents were averse to the risk of cancer. For a 20% increase in the probability of 80%-100% scalp hair regrowth, adults were willing to accept a mean (95% confidence interval) 3-year risk of serious infection, cancer, and blood clots of 7.4% (5.5-9.3), 2.5% (1.9-3.1), and 9.3% (6.4-12.2). Adolescents were willing to accept a 3-year risk of cancer of 3.3% (2.4-4.2). Patients with AA in the US and Europe are willing to accept substantial risks to obtain an effective treatment., (© 2023 Japanese Dermatological Association.)

Objective: Robotic-guided interventions are emerging techniques that are gradually becoming a common tool for performing biopsies and tumor ablations in liver. This systematic review aims to evaluate their advancements, challenges, and outcomes., Methods: A systematic review was conducted using the PubMed database to identify relevant articles published between January 2000 and February 2023. Inclusion criteria focused on studies that assessed robotic systems for percutaneous liver biopsies and tumor ablations. Data extraction was performed to collect information on study characteristics; robotic systems; components and software; imaging modality; degree of freedom; and needle insertion methods. The outcome measures analyzed were procedure time, radiation dose, and accuracy., Results: 10 studies met the inclusion criteria. The robotic devices used included MAXIO, EPIONE, ROBIO-EX, AcuBot, and ACE robotic systems. The data set consisted of 429 percutaneous thermal ablations and 57 biopsies, both robot-guided. On average, the mean deviation of probes was reduced by 30% (from 1.6 vs 3.3 mm to 2.4 vs 3.9 mm ( p < 0.001)), and 40% ( p < 0.05) fewer readjustments were required during the robotic-assisted interventions. Moreover, robotic systems contributed to a reduction in operating time, ranging from 15% (18.3 vs 21.7 min, p < 0.001) to 25% (63.5 vs 87.4 min, p < 0.001). Finally, the radiation dose delivered to both the patient and the operator was decreased by an average of 50% ( p < 0.05) compared to manual procedures., Advances in Knowledge: Robotic systems could provide precise navigation and guidance during liver biopsies and percutaneous ablations.

Targeting transcription replication conflicts, a major source of endogenous DNA double-stranded breaks and genomic instability could have important anticancer therapeutic implications. Proliferating cell nuclear antigen (PCNA) is critical to DNA replication and repair processes. Through a rational drug design approach, we identified a small molecule PCNA inhibitor, AOH1996, which selectively kills cancer cells. AOH1996 enhances the interaction between PCNA and the largest subunit of RNA polymerase II, RPB1, and dissociates PCNA from actively transcribed chromatin regions, while inducing DNA double-stranded breaks in a transcription-dependent manner. Attenuation of RPB1 interaction with PCNA, by a point mutation in RPB1's PCNA-binding region, confers resistance to AOH1996. Orally administrable and metabolically stable, AOH1996 suppresses tumor growth as a monotherapy or as a combination treatment but causes no discernable side effects. Inhibitors of transcription replication conflict resolution may provide a new and unique therapeutic avenue for exploiting this cancer-selective vulnerability., Competing Interests: Declaration of interests The authors declare the following competing financial interest(s): City of Hope’s Office of Technology Licensing has been awarded a patent on AOH1996 and its analogs. L.H. Malkas, R.J. Hickey, D. Horne, and L. Gu are listed as inventors., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To compare results of three preference elicitation methods for a cancer screening test., Methods: Participants (undergraduate students) completed a discrete choice experiment (DCE) and a threshold technique (TT) task. Accuracy (false positives, false negatives), benefits (lives saved), and cost for a cancer screening test were used as attributes in the DCE and branching logic for the TT. Participants were also asked a direct elicitation question regarding a hypothetical screening test for breast (women) or prostate (men) cancer without mortality benefit. Correlations assessed the relationship between DCE and TT thresholds. Thresholds were standardized and ranked for both methods to compare. A logistic regression used the thresholds to predict results of the direct elicitation., Results: DCE and TT estimates were not meaningfully correlated (max ρ = 0.17). Participant rankings of attributes matched only 20% of the time (58/292). Neither method predicted preference for being screened (ps > 0.21)., Conclusions: The DCE and TT yielded different preference estimates (and rank orderings) for the same participant. Neither method predicted patients' desires for a screening test., Practice Implications: Clinicians, patients, policy makers, and researchers should be aware that patient preference results may be sensitive to the method of eliciting preferences., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Millions of people are diagnosed with cancer each year in the USA and are living on systemic therapies designed to prolong their life. While these therapies are intended to treat the disease, most exacerbate cancer symptoms such as pain and anxiety. Oncologists and other healthcare providers are now challenged to deliver adjunctive therapies designed to improve quality of life of patients while they undergo cancer treatment, including minimizing already disruptive symptoms such as cancer pain and anxiety. Complementary and alternative medicines such as immersive virtual reality (VR) and neurofeedback (NF) are novel approaches to the management of cancer symptoms. While the evidence for combining VR and NF, specifically for management of cancer pain, while patients undergo systemic therapies, is still emerging; our preliminary findings suggest this treatment modality might offer relief of cancer symptoms. This paper briefly highlights the clinical need for supportive therapies such as VR and NF in the oncological setting and summarizes innovative research in this area., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Compared to the general population, cancer patients are at higher risk of morbidity and mortality following SARS-CoV-2 infection. The immune response to a two-dose regimen of mRNA vaccines in cancer patients is generally lower than in immunocompetent individuals. Booster doses may meaningfully augment immune response in this population. We conducted an observational study with the primary objective of determining the immunogenicity of vaccine dose three (100 μg) of mRNA-1273 among cancer patients and a secondary objective of evaluating safety at 14 and 28 days., Methods: The mRNA-1273 vaccine was administered ∼7 to 9 months after administering two vaccine doses (i.e., the primary series). Immune responses (enzyme-linked immunosorbent assay [ELISA]) were assessed 28 days post-dose three. Adverse events were collected at days 14 (± 5) and 28 (+5) post-dose three. Fisher exact or X 2 tests were used to compare SARS-CoV-2 antibody positivity rates, and paired t-tests were used to compare SARS-CoV-2 antibody geometric mean titers (GMTs) across different time intervals., Results: Among 284 adults diagnosed with solid tumors or hematologic malignancies, dose three of mRNA-1273 increased the percentage of patients seropositive for SARS-CoV-2 antibody from 81.7% pre-dose three to 94.4% 28 days post-dose three. GMTs increased 19.0-fold (15.8-22.8). Patients with lymphoid cancers or solid tumors had the lowest and highest antibody titers post-dose three, respectively. Antibody responses after dose three were reduced among those who received anti-CD20 antibody treatment, had lower total lymphocyte counts and received anticancer therapy within 3 months. Among patients seronegative for SARS-CoV-2 antibody pre-dose three, 69.2% seroconverted after dose three. A majority (70.4%) experienced mostly mild, transient adverse reactions within 14 days of dose three, whereas severe treatment-emergent events within 28 days were very rare (<2%)., Conclusion: Dose three of the mRNA-1273 vaccine was well-tolerated and augmented SARS-CoV-2 seropositivity in cancer patients, especially those who did not seroconvert post-dose two or whose GMTs significantly waned post-dose two. Lymphoid cancer patients experienced lower humoral responses to dose three of the mRNA-1273 vaccine, suggesting that timely access to boosters is important for this population., (© 2023 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.)

Objective: Distress is prevalent among lymphoma patients/survivors. Current processes of distress identification rely on self-reporting by patients/survivors, which may be limited by their willingness to report symptoms. To help identify patients/survivors at greater risk, this systematic review aims to comprehensively review factors that may contribute to distress in lymphoma patients/survivors., Methods: PubMed was systematically searched for peer-reviewed primary articles (1997-2022) consisting of standardised keywords "lymphoma" and "distress." Information from 41 articles was integrated via narrative synthesis., Results: Consistent risk factors of distress include younger age, relapsed disease, and greater comorbidities and symptom burden. Active treatment and the transition from treatment to post-treatment could be challenging phases. Adequate social support, adaptive adjustment to cancer, engaging in work and healthcare professionals' support may mitigate distress. There is some evidence that older age may be associated with greater depression and life changes/experiences may shape how individuals cope with lymphoma. Gender and marital status were not robust predictors of distress. Other clinical, psychological and socioeconomic factors are understudied or have mixed findings., Conclusions: While several factors of distress align with that of other cancers, more research is needed to identify significant factors of distress in lymphoma patients/survivors. The identified factors may support clinicians in identifying distressed lymphoma patients/survivors and providing interventions where necessary. The review also highlights avenues for future research and a need to routinely collect data on distress and its factors in registries., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: To identify the proportion of Emergency Department (ED) visits in cancer patients associated with a mental and substance use disorder (MSUD) and the subsequent healthcare costs., Methods: Nationally representative data on ED visits from 2009 to 2018 was obtained from the Nationwide Emergency Department Sample (NEDS). We identified cancer-related visits with or without a MSUD using the Clinical Classifications Software diagnoses documented during the ED visit. Survey-adjusted frequencies and proportions of ED visits among adult cancer patients with or without a MSUD was evaluated. Survey-adjusted multivariable logistic regression models were used to examine demographic and clinical predictors of the presence of an MSUD and the likelihood of hospital admission for patients with a primary MSUD., Results: Among 54,004,462 ED visits with a cancer diagnosis between 2009 and 2018, 11,803,966 (22%) were associated with a MSUD. Compared to a primary diagnosis of cancer, patients who presented to the ED with a chief complaint of MSUD were more likely to be female (54% vs. 49%), younger (median: 58 vs. 66), more likely to have Medicaid insurance, and more likely to be discharged home. The three most common MSUD diagnoses among cancer patients were alcohol-related disorders, anxiety disorders, and depressive disorders. The total costs associated with a primary MSUD from 2009 to 2018 was $3,133,432,103, of which alcohol-related disorders claimed the largest majority. Younger age (OR per 10-year increase: 0.86, 95% CI: 0.85, 0.86) and female sex (OR: 1.34, 95% CI: 1.33-1.35) were associated with higher odds of having an MSUD., Conclusions: Our findings demonstrate a high burden of psychiatric and substance use illness in the cancer population and provide the rationale for early psychosocial intervention to support these patients., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Abstract: The intent of this paper and the accompanying video series is to inform the scientific community about the historical foundations that underpin the linear no-threshold (LNT) model's use for cancer risk assessment. There is a clear distinction here: this effort is about the history of how LNT came to be the regulatory paradigm and model for cancer risk assessment that it is today and not a discussion of the pros and cons of the LNT model. The overarching goal of this effort is to reframe the conversation around low-dose response models in light of this history and to determine how this history influences the scientific understanding of low-dose radiation responses. The timing of this series is intentional, as the International Commission on Radiological Protection (ICRP) has embarked on a mission to review the entire system of radiation protection. This effort necessarily requires rigorous scientific debate that must be based in fact. The history of the LNT model is paramount to this discussion, and it warrants consideration. Unfortunately, rather than engendering respectful debate, the topic of cancer risks associated with low dose radiation exposures has forged two disparate and sometimes contentious camps: (1) low doses, no matter how low, present some form of health risk and (2) an alternative model better represents the actual risks. The video series, conceived by John Cardarelli II, current President of the Health Physics Society (HPS), features Edward Calabrese, professor of toxicology in the School of Public Health and Health Sciences at the University of Massachusetts at Amherst, being interviewed by HPS Past-President Barbara Hamrick, CHP, JD, with support from Daniel Sowers, the Chair of the HPS Public Information Committee, and HPS Executive Director Brett Burk. Emily Caffrey, the Chief Editor of our Ask-the-Experts website (https://hps.org/publicinformation/ate/), was invited to watch the completed series as an independent peer reviewer. Further, an email address, factcheck@hps.org, was created to allow for peer-review by the scientific community to facilitate ongoing discussion and allow for corrections to the record as necessary. It is the sincere hope of this team that this work inspires new discussions about the system of radiological protection. We encourage everyone in this field to watch all 22 episodes to be informed about the underpinnings of current regulatory policy in the US., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Health Physics Society.)

Purpose: More oncologists desire to treat their patients with immune checkpoint inhibitors (ICIs) in the inpatient setting as their use has become more widespread for numerous oncologic indications. This is cost-prohibitive to patients and institutions because of high drug cost and lack of reimbursement in the inpatient setting. We sought to examine current practice of inpatient ICI administration to determine if and in which clinical scenarios it may provide significant clinical benefit and therefore be warranted regardless of cost., Methods: We conducted a retrospective chart review of adult patients who received at least one dose of an ICI for treatment of an active solid tumor malignancy during hospitalization at a single academic medical center between January 2017 and June 2018. Patient, disease, and admission characteristics including mortality data were examined, and cost analysis was performed., Results: Sixty-five doses of ICIs were administered to 58 patients during the study period. Nearly 40% and 80% of patients died within 30 days and 180 days of ICI administration, respectively. There was a trend toward longer overall survival in patients with good prognostic factors including positive programmed death-ligand 1 (PD-L1) expression or microsatellite instability-high (MSI-H) status. Slightly over 70% of patients were discharged within 7 days of ICI administration. The total cost of inpatient ICI administration over the 18-month study period was $615,016 US dollars., Conclusion: Inpatient ICI administration is associated with high costs and poor outcomes in acutely ill hospitalized patients with advanced solid tumor malignancies and therefore should largely be avoided. Careful discharge planning to expedite outpatient treatment after discharge will be paramount in ensuring patients with good prognostic features who will benefit most from ICI therapy can be promptly treated in the outpatient setting as treating very close to discharge in the inpatient setting appears to be unnecessary, regardless of tumor features.

Unreliable predictions can occur when an artificial intelligence (AI) system is presented with data it has not been exposed to during training. We demonstrate the use of conformal prediction to detect unreliable predictions, using histopathological diagnosis and grading of prostate biopsies as example. We digitized 7788 prostate biopsies from 1192 men in the STHLM3 diagnostic study, used for training, and 3059 biopsies from 676 men used for testing. With conformal prediction, 1 in 794 (0.1%) predictions is incorrect for cancer diagnosis (compared to 14 errors [2%] without conformal prediction) while 175 (22%) of the predictions are flagged as unreliable when the AI-system is presented with new data from the same lab and scanner that it was trained on. Conformal prediction could with small samples (N = 49 for external scanner, N = 10 for external lab and scanner, and N = 12 for external lab, scanner and pathology assessment) detect systematic differences in external data leading to worse predictive performance. The AI-system with conformal prediction commits 3 (2%) errors for cancer detection in cases of atypical prostate tissue compared to 44 (25%) without conformal prediction, while the system flags 143 (80%) unreliable predictions. We conclude that conformal prediction can increase patient safety of AI-systems., (© 2022. The Author(s).)

Purpose: Cyclophosphamide is a commonly used cancer agent that is metabolically activated by polymorphic enzymes. This study aims to investigate the association between predicted activity of candidate pharmacogenes with severe toxicity during cyclophosphamide treatment., Methods: Genome-wide genetic data was collected from an institutional genetic data repository for CYP2B6, CYP3A4, CYP2C9, CYP2C19, GSTA1, GSTP1, ALDH1A1, ALDH3A1, ABCC1, ABCB1, and ERCC1. Treatment and toxicity data were retrospectively collected from the patient's medical record. The a priori selected primary hypothesis was that patients who have CYP2B6 reduced metabolizer activity (poor or intermediate (PM/IM) vs. normal (NM) metabolizer) have lower risk of severe toxicity or cyclophosphamide treatment modification due to toxicity., Results: In the primary analysis of 510 cyclophosphamide-treated patients with available genetic data, there was no difference in the odds of severe toxicity or treatment modification due to toxicity in CYP2B6 PM/IM vs. NM (odds ratio = 0.97, 95% Confidence Interval: 0.62-1.50, p = 0.88). In an exploratory, statistically uncorrected secondary analysis, carriers of the ALDH1A1 rs8187996 variant had a lower risk of the primary toxicity endpoint compared with wild-type homozygous patients (odds ratio = 0.31, 95% Confidence Interval: 0.09-0.78, p = 0.028). None of the other tested phenotypes or genotypes was associated with the primary or secondary endpoints in unadjusted analysis (all p > 0.05)., Conclusion: The finding that patients who carry ALDH1A1 rs8187996 may have a lower risk of cyclophosphamide toxicity than wild-type patients contradicts a prior finding for this variant and should be viewed with skepticism. We found weak evidence that any of these candidate pharmacogenetic predictors of cyclophosphamide toxicity may be useful to personalize cyclophosphamide dosing to optimize therapeutic outcomes in patients with cancer., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The proteome provides unique insights into disease biology beyond the genome and transcriptome. A lack of large proteomic datasets has restricted the identification of new cancer biomarkers. Here, proteomes of 949 cancer cell lines across 28 tissue types are analyzed by mass spectrometry. Deploying a workflow to quantify 8,498 proteins, these data capture evidence of cell-type and post-transcriptional modifications. Integrating multi-omics, drug response, and CRISPR-Cas9 gene essentiality screens with a deep learning-based pipeline reveals thousands of protein biomarkers of cancer vulnerabilities that are not significant at the transcript level. The power of the proteome to predict drug response is very similar to that of the transcriptome. Further, random downsampling to only 1,500 proteins has limited impact on predictive power, consistent with protein networks being highly connected and co-regulated. This pan-cancer proteomic map (ProCan-DepMapSanger) is a comprehensive resource available at https://cellmodelpassports.sanger.ac.uk., Competing Interests: Declaration of interests M.J.G. has received research funding from AstraZeneca, GSK, Astex Therapeutics, and Open Targets, a public-private initiative involving academia and industry, and is a co-founder of Mosaic Therapeutics. All other authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Cancer impacts caregivers as well as patients. Ambulatory oncology surgeries requiring a short hospital stay place additional responsibility on informal caregivers as they help patients navigate their post-operative recovery at home, and determine if symptoms are expected or emergent. Our objective was to explore the experience of informal caregivers during patients' ambulatory cancer surgery and then recovery at home with remote monitoring of symptoms via web-based patient-reported outcomes questionnaire ("Recovery Tracker")., Methods: Semi-structured interviews were conducted with caregivers from a larger sample participating in a randomized trial of the Recovery Tracker. Thematic analysis was applied to derive key themes and codes via NVivo qualitative analysis software (QSR International Inc.). Recruitment was conducted iteratively to ensure a heterogenous sample and thematic saturation., Results: Twenty-three semi-structured interviews were conducted. Four main themes emerged: (1) Predictability reduced stress among caregivers; (2) Unexpected events caused stress for caregivers; (3) The importance of a caregiver being present during the recovery process; and (4) Caregiver involvement in remote monitoring of symptoms was minimal., Conclusion: Caregivers report not being overly burdened by the ambulatory surgery process, but they are very sensitive to any deviations from what they expected to happen. Further research and clinical practice on caregivers in the ambulatory setting should focus on how to set expectations and avoid unexpected events., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: The objective of this study is to report disease outcomes and toxicity with the use of stereotactic body radiation therapy (SBRT) in the treatment of pediatric metastatic disease., Methods: All pediatric and adolescent young adult (AYA) patients' who received SBRT were included between the years 2000 and 2020. Study endpoints included local control (LC), progression-free survival (PFS), overall survival (OS), cumulative incidence (CI) of death or local failure and toxicity. The end points with respect to survival and LC were calculated using the Kaplan-Meier estimate. The cumulative incidence of local failure was calculated using death as a competing risk., Results: 16 patients with 36 lesions irradiated met inclusion criteria and formed the study cohort. The median OS and PFS for the entire cohort were 17 months and 15.7 months, respectively. The 1 year OS for the entire cohort was 75%. The 6- and 12 month local control was 85 and 78%, respectively. There were no local failures in irradiated lesions for patients who received a BED 10 ≥100 Gy. Patients who were treated with SBRT who had ≤5 metastatic lesions at first recurrence had a superior 1 year OS of 100  vs 50% for those with >5 lesions. One patient (6.3%) experienced a Grade 3 central nervous system toxicity., Conclusion: LC was excellent with SBRT delivered to metastatic disease, particularly for lesions receiving a BED 10 ≥100 Gy. High-grade toxicity was rare in our patient population. Patients with five or fewer metastatic sites have a significantly better OS compared to >5 sites., Advances in Knowledge: This study demonstrates that SBRT is safe and efficacious in the treatment of pediatric oligometastatic disease.

Purpose: Provider well-being has become the fourth pillar of the quadruple aim for providing quality care. Exacerbated by the global COVID-19 pandemic, provider well-being has become a critical issue for health care systems worldwide. We describe the prevalence and key system-level drivers of burnout in oncologists in Ontario, Canada., Methods: This is a cross-sectional survey study conducted in November-December 2019 of practicing cancer care physicians (surgical, medical, radiation, gynecologic oncology, and hematology) in Ontario, Canada. Ontario is Canada's largest province (with a population of 14.5 million), and has a single-payer publicly funded cancer system. The primary outcome was burnout experience assessed through the Maslach Burnout Inventory., Results: A total of 418 physicians completed the questionnaire (response rate was 44% among confirmed oncologists). Seventy-three percent (n = 264 of 362) of oncologists had symptoms of burnout (high emotional exhaustion and/or depersonalization scores). Significant drivers of burnout identified in multivariable regression modeling included working in a hectic or chaotic atmosphere (odds ratio [OR] = 15.5; 95% CI, 3.4 to 71.5; P < .001), feeling unappreciated on the job (OR = 7.9; 95% CI, 2.9 to 21.3; P < .001), reporting poor or marginal control over workload (OR = 7.9; 95% CI, 2.9 to 21.3; P < .001), and not being comfortable talking to peers about workplace stress (OR = 3.0; 95% CI, 1.1 to 7.9; P < .001). Older age (≥ 56 years) was associated with lower odds of burnout (OR = 0.16; 95% CI, 0.1 to 0.4; P < .001)., Conclusion: Nearly three quarters of participants met predefined standardized criteria for burnout. This number is striking, given the known impact of burnout on provider mental health, patient safety, and quality of care, and suggests Oncologists in Ontario may be a vulnerable group that warrants attention. Health care changes being driven by the COVID-19 pandemic provide an opportunity to rebuild new systems that address drivers of burnout. Creating richer peer-to-peer and leadership engagement opportunities among early- to mid-career individuals may be a worthwhile organizational strategy., Competing Interests: Simron SinghEmployment: Sanofi (I), AstraZeneca (I)Honoraria: Novartis, IpsenResearch Funding: Novartis Brett NichollsEmployment: McKesson Canada Andrea EisenOther Relationship: Cancer Care Ontario Conrad B. FalksonStock and Other Ownership Interests: AllScripts Maureen TrudeauStock and Other Ownership Interests: RNA DiagnosticsResearch Funding: Roche Canada, Novartis, Pfizer, Eisai, AstraZeneca, Astellas Pharma, Genomic Health Tait ShanafeltHonoraria: Multiple Healthcare OrganizationsResearch Funding: Pharmacyclics, GlaxoSmithKline, Genentech, Celgene, Hospira, Cephalon, Polyphenon E InternationalPatents, Royalties, Other Intellectual Property: Dr Shanafelt is coinventor of the Well-being Index Instruments (Physician Well-being Index; Nurse Well-being Index; Medical Student Well-being Index; Well-being Index) and the Mayo Clinic Participatory Management Leadership Index. Mayo Clinic holds the copyright to these instruments and has licensed them for use outside Mayo Clinic. Mayo Clinic pays Dr Shanafelt receives a portion of any royalties it receivesOther Relationship: Medical CentersOpen Payments Link: https://openpaymentsdata.cms.gov/physician/429217 Glenn BaumanHonoraria: BayerResearch Funding: SiemensNo other potential conflicts of interest were reported.

Introduction: Cancer patients are increasingly incorporating medical marijuana into the management of treatment-related side effects. Currently however, data is limited regarding the risks and benefits of therapeutic cannabis for cancer patients. We sought to characterize radiation oncologists' practices and opinions regarding therapeutic cannabis via a nationwide survey., Materials and Methods: An anonymous survey was distributed via email to 873 radiation oncologists in the American Society for Radiation Oncology member database. Radiation oncologists were asked their opinions and practices regarding the use of therapeutic cannabis for their patients. Bivariate analyses of potential predictors for responses were conducted using standard statistical techniques., Results: One hundred seven radiation oncologists completed the survey. According to the survey, 36% of respondents would recommend therapeutic cannabis to their patients to mitigate treatment toxicity. Physicians practicing in states where medical marijuana is legal were more likely to recommend it compared to physicians working in states that have not legalized medical marijuana (OR = 3.79, 1.19-12.1, p = 0.01). Seventy-one percent of respondents reported therapeutic cannabis as being effective at least some of the time for managing treatment-related toxicities. Fifty-eight percent of physicians reported lacking sufficient knowledge to advise patients regarding therapeutic cannabis, while 86% of respondents were interested in learning more about therapeutic cannabis for cancer patients., Conclusions: Although a majority of radiation oncologists believe there are benefits to therapeutic cannabis, many are hesitant to recommend for or against its use. Radiation oncologists appear to be interested in learning more about how therapeutic cannabis may play a role in their patients' care., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The development of an aptamer-based therapeutic has rapidly progressed following the first two reports in the 1990s, underscoring the advantages of aptamer drugs associated with their unique binding properties. In 2004, the US Food and Drug Administration (FDA) approved the first therapeutic aptamer for the treatment of neovascular age-related macular degeneration, Macugen developed by NeXstar. Since then, eleven aptamers have successfully entered clinical trials for various therapeutic indications. Despite some of the pre-clinical and clinical successes of aptamers as therapeutics, no aptamer has been approved by the FDA for the treatment of cancer. This review highlights the most recent and cutting-edge approaches in the development of aptamers for the treatment of cancer types most refractory to conventional therapies. Herein, we will review (1) the development of aptamers to enhance anti-cancer immunity and as delivery tools for inducing the expression of immunogenic neoantigens; (2) the development of the most promising therapeutic aptamers designed to target the hard-to-treat cancers such as brain tumors; and (3) the development of "carrier" aptamers able to target and penetrate tumors and metastasis, delivering RNA therapeutics to the cytosol and nucleus., Competing Interests: Declaration of interests B.S. is co-founder of Sebastian Bio, which has intellectual property (IP) on the AS1411-siTAP chimera. P.H.G. is employed by Wave Life Sciences and receives salary and shares from Wave Life Sciences., (Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Introduction: Sars-CoV-2 is a novel coronavirus responsible for COVID-19 officially declared pandemic in March 2020. Health systems worldwide responded with swift changes to increase workflow capacity while protecting the vulnerable, including those with cancer. This led to unprecedented and rapid restructuring of health service provision. Published data from the 2003 SARS pandemic focuses on medical and nursing staff, overlooking other departmental employees such as administration officers or food service workers. Our protocol aims to document directives and adjustments communicated to staff in two cancer care departments and correlate this with measures of distress and perceived preparedness across the spectrum of all staff involved in cancer care., Methods and Analysis: We use a semiqualitative approach comprising weekly diarising of events and simultaneous staff surveys. Principal investigators will document changes at a metropolitan quaternary cancer centre and a regional cancer centre. Communications, directives and changes will be diarised in real time in four executional domains. Simultaneously, prospective voluntary self-administered online surveys will be conducted at regular intervals by staff. The survey assesses the perceived institutional preparedness and personal well-being, with a combination of Likert scaled and open response questions. A semiquantitative self-assessment of distress adapted from National Comprehensive Cancer Network distress thermometer is incorporated. Additionally, open-text personal reflections on themes including difficult decisions will be invited. Survey participants will be drawn from various work areas of the cancer care departments: administrative staff, health professionals, for example, allied health, ancillary workers, nursing and medical., Ethics and Dissemination: The study has been reviewed and approved by the Human Research Ethics Committee (LNR/2020/QRBW/62982). Published literature on domains of distress neglects categories of healthcare worker who form an essential part of the care delivery team. Our study hopes to gather insights about psychosocial impact and adjustment which could direct responses in future emergencies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Dihydroartemisinin (DHA) is an FDA-approved antimalarial drug that has been repurposed for cancer therapy because of its preferential antiproliferative effects on cancer versus normal cells. Mitochondria represent an attractive target for cancer therapy based on their regulatory role in proliferation and cell death. This study investigates whether DHA conjugated to innately fluorescent N-alkyl triphenylvinylpyridinium (TPVP) perturbs mitochondrial functions resulting in a differential toxicity of cancer versus normal cells. TPVP-DHA treatments resulted in a dose-dependent toxicity of human melanoma and pancreatic cancer cells, whereas normal human fibroblasts were resistant to this treatment. TPVP-DHA treatments resulted in a G 1 -delay of the cancer cell cycle, which was also associated with a significant inhibition of the mTOR-metabolic and ERK1/2-proliferative signaling pathways. TPVP-DHA treatments perturbed mitochondrial functions, which correlated with increases in mitochondrial fission. In summary, TPVP mediated mitochondrial targeting of DHA enhanced cancer cell toxicity by perturbing mitochondrial functions and morphology., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of Competing Interest None of the authors has conflict of interest or disclosures, except for Ashley Rosko, who is an associate editor for JGO.

Objective: To understand the prevalence of behavioral and characterological self-blame and their associations with stated preferences for life-extension and the use of pain-relief medication in a multi-country cohort of advanced cancer patients., Methods: The prevalence of self-blame and reasons participants attributed to their diagnosis was assessed in a sample of 968 advanced cancer patients enrolled in one of five sites from four Asian countries of the multi-country cross-sectional survey titled APRROACH. Ordered probit and Firth logistic regressions were used to determine associations between each type of self-blame and two treatment-related outcomes: participants' stated preference for life-extension and the use of pain-relief medication in the last 24 h., Results: Behavioral and characterological self-blame were reported by 41% and 49% of the participants respectively, with only 19% and 2% of participants providing a logically consistent reason for the two types of self-blame. We observed no statistically significant differences in stated preferences for life-extension for either type of self-blame and in the use of pain-relief medication for participants reporting behavioral self-blame. However, participants reporting characterological self-blame were 9.7% (95% CI, 2.0% to 17.3%; p = 0.014) more likely to report using pain-relief medication compared to participants not reporting characterological self-blame., Conclusions: A substantial proportion of patients report self-blame and those reporting characterological self-blame appear more likely to use pain medication. Therefore, developing interventions aimed at reducing characterological self-blame might help patients receive only appropriate treatments as opposed to treatments pursued in response to feelings of self-blame., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: The COVID-19 pandemic has presented challenges to delivering safe and timely care for cancer patients. The oncology community has undertaken substantial workflow adaptations to reduce transmission risk for patients and providers. While various control measureshave been proposed and implemented, little is known about their impact on safety of the radiation oncology workflow and potential for transmission. The objective of this study was to assess potential safety impacts of control measures employed during the COVID-19 pandemic., Methods: A multi-institutional study was undertaken to assess the risks of pandemic-associated workflow adaptations using failure mode and effects analysis (FMEA). Failure modes were identified and scored using FMEA formalism. FMEA scores were used to identify highest-risk aspects of the radiation therapy process. The impact of control measures on overall risk was quantified. Agreement among institutions was evaluated., Results: Thirty three failure modes and 22 control measures were identified. Control measures resulted in risk score reductions for 22 of the failure modes, with the largest reductions from screening of patients and staff, requiring use of masks, and regular cleaning of patient areas. The median risk score for all failure modes was reduced from 280 to 168. There was high institutional agreement for 90.3% of failure modes but only 47% of control measures., Conclusions: COVID-related risks are similar across oncology practices in this study. While control measures can reducerisk, their use varied. The effectiveness of control measures on risk may guide selection of the highest-impact workflow adaptions to ensure safe care in oncology., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Aim: Patients with acute ischemic stroke associated with cancer have D-dimer elevations greater than those with acute ischemic stroke or cancer alone. While D-dimer has been proposed as a screening tool to identify such patients, its use in clinical practice to identify malignancy and to inform the use of CT scanning has not been well characterized., Methods: We conducted a retrospective cohort study of patients with acute ischemic stroke to evaluate how D-dimer levels and CT chest, abdomen, and pelvis scanning were used in practice to screen for occult malignancy. Patients were excluded if they had known active cancer and or received tPA., Results: Of 480 patients, 254 (53%) had D-dimer measured, 49 (10%) underwent CT screening for cancer, and 11 (2%) had findings concerning for malignancy. There was no difference in D-dimer level between patients who underwent CT evaluation for cancer and those who did not (median 1.01 vs 0.85 p = 0.19). Patients with CT concerning for cancer had higher D-dimer levels than those with a negative CT (median 2.52 vs 0.74 p = 0.01). D-dimer demonstrated moderate discrimination with a c-statistic of 0.77. Selecting a cut point of >1.2 ug/mL (60 th percentile of our cohort and 2.4-times the upper limit of normal for our institution's D-dimer assay) provided a sensitivity of 85% and specificity of 65%, a positive likelihood ratio of 2.32, and an odds ratio of 9.6 (95% confidence interval 2.1-44.1, p = 0.004) for having a CT scan concerning for malignancy., Conclusions: Elevated D-dimer levels are suggestive of occult malignancy in acute ischemic stroke patients and should inform selective use of CT to screen for cancer., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Foci of necrosis are frequently seen in malignant tumours and may be due to a variety of causes. Different types of necrosis are given various names based upon their morphological features and presumed pathogenesis, such as coagulative, liquefactive and fibrinoid necrosis. Here, we propose the term 'granular necrosis' (GN) for a specific form of tumour necrosis characterised by the presence of well-defined necrotic foci being sharply demarcated from adjacent viable tumour. A constant feature is loss of architecture resulting in an amorphous necrotic mass containing granular nuclear and cytoplasmic debris, without an associated neutrophilic infiltrate. There is usually extensive karyorrhexis, which in larger tumours is more prominent at the periphery. These foci are often microscopic but may range up to several millimetres or larger in size. This distinctive form of necrosis has been erroneously given a variety of names in the literature including coagulative necrosis and microscopic necrosis, which on the basis of the aforementioned gross and microscopic findings is inappropriate. It is apparent that this is a specific form of necrosis, hence the descriptive term 'granular necrosis' that differentiates this form of necrosis from other types. The presence of GN is recognised as occurring in a variety of tumour types, being commonly seen in renal cell carcinoma, where it has been shown to have independent prognostic significance. In some epithelial and stromal tumours of the uterus, the presence of GN also has prognostic significance and is a defining feature for the differentiation of uterine leiomyoma and leiomyosarcoma. The pathogenesis of GN is unresolved. It does not show the features of apoptosis and in recent studies has been shown to have some of the molecular changes associated with necroptosis., (Copyright © 2020. Published by Elsevier B.V.)

Vaccination of patients against neoantigens expressed in concurrent tumors, recurrent tumors, or tumors developing in individuals at risk of cancer is posing major challenges in terms of which antigens to target and is limited to patients expressing neoantigens in their tumors. Here, we describe a vaccination strategy against antigens that were induced in tumor cells by downregulation of the peptide transporter associated with antigen processing (TAP). Vaccination against TAP downregulation-induced antigens was more effective than vaccination against mutation-derived neoantigens, was devoid of measurable toxicity, and inhibited the growth of concurrent and future tumors in models of recurrence and premalignant disease. Human CD8 + T cells stimulated with TAP low dendritic cells elicited a polyclonal T-cell response that recognized tumor cells with experimentally reduced TAP expression. Vaccination against TAP downregulation-induced antigens overcomes the main limitations of vaccinating against mostly unique tumor-resident neoantigens and could represent a simpler vaccination strategy that will be applicable to most patients with cancer., (©2020 American Association for Cancer Research.)

Purpose: The Electronic Medical Record Search Engine (EMERSE) is a software tool built to aid research spanning cohort discovery, population health, and data abstraction for clinical trials. EMERSE is now live at three academic medical centers, with additional sites currently working on implementation. In this report, we describe how EMERSE has been used to support cancer research based on a variety of metrics., Methods: We identified peer-reviewed publications that used EMERSE through online searches as well as through direct e-mails to users based on audit logs. These logs were also used to summarize use at each of the three sites. Search terms for two of the sites were characterized using the natural language processing tool MetaMap to determine to which semantic types the terms could be mapped., Results: We identified a total of 326 peer-reviewed publications that used EMERSE through August 2019, although this is likely an underestimation of the true total based on the use log analysis. Oncology-related research comprised nearly one third (n = 105; 32.2%) of all research output. The use logs showed that EMERSE had been used by multiple people at each site (nearly 3,500 across all three) who had collectively logged into the system > 100,000 times. Many user-entered search queries could not be mapped to a semantic type, but the most common semantic type for terms that did match was "disease or syndrome," followed by "pharmacologic substance.", Conclusion: EMERSE has been shown to be a valuable tool for supporting cancer research. It has been successfully deployed at other sites, despite some implementation challenges unique to each deployment environment.

Background: Initially characterized as axon guidance factors, semaphorins also have been implicated to have critical roles in multiple physiological and developmental functions, including the regulation of immune responses, angiogenesis, organ formation, and the etiology of multiple forms of cancer. Moreover, their contribution in immunity and the regulation of tumour microenvironment is becoming increasingly recognized. Here, we provide a comprehensive analysis of class-3 semaphorins, the only secreted family of genes among veterbrate semaphorins, in terms of their expression profiles and their association with patient survival. We also relate their role with immune subtypes, tumour microenvironment, and drug sensitivity using a pan-cancer study., Results: Expression profiles of class-3 semaphorins (SEMA3s) and their association with patient survival and tumour microenvironment were studied in 31 cancer types using the TCGA pan-cancer data. The expression of SEMA3 family varies in different cancer types with striking inter- and intra- cancer heterogeneity. In general, our results show that SEMA3A, SEMA3C, and SEMA3F are primarily upregulated in cancer cells, while the rest of SEMA3s are mainly down-regulated in the tested tumours. The expression of SEMA3 family members was frequently associated with patient overall survival. However, the direction of the association varied with regards to the particular SEMA3 isoform queried and the specific cancer type tested. More specifically, SEMA3A and SEMA3E primarily associate with a poor prognosis of survival, while SEMA3G typically associates with survival advantage. The rest of SEMA3s show either survival advantage or disadvantage dependent on cancer type. In addition, all SEMA3 genes show significant association with immune infiltrate subtypes, and they also correlate with level of stromal cell infiltration and tumour cell stemness with various degrees. Finally, our study revealed that SEMA3 genes, especially SEMA3C and SEMA3F may contribute to drug induced cancer cell resistance., Conclusions: Our systematic analysis of class-3 semaphorin gene expression and their association with immune infiltrates, tumour microenvironment and cancer patient outcomes highlights the need to study each SEMA3 member as a separate entity within each specific cancer type. Also our study validated the identification of class-3 semaphorin signals as promising therapeutic targets in cancer although further laboratory validation still needed.

Cytotoxic molecules can kill cancer cells by disrupting critical cellular processes or by inducing novel activities. 6-(4-(Diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2 H )-one (DNMDP) is a small molecule that kills cancer cells by generation of novel activity. DNMDP induces complex formation between phosphodiesterase 3A (PDE3A) and schlafen family member 12 (SLFN12) and specifically kills cancer cells expressing elevated levels of these two proteins. Here, we examined the characteristics and covariates of the cancer cell response to DNMDP. On average, the sensitivity of human cancer cell lines to DNMDP is correlated with PDE3A expression levels. However, DNMDP could also bind the related protein, PDE3B, and PDE3B supported DNMDP sensitivity in the absence of PDE3A expression. Although inhibition of PDE3A catalytic activity did not account for DNMDP sensitivity, we found that expression of the catalytic domain of PDE3A in cancer cells lacking PDE3A is sufficient to confer sensitivity to DNMDP, and substitutions in the PDE3A active site abolish compound binding. Moreover, a genome-wide CRISPR screen identified the aryl hydrocarbon receptor-interacting protein (AIP), a co-chaperone protein, as required for response to DNMDP. We determined that AIP is also required for PDE3A-SLFN12 complex formation. Our results provide mechanistic insights into how DNMDP induces PDE3A-SLFN12 complex formation, thereby killing cancer cells with high levels of PDE3A and SLFN12 expression., (© 2020 Wu et al.)

Purpose: Cancer patients are at a higher risk of venous thromboembolism (VTE) than the general population. In the general population, blacks are at a higher risk of VTE compared with whites. The influence of race on cancer-associated VTE remains unexplored. We examined whether black cancer patients are at a higher risk of VTE and whether these differences are present in specific cancer types., Design: A retrospective study was performed in the largest safety net hospital of New England using a cohort of cancer patients characterized by a substantial number of nonwhites., Results: We identified 16,498 subjects with solid organ and hematologic malignancies from 2004 to 2018. Among them, we found 186 unique incident VTE events, of which the majority of the events accrued within the first 2 years of cancer diagnosis. Overall, blacks showed a 3-fold higher incidence of VTE (1.8%) compared with whites (0.6%; P<0.001). This difference was observed in certain cancer types such as lung, gastric and colorectal. In lung cancer, the odds of developing VTE in blacks was 2.77-times greater than those in white patients (confidence interval, 1.33-5.91; P=0.007). Despite the greater incidence of cancer-associated VTE in blacks, their Khorana risk score of VTE was not higher., Conclusions: In a diverse cancer cohort, we observed a higher incidence of cancer-associated VTE in blacks compared with patients from other races. This study indicates the consideration of race in the risk assessment of cancer-associated VTE. It could also lead to future mechanistic studies aiming at identifying reasons for differential VTE risk depending on cancer type.

Biomarkers based on transcriptional profiling can be useful in the measurement of complex and/or dynamic physiological states where other profiling strategies such as genomic or proteomic characterization are not able to adequately measure the biology. One particular advantage of transcriptional biomarkers is the ease with which they can be measured in the clinical setting using robust platforms such as the NanoString nCounter system. The nCounter platform enables digital quantitation of multiplexed RNA from small amounts of blood, formalin-fixed, paraffin-embedded tumors, or other such biological samples that are readily available from patients, and the chapter uses it as the primary example for diagnostic assay development. However, development of diagnostic assays based on RNA biomarkers on any platform requires careful consideration of all aspects of the final clinical assay a priori, as well as design and execution of the development program in a way that will maximize likelihood of future success. This chapter introduces transcriptional biomarkers and provides an overview of the design and development process that will lead to a locked diagnostic assay that is ready for validation of clinical utility.

The cancer tissue proteome has enormous potential as a source of novel predictive biomarkers in oncology. Progress in the development of mass spectrometry (MS)-based tissue proteomics now presents an opportunity to exploit this by applying the strategies of comprehensive molecular profiling and big-data analytics that are refined in other fields of 'omics research. ProCan (ProCan is a registered trademark) is a program aiming to generate high-quality tissue proteomic data across a broad spectrum of cancer types. It is based on data-independent acquisition-MS proteomic analysis of annotated tissue samples sourced through collaboration with expert clinical and cancer research groups. The practical requirements of a high-throughput translational research program have shaped the approach that ProCan is taking to address challenges in study design, sample preparation, raw data acquisition, and data analysis. The ultimate goal is to establish a large proteomics knowledge-base that, in combination with other cancer 'omics data, will accelerate cancer research., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Neoantigen burden is a major determinant of tumor immunogenicity, underscored by recent clinical experience with checkpoint blockade therapy. Yet the majority of patients do not express, or express too few, neoantigens, and hence are less responsive to immune therapy. Here we describe an approach whereby a common set of new antigens are induced in tumor cells in situ by transient downregulation of the transporter associated with antigen processing (TAP). Administration of TAP siRNA conjugated to a broad-range tumor-targeting nucleolin aptamer inhibited tumor growth in multiple tumor models without measurable toxicity, was comparatively effective to vaccination against prototypic mutation-generated neoantigens, potentiated the antitumor effect of PD-1 antibody or Flt3 ligand, and induced the presentation of a TAP-independent peptide in human tumor cells. Treatment with the chemically-synthesized nucleolin aptamer-TAP siRNA conjugate represents a broadly-applicable approach to increase the antigenicity of tumor lesions and thereby enhance the effectiveness of immune potentiating therapies.

Purpose: Travel for patients with cancer has become more achievable because of gains in quality of life and overall survival. The risk assessment of these patients is complex, and there is a paucity of data to which clinicians can refer. We present the challenges of traveling with cancer and a review of the literature., Methods: A review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed. A search using the terms "cancer," "advanced cancer," "metastases," "brain edema," "lymphoedema," "pneumothorax," "pleural effusion," "pericardial effusion," pneumonitis," "hypoxia," "end-of-life," and "shunt," combined with "flying" and "air travel," was conducted. The PubMed and Cochrane databases were searched for English-language studies up to December 2018. Studies, case reports, or guidelines referring to travel in the context of adult patients with malignancies were included. A total of 745 published articles were identified; 16 studies were included. An inclusive approach to data extraction was used., Results: There were no specific criteria to deem a patient with cancer fit to travel. Neurologic, respiratory, and cardiac implications, and time from recent surgery or procedure need to be considered There was a lack of high-quality studies to inform decisions, but the British Thoracic Society and Aerospace Medical Association Medical Guidelines included recommendations for fitness to fly for patients with cancer., Conclusion: In the absence of large prospective studies, individual fitness to travel should be assessed on a case-by-case basis, bearing in mind that maximizing a patient's ability to safely travel is an important goal for many individuals with cancer.

Background: Rapid advances in science challenge the timely adoption of evidence-based care in community settings. To bridge the gap between what is possible and what is practiced, we researched approaches to developing an artificial intelligence (AI) application that can provide real-time patient-specific decision support., Materials and Methods: The Oncology Expert Advisor (OEA) was designed to simulate peer-to-peer consultation with three core functions: patient history summarization, treatment options recommendation, and management advisory. Machine-learning algorithms were trained to construct a dynamic summary of patients cancer history and to suggest approved therapy or investigative trial options. All patient data used were retrospectively accrued. Ground truth was established for approximately 1,000 unique patients. The full Medline database of more than 23 million published abstracts was used as the literature corpus., Results: OEA's accuracies of searching disparate sources within electronic medical records to extract complex clinical concepts from unstructured text documents varied, with F1 scores of 90%-96% for non-time-dependent concepts (e.g., diagnosis) and F1 scores of 63%-65% for time-dependent concepts (e.g., therapy history timeline). Based on constructed patient profiles, OEA suggests approved therapy options linked to supporting evidence (99.9% recall; 88% precision), and screens for eligible clinical trials on ClinicalTrials.gov (97.9% recall; 96.9% precision)., Conclusion: Our results demonstrated technical feasibility of an AI-powered application to construct longitudinal patient profiles in context and to suggest evidence-based treatment and trial options. Our experience highlighted the necessity of collaboration across clinical and AI domains, and the requirement of clinical expertise throughout the process, from design to training to testing., Implications for Practice: Artificial intelligence (AI)-powered digital advisors such as the Oncology Expert Advisor have the potential to augment the capacity and update the knowledge base of practicing oncologists. By constructing dynamic patient profiles from disparate data sources and organizing and vetting vast literature for relevance to a specific patient, such AI applications could empower oncologists to consider all therapy options based on the latest scientific evidence for their patients, and help them spend less time on information "hunting and gathering" and more time with the patients. However, realization of this will require not only AI technology maturation but also active participation and leadership by clincial experts., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)