US National Cancer Research Articles

Operative versus Nonoperative Treatment in Patients with Advanced Non-Small-Cell Lung Cancer: Recommended for Surgery.

There is currently limited evidence for a correlation between the recommended operation and overall survival (OS) in patients with advanced non-small-cell lung cancer (NSCLC). NSCLC patients with stages III and IV, recommended for operation, were identified in the US National Cancer Institute Surveillance, Epidemiology, and End Results database (SEER).We used propensity score matching (PSM) and multivariable Cox proportional hazards regression to ensure the robustness of our findings. The cumulative rates of death were compared between patients with and without recommended operations using the Kaplan-Meier curves. Operation was recommended for 3331 patients but was not performed in 912 (27.4%) patients (then on-operative group). After PSM, 553 pairs matched. Compared to the nonoperative group, the hazard ratios (HRs) in the operative group were 0.46 (95% CI 0.23-0.95 and p=0.037) in stage IIIA and 0.54 (95% CI 0.42-0.68 and p < 0.001) in stage IVA. However, in stages IIIB, IIIC, and IVB, the recommended operative group was not associated with better OS. The OS was not different in stage IIIA-N2, stage IVA-N1, and stage IVA-N3 patients between groups (p=0.28, p=0.14, and p=0.79, respectively). Moreover, the recommended operative group had better OS than the nonoperative group in stage IIIA-N0 (p=0.00085), stage IIIA-N1 (p=0.009), stage IVA-N0 (p < 0.001), and stage IVA-N2 (p=0.034). Compared to the nonoperative group, recommended operation improved survival in NSCLC patients with stage IIIA-N0, stage IIIA-N1, stage IVA-N0, and stage IVA-N2. However, in stages IIIA-N2, IIIB, IIIC, IVA-N1, IVA-N3, and IVB, recommended operation did not lead to significantly improved survival time.

Incidence of thymic malignancies in China: A longitudinal study based on a national commercial claims database from 2007 to 2016.

Incidence of thymic malignancies in China: A longitudinal study based on a national commercial claims database from 2007 to 2016.

Evaluation of race/ethnicity-specific survival machine learning models for Hispanic and Black patients with breast cancer

ObjectivesSurvival machine learning (ML) has been suggested as a useful approach for forecasting future events, but a growing concern exists that ML models have the potential to cause racial disparities...

Relationship between RANO-PRO Working Group standardised priority constructs and disease progression among malignant glioma patients: A retrospective cohort study.

Recognising the importance of clinical outcomes assessments (COAs), the Response Assessment in Neuro-Oncology-Patient Reported Outcome (RANO-PRO) Working Group recommended inclusion of core symptoms and functions in clinical care or research for malignant glioma patients. This study evaluated the association of the recommended symptoms (pain, perceived cognition, seizures, aphasia, symptomatic adverse events) and functions (weakness, walking, work, usual activities) with disease progression in these patients. In this retrospective cohort study, patients with malignant glioma were included from the US National Cancer Institute Neuro-Oncology Branch Natural History Study (NOB-NHS) which follows primary central nervous system tumour patients aged 18 years and older throughout their disease trajectory. The M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT), EQ-5D-3L, Karnofsky Performance Status (KPS), and Neurologic Function scores (NFS) were evaluated in relation to disease progression by chi-square tests, independent- and paired-samples t-tests, adjusted for multiple comparisons at first assessment and over time to a second assessment. Radiographic disease progression was determined on the interpretation of the imaging study by a radiologist and neuro-oncologist using standard criteria as part of clinical trial participation or routine standard of care. The priority constructs were evaluated to provide initial evidence of their relevance, relationship to disease status over time, and sensitivity to change in a diverse group of patients with malignant glioma. Seven hundred and sixty-five patients had enrolled into the NOB-NHS between September 1, 2016 and January 31, 2020. Three hundred and thirty-six patients had a diagnosis of a malignant glioma (anaplastic astrocytoma, anaplastic oligodendroglioma, glioblastoma, and gliosarcoma) and were included in the current study. The sample was 64% male (n=215), 36% female (n=121), median age of 52 years (IQR=18.75), 82% White (n=276), and 65% had tumour recurrence (n=219). One hundred and fifty-four (46%) had radiographic disease progression. Difficulty remembering, fatigue, and weakness were worse in the group whose imaging was interpreted as radiographic disease progression versus stable disease, as well as the functions of walking, work, activity, and self-care (1.1 < difference < 1.8). Patients with disease progression were four times more likely to have a poor KPS (≤80) and worse NFS. Among patients with disease progression at a second assessment (n=112), all symptoms, except seizures, worsened between first assessment and disease progression and up to 22% of patients (n=25) reported worsening mobility, self-care, and usual activity; 46% (n=51) and 35% (n=30) had worsened KPS and NFS, respectively. On average, 4 symptoms or functions (SD=3) were reported as moderate-to-severe and 30% (n=33) and 23% (n=26) had a change to moderate-to-severe fatigue and walking, respectively, at time of disease progression. Over 7% of patients with worsening (n=7 of 100) reported every symptom and function as having changed the most severely including seizures with fatigue and activity reported as the top symptom and function, respectively. The identified core symptoms and functions worsened at the time of progression, supporting the relevance and sensitivity of the priority constructs identified by the RANO-PRO Working Group for clinical care and clinical trials for malignant glioma patients. The Natural History Study is supported by Intramural Project 1ZIABC011786-03.

Is There Horizontal Transmission of Creutzfeldt-Jakob Disease?

Background: Sporadic Creutzfeldt-Jakob disease (s-CJD) is a rare, fatal neurodegenerative disorder. Familial cases of Creutzfeldt-Jakob disease (f-CJD) due to mutations in the PRNP gene are even rarer around the world; however, in Israel there is a focus of f-CJD patients carrying the E200K mutation. As the number of CJD E200K carriers in Israel is high and increasing, transmission of CJD to normal people was suspected. If such transmission occurs, the incidence of s-CJD would be expected to increase as well, resulting in changes of the ratio of familial/sporadic cases. Methods: Using data from the National CJD Registry and official statistics on the Israeli population, we studied incidence rates of f-CJD and s-CJD for the period from 1985 to 2018 applying the Surveillance Epidemiology and End Results (SEER) statistical packet developed in the US National Cancer Institute. Results: In total, 621 CJD patients (405 f-CJD and 216 s-CJD) cases are included in the registry. In the cohort of f-CJD patients, the mean age-adjusted annual incidence rate over the abovementioned period was 1.88 ± 0.09 (95% CI: 1.7–2.08) per 1,000,000. In the cohort of s-CJD patients, the mean age-adjusted incidence rate over the same period was 0.93 ± 0.06 (95% CI: 0.81–1.06) per 1,000,000 people. No significant time trends were found over the observation period in either s-CJD or f-CJD. The ratio f-CJD/s-CJD decreases over the observation period from 2.2 to 1.80. Conclusion: Israel has a high predominance of f-CJD compared to s-CJD. The mean incidence rate of s-CJD in Israel is similar to most countries. Between 1985 and 2018, the annual age-adjusted incidence rates for both forms of CJD remained stable. Thus, there is no evidence that CJD is transmitted from affected individuals to others.

The Prevalence and Prognosis of Microsatellite Instability-High/Mismatch Repair-Deficient Colorectal Adenocarcinomas in the United States.

Microsatellite instability (MSI) and DNA mismatch repair (MMR) status is an indispensable biomarker in the management of colorectal cancers. We therefore examined the epidemiology of MSI-high/MMR-deficient colorectal cancers in the United States. Adults presenting with colorectal adenocarcinoma in 2018-2019 were identified from the US National Cancer Database. Attributes associated with MSI-high/MMR-deficiency were identified using multivariable logistic regression and reported using average adjusted probabilities (%AAP) and 99.9% CIs. As a secondary aim, the survival associated with MSI/MMR status was assessed. Among 101,259 colorectal adenocarcinomas in 2018-2019, 82.0% were microsatellite stable/MMR-proficient, 3.8% MSI-low, and 14.2% MSI-high/MMR-deficient-including 16.6%, 19.9%, 12.4%, and 7.3% of stage I, II, III, and IV cancers, respectively. In locoregional cancers, MSI-high/MMR-deficiency was associated with a bimodal age distribution, female sex, right-sided colonic origin, wild-type KRAS, and a prior diagnosis of cancer (all P < .001). By race/ethnicity, colorectal adenocarcinomas were MSI-high/MMR-deficient in 16.9%AAP of non-Hispanic White (99.9% CI, 16.5 to 17.4) patients, compared with 11.3%AAP of non-Hispanic Black (99.9% CI, 10.3 to 12.4), 12.4%AAP of Asian/Pacific Islander (99.9% CI, 10.5 to 14.3), and 15.1%AAP of Hispanic (99.9% CI, 13.4 to 16.7) patients (all P < .001). Histologically, MSI-high/MMR-deficiency was associated with increasing grade, from 11.3%AAP of well-differentiated tumors (99.9% CI, 10.2 to 12.4) to 28.4%AAP of poorly differentiated cases (99.9% CI, 27.1 to 29.8; P < .001). Compared with conventional histology (15.2%AAP, 99.9% CI, 14.8 to 15.6), medullary (41.1%AAP, 99.9% CI, 33.0 to 49.3; P < .001) and mucinous (24.6%AAP, 99.9% CI, 22.8 to 26.3; P < .001) subtypes-but not signet-ring cell histology (15.5%AAP, 99.9% CI, 11.6 to 19.4; P = .79)-were more frequently MSI-high/MMR-deficient when adjusting for clinicopathologic features including grade. Our findings establish the epidemiology, features, and prognostic implications of MSI-high/MMR-deficiency among colorectal adenocarcinoma patients in the United States.

Proton Therapy With Concurrent Chemotherapy for Thoracic Esophageal Cancer: Toxicity, Disease Control, and Survival Outcomes.

When treating esophageal cancer with radiation therapy, it is critical to limit the dose to surrounding structures, such as the lung and/or heart, as much as possible. Proton radiation therapy allows a reduced radiation dose to both the heart and lungs, potentially reducing the risk of cardiopulmonary toxicity. Here, we report disease control, survival, and toxicity outcomes among patients with esophageal cancer treated with proton radiation therapy and concurrent chemotherapy (chemoradiation therapy; CRT) with or without surgery. We enrolled 17 patients with thoracic esophageal carcinoma on a prospective registry between 2010 and 2021. Patients received proton therapy to a median dose of 50.4-GyRBE (range, 50.4-64.8) in 1.8-Gy fractions.Acute and late toxicities were graded per the Common Terminology Criteria for Adverse Events, version 4.0 (US National Cancer Institute, Bethesda, Maryland). In addition, disease control, patterns of failure, and survival outcomes were collected. Nine patients received preoperative CRT, and 8 received definitive CRT. Overall, 88% of patients had adenocarcinoma, and 12% had squamous cell carcinoma. With a median follow-up of 2.1 years (range, 0.5-9.4), the 3-year local progression-free, disease-free, and overall survival rates were 85%, 66%, and 55%, respectively. Two patients (1 with adenocarcinoma and 1 with squamous cell carcinoma) recurred at the primary site after refusing surgery after a complete clinical response to CRT. The most common acute nonhematologic and hematologic toxicities, respectively, were grades 1 to 3 esophagitis and grades 1 to 4 leukopenia, both affecting 82% of patients. No acute cardiopulmonary toxicities were observed in the absence of surgical resection. Reagarding surgical complications, 3 postoperative cardiopulmonary complications occurred as follows: 1 grade 1 pleural effusion, 1 grade 3 pleural effusion, and 1 grade 2 anastomotic leak. Two severe late CRT toxicities occurred: 1 grade 5 tracheoesophageal fistula and 1 grade 3 esophageal stenosis requiring a feeding tube. Proton radiation therapy is a safe, effective treatment for esophageal cancer with increasing evidence supporting its role in reducing cardiopulmonary toxicity.

Impact of tumour characteristics and cancer treatment on cerebrovascular mortality after glioma diagnosis: Evidence from a population-based cancer registry.

We aimed to examine brain tumour grade, a marker of biological aggressiveness, tumour size and cancer treatment are associated with cerebrovascular mortality among patients with malignant glioma, the most common and aggressive type of brain tumour. We conducted a retrospective, observational cohort study using the US National Cancer Institute's state and regional population-based cancer registries. We identified adult patients with glioma in 2000 to 2018 (N=72,916). The primary outcome was death from cerebrovascular disease. Cox regression modelling was used to estimate the associations with cerebrovascular mortality of tumour grade, tumour size and treatment (surgery, radiotherapy, chemotherapy), calculating hazard ratios (HR) adjusted for these factors as well as for age, sex, race, marital status and calendar year. Higher grade (Grade IV vs Grade II: HR=2.47, 95% CI=1.69-3.61, p<0.001) and larger brain tumours (size 3 to <6 cm: HR=1.40, 95% CI=1.03 -1.89, p<0.05; size ≥ 6 cm: HR=1.47, 95% CI=1.02-2.13, p<0.05 compared to size < 3cm) were associated with increased cerebrovascular mortality. Cancer treatment was associated with decreased risk (surgery: HR= 0.60, p<0.001; chemotherapy: HR=0.42, p<0.001; radiation: HR= 0.69, p<0.05). However, among patents surviving five years or more from cancer diagnosis radiotherapy was associated with higher risk of cerebrovascular mortality (HR 2.73, 95% CI 1.49-4.99, p<0.01). More aggressive tumour characteristics are associated with increased cerebrovascular mortality. Radiotherapy increased risk of cerebrovascular mortality five-year after cancer diagnosis. Further research is needed to better understand the long-term cardiovascular consequences of radiation therapy, and whether the consequent risk can be mitigated.

Brain cancer after radiation exposure from CT examinations of children and young adults: results from the EPI-CT cohort study

The European EPI-CT study aims to quantify cancer risks from CT examinations of children and young adults. Here, we assess the risk of brain cancer. We pooled data from nine European countries for this cohort study. Eligible participants had at least one CT examination before age 22 years documented between 1977 and 2014, had no previous diagnosis of cancer or benign brain tumour, and were alive and cancer-free at least 5 years after the first CT. Participants were identified through the Radiology Information System in 276 hospitals. Participants were linked with national or regional registries of cancer and vital status, and eligible cases were patients with brain cancers according to WHO International Classification of Diseases for Oncology. Gliomas were analysed separately to all brain cancers. Organ doses were reconstructed using historical machine settings and a large sample of CT images. Excess relative risks (ERRs) of brain cancer per 100 mGy of cumulative brain dose were calculated with linear dose-response modelling. The outcome was the first reported diagnosis of brain cancer after an exclusion period of 5 years after the first electronically recorded CT examination. We identified 948 174 individuals, of whom 658 752 (69%) were eligible for our study. 368 721 (56%) of 658 752 participants were male and 290 031 (44%) were female. During a median follow-up of 5·6 years (IQR 2·4-10·1), 165 brain cancers occurred, including 121 (73%) gliomas. Mean cumulative brain dose, lagged by 5 years, was 47·4 mGy (SD 60·9) among all individuals and 76·0 mGy (100·1) among people with brain cancer. A significant linear dose-response relationship was observed for all brain cancers (ERR per 100 mGy 1·27 [95% CI 0·51-2·69]) and for gliomas separately (ERR per 100 mGy 1·11 [0·36-2·59]). Results were robust when the start of follow-up was delayed beyond 5 years and when participants with possibly previously unreported cancers were excluded. The observed significant dose-response relationship between CT-related radiation exposure and brain cancer in this large, multicentre study with individual dose evaluation emphasises careful justification of paediatric CTs and use of doses as low as reasonably possible. EU FP7; Belgian Cancer Registry; La Ligue contre le Cancer, L'Institut National du Cancer, France; Ministry of Health, Labour and Welfare of Japan; German Federal Ministry of Education and Research; Worldwide Cancer Research; Dutch Cancer Society; Research Council of Norway; Consejo de Seguridad Nuclear, Generalitat de Catalunya, Spain; US National Cancer Institute; UK National Institute for Health Research; Public Health England.

Defining targets to improve care delivery for T4 larynx squamous cell carcinoma.

United States oncology trends consistently demonstrate that nearly half of T4a larynx carcinoma patients are treated with larynx preservation, despite national guidelines favoring laryngectomy. This study identifies clinical decision-making drivers and defines patient subsets that should become targets for care improvement. Retrospective analysis of patients with cT4 squamous cell carcinoma of the larynx from US National Cancer Database 2005-2016. Demographic data and survival rates between clinical pathways were compared. Survival was estimated by Kaplan-Meier method with statistical comparisons assessed by log-rank test. Of 11,556 patients with cT4 disease, laryngectomy (TL) was the initial treatment for 4627 (40%) patients. Larynx preservation via chemoradiation (CRT) occurred for 4307 patients. TL and CRT patients had similar Charlson-Deyo comorbidity indices and insurance status. TL patients had higher total tumor size, lower N3 rates and were more often seen at academic institutions (p < .0001). N0 surgery patients with adjuvant treatment demonstrated superior median survival (MS) compared to CRT (surgery + radiation MS: 69 months, surgery + chemoradiation MS: 66, CRT MS: 37.7), p < .0001. MS for N1/N2 disease patients was 56.5months for surgery + radiation and 35.5months for surgery + CRT, superior to CRT, MS 30.8months, p < .0001. Tri-modality N3 patients with up front surgery had similar MS compared to CRT (surgery + chemoradiation 21.3months vs. CRT 16.1), p=.95. National quality improvement initiatives are needed to promote guideline adherence and improve survival in advanced larynx cancer. Targets for such initiatives should be patients with limited or no nodal disease burden, that meet clear T4a imaging criteria. Level IV, non-randomized controlled cohort.

Safety and Efficacy of Tinostamustine in Pre-Treated Patients with Relapsed/Refractory (R/R) Hodgkin Lymphoma (HL): Early Results from an Additional Expansion Cohort of a Phase I Study

Background: Despite recent therapeutic advances, there remains an unmet medical need for patients with R/R HL. The alkylating deacetylase inhibitor tinostamustine is a multi-action therapy designed to improve drug access to DNA strands, induce DNA damage and counteract its repair in cancer cells. Tinostamustine was well tolerated, with signals of efficacy during both the dose-escalation and cohort expansion stages of a Phase I study in patients with R/R haematological malignancies, including HL (Zinzani et al. HemaSphere. 2019; 3(S1):102: PF300; Pinto et al. Hematological Oncology. 2019; 37(S2): 273; Ghesquières et al. Blood. 2021; 138 (S1): 2472). Aims: Here we report further safety and efficacy data for tinostamustine derived from an additional R/R HL expansion cohort of a Phase I study (NCT02576496). Methods: Patients with R/R HL who had received at least 2 lines of prior therapy and for whom no other therapy with proven clinical benefit was available were eligible for an expansion cohort to receive the recommended Phase II dose (RP2D) of tinostamustine. The RP2D was determined during dose-escalation and administered according to baseline platelet count: 80mg/m2 (>100x109/l to <200x109/l platelets), and 100mg/m2 (≥200x109/l platelets) over 60 min on Day 1 of a 21-day cycle. The dose was subsequently revised to 100mg/m2 for ≥100x109/l platelets. Adverse events (AEs) were summarised by US National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE; version 4.03) grade for all treated patients. Treatment-related AEs, AEs leading to death, serious adverse events (SAEs), and AEs resulting in trial discontinuation were recorded. Efficacy variables included overall response rate (ORR; complete response [CR] + partial response [PR]) and survival outcomes evaluated from Cycle 3 until progression or toxicity. Results: Twenty patients with R/R HL were recruited. Patients had a median age of 35.0 (range 25.0-74.0) years and were predominantly male (n/N=14/20, 70.0%). Most patients had an ECOG Performance Status of 0 (14/20, 70.0%) at screening and had received a median of 5 (range 3-9) lines of prior therapy; 10/20 (50.0%) were judged by the investigators to have refractory disease. At data cut-off of 30 June 2022, patients had received a median of 3 (range 1-12) cycles of tinostamustine. No unexpected AEs were observed following tinostamustine treatment. Treatment-emergent adverse events (TEAEs) were principally haematological (71 events in 13/20 patients; 65.0%) and included thrombocytopenia, neutropenia, anaemia and lymphopenia (41 events in 11 patients were Grade ≥3). Gastrointestinal AEs were observed in 14/20 patients (39 events), the majority of which were nausea or vomiting (all Grade 1 or 2). Serious TEAEs that were considered related to tinostamustine occurred in 8 patients (40.0%), including thrombocytopenia (n=1) and infusion-related reaction (n=1). Treatment discontinuation due to TEAEs occurred in 5/20 patients (25.0%; thrombocytopenia: n=4). No fatal TEAEs, or incidences of within-cycle QTc prolongations ≥500 ms, or increases from baseline ≥60 ms, were observed. 9/20 patients (45.0%) discontinued due to progressive disease. Mean ± SD time to disease progression was 5.2 ± 3.7 months (range 1.6-14.0 months). At data cut-off, all patients had progressed. 2/20 (10%) patients achieved a CR as best response following a median of 2 (range 1-3) cycles, 6/20 (30%) a PR (median of 4.5 [range 1-7] cycles) and 3/20 had stable disease (median of 3 [range 3-3] cycles). ORR was 40% (8/20 patients; 95% confidence interval: 19%, 64%) and median progression-free survival (PFS) was 3.8 months (95% confidence interval 2.3-7.6). Conclusions: Initial results from two expansion cohorts of a Phase I study further demonstrate that tinostamustine administered on Day 1 of a 21-day cycle to patients with R/R HL was relatively well tolerated with no unexpected AEs. The main TEAEs were haematological (thrombocytopenia, neutropenia, anaemia and lymphopenia), with thrombocytopenia being the main TEAE leading to treatment discontinuation. An ORR of 40% and a median PFS of 3.8 months were observed, revealing signals of efficacy in this heavily pre-treated patient population. Based on these findings, tinostamustine appears to warrant further investigation. Updated data will be presented at the congress. Funding: Mundipharma Research Limited and Purdue Pharmaceutical Products LP

NCMP-09. IMPACT OF TUMOUR CHARACTERISTICS AND CANCER TREATMENT ON CEREBROVASCULAR MORTALITY AFTER GLIOMA DIAGNOSIS: EVIDENCE FROM A POPULATION-BASED CANCER REGISTRY

Abstract BACKGROUND Brain tumour patients have the highest stroke mortality rates among cancer types, but the factors associated with fatal stroke remain unknown. We aimed to examine to what extent brain tumour grade, a marker of biological aggressiveness, tumour size and cancer treatment are associated with cerebrovascular mortality among patients with malignant glioma, the most common and aggressive brain tumour. METHODS We conducted a retrospective, observational cohort study using the US National Cancer Institute’s state and regional population-based cancer registries (NCI SEER). We identified adult patients with a diagnosis of malignant glioma (2000 to 2018, Nf72,916). The primary outcome of interest was death from cerebrovascular disease. Cox regression modelling estimated the associations with cerebrovascular mortality of tumour grade, tumour size and treatment (surgery, radiotherapy, chemotherapy), calculating hazard ratios (HR) adjusted for these factors as well as for age, sex, race, marital status and calendar year. RESULTS Higher grade (Grade IV vs Grade II: HR=2.47, 95% CI=1.69-3.61, p&amp;lt; 0.001) and larger brain tumours (size 3 to &amp;lt; 6 cm: HR=1.40, 95% CI=1.03 -1.89, p&amp;lt; 0.05; size ≥ 6 cm: HR=1.47, 95% CI=1.02-2.13, p&amp;lt; 0.05 compared to size &amp;lt; 3cm) were associated with increased cerebrovascular mortality. Having cancer treatment was associated with decreased risk (surgery: HR= 0.60, p&amp;lt; 0.001; chemotherapy: HR=0.42, p&amp;lt; 0.001; radiation: HR= 0.69, p&amp;lt; 0.05). However, among patents surviving five years or more from their cancer diagnosis radiotherapy was associated with higher risk of cerebrovascular mortality (HR 2.73, 95% CI 1.49-4.99, p&amp;lt; 0.01). CONCLUSIONS More aggressive tumour characteristics are associated with increased cerebrovascular mortality, and treatment was associated with lower risk within 5 years of diagnosis. Radiotherapy increased risk of fatal cerebrovascular outcome five-years after cancer diagnosis. Further research is needed to better understand the long-term cardiovascular consequences of radiation therapy, and whether the consequent risk can be mitigated.

Exploring approaches for predictive cancer patient digital twins: Opportunities for collaboration and innovation.

We are rapidly approaching a future in which cancer patient digital twins will reach their potential to predict cancer prevention, diagnosis, and treatment in individual patients. This will be realized based on advances in high performance computing, computational modeling, and an expanding repertoire of observational data across multiple scales and modalities. In 2020, the US National Cancer Institute, and the US Department of Energy, through a trans-disciplinary research community at the intersection of advanced computing and cancer research, initiated team science collaborative projects to explore the development and implementation of predictive Cancer Patient Digital Twins. Several diverse pilot projects were launched to provide key insights into important features of this emerging landscape and to determine the requirements for the development and adoption of cancer patient digital twins. Projects included exploring approaches to using a large cohort of digital twins to perform deep phenotyping and plan treatments at the individual level, prototyping self-learning digital twin platforms, using adaptive digital twin approaches to monitor treatment response and resistance, developing methods to integrate and fuse data and observations across multiple scales, and personalizing treatment based on cancer type. Collectively these efforts have yielded increased insights into the opportunities and challenges facing cancer patient digital twin approaches and helped define a path forward. Given the rapidly growing interest in patient digital twins, this manuscript provides a valuable early progress report of several CPDT pilot projects commenced in common, their overall aims, early progress, lessons learned and future directions that will increasingly involve the broader research community.

Current Challenges and Perspectives on Developing a Clinical Trial Design for ADPKD.

Current Challenges and Perspectives on Developing a Clinical Trial Design for ADPKD.

Effect of dexamethasone on dyspnoea in patients with cancer (ABCD): a parallel-group, double-blind, randomised, controlled trial.

Systemic corticosteroids are commonly prescribed for palliation of dyspnoea in patients with cancer, despite scarce evidence to support their use. We aimed to assess the effect of high-dose dexamethasone versus placebo on cancer-related dyspnoea. The parallel-group, double-blind, randomised, controlled ABCD (Alleviating Breathlessness in Cancer Patients with Dexamethasone) trial was done at the at the University of Texas MD Anderson Cancer Center and the general oncology clinic at Lyndon B Johnson General Hospital (both in Houston, TX, USA). Ambulatory patients with cancer, aged 18 years or older, and with an average dyspnoea intensity score on an 11-point numerical rating scale (NRS; 0=none, 10=worst) over the past week of 4 or higher were randomly assigned (2:1) to receive dexamethasone 8 mg orally every 12 h for 7 days followed by 4 mg orally every 12 h for 7 days, or matching placebo capsules for 14 days. Pharmacists did permuted block randomisation with a block size of six, and patients were stratified by baseline dyspnoea score (4-6 vs 7-10) and study site. Patients, research staff, and clinicians were masked to group assignment. The primary outcome was change in dyspnoea NRS intensity over the past 24 h from baseline to day 7 (±2 days). Analyses were done by modified intention-to-treat (ie, including all patients who were randomly assigned and started the study treatment, regardless of whether they completed the study). Enrolment was stopped after the second preplanned interim analysis, when the futility criterion was met. This study is registered with ClinicalTrials.gov (NCT03367156) and is now completed. Between Jan 11, 2018, and April 23, 2021, we screened 2867 patients, enrolled 149 patients, and randomly assigned 128 to dexamethasone (n=85) or placebo (n=43). The mean change in dyspnoea NRS intensity from baseline to day 7 (±2 days) was -1·6 (95% CI -2·0 to -1·2) in the dexamethasone group and -1·6 (-2·3 to -0·9) in the placebo group, with no significant between-group difference (mean 0 [95% CI -0·8 to 0·7]; p=0·48). The most common all-cause grade 3-4 adverse events were infections (nine [11%] of 85 patients in the dexamethasone group vs three [7%] of 43 in the placebo group), insomnia (seven [8%] vs one [2%]), and neuropsychiatric symptoms (three [4%] vs none [0%]). Serious adverse events, all resulting in hospital admissions, were reported in 24 (28%) of 85 patients in the dexamethasone group and in three (7%) of 43 patients in the placebo group. No treatment-related deaths occurred in either group. High-dose dexamethasone did not improve dyspnoea in patients with cancer more effectively than placebo and was associated with a higher frequency of adverse events. These data suggest that dexamethasone should not be routinely given to unselected patients with cancer for palliation of dyspnoea. US National Cancer Institute.

Recurrence-free survival versus overall survival as a primary endpoint for studies of resected colorectal liver metastasis: a retrospective study and meta-analysis.

Recurrence-free survival has been used as a surrogate endpoint for overall survival in trials involving patients with resected colorectal liver metastases. We aimed to assess the correlation between recurrence-free survival and overall survival after resection of colorectal liver metastases to determine the adequacy of this surrogate endpoint. In this retrospective study and meta-analysis, we compiled an institutional cohort of consecutive patients who had complete resection of colorectal liver metastases from the Memorial Sloan Kettering Cancer Center (New York, NY, USA) prospective database. Patients were eligible for inclusion if they were aged 18 years or older, and underwent hepatectomy, with or without operative ablation, between Jan 1, 1991, and April 30, 2019. We estimated overall survival and recurrence-free survival probabilities at various timepoints using the Kaplan-Meier method, and we assessed pairwise associations between these endpoints using Spearman's rank correlation. We also did a meta-analysis of adjuvant phase 3 clinical trials for colorectal liver metastases to assess the correlation between hazard ratios (HRs) for recurrence-free survival and overall survival. We searched MEDLINE for articles of phase 3 randomised controlled trials analysing adjuvant treatment strategies for resected colorectal metastases from database inception to Jan 1, 2022. The titles and abstracts of identified studies were screened before full-text screening and summary data were either recalculated or extracted manually from the published Kaplan-Meier curves (depending on data availability). Data were available for 3299 patients in the institutional database, of whom 2983 were eligible for inclusion in our cohort. Median follow-up was 8·4 years (95% CI 7·9-9·1) , during which time there were 1995 (67%) disease recurrences and 1684 (56%) deaths. Median recurrence-free survival was 1·3 years (95% CI 1·3-1·4) and median overall survival was 5·2 years (95% CI 5·0-5·5). 1428 (85%) of 1684 deaths were preceded by recurrence, and median time from recurrence to death was 2·0 years (IQR 1·0-3·4). Pairwise correlations between recurrence-free survival and overall survival were low to moderate, with a correlation estimate ranging from 0·30 (SD 0·17) to 0·56 (0·13). In the meta-analysis of adjuvant clinical trials, the Spearman's correlation coefficient between recurrence-free survival HR and overall survival HR was r=0·20 (p=0·71). We found a minimal correlation between recurrence-free survival and overall survival after resection of colorectal liver metastases. Recurrence-free survival is an inadequate surrogate endpoint for overall survival in this disease setting. US National Cancer Institute.

Trends and risk of lung cancer among people living with HIV in the USA: a population-based registry linkage study

Lung cancer is a common cancer in people living with HIV, but the risk of cancer in this group has not been investigated for over a decade. We investigated trends in relative and absolute risk of lung cancer among people living with HIV of various age groups in the USA. In this population-based registry linkage study, we used 2001-16 data from the HIV/AIDS Cancer Match study, which links data from HIV and cancer registries from 13 regions in the USA. We included non-Hispanic White, non-Hispanic Black, and Hispanic individuals living with HIV aged 20-89 years in our study population. Average annual percentage changes in lung cancer rates were estimated with multivariable Poisson regression, and standardised incidence ratios (SIRs) and excess absolute risks were estimated comparing people living with HIV with the general US population. We used non-parametric cumulative incidence curves to estimate the 5-year cumulative incidence of lung cancer and two AIDS-defining cancers (non-Hodgkin lymphoma and Kaposi sarcoma). There were 3426 lung cancers in 4 310 304 person-years of follow-up in our study population. Age-standardised lung cancer incidence rates in people living with HIV declined by 6% per year (95% CI -7 to -5) during 2001-16, with greater declines in the 20-29 age group (-11%, -16 to 6) than in the older age groups (eg, -3% [-6 to 1] in those aged 70-89 years). During 2013-16, the SIR of lung cancer in people living with HIV was 2·01 (95% CI 1·52 to 2·61) in those aged 40-49 years, and 1·31 (1·12 to 1·52) in those aged 60-69 years, whereas the excess absolute risk among people living with HIV was 11·87 (3·95 to 21·89) per 100 000 person-years for those aged 40-49 years and 48·23 (6·88 to 95·47) per 100 000 person-years for those aged 60-69 years. Beginning in 2011, the 5-year cumulative incidence for lung cancer (1·36%, 95% CI 1·17 to 1·53) surpassed that of Kaposi sarcoma (0·12%, 0·06 to 0·17) and non-Hodgkin lymphoma (0·45%, 0·35 to 0·56) for people living with HIV aged 60-69 years. Between 2001 and 2016, the risk of lung cancer decreased for people living with HIV aged 20-69 years, but remained substantially elevated compared with the general population, probably due to a combination of smoking and immunosuppression. For people living with HIV aged 60 years and older, the risk of lung cancer exceeds that of two of the most common AIDS-defining cancers, highlighting the importance of lung cancer among the growing older population of people living with HIV. Intramural Research Program of the US National Cancer Institute.

Adolescent self-efficacy mediates the relationship between perceived parenting practices and fruit and vegetable consumption in the FLASHE study

Objective: In the USA, few adolescents meet the national recommendations for fruit and vegetable consumption (FVC). This study examined the associations between two perceived food parenting practice scales (Promote and Ensure FVC Intake) and adolescent FVC, and assessed whether these associations were mediated by adolescent self-efficacy. Design: The study took the form of a secondary data analysis of publicly available data from the Family Life, Activity, Sun, Health, and Eating Study (FLASHE), a cross-sectional, Internet-based study administered by the US National Cancer Institute (NCI) between April and October 2014. Methods: Data from 1,354 parent–adolescent dyads were analysed. The PROCESS macro was used to conduct mediation analyses to estimate the indirect effect (IE) of each parenting practice on FVC through adolescent self-efficacy, adjusted for parental and adolescent characteristics. In addition, we examined whether adolescent age, gender, race/ethnicity or weight status moderated the mediation model. Results: The IEs were each statistically significant (Promote FV Intake: IE = 0.063, 95% bootstrap confidence interval [CI] = 0.046, 0.080; Ensure FV Intake: IE = 0.014, 95% bootstrap CI = 0.004, 0.024; p &lt; .05 each), indicating significant mediation by adolescent self-efficacy. However, no adolescent characteristics moderated the effects of parenting practices on FVC through self-efficacy. Conclusions: Interventions should continue to promote parenting skills to improve adolescent self-efficacy and FVC. Insufficient evidence for moderation of the mediation effect by adolescent age, sex, race/ethnicity or weight status implies that the significant relationship between food parenting practices and FVC, mediated by self-efficacy, may operate similarly for adolescents that differ in each of these characteristics.

The Relationships Between Social Media and Human Papillomavirus Awareness and Knowledge: Cross-sectional Study.

BackgroundHuman papillomavirus (HPV) is the most common sexually transmitted infection. HPV can infect both females and males, and it can cause many cancers, including anal, cervical, vaginal, vulvar, and penile cancers. HPV vaccination rates are lower than vaccination rates within other national vaccination programs, despite its importance. Research literature indicates that people obtain health-related information from internet sources and social media; however, the association between such health-seeking behavior on social media and HPV-related behaviors has not been consistently demonstrated in the literature.ObjectiveThis study aims to examine the association between social media usage and HPV knowledge and HPV awareness.MethodsThis study analyzed public health data collected through the Health Information National Trends Survey (HINTS) conducted by the US National Cancer Institute. The analysis used data collected in 2020; in total, 2948 responses were included in the analysis. Six HPV-related questions were used to identify HPV awareness, HPV vaccine awareness, and HPV knowledge about HPV-related cancers. Four questions about social media usage and one question about online health information–seeking behavior were used to analyze the associations between social media usage and HPV-related behaviors. Initially, six logistic regressions were conducted using replicate weights. Based on the results, significant factors were included in a second set of regression analyses that also included demographic variables.ResultsAbout half of the respondents were aware of HPV (68.40%), the HPV vaccine (64.04%), and the relationship between HPV and cervical cancer (48.00%). However, fewer respondents were knowledgeable about the relationships between HPV and penile cancer (19.18%), anal cancer (18.33%), and oral cancer (19.86%). Although social media usage is associated with HPV awareness, HPV vaccine awareness, and knowledge of cervical cancer, these associations were not significant after adjusting for demographic variables. Those less likely to report HPV awareness and knowledge included older participants, males, those with a household income of less than US $20,000, those with a formal education equal to or less than high school, or those who resided in a household where adults are not fluent in English.ConclusionsAfter adjusting for demographic variables, social media use was not related to HPV knowledge and awareness, and survey respondents were generally not aware that HPV can lead to specific types of cancer, other than cervical cancer. These results suggest that perhaps a lack of high-quality information on social media may impede HPV awareness and knowledge. Efforts to educate the public about HPV via social media might be improved by using techniques like storytelling or infographics, especially targeting vulnerable populations, such as older participants, males, those with low incomes, those with less formal education, or those who reside in the United States but are not fluent in English.

Comparing one dose of HPV vaccine in girls aged 9–14 years in Tanzania (DoRIS) with one dose of HPV vaccine in historical cohorts: an immunobridging analysis of a randomised controlled trial

Human papillomavirus (HPV) vaccines are given as a two-dose schedule in children aged 9-14 years, or as three doses in older individuals. We compared antibody responses after one dose of HPV vaccine in the Dose Reduction Immunobridging and Safety Study (DoRIS), a randomised trial of different HPV vaccine schedules in Tanzania, to those from two observational HPV vaccine trials that found high efficacy of one dose up to 11 years against HPV16 and HPV18 (Costa Rica Vaccine Trial [CVT] and Institutional Agency for Research on Cancer [IARC] India trial). In this immunobridging analysis of an open-label randomised controlled trial, girls were recruited from 54 government schools in Mwanza, Tanzania, into the DoRIS trial. Girls were eligible if they were aged 9-14 years, healthy, and HIV negative. Participants were randomly assigned (1:1:1:1:1:1), using permutated block sizes of 12, 18, and 24, to one, two, or three doses of the 2-valent vaccine (Cervarix, GSK Biologicals, Rixensart, Belgium) or the 9-valent vaccine (Gardasil 9, Sanofi Pasteur MSD, Lyon, France). For this immunobridging analysis, the primary objective was to compare geometric mean concentrations (GMCs) at 24 months after one dose in the per-protocol population compared with in historical cohorts: the one-dose 2-valent vaccine group in DoRIS was compared with recipients of the 2-valent vaccine Cervarix from CVT and the one-dose 9-valent vaccine group in DoRIS was compared with recipients of the 4-valent vaccine Gardasil (Merck Sharp & Dohme, Whitehouse Station, NJ, USA) from the IARC India trial. Samples were tested together with virus-like particle ELISA for HPV16 and HPV18 IgG antibodies. Non-inferiority of GMC ratios (DoRIS trial vs historical cohort) was predefined as when the lower bound of the 95% CI was greater than 0·50. This study is registered with ClinicalTrials.gov, NCT02834637. Between Feb 23, 2017, and Jan 6, 2018, we screened 1002 girls for eligibility, of whom 930 were enrolled into DoRIS and 155 each were assigned to one dose, two doses, or three doses of 2-valent vaccine, or one dose, two doses, or three doses of 9-valent vaccine. 154 (99%) participants in the one-dose 2-valent vaccine group (median age 10 years [IQR 9-12]) and 152 (98%) in the one-dose 9-valent vaccine group (median age 10 years [IQR 9-12]) were vaccinated and attended the 24 month visit, and so were included in the analysis. 115 one-dose recipients from the CVT (median age 21 years [19-23]) and 139 one-dose recipients from the IARC India trial (median age 14 years [13-16]) were included in the analysis. At 24 months after vaccination, GMCs for HPV16 IgG antibodies were 22·9 international units (IU) per mL (95% CI 19·9-26·4; n=148) for the DoRIS 2-valent vaccine group versus 17·7 IU/mL (13·9-22·5; n=97) for the CVT (GMC ratio 1·30 [95% CI 1·00-1·68]) and 13·7 IU/mL (11·9-15·8; n=145) for the DoRIS 9-valent vaccine group versus 6·7 IU/mL (5·5-8·2; n=131) for the IARC India trial (GMC ratio 2·05 [1·61-2·61]). GMCs for HPV18 IgG antibodies were 9·9 IU/mL (95% CI 8·5-11·5: n=141) for the DoRIS 2-valent vaccine group versus 8·0 IU/mL (6·4-10·0; n=97) for the CVT trial (GMC ratio 1·23 [95% CI 0·95-1·60]) and 5·7 IU/mL (4·9-6·8; n=136) for the DoRIS 9-valent vaccine group versus 2·2 IU/mL (1·9-2·7; n=129) for the IARC India trial (GMC ratio 2·12 [1·59-2·83]). Non-inferiority of antibody GMCs was met for each vaccine for both HPV16 and HPV18. One dose of HPV vaccine in young girls might provide sufficient protection against persistent HPV infection. A one-dose schedule would reduce costs, simplify vaccine delivery, and expand access to the vaccine. UK Department for International Development/UK Medical Research Council/Wellcome Trust Joint Global Health Trials Scheme, The Bill & Melinda Gates Foundation, and the US National Cancer Institute. For the KiSwahili translation of the abstract see Supplementary Materials section.