Fred Hutch Cancer Center

Importance Cancer mortality has decreased over time, but the contributions of different interventions across the cancer control continuum to averting cancer deaths have not been systematically evaluated across major cancer sites. Objective To quantify the contributions of prevention, screening (to remove precursors [interception] or early detection), and treatment to cumulative number of cancer deaths averted from 1975 to 2020 for breast, cervical, colorectal, lung, and prostate cancers. Design, Setting, and Participants In this model-based study using population-level cancer mortality data, outputs from published models developed by the Cancer Intervention and Surveillance Modeling Network were extended to quantify cancer deaths averted through 2020. Model inputs were based on national data on risk factors, cancer incidence, cancer survival, and mortality due to other causes, and dissemination and effects of prevention, screening (for interception and early detection), and treatment. Simulated or modeled data using parameters derived from multiple birth cohorts of the US population were used. Interventions Primary prevention via smoking reduction (lung), screening for interception (cervix and colorectal) or early detection (breast, cervix, colorectal, and prostate), and therapy (breast, colorectal, lung, and prostate). Main Outcomes and Measures The estimated cumulative number of cancer deaths averted with interventions vs no advances. Results An estimated 5.94 million cancer deaths were averted for breast, cervical, colorectal, lung, and prostate cancers combined. Cancer prevention and screening efforts averted 8 of 10 of these deaths (4.75 million averted deaths). The contribution of each intervention varied by cancer site. Screening accounted for 25% of breast cancer deaths averted. Averted cervical cancer deaths were nearly completely averted through screening and removal of cancer precursors as treatment advances were modest during the study period. Averted colorectal cancer deaths were averted because of screening and removal of precancerous polyps or early detection in 79% and treatment advances in 21%. Most lung cancer deaths were avoided by smoking reduction (98%) because screening uptake was low and treatment largely palliative before 2014. Screening contributed to 56% of averted prostate cancer deaths. Conclusions and Relevance Over the past 45 years, cancer prevention and screening accounted for most cancer deaths averted for these causes; however, their contribution varied by cancer site according to these models using population-level cancer mortality data. Despite progress, efforts to reduce the US cancer burden will require increased dissemination of effective interventions and new technologies and discoveries.

Objective Two randomized trials for patients with diffuse systemic sclerosis (SSc) demonstrated an overall survival (OS) and event‐free survival (EFS) advantage of autologous hematopoietic stem cell transplantation (AHSCT) using CD34+ selected peripheral blood stem cells (PBSC) compared to monthly cyclophosphamide. We asked if an unmodified PBSC graft followed by maintenance mycophenolate mofetil (MMF) after AHSCT, instead of CD34+ selected graft, could provide comparable AHSCT outcomes. Methods 20 patients with high‐risk SSc were enrolled in a prospective, single‐arm trial with cyclophosphamide 200 mg/kg and horse anti‐thymocyte globulin (CY200/ATG), followed by unmanipulated autologous PBSC, then MMF maintenance starting at 2 months after AHSCT. Results Point estimates of OS and EFS at 5 years after AHSCT were 85% (95% CI, 60.4%‐94.9%) and 75% (95% CI, 50%‐88.7%), respectively. Median follow‐up was 7.5 years (range, 5.6‐11.6) after transplant for living patients. Eight patients (40%) required intensive care unit treatment early after transplant. Early transplant‐related mortality occurred in 2 patients (10%). Five patients developed relapse/progression of SSc after AHSCT. Four of 9 patients with anti‐RNA polymerase‐III antibody had both prior scleroderma renal crisis and the lowest quartile of estimated glomerular filtration rate (eGFR) upon study entry; all 4 patients developed prolonged organ failure/death early post‐transplant. Conclusion We observed favorable OS and EFS after AHSCT for SSc patients, using CY200/ATG, unmanipulated PBSC and MMF post‐transplant maintenance, that was comparable to trials with CD34+ graft selection. We identified a possible risk factor, pretransplant low eGFR, for adverse outcome after AHSCT.

PURPOSE Clinicopathological factors and the 21-gene Oncotype DX Breast Recurrence Score (RS) test both influence prognosis. Our goal was to develop a new tool, RSClinN+, to individualize recurrence risk and chemotherapy benefit predictions by menopausal status for patients with HR+/human epidermal growth factor receptor 2–negative, lymph node–positive breast cancer by integrating the RS result with clinicopathological factors (grade, tumor size, age). METHODS We used patient-level data from 5,283 patients treated with chemoendocrine therapy (CET) versus endocrine therapy alone (ET) in the S1007 (N = 4,916) and S8814 (N = 367) trials to develop the tool. Cox proportional hazards regression models stratified by trial were used to estimate 5-year invasive disease-free survival for pre- and postmenopausal woman, respectively. The integrated RSClinN+ model was compared with RS alone and clinicopathological models using likelihood ratio tests. Absolute CET benefit was estimated as the difference between ET and CET risk estimates. Validation of RSClinN+ was performed in 592 patients with node-positive disease in the Clalit Health Services registry. RESULTS RSClinN+ provides better prognostic information than RS model alone (premenopausal P = .034; postmenopausal P < .001) or clinicopathological model alone (premenopausal P = .002; postmenopausal, P < .001). In postmenopausal women, RS showed interaction with CET benefit ( P = .016), with RSClinN+ absolute CET benefit ranging from <0.1% to 21.5% over RS ranges 0-50. In premenopausal patients with RS ≤25, there was no significant interaction between RS and CET benefit. In external validation, RSClinN+ risk estimates were prognostic (hazard ratio, 1.75 [95% CI, 1.38 to 2.20]) and concordant with observed risk (Lin's concordance, 0.92). CONCLUSION RSClinN+ provides improved estimates of prognosis and absolute CET benefit for individual patients compared with RS or with clinical data alone and could be used in patient counseling.

Current US clinical practice guidelines for advanced prostate cancer management contain recommendations based on high‐level evidence from randomized controlled trials; however, these guidelines do not address the nuanced clinical questions that are unanswered by prospective trials but nonetheless encountered in day‐to‐day practice. To address these practical questions, the 2024 US Prostate Cancer Conference (USPCC 2024) was created to generate US‐focused expert clinical decision‐making guidance for circumstances in which level 1 evidence is lacking. At the second annual USPCC meeting (USPCC 2024), a multidisciplinary panel of experts convened to discuss ongoing clinical challenges related to 5 topic areas: biochemical recurrence; metastatic, castration‐resistant prostate cancer; poly [ADP‐ribose] polymerase inhibitors; prostate‐specific membrane antigen radioligand therapy; and metastatic, castration‐resistant prostate cancer. Through a modified Delphi process, 34 consensus recommendations were developed and are intended to provide clinicians who manage prostate cancer with guidance related to the implementation of novel treatments and technologies. In this report, the authors review the areas of consensus identified by the USPCC 2024 experts and evaluate ongoing unmet needs regarding translational application of the current clinical evidence.

TV viewing is associated with health risks, but existing measures of TV viewing are imprecise due to relying on self-report. We developed the Family Level Assessment of Screen use in the Home (FLASH)-TV, a machine learning pipeline with state-of-the-art computer vision methods to measure children’s TV viewing. In three studies, lab pilot (n = 10), lab validation (n = 30), and home validation (n = 20), we tested the validity of FLASH-TV 3.0 in task-based protocols which included video observations of children for 60 min. To establish a gold-standard to compare FLASH-TV output, the videos were labeled by trained staff at 5-second epochs for whenever the child watched TV. For the combined sample with valid data (n = 59), FLASH-TV 3.0 provided a mean 85% (SD 8%) accuracy, 80% (SD 17%) sensitivity, 86% (SD 8%) specificity, and 0.71 (SD 0.15) kappa, compared to gold-standard. The mean intra-class correlation (ICC) of child’s TV viewing durations of FLASH-TV 3.0 to gold-standard was 0.86. Overall, FLASH-TV 3.0 correlated well with the gold standard across a diverse sample of children, but with higher variability among Black children than others. FLASH-TV provides a tool to estimate children’s TV viewing and increase the precision of research on TV viewing’s impact on children’s health. Supplementary Information The online version contains supplementary material available at 10.1038/s41598-024-81136-0.

Opinion Statement As the peak incidence of isocitrate dehydrogenase (IDH)-mutant gliomas is amongst young adults, there is a need to balance tumor control with long term side effects of therapy. Following initial clinical presentation and acquisition of contrasted diagnostic imaging, tissue diagnosis is essential in suspected diffuse glioma. Depending on the location and extent of disease, maximal surgical resection is preferred both for histologic diagnosis and initial therapy. Partial resection or biopsy alone is considered when the tumor cannot be completely resected or if there are clinical reservations regarding a more significant operation. The classification of diffuse glioma has evolved over time, with histopathology and molecular marker status guiding discussions of prognosis and postoperative management. In patients with IDH-mutant grade 2 glioma and low-risk features, observation with active surveillance is generally recommended following a gross total resection. For those with high-risk features, which historically included age > 40 years or subtotal resection, adjuvant chemotherapy and radiation therapy are generally recommended, however decisions for adjuvant therapy pose challenges as many of the landmark historical trials guiding adjuvant therapy were performed prior to the molecularly defined era. This is an area where multiple clinical trials are ongoing and hold promise to inform treatment paradigms, including recent data on the use of IDH-mutant inhibitors in grade 2 tumors with recurrent or residual disease. For IDH-mutant grade 3 and 4 glioma, adjuvant chemotherapy and radiation are recommended for all patients after initial resection.

Objective Characterize the association between Medicare Accountable Care Organizations’ (ACOs) behavioral health integration capability and quality and utilization among adults with serious mental illness (SMI). Background Controlled research supports the efficacy of integrating physical and mental health care for adults with SMI, yet little is known about the organizations integrating care and associations between integration capability and quality. Methods We surveyed Medicare ACOs (2017–2018 National Survey of ACOs, response rate 69%) and linked responses to 2016–2017 fee-for-service Medicare claims for beneficiaries with SMI. We examined the cross-sectional association between ACO-reported integration capability (tertiles of a 14-item index) and 7 patient-level quality and utilization outcomes. We fit generalized linear models for each outcome as a function of ACO integration capability, adjusting for ACO and beneficiary characteristics. Results Study sample included 274,928 beneficiary years (199,910 unique beneficiaries) attributed to 265 Medicare ACOs. ACOs with high behavioral health integration capability (top-tertile) served more dual-eligible beneficiaries (67.8%) than bottom-tertile (63.7%) and middle-tertile ACOs (63.3%). Most beneficiaries received follow-up 30 days after mental health hospitalization and chronic disease monitoring–exceeding national quality benchmarks–but beneficiaries receiving care from top-tertile (vs bottom-tertile) ACOs were modestly less likely to receive follow-up [−2.17 percentage points (pp), P < 0.05], diabetes monitoring (−2.19 pp, P < 0.05), and cardiovascular disease monitoring (−6.07 pp, P < 0.05). Integration capability was not correlated with utilization. Conclusions ACOs serving adults with substantial physical and mental health needs were more likely to report comprehensive integration capability but were not yet meeting the primary care needs of many adults with SMI.

For decades, it has been repeatedly claimed that the potent bacterial helicase-nuclease RecBCD (exonuclease V) destroys foreign (non-self) DNA, such as that of phages, but repairs and recombines cellular (self) DNA. While this would constitute a strong host-survival mechanism, no phage destroyed by RecBCD is ever specified in those claims. To determine which phages are destroyed by RecBCD, we searched for phage isolates that grow on Escherichia coli ΔrecBCD but not on recBCD+. In contrast to the prevailing claim, we found none among >80 new isolates from nature and >80 from previous collections. Based on these and previous observations, we conclude that RecBCD repairs broken DNA that can recombine but destroys DNA that cannot recombine and recycles the nucleotides.

Studies among men who have sex with men (MSM) in sub-Saharan Africa (SSA) focus mainly on HIV epidemiology, revealing little about the diversity within this population. We utilized data from the HIV Prevention Trials Network (HPTN) 075 study, to explore demographic and psychosexual characteristics of MSM in SSA who also have sex with women. Persons included in the analyses were aged 18–44 years and assigned male sex at birth and identified as male, reported anal sex with a man in the past 3 months, and had enrolled at one of four study sites (Kisumu, Kenya; Blantyre, Malawi; Cape Town and Soweto, South Africa). Nearly a quarter of the participants had recently engaged in sex with both men and women (MSMW). These men differed in terms of demographic and psychosexual characteristics, and sexual behavior from men who only had had sex with men (MSME). Compared to the latter, MSMW were more likely to prefer the insertive sexual role, reported more sexual partners in the past three months, and had more instances of condomless insertive anal intercourse with a man. These findings suggest that men who have sex with both men and women have specific characteristics and need tailored interventions that take their specific needs into account.

To prevent sexually-acquired HIV-1 infection by immunoprophylaxis, effective concentrations of broadly neutralizing antibodies are likely needed at mucosal sites of exposure. Here, we examine the biodistribution of monoclonal antibody VRC01 and its extended half-life variant, VRC01LS, in colorectal and genitourinary tracts of healthy adults 1-52 weeks after intravenous infusion. At 1-2 weeks, VRC01LS levels are ~3-4 times higher than VRC01 in serum (p = 0.048), rectal (p = 0.067), vaginal (p = 0.003) and cervical tissues (p = 0.003); these differences increase over time. Both antibodies primarily localize within rectal lamina propria and cervicovaginal stroma, with limited and variable epithelial distribution. Although 8-28% of serum mAb levels reach mucosal tissues, <3% are in seminal and rectal secretions. Elimination half-lives in mucosal tissues are 20-28 days for VRC01 and 51-68 days for VRC01LS. Thus, VRC01LS infusion achieves higher, sustained concentrations in human mucosal tissues than VRC01, supporting the future investigation of potent, long-acting LS-modified antibodies to prevent HIV-1.

The details of the pediatric immune system that supports induction of antibodies capable of neutralizing geographically-diverse or heterologous HIV-1 is currently unclear. Here we explore the pediatric immune environment in neonatal macaque undergoing Simian-HIV infection. Simian-HIV infection of 11 pairs of therapy-naive dams and infant rhesus macaques for 24 months results in heterologous HIV-1 neutralizing antibodies in 64% of young macaques compared to 18% of adult macaques. Heterologous HIV-1 neutralizing antibodies emerge by 12 months post-infection in young macaques, in association with lower expression of immunosuppressive genes, fewer germinal center CD4 + T regulatory cells, and a lower ratio of CD4 + T follicular regulatory to helper cells. Antibodies from peripheral blood B cells in two young macaques following SHIV infection neutralize 13% of 119 heterologous HIV-1 strains and map to regions of canonical broadly neutralizing antibody epitopes on the envelope surface protein. Here we show that pediatric immunity to SHIV infection in a macaque model may inform vaccine strategies to induce effective HIV-1 neutralizing antibodies in infants and children prior to viral exposure.

The success of allogeneic hematopoietic cell transplantation (alloHCT) in curing hematologic disorders is limited by its short- and long-term toxicities. One such toxicity is oral mucositis (OM), causing pain, speech/swallowing difficulty, and prolonged hospitalization. Although conditioning chemoradiotherapy is the direct cause of OM, potential host-intrinsic mediators of mucosal injury remain elusive. We hypothesized that the oral microbiota may influence OM severity. We used a validated comprehensive scoring system based on specialized Oral Medicine examinations to longitudinally quantify OM severity in alloHCT recipients. High-throughput multi-site profiling of the oral microbiota was performed in parallel. We identify a sex-dependent commensal bacterium, Oribacterium asaccharolyticum, whose presence in saliva before transplantation is associated with more severe OM 14 days after transplantation. The sex predilection of this species correlated with higher uric acid levels in men. Our findings represent the first sex-dependent microbiota-mediated pathway in OM pathogenesis and introduce novel targets for preventative interventions.

Lineage plasticity and histologic transformation from prostate adenocarcinoma to neuroendocrine prostate cancer (NEPC) occurs in up to 15-20% of patients with castration-resistant prostate cancer (CRPC) as mechanism of treatment resistance and is associated with aggressive disease and poor prognosis. NEPC tumors typically display small cell carcinoma morphology with loss of androgen receptor (AR) expression and gain of neuroendocrine (NE) lineage markers. However, there is a spectrum of phenotypes that are observed during the lineage plasticity process, and the clinical significance of mixed histologies or those that co-express AR and NE markers or lack all markers is not well defined. Translational research studies investigating NEPC have used variable definitions making clinical trial design challenging. Here we discuss the diagnostic workup of metastatic biopsies to help guide the reproducible classification of phenotypic CRPC subtypes. We recommend classifying CRPC tumors based on histomorphology (adenocarcinoma, small cell carcinoma, poorly differentiated carcinoma, other morphologic variant, or mixed morphology) and immunohistochemical markers with a priority for AR, NKX3.1, INSM1, synaptophysin and cell proliferation based on Ki-67 positivity, with additional markers to be considered based on the clinical context. Ultimately, a unified workup of metastatic CRPC biopsies can improve clinical trial design and eventually practice.

Adenocarcinomas from multiple tissues can converge to treatment-resistant small cell neuroendocrine (SCN) cancers composed of ASCL1, POU2F3, NEUROD1, and YAP1 subtypes. We investigated how mitochondrial metabolism influences SCN cancer (SCNC) progression. Extensive bioinformatics analyses encompassing thousands of patient tumors and human cancer cell lines uncovered enhanced expression of proliferator-activatedreceptor gamma coactivator 1-alpha (PGC-1α), a potent regulator of mitochondrial oxidative phosphorylation (OXPHOS), across several SCNCs. PGC-1α correlated tightly with increased expression of the lineage marker Achaete-scute homolog 1, (ASCL1) through a positive feedback mechanism. Analyses using a human prostate tissue-based SCN transformation system showed that the ASCL1 subtype has heightened PGC-1α expression and OXPHOS activity. PGC-1α inhibition diminished OXPHOS, reduced SCNC cell proliferation, and blocked SCN prostate tumor formation. Conversely, PGC-1α overexpression enhanced OXPHOS, validated by small-animal Positron Emission Tomography mitochondrial imaging, tripled the SCN prostate tumor formation rate, and promoted commitment to the ASCL1 lineage. These results establish PGC-1α as a driver of SCNC progression and subtype determination, highlighting metabolic vulnerabilities in SCNCs across different tissues.