The formation of mammalian dendritic cells (DCs) is controlled by multiple hematopoietic transcription factors, including IRF8. Loss of IRF8 exerts a differential effect on DC subsets, including ...plasmacytoid DCs (pDCs) and the classical DC lineages cDC1 and cDC2. In humans, cDC2-related subsets have been described including AXL+SIGLEC6+ pre-DC, DC2 and DC3. The origin of this heterogeneity is unknown. Using high-dimensional analysis, in vitro differentiation, and an allelic series of human IRF8 deficiency, we demonstrated that cDC2 (CD1c+DC) heterogeneity originates from two distinct pathways of development. The lymphoid-primed IRF8hi pathway, marked by CD123 and BTLA, carried pDC, cDC1, and DC2 trajectories, while the common myeloid IRF8lo pathway, expressing SIRPA, formed DC3s and monocytes. We traced distinct trajectories through the granulocyte-macrophage progenitor (GMP) compartment showing that AXL+SIGLEC6+ pre-DCs mapped exclusively to the DC2 pathway. In keeping with their lower requirement for IRF8, DC3s expand to replace DC2s in human partial IRF8 deficiency.
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•Distinct development trajectories of DC2 and DC3 underpin human cDC2 heterogeneity•pDC, cDC1, and DC2 (classical DCs) develop from LMPPs along a CD123+ IRF8high pathway•DC3 and monocytes develop from CD33+ GMPs along an IRF8low SIRPA+ pathway•IRF8 deficiency causes gene dose-dependent loss of IRF8high then IRF8low pathway DCs
Heterogeneity of human CD1c+ dendritic cells (cDC2s) is described, but how this arises is unknown. Cytlak and colleagues demonstrate that the cDC2 subsets, DC2 and DC3, develop along distinct hematopoietic trajectories, defined by differential IRF8 expression. DC2s develop from LMPPs along an IRF8hi pathway, while DC3 differentiation follows an IRF8low trajectory.
To evaluate the technical feasibility and safety of video-assisted thoracic surgery (VATS) lobectomy for small lung cancers.
The Cancer and Leukemia Group B 39802 trial was a prospective, ...multi-institutional study designed to elucidate the technical feasibility of VATS in early non-small-cell lung cancer (NSCLC) using a standard definition for VATS lobectomy (one 4- to 8-cm access and two 0.5-cm port incisions) that mandated videoscopic guidance and a traditional hilar dissection without rib spreading. Between 1998 and 2001, 128 patients with peripheral lung nodules < or = 3 cm in size with suspected NSCLC were prospectively registered for VATS lobectomy.
One hundred twenty-seven patients (66 males and 61 females; median age, 66 years; range, 37 to 86 years), with a performance status of 0 (74%) or 1 (26%), underwent surgery. Patients with lymph nodes more than 1 cm by computed tomography scan underwent mediastinal lymph node sampling to rule out N2 disease. One hundred eleven patients (87%) had stage I lung cancer, and 96 (86.5%) of these 111 patients underwent successful VATS lobectomies. The median procedure length was 130 minutes (range, 47 to 428 minutes), and median chest tube duration was 3 days (range, 1 to 14 days). Fifty-eight (60%) of 97 patients underwent diagnostic biopsy at lobectomy. Within 30 days, three (2.7%) of 111 patient deaths occurred, none of which were directly related to VATS technique; seven (7.4%) of 95 patients had grade 3 or greater complications, with only one case of bleeding.
A standardized approach to VATS lobectomy as specifically defined with avoidance of rib spreading is feasible.
Cyclin-dependent kinase 9 (CDK9), an important regulator of transcriptional elongation, is a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation. We ...characterized NVP-2, a selective ATP-competitive CDK9 inhibitor, and THAL-SNS-032, a selective CDK9 degrader consisting of a CDK-binding SNS-032 ligand linked to a thalidomide derivative that binds the E3 ubiquitin ligase Cereblon (CRBN). To our surprise, THAL-SNS-032 induced rapid degradation of CDK9 without affecting the levels of other SNS-032 targets. Moreover, the transcriptional changes elicited by THAL-SNS-032 were more like those caused by NVP-2 than those induced by SNS-032. Notably, compound washout did not significantly reduce levels of THAL-SNS-032-induced apoptosis, suggesting that CDK9 degradation had prolonged cytotoxic effects compared with CDK9 inhibition. Thus, our findings suggest that thalidomide conjugation represents a promising strategy for converting multi-targeted inhibitors into selective degraders and reveal that kinase degradation can induce distinct pharmacological effects compared with inhibition.
Standard therapy for unresectable stage III non-small-cell lung cancer includes concomitant chemoradiotherapy. In Cancer and Leukemia Group B 39801, we evaluated whether induction chemotherapy before ...concurrent chemoradiotherapy would result in improved survival.
Between July 1998 and May 2002, 366 patients were randomly assigned to arm A, which involved immediate concurrent chemoradiotherapy with carboplatin area under the concentration-time curve (AUC) of 2 and paclitaxel 50 mg/m2 given weekly during 66 Gy of chest radiotherapy, or arm B, which involved two cycles of carboplatin AUC 6 and paclitaxel 200 mg/m2 administered every 21 days followed by identical chemoradiotherapy. The accrual goal was 360 patients.
Thirty-four percent of patients were female, 66% were male, and the median age was 63 years. Grade 3 or 4 toxicities during induction chemotherapy on arm B consisted mainly of neutropenia (18% and 20%, respectively). During concurrent chemoradiotherapy, there was no difference in severity of in-field toxicities of esophagitis (grade 3 and 4 were, respectively, 30% and 2% for arm A v 28% and 8% for arm B) and dyspnea (grade 3 and 4 were, respectively, 11% and 3% for arm A v 15% and 4% for arm B). Survival differences were not statistically significant (P = .3), with a median survival on arm A of 12 months (95% CI, 10 to 16 months) versus 14 months (95% CI, 11 to 16 months) on arm B and a 2-year survival of 29% (95% CI, 22% to 35%) and 31% (95% CI, 25% to 38%). Age, weight loss before therapy, and performance status were statistically significant predictive factors.
The addition of induction chemotherapy to concurrent chemoradiotherapy added toxicity and provided no survival benefit over concurrent chemoradiotherapy alone. The median survival achieved in each of the treatment groups is low, and the routine use of weekly carboplatin and paclitaxel with simultaneous radiotherapy should be re-examined.
Protected areas vary enormously in their contribution to conserving biodiversity, and the inefficiency of protected area systems is widely acknowledged. However, conservation plans focus ...overwhelmingly on adding new sites to current protected area estates. Here we show that the conservation performance of a protected area system can be radically improved, without extra expenditure, by replacing a small number of protected areas with new ones that achieve more for conservation. Replacing the least cost-effective 1% of Australia's 6,990 strictly protected areas could increase the number of vegetation types that have 15% or more of their original extent protected from 18 to 54, of a maximum possible of 58. Moreover, it increases markedly the area that can be protected, with no increase in overall spending. This new paradigm for protected area system expansion could yield huge improvements to global conservation at a time when competition for land is increasingly intense.
Adjuvant chemotherapy for resected non-small-cell lung cancer (NSCLC) is now accepted on the basis of several randomized clinical trials (RCTs) that demonstrated improved survival. Although there is ...strong evidence that adjuvant chemotherapy is effective in stages II and IIIA NSCLC, its utility in stage IB disease is unclear. This report provides a mature analysis of Cancer and Leukemia Group B (CALGB) 9633, the only RCT designed specifically for stage IB NSCLC.
Within 4 to 8 weeks of resection, patients were randomly assigned to adjuvant chemotherapy or observation. Eligible patients had pathologically confirmed T2N0 NSCLC and had undergone lobectomy or pneumonectomy. Chemotherapy consisted of paclitaxel 200 mg/m(2) intravenously over 3 hours and carboplatin at an area under the curve dose of 6 mg/mL per minute intravenously over 45 to 60 minutes every 3 weeks for four cycles. The primary end point was overall survival.
Three hundred-forty-four patients were randomly assigned. Median follow-up was 74 months. Groups were well-balanced with regard to demographics, histology, and extent of surgery. Grades 3 to 4 neutropenia were the predominant toxicity; there were no treatment-related deaths. Survival was not significantly different (hazard ratio HR, 0.83; CI, 0.64 to 1.08; P = .12). However, exploratory analysis demonstrated a significant survival difference in favor of adjuvant chemotherapy for patients who had tumors > or = 4 cm in diameter (HR, 0.69; CI, 0.48 to 0.99; P = .043).
Because a significant survival advantage was not observed across the entire cohort, adjuvant chemotherapy should not be considered standard care in stage IB NSCLC. Given the magnitude of observed survival differences, CALGB 9633 was underpowered to detect small but clinically meaningful improvements. A statistically significant survival advantage for patients who had tumors > or = 4 cm supports consideration of adjuvant paclitaxel/carboplatin for stage IB patients who have large tumors.
The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a severe international shortage of the nasopharyngeal swabs that are required for collection of optimal ...specimens, creating a critical bottleneck blocking clinical laboratories' ability to perform high-sensitivity virological testing for SARS-CoV-2. To address this crisis, we designed and executed an innovative, cooperative, rapid-response translational-research program that brought together health care workers, manufacturers, and scientists to emergently develop and clinically validate new swabs for immediate mass production by 3D printing. We performed a multistep preclinical evaluation of 160 swab designs and 48 materials from 24 companies, laboratories, and individuals, and we shared results and other feedback via a public data repository (http://github.com/rarnaout/Covidswab/). We validated four prototypes through an institutional review board (IRB)-approved clinical trial that involved 276 outpatient volunteers who presented to our hospital's drive-through testing center with symptoms suspicious for COVID-19. Each participant was swabbed with a reference swab (the control) and a prototype, and SARS-CoV-2 reverse transcriptase PCR (RT-PCR) results were compared. All prototypes displayed excellent concordance with the control (κ = 0.85 to 0.89). Cycle threshold (
) values were not significantly different between each prototype and the control, supporting the new swabs' noninferiority (Mann-Whitney U MWU test,
> 0.05). Study staff preferred one of the prototypes over the others and preferred the control swab overall. The total time elapsed between identification of the problem and validation of the first prototype was 22 days. Contact information for ordering can be found at http://printedswabs.org Our experience holds lessons for the rapid development, validation, and deployment of new technology for this pandemic and beyond.
A concerted commitment across research stakeholders is necessary to increase equity, diversity, and inclusion (EDI) and address barriers to cancer clinical trial recruitment and participation. Racial ...and ethnic diversity among trial participants is key to understanding intrinsic and extrinsic factors that may affect patient response to cancer treatments. This ASCO and Association of Community Cancer Centers (ACCC) Research Statement presents specific recommendations and strategies for the research community to improve EDI in cancer clinical trials. There are six overarching recommendations: (1) clinical trials are an integral component of high-quality cancer care, and every person with cancer should have the opportunity to participate; (2) trial sponsors and investigators should design and implement trials with a focus on reducing barriers and enhancing EDI, and work with sites to conduct trials in ways that increase participation of under-represented populations; (3) trial sponsors, researchers, and sites should form long-standing partnerships with patients, patient advocacy groups, and community leaders and groups; (4) anyone designing or conducting trials should complete recurring education, training, and evaluation to demonstrate and maintain cross-cultural competencies, mitigation of bias, effective communication, and a commitment to achieving EDI; (5) research stakeholders should invest in programs and policies that increase EDI in trials and in the research workforce; and (6) research stakeholders should collect and publish aggregate data on racial and ethnic diversity of trial participants when reporting results of trials, programs, and interventions to increase EDI. The recommendations are intended to serve as a guide for the research community to improve participation rates among people from racial and ethnic minority populations historically under-represented in cancer clinical trials. ASCO and ACCC will work at all levels to advance the recommendations in this publication.
Tissue-resident lymphocytes play a key role in immune surveillance, but it remains unclear how these inherently stable cell populations respond to chronic inflammation. In the setting of celiac ...disease (CeD), where exposure to dietary antigen can be controlled, gluten-induced inflammation triggered a profound depletion of naturally occurring Vγ4+/Vδ1+ intraepithelial lymphocytes (IELs) with innate cytolytic properties and specificity for the butyrophilin-like (BTNL) molecules BTNL3/BTNL8. Creation of a new niche with reduced expression of BTNL8 and loss of Vγ4+/Vδ1+ IELs was accompanied by the expansion of gluten-sensitive, interferon-γ-producing Vδ1+ IELs bearing T cell receptors (TCRs) with a shared non-germline-encoded motif that failed to recognize BTNL3/BTNL8. Exclusion of dietary gluten restored BTNL8 expression but was insufficient to reconstitute the physiological Vγ4+/Vδ1+ subset among TCRγδ+ IELs. Collectively, these data show that chronic inflammation permanently reconfigures the tissue-resident TCRγδ+ IEL compartment in CeD.
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•Innate-like Vδ1+ IELs are superseded by interferon-γ-producing Vδ1+ IELs in CeD•The Vδ1+ IEL TCR repertoire is permanently reshaped in CeD•A molecular signature defines Vδ1+ IEL expansions in active CeD•Loss of BTNL8 expression coincides with permanent loss of BTNL3/8-reactive γδ+ IELs in CeD
Chronic inflammation, driven in the context of celiac disease by persistent antigenic challenge with dietary gluten, permanently reshapes the tissue-resident innate-like TCRγδ+ intraepithelial lymphocyte compartment.
We compared the efficacy of combination chemotherapy versus single-agent therapy in patients with advanced non-small-cell lung cancer.
A total of 561 eligible patients were randomly assigned to ...receive paclitaxel alone or in combination with carboplatin.
The response rate was 17% in the paclitaxel arm and 30% in the carboplatin-paclitaxel arm (P < .0001). Median failure-free survival was 2.5 months in the paclitaxel arm and 4.6 months in the carboplatin-paclitaxel arm (P = .0002). Median survival times were 6.7 months (95% CI, 5.8 to 7.8) and 8.8 months (95% CI, 8.0 to 9.9), and 1-year survival rates were 32% (95% CI, 27% to 38%), and 37% (95% CI, 32% to 43%), respectively. The overall survival distributions were not statistically different: hazard ratio = 0.91 (95% CI, 0.77 to 1.17; P = .25). Hematological toxicity and nausea were more frequent in the combination arm, but febrile neutropenia and toxic deaths were equally low in both arms. There was no significant survival difference in elderly patients. Performance status 2 patients treated with combination chemotherapy had a better survival rate than those treated with single-agent therapy (P = .019).
Combination chemotherapy improves response rate and failure-free survival compared with single-agent therapy, but there was no statistically significant difference in the primary end point of overall survival. The results in elderly patients were similar to younger patients. Performance status 2 patients had a superior outcome when treated with combination chemotherapy.
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