Статті в журналах з теми "Predictive maintenance ICTs"

This paper discusses the integration of emergent ICTs, such as the Internet of Things (IoT), the Arrowhead Framework, and the best practices from the area of condition monitoring and maintenance. These technologies are applied, for instance, for roller element bearing fault diagnostics and analysis by simulating faults. The authors first undertook the leading industry standards for condition-based maintenance (CBM), i.e., open system architecture–condition-based maintenance (OSA–CBM) and Machinery Information Management Open System Alliance (MIMOSA), which has been working towards standardizing the integration and interchangeability between systems. In addition, this paper highlights the predictive health monitoring methods that are needed for an effective CBM approach. The monitoring of industrial machines is discussed as well as the necessary details are provided regarding a demonstrator built on a metal sheet bending machine of the Greenbender family. Lastly, the authors discuss the benefits of the integration of the developed prototypes into a service-oriented platform, namely the Arrowhead Framework, which can be instrumental for the remotization of maintenance activities, such as the analysis of various equipment that are geographically distributed, to push forward the grand vision of the servitization of predictive health monitoring methods for large-scale interoperability.

Background: In advanced bladder cancer (BCa), platinum-based chemotherapy represents the first-choice treatment. In the last ten years, immune checkpoint inhibitors (ICIs) have changed the therapeutic landscape of many solid tumors. Our review aims to summarize the main findings regarding the clinical use of ICIs in advanced BCa. Methods: We searched PubMed, Embase, and Cochrane databases, and conference abstracts from international congresses (ASCO, ESMO, ASCO GU) for clinical trials, focusing on ICIs as monotherapy and combinations in metastatic BCa. Results: 18 studies were identified. ICIs targeting PD1 (nivolumab, pembrolizumab), PD-L1 (avelumab, atezolizumab, durvalumab), and CTLA4 (ipilimumab, tremelimumab) were used. Survival outcomes have been improved by second-line ICIs, whereas first-line results are dismal. Avelumab maintenance in patients obtaining disease control with chemotherapy has achieved the highest survival rates. Conclusions: ICIs improve survival after platinum-based chemotherapy. Avelumab maintenance represents a new practice-changing treatment. The combinations of ICIs and other compounds, such as FGFR-inhibitors, antibody-drug conjugates, and anti-angiogenic drugs, represent promising therapeutic approaches. Biomarkers with predictive roles and sequencing strategies are warranted for best patient selection.

The offshore plant equipment usually has a long life cycle. During its O&M (Operation and Maintenance) phase, since the accidental occurrence of offshore plant equipment causes catastrophic damage, it is necessary to make more efforts for managing critical offshore equipment. Nowadays, due to the emerging ICTs (Information Communication Technologies), it is possible to send health monitoring information to administrator of an offshore plant, which leads to much concern on CBM (Condition-Based Maintenance). This study introduces three approaches for predicting the next failure time of offshore plant equipment (gas compressor) with case studies, which are based on finite state continuous time Markov model, linear regression method, and their hybrid model.

The architecture design of industrial data analytics system addresses industrial process challenges and the design phase of the industrial Big Data management drivers that consider the novel paradigm in integrating Big Data technologies into industrial cyber-physical systems (iCPS). The goal of this paper is to support the design of analytics Big Data solutions for iCPS for the modeling of data elements, predictive analysis, inference of the key performance indicators, and real-time analytics, through the proposal of an architecture that will support the integration from IIoT environment, communications, and the cloud in the iCPS. An attribute driven design (ADD) approach has been adopted for architectural design gathering requirements from smart production planning, manufacturing process monitoring, and active preventive maintenance, repair, and overhaul (MRO) scenarios. Data management drivers presented consider new Big Data modeling analytics techniques that show data is an invaluable asset in iCPS. An architectural design reference for a Big Data analytics architecture is proposed. The before-mentioned architecture supports the Industrial Internet of Things (IIoT) environment, communications, and the cloud in the iCPS context. A fault diagnosis case study illustrates how the reference architecture is applied to meet the functional and quality requirements for Big Data analytics in iCPS.

Lung cancer is the leading cause of cancer-related deaths worldwide despite major advances in platinum-based chemotherapy and targeted therapy based on activating driving mutations. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigms in lung cancers. When used as a second-line or later treatment for non-small cell lung cancer (NSCLC), ICIs improve overall survival and exhibit better safety profiles than the standard chemotherapeutic agent, docetaxel. In front-line treatment, ICI monotherapy is significantly associated with improved clinical outcomes and fewer adverse events than platinum-based chemotherapy in patients with advanced NSCLC, who express programmed death-ligand 1 in at least 50% of all tumor cells. Moreover, ICIs combined with platinumbased chemotherapy have become the standard first-line treatment for patients with metastatic NSCLC without sensitizing mutations in the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene, regardless of programmed death-ligand 1 expression. Additionally, maintenance treatment using ICIs has also been demonstrated to improve clinical outcomes in patients with stage III unresectable NSCLC following chemoradiotherapy. Recently, the addition of ICIs to chemotherapy as the first-line treatment for extensive-stage small-cell lung cancer resulted in significantly longer overall survival and progression-free survival compared with chemotherapy alone. Although immune checkpoint inhibitors significantly improved overall survival and showed a durable response in lung cancer compared with platinum-based chemotherapy, we should foster further prospective studies to identify predictive biomarkers to determine those individuals who may benefit more from ICIs. It is also essential to overcome the development of drug resistance in patients treated with ICIs.

Техническое обслуживание по состоянию (condition-based maintenance, CBM) использует реальные условия эксплуатации компонентов для принятия решения об их замене и/или обслуживании, таким образом увеличивая срок службы оборудования и сводя к минимуму помехи при обслуживании. Система CBM выявляет существенные изменения и колебания сигналов и переменных на основе информации датчика, чтобы избежать или предотвратить поломку машин. Таким образом, в данной работе разрабатывается новая модель прогнозирования на CBM в машинах класса II, в которой скорость вибрации и среднее время рассматриваются в качестве входных параметров и, соответственно, прогнозируются доступность и надежность машин. Предлагаемая схема состоит из двух основных этапов, таких как (1) выделение признаков и (2) предсказание. Сначала выполняется выделение статистических и статистических признаков более высокого порядка. Найденные признаки передаются классификатору нейронной сети (NN), который предсказывает конечный результат (доступность и надежность машин). Чтобы повысить точность прогноза классификатора, веса NN точно настраиваются с помощью оптимизации Levy Flight Adopted Gray Wolf (LF_GWO). Доказано преимущество представленного подхода по отношению к различным мерам. Condition-based maintenance (CBM) utilizes the real conditions of the components to make a decision when to replace and/or maintain the components, thus maximizing the life span of the machineries, whilst minimizing the count of service interferences. Particularly, CBM system identifies the noteworthy variations and fluctuations of signals and variables on the basis of sensor information so as to avoid or prevent the breakdown in machines. Thereby, this work develops a new prediction model on CBM in class II machines, where vibration velocity and average time are considered as input parameters and accordingly, the availability and reliability are predicted. Here, the proposed scheme consists of 2 chief phases like (1) feature extraction and (2) prediction. At first, feature extraction is performed, wherein statistical and higher-order statistical features are extracted. Subsequent to this, the extracted features are given to the Neural Network (NN) classifier that predicts the final output (availability and reliability of machines). To enhance the prediction accuracy of the classifier, the weights of NN are fine-tuned via Levy Flight Adopted Grey Wolf Optimization (LF-GWO). At last, the supremacy the presented approach is proved with respect to varied measures.

The wear of the piston ring-cylinder system is inevitable in the operation of the internal combustion engines (ICEs). If wear exceeds the maximum, the piston ring-cylinder system will be failure. A novel wear assessment model is proposed based on the support vector regression, and the fuzzy uncertainty is modeled to describe the random behavior under small sample. To verify the proposed model, the sample data of cylinder liner wear is applied. For best results, the particle swarm optimization (PSO) algorithm is used to optimize the model parameters. A back propagation neural network (BPNN) is employed to verify the effectiveness of the proposed model. The results show that the novel support vector regression has better prediction accuracy than other methods for cylinder wear in this paper, the proposed model can evaluate the cylinder liner wear of the ICEs effectively. The work provides a technical support for evaluating the service performance of the piston ring-cylinder liner and a reference for regular maintenance of the ships.

2573 Background: Immune checkpoint inhibitors (ICIs) have demonstrated durable clinical responses and improved survival in patients (pts) across numerous indications. Despite this progress, the benefit of ICIs is limited to a minority of overall metastatic cancer patients. There is a critical need for biomarkers agnostic of tumor type to inform which pts will benefit from nivo alone versus ipi/nivo combination treatment. Both pre-treatment tumoral CD8 + cells and recruitment of CD8+ T cells in response to ICIs are associated with improved clinical outcomes in patients treated with anti-PD-1 therapy. 1,2,3,4 Here we report the final results of a prospective clinical study in which pts with varying advanced solid tumors were assigned to nivo, with or without ipi, based on the percentage of tumoral CD8 cells at the time of treatment. Methods: We performed a prospective, non-randomized, open-label, multicenter study in which pts with tumoral CD8+ cells ≥ 15% (CD8+ high) received nivo 360mg IV Q3W, followed by nivo maintenance 480mg Q4W. Pts with tumoral CD8+ cells < 15% (CD8+ low) received nivo 360 mg IV Q3W, and ipi at 1 mg/kg IV Q3W for 2 doses and then Q6W for 2 doses, followed by nivo maintenance 480 mg IV Q4W until PD or intolerable toxicity. Primary endpoints were Disease Control Rate (DCR: CR, PR, or SD ≥ 6 months) and CD8 low to high conversion (< 15% to ≥ 15%). Baseline and on-treatment tumor, blood and stool samples were collected for multiomic biomarker analyses. This study was not powered for formal statistical analysis. Up to 200 pts could be enrolled to allow for adaptive exploration of response and CD8 changes. Results: N = 79 pts were enrolled:7 in CD8+ high arm (nivo) and 72 in CD8+ low arm (ipi/nivo). The study enrolled a wide variety of primary solid tumors; the most common were gynecological (n = 15), prostate (12), and head and neck (7). DCR was 14% (1/7; 95% CI 1 - 44) and 24% (17/72; 95% CI 15 - 34) in the CD8 high and CD8 low arms, respectively. Of 39 pts in CD8 low arm with an on-treatment biopsy, 14 (36%; 95% CI 22 - 51) had CD8 conversion; 7/14 pts (50%) who converted had DCR. Immune-related AEs (irAEs) were consistent with known safety profile of both drugs. Conclusions: Ipi/nivo demonstrated clinical responses and increased CD8% in a range of “cold” tumors with low tumoral CD8 cells. There may be an association between increasing CD8% and response. Baseline high CD8% alone does not appear to be sufficient as a pan-cancer predictive biomarker of response to nivo monotherapy. CD8 conversion, response, and irAEs associated with circulating and stool-based biomarkers are under evaluation as composite biomarkers may improve their predictive value. Clinical trial information: 03651271.

Background: Demographic and disease characteristics have been associated with the risk of chronic obstructive pulmonary disease (COPD) exacerbations. Using previously collected multinational clinical trial data, we developed models that use baseline risk factors to predict an individual’s rate of moderate/severe exacerbations in the next year on various pharmacological treatments for COPD. Methods: Exacerbation data from 20,054 patients in the ETHOS, KRONOS, TELOS, SOPHOS, and PINNACLE-1, PINNACLE-2, and PINNACLE-4 studies were pooled. Machine learning was used to identify predictors of moderate/severe exacerbation rates. Important factors were selected for generalized linear modeling, further informed by backward variable selection. An independent test set was held back for validation. Results: Prior exacerbations, eosinophil count, forced expiratory volume in 1 s percent predicted, prior maintenance treatments, reliever medication use, sex, COPD Assessment Test score, smoking status, and region were significant predictors of exacerbation risk, with response to inhaled corticosteroids (ICSs) increasing with higher eosinophil counts, more prior exacerbations, or additional prior treatments. Model fit was similar in the training and test set. Prediction metrics were ~10% better in the full model than in a simplified model based only on eosinophil count, prior exacerbations, and ICS use. Conclusion: These models predicting rates of moderate/severe exacerbations can be applied to a broad range of patients with COPD in terms of airway obstruction, eosinophil counts, exacerbation history, symptoms, and treatment history. Understanding the relative and absolute risks related to these factors may be useful for clinicians in evaluating the benefit: risk ratio of various treatment decisions for individual patients. Clinical trials registered with www.clinicaltrials.gov (NCT02465567, NCT02497001, NCT02766608, NCT02727660, NCT01854645, NCT01854658, NCT02343458, NCT03262012, NCT02536508, and NCT01970878)

e21207 Background: The synergetic effect of ICIs plus chemotherapy has been demonstrated in first line setting for patients with advanced NSCLC. As previously reported, sintilimab plus docetaxel in advanced Chinese NSCLC pts who had failed first-line chemotherapy showed encouraging efficacy and tolerable safety profile. This exploratory study aims to investigate putative biomarker(s) predicting therapeutic response and long-term outcome for eligible patients. Methods: Advanced NSCLC pts who had failed standard platinum doublet without receiving any ICIs before would receive docetaxel (75mg/m2, day 1) plus sintilimab (200mg, day 3) every 3 weeks for 4-6 cycles followed by sintilimab maintenance until disease progression, unacceptable toxicity, or up to 2 years. Thirty-nine eligible patients received comprehensive genomic profiling of circulating tumor DNA (ctDNA) via a 448-gene panel before treatment. ctDNA from twenty-three patients were dynamically assessed after two courses (at 6th week). Eventually, 22 patients were enrolled into analysis, one patient was lost. White blood cells were used to filter germline variants from ctDNA sequencing data. Results: Of 22 patients with paired ctDNA profiling results at 6th week, 11 patients (50%) were defined as ctDNA residual due to presence of ≥2 somatic variants; Another 11 patients (50%) who had ≤1 somatic variant were defined as non-ctDNA residual. Significant difference of best objective response rate (ORR) (63.64% vs 0%, P=0.0039, two-sided Fisher’s Exact Testing for non-ctDNA residual vs ctDNA residual patients) was observed between these two populations. And numerically higher disease control rate (DCR) was seen in non-ctDNA residual patients (100% vs 63.64%, non-ctDNA residual vs ctDNA residual). Further, patients with ctDNA residual after 2 courses of sintilimab plus docetaxel (at 6th week) displayed higher risk of disease progression [Hazard Ratio (95%CI), 9.91(2.09-46.97), P=0.0038] and inferior prognosis (median PFS, ctDNA residual vs non-ctDNA residual, 3.0 months vs NR, P=0.0007). In addition, mutations of EGFR and LRP1B were enriched in ctDNA residual group. Especially, LRP1B gene mutations associated with shorter PFS period, which should be further investigated. Conclusions: Residual of ctDNA at 6th week was able to indicate inferior response to sintilimab plus docetaxel in patients with previously treated advanced NSCLC. Further validation of ctDNA residual as a robust predictive biomarker is warranted. [Table: see text]

<abstract> <p>Immune checkpoint genes (ICGs) have recently been proven to perform instrumental functions in the maintenance of immune homeostasis and represent a promising therapeutic strategy; however, their expression patterns and prognostic values are not fully elucidated in hepatocellular carcinoma (HCC). In this investigation, we focused on establishing and validating a prognostic gene signature to facilitate decision-making in clinical practice. Clinical information, as well as transcriptome data, was obtained from the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) database. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) Cox method were employed to build a multi-gene signature in the TCGA database, while the ICGC database was used for validation. Subsequently, utilizing the six-gene signature, we were able to categorize patients into high- and low-risk groups. In two cohorts, survival analysis findings revealed a dismal outlook for the high-risk group. The receiver operating characteristic curves were utilized to estimate the gene signature's prediction ability. Moreover, correlation analysis showed high-risk group was linked to advanced pathological stage, infiltration of immune cells and therapeutic response. In summary, this unique gene profile might serve not only as a useful prognostic indicator but also as a marker of therapy responsiveness in HCC.</p> </abstract>

BackgroundEsophageal carcinoma is a disease with high morbidity and mortality in China and, recently, Immune checkpoint inhibitors(ICIs) combined with chemotherapy have shown good efficacy and safety for treatment; however, some patients still suffer from tumor progression or metastasis after treatment. Clinical studies have confirmed that immunotherapy combined with chemoradiotherapy can significantly improve the prognosis of patients with advanced esophageal cancer, but the efficacy and safety of adding radiotherapy to immunotherapy and chemotherapy have been less reported.MethodsThis is an open-label, single-arm, and single-center phase ll trial.Patients with unresectable stage IV esophageal squamous cell carcinoma(ESCC) who had not received prior systemic therapy were enrolled. The patients were treated with two cycles of toripalimab (240 mg d1, Q3W) combined with induction chemotherapy (paclitaxel 135–175 mg/m2, d1+carboplatin AUC=4–6, d1, Q3W), sequentially combined with concurrent chemoradiotherapy (30–50 Gy in 15–25 fractions, paclitaxel 135–175 mg/m2, d1+carboplatin AUC=4–6 d1, Q3W), followed by maintenance treatment with toripalimab (240 mg d1, Q3W) for 1 year. The primary objective of this trial is to evaluate the progression-free survival (PFS) of this combination therapy;and the secondary objective is related to the assessment of objective response rate (ORR), the disease control rate (DCR), the duration of remission (DOR), the 1- and 2-year overall survival(OS) rates, the safety and tolerability of patients to treatment, and the identification of the changes in the health-related quality of life (HRQoL) of patients. Furthermore, we aimed to identify predictive biomarkers (such as the expression of PD-L1 ctDNA and cytokines) and to explore the relationship between these biomarkers and tumor response to the study treatment.AcknowledgementsWe thank all the participants and their advisors involving in this study. We owe thanks to the patients in our study and their family members.Trial RegistrationChiCTR(ChiCTR2100046715). Registered on the 27th of May 2021.Ethics ApprovalThe study protocol is approved by Ethics Committee of Sichuan Cancer Hospital (SCCHEC-02-2021-021).Changes to the protocol will be communicated via protocol amendment by the study principal investigators. Written informed consent will be obtained from all participants.

Object. The goal of this study was to elucidate the optimal time for rewarming of patients who have been treated with hypothermia for severe head injury. Methods. Eleven patients with severe head injuries who had been treated by hypothermia underwent transcranial Doppler (TCD) ultrasonography examinations. The patients were divided into two groups: Group A consisted of three patients in whom acute brain swelling occurred during the rewarming period and Group B was composed of eight patients who displayed no significant intracranial hypertension during or after hypothermia therapy. In all patients, the mean flow velocity of the middle cerebral artery (FVMCA) recorded transcranially and the mean flow velocity of the internal carotid artery (FVICA), recorded high in the neck, were monitored at 24-hour intervals after the patient was admitted to the hospital. In Group A, the FVMCA was normal at 48 hours (maintenance state of hypothermia) in each patient, and abnormal increases and peak values (> 100 cm/second) occurred from 96 to 144 hours postinjury (rewarming period). The FVICA, which was monitored concurrently also varied as the FVMCA increased. The pulsatility indices in the arteries decreased at the time of the peak FVMCA. The enhanced FVMCA was consistent with hyperemia because of the low FVMCA/FVICA ratios (< 3). Two patients in whom jugular venous oxygen saturation was monitored were found to have high values (> 80%), representing hyperemia. All intracranial pressures (ICPs) that lay within the normal range at 48 hours postinjury elevated acutely after the peak FVMCA. In Group B, both FVMCA and FVICA values were normal at 48 hours postinjury and remained stable throughout the rewarming period. Values of ICP were also maintained within the normal range until the patients were weaned from hypothermia therapy. Conclusions. Hyperemia, detectable by TCD ultrasonography, may serve as an index in the prediction of acute brain swelling, and rewarming should be terminated when such a hemodynamic phenomenon is observed.

We conducted a trial of bortezomib in patients with steroid-refractory cGVHD. Patients received 1.6 mg/m2 q wk x 4 followed by one week of rest, for up to six cycles, with some going on to a maintenance phase of treatment every other week for an additional 6 months. Twenty-one patients were registered on trial two patients withdrew before beginning treatment. Nineteen patients received between two and twelve months of treatment. The treatment was well tolerated with no grade 3 or higher adverse events (AE). Six patients had either CR or near CR. Average Rodnan scores on the 8 patients with sclerosis completing 2 or more cycles of therapy decreased from 22.6 ± 12.8 to 5.9 ± 6.2, p<0.005. One patient with non-healing suppurating lesions of his lower extremities had marked healing, another had significant decrease in chronic diarrhea. Weekly bortezomib for cGVHD was well tolerated and resulted in early improvement in a subset of patients with long standing refractory disease. Differential gene expression analysis was performed on the blood of patients prior to starting therapy, after two cycles and after their final cycle of therapy. All samples were run simultaneously at the end of the trial. Patients were classified as High (CR or near CR), intermediate (PR or stable disease), or poor responders (progression or not evaluable) based on clinical response. At baseline cGVHD patients express an overall decrease in T cell markers such as lineage (CD4), chemokine receptors (CCR6, CXCR3 and CCR7), and co-stimulatory molecules (CD40L, ICOS, CD28, and CD27), as well as decreases in IL23 and Granzyme K message compared to healthy controls. Increases were seen in myeloid/macrophage markers (CD163 and OSCAR). Baseline profiles of good responders were closer to those of healthy controls as compared to poor responders (figure below). Inflammation, cell death and apoptosis modules are up regulated and immune response modules are down-regulated in low and medium responders HC – Healthy Control; DC – Disease Control (allogeneic BMT recipients without cGVHD) Weekly bortezomib for cGVHD appears to be well tolerated and results in early improvement in long standing refractory disease in a subset of patients. Gene expression profiles at the initiation of treatment correlated with response and may be useful in predicting which patients will respond to bortezomib. Disclosures: Miller: Millennium Pharmaceuticals: Research Funding. Off Label Use: Bortezomib for chronic graft vs. host disease.

Background: Relapse is the major cause of failure after autologous stem cell transplantation (autoSCT) for patients (pts) with lymphoma. Targeting immune checkpoints with ipilimumab (Ipi) could result in lasting responses but only in few pts. We have previously reported that combination strategies of Ipi with lenalidomide (LEN) 10 mg (Ipi+LEN) resulted in enhanced immune activity manifested by a significant increase in the numbers of ICOS+CD4+FoxP3- T cells (Khouri I et al. Clin Cancer Res 2018:1011-1018). We have demonstrated proof-of-principle of this activity in one pt with refractory double hit lymphoma (DHL) (failed an autoSCT then relapsed after an allogeneic SCT) and another pt with CLL (failed ibrutinib, CART cell, and allogeneic SCT). Both pts then achieved complete remission with Ipi+LEN that has lasted 5+ and 4+ years, respectively. Hence, we have used Ipi+LEN to prevent relapse after autoSCT in pts with high-risk lymphoma, including double-expressor (DEL)/DHL who have been reported to have a 0% progression-free survival (PFS) rate at 4-years after autoSCT (Herrera et al. J Clin Oncol. 2017; 35:24-33). Patients andMethods: In this prospective trial, pts with lymphoma were enrolled within 6 months post-autoSCT. Inclusion criteria included: age 18 to 80 years; an ECOG PS 0-2; adequate liver (bilirubin and liver enzyme concentrations up to two times the upper limit of normal), renal (serum creatinine &lt; 1.6 mg/dl) , cardiac (ejection fraction 45%), and pulmonary (diffusing capacity of the lung for carbon monoxide 40% of predictive value) function; no active infections; ANC ≥ 1.5x109/L and a platelet count ≥ 75x109/L. Treatment consisted of LEN 10 mg PO daily for 21 days (cycles 1) alternating with Ipi 3 mg/kg IV on day 1 (Cycle 2) for up to 8 cycles. LEN dose reduction was permitted to 5 mg based on standard clinical practice. Results: Twenty-three pts were enrolled in the study. The median age at autoSCT was 56 years (range, 33-74). Fifteen (65%) were males and 5 (22%) pts had an HCT-CI ≥ 3. The median # of prior chemotherapies excluding their SCT was 2 (range, 1-5). Two pts had failed a prior autoSCT and were enrolled after a second transplant. Histologies included [DEL/DHL (n=8, 35%), DLBCL nonDEL/nonDHL (n=6, 23%), mantle cell lymphoma (MCL) (n=4, 17%; including 2 with 2 prior transplants, 1 with CNS involvement, 2 had blastoid histology, 1 in partial response to induction chemotherapy), follicular lymphoma (n=1; 4%; 3 prior therapies) Hodgkin's disease (n=2, 9%; including 1 with persistent PET+ post-transplant), angioimmunoblastic t-cell lymphoma (n=2, 9%). Most pts received R-BEAM (n=17, 74%) or BEAM (n=3, 13%) conditioning for their autoSCT. Median # of cycles of immunotherapy received after autoSCT was 5 (range, 2-8). Two pts are continuing their pre-planned treatment. Median follow-up duration was 35 months (range, 4-78 months). The 3-year rates of overall survival (OS) and PFS were 92% and 73%, respectively (Figure 1). Only 1 death was observed: this occurred in a pt with MCL who received 2 prior autoSCT and then developed post-transplant lymphoproliferative disorder without any evidence of MCL recurrence. The most common other grade 3-4 AEs were 10 events of neutropenia, anemia (1), perianal infection (1), and one developed pulmonary embolism on therapy. All AEs resolved. An immune-related AE occurred in one patient (dermatitis, gr 3) after the second ipilimumab dose and resolved with steroids. DEL/DHL group (n=8): This group was heavily pre-treated. The median # of prior chemotherapies excluding their SCT was 3 (range, 1-5). Five have failed DA-REPOCH, one had failed R-Hyper-CVAD and one was induced with R-CHOP. With a median follow-up of 35 months (range, 4-78months), all pts remain alive. One patient with DEL/DHL who was transplanted during second remission relapsed at 1.6 months after initiating therapy (just after finishing the cycle 2). All others remain in complete remission (Figure 2). Conclusions: Maintenance therapy with Ipi+LEN after autoSCT for high-risk lymphoma shows encouraging survival rates, including pts with DEL/DHL who usually have dismal outcomes. The treatment has favorable toxicity profile. These results warrant a randomized trial for confirmation. Disclosures Khouri: Bristol Myers Squibb: Research Funding; Pfizer: Research Funding. Jabbour:Genentech: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding. Lee:Seattle Genetics: Research Funding; Oncternal Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Aptitude Health: Speakers Bureau; Guidepoint Blogal: Consultancy; Celgene: Research Funding; Takeda: Research Funding. Nastoupil:Pfizer: Honoraria, Research Funding; Gilead/KITE: Honoraria; Merck: Research Funding; Genentech, Inc.: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; LAM Therapeutics: Research Funding; Gamida Cell: Honoraria; Bayer: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Karus Therapeutics: Research Funding. Iyer:Merck: Research Funding; Afffimed: Research Funding; Spectrum: Research Funding; Target Oncology: Honoraria; Legend Biotech: Consultancy; CRISPR: Research Funding; Curio Biosciences: Honoraria; Rhizen: Research Funding; Seattle Genetics, Inc.: Research Funding; Trillium: Research Funding; Daiichi Sankyo: Consultancy. Flowers:TG Therapeutics: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Burroughs Wellcome Fund: Research Funding; V Foundation: Research Funding; National Cancer Institute: Research Funding; Bayer: Consultancy; Kite: Research Funding; Eastern Cooperative Oncology Group: Research Funding; AbbVie: Consultancy, Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; Celgene: Consultancy, Research Funding; Acerta: Research Funding; BeiGene: Consultancy; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy; Karyopharm: Consultancy; OptumRx: Consultancy; Gilead: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding. Champlin:Genzyme: Speakers Bureau; Johnson and Johnson: Consultancy; Omeros: Consultancy; Actinium: Consultancy; Takeda: Patents & Royalties; DKMS America: Membership on an entity's Board of Directors or advisory committees; Cytonus: Consultancy. Sharma:BioAlta: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Achelois: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Apricity Health: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Constellation: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Dragonfly Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Forty-Seven Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Hummingbird: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Lava Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Lytix Biopharma: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Marker Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Oncolytics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Glympse: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Polaris: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Jounce Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; BioNTech: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Codiak BioSciences: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; ImaginAb: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Infinity Pharma: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Maintenance therapy with Ipilimumab and Lenalidomide after transplantation

Abstract Background: Immune checkpoint inhibitor (ICI) therapy has improved outcomes in non-small cell lung cancer (NSCLC), particularly in patients with high tumor infiltrating lymphocytes (TILs). Identifying the pharmacodynamic (PD) impact of ICI on immune cells in the tumor microenvironment (TME) can inform therapeutic development for patients with progressive disease. We sought to identify PD changes in the TME from patients before and after ICI therapy using a spatial transcriptomics platform that allows highly multiplexed profiling of 1,800 genes (Nanostring Digital Spatial Profiler [DSP]). Methods: Formalin fixed, paraffin embedded (FFPE) tumor tissue from 22 patients was sourced commercially. Patients were treated with neoadjuvant chemotherapy, then underwent a surgical tumor resection. After surgery an adjuvant chemotherapy was administered until progression; patients then received monotherapy ICI (nivolumab or pembrolizumab). Once progressed on ICI, another resection was performed. Patients were then treated with chemotherapy and followed until progression and/or death. The DSP technology was used to independently profile RNA from PanCK+ (tumor) and PanCK- (stroma) regions in the tissue based on fluorescence staining. Six circular regions of 600μm in diameter were selected for analysis using the GeoMx instrument; each area contained CD3+ cells. Additionally, immunohistochemistry for PDL1 and CD3 was performed, images were scored by a pathologist and analyzed with digital pathology algorithms. Results: Spatial transcriptomic analysis of pre- vs post-ICI treatment in stroma revealed significant increases in T cell genes (CD3E, TCRB, NKG7), T-cell activation markers (CD69, IFNG, OX40, GZMB, ICOS), costimulatory signaling (CD28, CD80, CD86), and immune checkpoints (CTLA4, TIGIT). Ayers et al., JCI 2017 identified 28 genes predictive of ICI response, 12 were significantly upregulated in the stroma post-ICI (26 were present in the DSP panel). We identified genes in the pre-ICI stromal microenvironment that were highly expressed in patients with partial response to ICI, the most significant genes were involved in immune regulation (IFIT1) and extracellular matrix remodeling (MMP3). In contrast, stromal genes highly expressed in patients with progressive disease were associated with T-cell maintenance (ETS1, IL7R, CCL19). Conclusions: In this study we used spatial transcriptomics to profile tissue regions where T-cells were in close proximity to tumor cells (microns). This focused, local PD analysis confirmed activated T-cells are present post-ICI. Ongoing studies in a larger cohort will be used to identify tumoral mechanisms of resistance and immune dysfunction to inform future therapeutics and combinations. Citation Format: Li Fan, Omar Jabado, Nora Pencheva, Patricia Coutinho de Souza, Brandon Higgs, Angelo Harris, Patrick Franken, Anantharaman Muthuswamy, Maria Jure-Kunkel, Suzana Couto, Kate Sasser, Mark Fereshteh. Spatial transcriptomics identifies unique pharmacodynamic effects of checkpoint inhibitor treatment on the tumor microenvironment in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2034.

Neuroendocrine neoplasias (NENs) are a heterogeneous group of rare tumors scattered throughout the body. Surgery, locoregional or ablative therapies as well as maintenance treatments are applied in well-differentiated, low-grade NENs, whereas cytotoxic chemotherapy is usually applied in high-grade neuroendocrine carcinomas. However, treatment options for patients with advanced or metastatic NENs are limited. Immunotherapy has provided new treatment approaches for many cancer types, including neuroendocrine tumors, but predictive biomarkers of immune checkpoint inhibitors (ICIs) in the treatment of NENs have not been fully reported. By reviewing the literature and international congress abstracts, we summarize the current knowledge of ICIs, potential predicative biomarkers in the treatment of NENs, implications and efficacy of ICIs as well as biomarkers for NENs of gastroenteropancreatic system, lung NENs and Merkel cell carcinoma in clinical practice.

Gastroesophageal cancers (GECs) comprise malignancies in the stomach, esophagus, and gastroesophageal junction. Despite ongoing improvements in chemoradiotherapy, the clinical outcomes of GEC have not significantly improved over the years, and treatment remains challenging. Immune checkpoint inhibitors (ICIs) have been the subject of clinical trials worldwide for several years. Encouraging results have been reported in different countries, but further research is required to apply ICIs in the clinical care of patients with GEC. This review summarizes completed and ongoing clinical trials with programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway blockers in GEC and current biomarkers used for predicting PD-1/PD-L1 blockade efficacy. This review captures the main findings of PD-1/PD-L1 antibodies combined with chemotherapy as an effective first-line treatment and a monotherapy in second-line or more treatment and in maintenance therapy. This review aims to provide insight that will help guide future research and clinical trials, thereby improving the outcomes of patients with GEC.

High-quality source code comments are valuable for software development and maintenance, however, code often contains low-quality comments or lacks them altogether. We name such source code comments as suboptimal comments. Such suboptimal comments create challenges in code comprehension and maintenance. Despite substantial research on low-quality source code comments, empirical knowledge about commenting practices that produce suboptimal comments and reasons that lead to suboptimal comments are lacking. We help bridge this knowledge gap by investigating (1) independent comment changes (ICCs) —comment changes committed independently of code changes—which likely address suboptimal comments, and (2) commenting guidelines and (3) comment-checking tools and comment-generating tools, which are often employed to help commenting practice—especially to prevent suboptimal comments. We collect 24M+ comment changes from 4,392 open-source GitHub Java repositories and find that ICCs widely exist. The ICC ratio —proportion of ICCs among all comment changes—is ∼ 15.5%, with 98.7% of the repositories having ICC. Our thematic analysis of 3,533 randomly sampled ICCs provides a three-dimensional taxonomy for what is changed (four comment categories and 13 subcategories), how it changed (six commenting activity categories), and what factors are associated with the change (three factors). We investigate 600 repositories to understand the prevalence, content, impact, and violations of commenting guidelines. We find that only 15.5% of the 600 sampled repositories have any commenting guidelines. We provide the first taxonomy for elements in commenting guidelines: where and what to comment are particularly important. The repositories without such guidelines have a statistically significantly higher ICC ratio, indicating the negative impact of the lack of commenting guidelines. However, commenting guidelines are not strictly followed: 85.5% of checked repositories have violations. We also systematically study how developers use two kinds of tools, comment-checking tools and comment-generating tools, in the 4,392 repositories. We find that the use of Javadoc tool is negatively correlated with the ICC ratio, while the use of Checkstyle has no statistically significant correlation; the use of comment-generating tools leads to a higher ICC ratio. To conclude, we reveal issues and challenges in current commenting practice, which help understand how suboptimal comments are introduced. We propose potential research directions on comment location prediction, comment generation, and comment quality assessment; suggest how developers can formulate commenting guidelines and enforce rules with tools; and recommend how to enhance current comment-checking and comment-generating tools.

Abstract Background Regimens combining pemetrexed (PEM) and immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) or programmed death-ligand 1 (PD-L1) are widely used for the treatment of advanced non-squamous non-small-cell lung cancer (NSq-NSCLC). Recently, PEM was shown to induce immunogenic cell death (ICD) and to enhance immune-regulatory genes. Some patients demonstrate an extremely long-term response to PEM. It is possible that the continued response in these patients is dependent on not only the pharmacological induction of cytotoxic cell death but also antitumor immunity. However, factors that can predict outcomes associated with long-term PEM administration using blood test results have not yet been elucidated. We investigated the clinical characteristics and predictive factors in patients with advanced NSq-NSCLC who underwent long-term PEM maintenance therapy. Methods In total, 504 patients with advanced NSq-NSCLC who received PEM combination therapy/monotherapy (n = 414) or paclitaxel (PTX) combination therapy (n = 90) between January 2010 and November 2019 were recruited; 381 patients were retained for the final analysis. Patients treated with PEM (n = 301) were divided into subgroups according to the total cycles of PEM (≥ 17 [n = 25] for the long-term administration group and ≤ 16 [n = 276] for the intermediate/short-term group) and compared with another population (n = 80) treated with PTX combination regimen. We investigated clinical features and predictive biomarkers, focusing on immune-regulatory factors, absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), and PD-1 and PD-L1 expression, to predict long-term response to PEM. Results The long-term PEM administration group exhibited a higher ALC and a lower NLR than the shorter-term group did. Both these markers displayed greater association with progression-free survival and overall survival in the PEM combination therapy group than in the PTX combination therapy group. Increased PD-1 lymphocytes were associated with the long-term PEM response group, as PD-L1 expression in tumors was associated with a high incidence of immune-related adverse effects following ICI administration. Conclusions ALC, NLR, and PD-1 expression are PEM-mediated predictive biomarkers that are indirectly related to tumor immunity and can provide useful predictive information on the long-term response to PEM in patients with NSq-NSCLC.