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PURPOSE Relapsed or refractory extranodal natural killer/T-cell lymphoma (R/R ENKTL) is a rare and aggressive type of non-Hodgkin lymphoma with limited treatment options. This phase II study evaluated the efficacy and safety of sugemalimab, an anti–PD-L1 monoclonal antibody, in R/R ENKTL. METHODS Eligible patients received sugemalimab 1,200 mg intravenously once every 3 weeks for up to 24 months or until progression, death, or study withdrawal. The primary end point was objective response rate (ORR) assessed by an independent radiologic review committee. Key secondary end points included ORR assessed by the investigators, complete response rate, duration of response, and safety. RESULTS At the data cutoff (February 23, 2022), 80 patients were enrolled and followed for a median of 18.7 months. At baseline, 54 (67.5%) had stage IV disease and 39 (48.8%) had received ≥2 lines of prior systemic therapy. Independent radiologic review committee–assessed ORR was 44.9% (95% CI, 33.6 to 56.6); 28 (35.9%) patients achieved a complete response and seven (9.0%) achieved a partial response, with a 12-month duration of response rate of 82.5% (95% CI, 62.0 to 92.6). Investigator-assessed ORR was 45.6% (95% CI, 34.3 to 57.2), and 24 (30.4%) patients achieved a complete response. Most treatment-emergent adverse events were grade 1-2 in severity, and grade ≥ 3 events were reported in 32 (40.0%) patients. CONCLUSION Sugemalimab showed robust and durable antitumor activity in R/R ENKTL. Treatment was well tolerated with expected safety profile for this drug class.

We used a mouse model to study how Mycobacterium tuberculosis subverts host defenses to persist in macrophages despite immune pressure. CD4 T cells can recognize macrophages infected with a single bacillus in vitro. Under identical conditions, CD8 T cells inefficiently recognize infected macrophages and fail to restrict M. tuberculosis growth, although they can inhibit M. tuberculosis growth during high-burden intracellular infection. We show that high intracellular M. tuberculosis numbers cause macrophage death, leading other macrophages to scavenge cellular debris and cross-present the TB10.4 Ag to CD8 T cells. Presentation by infected macrophages requires M. tuberculosis to have a functional ESX-1 type VII secretion system. These data indicate that phagosomal membrane damage and cell death promote MHC class I presentation of the immunodominant Ag TB10.4 by macrophages. Although this mode of Ag presentation stimulates cytokine production that we presume would be host beneficial, killing of uninfected cells could worsen immunopathology. We suggest that shifting the focus of CD8 T cell recognition to uninfected macrophages would limit the interaction of CD8 T cells with infected macrophages and impair CD8 T cell–mediated resolution of tuberculosis.

Leading researchers at the intersection of infectious disease and systems biology speak about how systems approaches have influenced modern infectious disease research and what these tools can offer for the future of the field.

OBJECTIVE Intracranial pressure (ICP) is an important therapeutic target in many critical neuropathologies. The current tools for ICP measurements are invasive; hence, these are only selectively applied in critical cases where the benefits surpass the risks. To address the need for low-risk ICP monitoring, the authors developed a noninvasive alternative. METHODS The authors recently demonstrated noninvasive quantification of ICP in an animal model by using morphological analysis of microvascular cerebral blood flow (CBF) measured with diffuse correlation spectroscopy (DCS). The current prospective observational study expanded on this preclinical study by translating the method to pediatric patients. Here, the CBF features, along with mean arterial pressure (MAP) and heart rate (HR) data, were used to build a random decision forest, machine learning model for estimation of ICP; the results of this model were compared with those of invasive monitoring. RESULTS Fifteen patients (mean age ± SD [range] 9.8 ± 5.1 [0.3–17.5] years; median age [interquartile range] 11 [7.4] years; 10 males and 5 females) who underwent invasive neuromonitoring for any purpose were enrolled. Estimated ICP (ICPest) very closely matched invasive ICP (ICPinv), with a root mean square error (RMSE) of 1.01 mm Hg and 95% limit of agreement of ≤ 1.99 mm Hg for ICPinv 0.01–41.25 mm Hg. When the ICP range (ICPinv 0.01–29.05 mm Hg) was narrowed on the basis of the sample population, both RMSE and limit of agreement improved to 0.81 mm Hg and ≤ 1.6 mm Hg, respectively. In addition, 0.3% of the test samples for ICPinv ≤ 20 mm Hg and 5.4% of the test samples for ICPinv > 20 mm Hg had a limit of agreement > 5 mm Hg, which may be considered the acceptable limit of agreement for clinical validity of ICP sensing. For the narrower case, 0.1% of test samples for ICPinv ≤ 20 mm Hg and 1.1% of the test samples for ICPinv > 20 mm Hg had a limit of agreement > 5 mm Hg. Although the CBF features were crucial, the best prediction accuracy was achieved when these features were combined with MAP and HR data. Lastly, preliminary leave-one-out analysis showed model accuracy with an RMSE of 6 mm Hg and limit of agreement of ≤ 7 mm Hg. CONCLUSIONS The authors have shown that DCS may enable ICP monitoring with additional clinical validation. The lower risk of such monitoring would allow ICP to be estimated for a wide spectrum of indications, thereby both reducing the use of invasive monitors and increasing the types of patients who may benefit from ICP-directed therapies.

Respiratory failure is a common cause of pulseless electrical activity (PEA) and asystolic cardiac arrest, but the changes in heart rate (HR) pre-arrest are not well described. We describe HR dynamics prior to in-hospital cardiac arrest (IHCA) among PEA/asystole arrest patients with respiratory etiology.In this retrospective study, we evaluated 139 patients with 3-24 hours of continuous electrocardiogram data recorded preceding PEA/asystole IHCA from 2010-2017. We identified respiratory failure cases by chart review and evaluated electrocardiogram data to identify patterns of HR changes, sinus bradycardia or sinus arrest, escape rhythms, and development right ventricular strain prior to IHCA.A higher proportion of respiratory cases (58/73, 79 %) fit a model of HR response characterized by tachycardia followed by rapid HR decrease prior to arrest, compared to non-respiratory cases (30/66, 45 %, p 0.001). Among the 58 respiratory cases fitting this model, 36 (62 %) had abrupt increase in HR occurring 64 (IQR 23-191) minutes prior to arrest, while 22 (38 %) had stable tachycardia until time of HR decrease. Mean peak HR was 123 ± 21 bpm. HR decrease occurred 3.0 (IQR 2.0-7.0) minutes prior to arrest. Sinus arrest occurred during the bradycardic phase in 42/58 of cases; escape rhythms were present in all but 2/42 (5 %) cases. Right ventricular strain ECG pattern, when present, occurred at a median of 2.2 (IQR -0.05-17) minutes prior to onset of HR decrease.IHCAs of respiratory etiology follow a model of HR increase from physiologic compensation to hypoxia, followed by rapid HR decrease prior to arrest.

Background: The high incidence of early recurrence after hepatectomy for intrahepatic cholangiocarcinoma (ICC) has a detrimental effect on overall survival (OS). Machine-learning models may improve the accuracy of outcome prediction for malignancies. Methods: Patients who underwent curative-intent hepatectomy for ICC were identified using an international database. Three machine-learning models were trained to predict early recurrence (< 12 months after hepatectomy) using 14 clinicopathologic characteristics. The area under the receiver operating curve (AUC) was used to assess their discrimination ability. Results: In this study, 536 patients were randomly assigned to training (n = 376, 70.1%) and testing (n = 160, 29.9%) cohorts. Overall, 270 (50.4%) patients experienced early recurrence (training: n = 150 [50.3%] vs testing: n = 81 [50.6%]), with a median tumor burden score (TBS) of 5.6 (training: 5.8 [interquartile range {IQR}, 4.1–8.1] vs testing: 5.5 [IQR, 3.7–7.9]) and metastatic/undetermined nodes (N1/NX) in the majority of the patients (training: n = 282 [75.0%] vs testing n = 118 [73.8%]). Among the three different machine-learning algorithms, random forest (RF) demonstrated the highest discrimination in the training/testing cohorts (RF [AUC, 0.904/0.779] vs support vector machine [AUC, 0.671/0.746] vs logistic regression [AUC, 0.668/0.745]). The five most influential variables in the final model were TBS, perineural invasion, microvascular invasion, CA 19-9 lower than 200 U/mL, and N1/NX disease. The RF model successfully stratified OS relative to the risk of early recurrence. Conclusions: Machine-learning prediction of early recurrence after ICC resection may inform tailored counseling, treatment, and recommendations. An easy-to-use calculator based on the RF model was developed and made available online.

With advances in machine learning (ML)-assisted protein engineering, models based on data, biophysics, and natural evolution are being used to propose informed libraries of protein variants to explore. Synthesizing these libraries for experimental screens is a major bottleneck, as the cost of obtaining large numbers of exact gene sequences is often prohibitive. Degenerate codon (DC) libraries are a cost-effective alternative for generating combinatorial mutagenesis libraries where mutations are targeted to a handful of amino acid sites. However, existing computational methods to optimize DC libraries to include desired protein variants are not well suited to design libraries for ML-assisted protein engineering. To address these drawbacks, we present DEgenerate Codon Optimization for Informed Libraries (DeCOIL), a generalized method which directly optimizes DC libraries to be useful for protein engineering: to sample protein variants that are likely to have both high fitness and high diversity in the sequence search space. Using computational simulations and wet-lab experiments, we demonstrate that DeCOIL is effective across two specific case studies, with potential to be applied to many other use cases. DeCOIL offers several advantages over existing methods, as it is direct, easy-to-use, generalizable, and scalable. With accompanying software (https://github.com/jsunn-y/DeCOIL), DeCOIL can be readily implemented to generate desired informed libraries.Abstract Figure

A substantial proportion of patients with unresectable stage III non-small-cell lung cancer (NSCLC) cannot either tolerate or access concurrent chemoradiotherapy, so sequential chemoradiotherapy is commonly used. We assessed the efficacy and safety of sugemalimab, an anti-PD-L1 antibody, in patients with stage III NSCLC whose disease had not progressed after concurrent or sequential chemoradiotherapy.GEMSTONE-301 is a randomised, double-blind, placebo-controlled, phase 3 trial in patients with locally advanced, unresectable, stage III NSCLC, done at 50 hospitals or academic research centres in China. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 who had not progressed after concurrent or sequential chemoradiotherapy. We randomly assigned patients (2:1, using an interactive voice-web response system) to receive sugemalimab 1200 mg or matching placebo, intravenously every 3 weeks for up to 24 months. Stratification factors were ECOG performance status, previous chemoradiotherapy, and total radiotherapy dose. The investigators, trial coordination staff, patients, and study sponsor were masked to treatment allocation. The primary endpoint was progression-free survival as assessed by blinded independent central review (BICR) in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of assigned study treatment. The study has completed enrolment and the results of a preplanned analysis of the primary endpoint are reported here. The trial is registered with ClinicalTrials.gov, NCT03728556.Between Aug 30, 2018 and Dec 30, 2020, we screened 564 patients of whom 381 were eligible. Study treatment was received by all patients randomly assigned to sugemalimab (n=255) and to placebo (n=126). At data cutoff (March 8, 2021), median follow-up was 14·3 months (IQR 6·4-19·4) for patients in the sugemalimab group and 13·7 months (7·1-18·4) for patients in the placebo group. Progression-free survival assessed by BICR was significantly longer with sugemalimab than with placebo (median 9·0 months [95% CI 8·1-14·1] vs 5·8 months [95% CI 4·2-6·6]; stratified hazard ratio 0·64 [95% CI 0·48-0·85], p=0·0026). Grade 3 or 4 treatment-related adverse events occurred in 22 (9%) of 255 patients in the sugemalimab group versus seven (6%) of 126 patients in the placebo group, the most common being pneumonitis or immune-mediated pneumonitis (seven [3%] of 255 patients in the sugemalimab group vs one [1%] of 126 in the placebo group). Treatment-related serious adverse events occurred in 38 (15%) patients in the sugemalimab group and 12 (10%) in the placebo group. Treatment-related deaths were reported in four (2%) of 255 patients (pneumonia in two patients, pneumonia with immune-mediated pneumonitis in one patient, and acute hepatic failure in one patient) in the sugemalimab group and none in the placebo group.Sugemalimab after definitive concurrent or sequential chemoradiotherapy could be an effective consolidation therapy for patients with stage III NSCLC whose disease has not progressed after sequential or concurrent chemoradiotherapy. Longer follow-up is needed to confirm this conclusion.CStone Pharmaceuticals and the National Key Research and Development Program of China.For the Chinese translation of the abstract see Supplementary Materials section.

PD-1 inhibitor plus chemotherapy had been shown to be an effective first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC). However, there was no robust evidence showing a PD-L1 inhibitor combined with chemotherapy benefited patients with squamous and non-squamous NSCLC. GEMSTONE-302 aimed to evaluate the efficacy and safety of a PD-L1 inhibitor, sugemalimab, plus chemotherapy for patients with metastatic squamous or non-squamous NSCLC.This randomised, double-blind, phase 3 trial was done in 35 hospitals and academic research centres in China. Eligible patients were aged 18-75 years, had histologically or cytologically confirmed stage IV squamous or non-squamous NSCLC without known EGFR sensitising mutations, ALK, ROS1, or RET fusions, no previous systemic treatment for metastatic disease, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned (2:1) to receive sugemalimab (1200 mg, intravenously, every 3 weeks) plus platinum-based chemotherapy (carboplatin [area under the curve (AUC) 5 mg/mL per min, intravenously] and paclitaxel [175 mg/mBetween Dec 13, 2018, and May 15, 2020, 846 patients were assessed for eligibility; 367 were ineligible, and the remaining 479 patients were randomly assigned to the sugemalimab group (n=320) or placebo group (n=159). At the preplanned interim analysis (data cutoff June 8, 2020; median follow-up 8·6 months [IQR 6·1-11·4]), GEMSTONE-302 met its primary endpoint, with significantly longer progression-free survival in the sugemalimab group compared with the placebo group (median 7·8 months [95% CI 6·9-9·0] vs 4·9 months [4·7-5·0]; stratified hazard ratio [HR] 0·50 [95% CI 0·39-0·64], p0·0001]). At the final analysis (March 15, 2021) with a median follow-up of 17·8 months (IQR 15·1-20·9), the improvement in progression-free survival was maintained (median 9·0 months [95% CI 7·4-10·8] vs 4·9 months [4·8-5·1]; stratified HR 0·48 [95% CI 0·39-0·60], p0·0001). The most common grade 3 or 4 any treatment-related adverse events were neutrophil count decreased (104 [33%] of 320 with sugemalimab vs 52 [33%] of 159 with placebo), white blood cell count decreased (45 [14%] vs 27 [17%]), anaemia (43 [13%] vs 18 [11%]), platelet count decreased (33 [10%] vs 15 [9%]), and neutropenia (12 [4%] vs seven [4%]). Any treatment-related serious adverse events occurred in 73 (23%) patients in the sugemalimab group and 31 (20%) patients in the placebo group. Any treatment-related deaths were reported in ten (3%) patients in the sugemalimab group (pneumonia with respiratory failure in one patient; myelosuppression with septic shock in one patient; pneumonia in two patients; respiratory failure, abdominal pain, cardiac failure, and immune-mediated pneumonitis in one patient each; the other two deaths had an unspecified cause) and in two (1%) patients in the placebo group (pneumonia and multiple organ dysfunction syndrome).Sugemalimab plus chemotherapy showed a statistically significant and clinically meaningful progression-free survival improvement compared with placebo plus chemotherapy, in patients with previously untreated squamous and non-squamous metastatic NSCLC, regardless of PD-L1 expression, and could be a newfirst-line treatment option for both squamous and non-squamous metastatic NSCLC.CStone Pharmaceuticals.For the Chinese translation of the abstract see Supplementary Materials section.