We aimed to assess patient-, tooth- and treatment-level covariates on the failure of root canal treatments (RT) and to predict failure using machine learning (ML).
Teeth receiving RT at one large ...university hospital from 2016 to 2020 with a minimum follow-up of ≥6 months were included. Failure compromised absent radiographic healing and/or the presence of clinical symptoms. Covariates were selected on tooth-, treatment- and patient-level. We used logistic regression (logR) to determine associations in the full dataset, and logR as well as more advanced ML (random forests (RF), gradient boosting machine (GBM) and extremely gradient boosting (XGB)) for predictive modeling (area-under-the-receiver operating characteristic-curve (ROCAUC)) and testing on a separate test dataset.
458 patients (female/male 47.2/52.8%) with 591 permanent teeth were included (overall success rate 79.5%). In logR, tooth-level covariates showed strong associations with failure: Alveolar bone loss 66–100% (ABL, OR 6.48, 95% CI 2.86, 14.89, p<0.001); Periapical index (PAI) score≥4 (OR 4.59, 2.44, 8.79, p<0.001); ABL 33–66% (OR 2.59 1.49, 4.49, p<0.001); PAI=3 (OR 2.45, 1.43, 4.34, p<0.01); Treatment type “retreatment” (OR 1.77, 1.01, 2.86, p<0.01). On patient level only smoking (OR 2.05, 1.18, 3.53, p<0.05) was significantly associated with risk of failure. For predictive modeling, the predictive power of all models was limited (ROCAUC: logR 0.63, 0.53, 0.73; GBM 0.59, 0.50, 0.68; RF 0.59, 0.50, 0.68; XGB 0.60, 0.50, 0.70).
Failure of RT was associated mainly with tooth-level covariates. Predicting failure was only limitedly possible, also with more complex ML.
Identifying specific risk factors for failure of RT and predicting the outcome of RT is relevant for treatment planning and informed shared decision-making. The present study found tooth-level factors to be associated with failure. Notably, predicting failure was only limitedly possible.
The biological determinants of sensitivity and resistance to immune checkpoint blockers are not completely understood. To elucidate the role of intratumoral T-cells and their association with the ...tumor genomic landscape, we perform paired whole exome DNA sequencing and multiplexed quantitative immunofluorescence (QIF) in pre-treatment samples from non-small cell lung carcinoma (NSCLC) patients treated with PD-1 axis blockers. QIF is used to simultaneously measure the level of CD3+ tumor infiltrating lymphocytes (TILs), in situ T-cell proliferation (Ki-67 in CD3) and effector capacity (Granzyme-B in CD3). Elevated mutational load, candidate class-I neoantigens or intratumoral CD3 signal are significantly associated with favorable response to therapy. Additionally, a "dormant" TIL signature is associated with survival benefit in patients treated with immune checkpoint blockers characterized by elevated TILs with low activation and proliferation. We further demonstrate that dormant TILs can be reinvigorated upon PD-1 blockade in a patient-derived xenograft model.
Although EGFR mutant tumors exhibit low response rates to immune checkpoint blockade overall, some EGFR mutant tumors do respond to these therapies; however, there is a lack of understanding of the ...characteristics of EGFR mutant lung tumors responsive to immune checkpoint blockade.
We retrospectively analyzed de-identified clinical and molecular data on 171 cases of EGFR mutant lung tumors treated with immune checkpoint inhibitors from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, University of California Los Angeles, and Dana Farber Cancer Institute. A separate cohort of 383 EGFR mutant lung cancer cases with sequencing data available from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, and The Cancer Genome Atlas was compiled to assess the relationship between tumor mutation burden and specific EGFR alterations.
Compared with 212 EGFR wild-type lung cancers, outcomes with programmed cell death 1 or programmed death-ligand 1 (PD-(L)1) blockade were worse in patients with lung tumors harboring alterations in exon 19 of EGFR (EGFRΔ19) but similar for EGFRL858R lung tumors. EGFRT790M status and PD-L1 expression did not impact response or survival outcomes to immune checkpoint blockade. PD-L1 expression was similar across EGFR alleles. Lung tumors with EGFRΔ19 alterations harbored a lower tumor mutation burden compared with EGFRL858R lung tumors despite similar smoking history.
EGFR mutant tumors have generally low response to immune checkpoint inhibitors, but outcomes vary by allele. Understanding the heterogeneity of EGFR mutant tumors may be informative for establishing the benefits and uses of PD-(L)1 therapies for patients with this disease.
First we aimed to identify significant associations between preoperative risk factors and achieving optimal root filling length (RFL) during orthograde root canal treatments (RCT) and second to ...predict successful RFL using machine learning.
Teeth receiving RCT at one university clinic from 2016-2020 with complete documentation were included. Successful RFL was defined to be 0-2mm of the apex, suboptimal RFL >2mm or beyond the apex. Logistic regression (logR) was used for association analyses; logR and more advanced machine learning (random forest (RF), support vector machine (SVM), decision tree (DT), gradient boosting machine (GBM) and extreme gradient boosting (XGB)) were employed for predictive modeling.
555 completed RCT (343 patients, female/male 32.1/67.9%) were included. In our association analysis (involving the full dataset), unsuccessful RFL was more likely in undergraduate students (US): OR 2.74, 95% CI 1.61, 4.75, p < 0.001), teeth with indistinct canal paths (OR 11.04, 2.87, 44.88, p < 0.001), root canals reduced in size (OR 2.56, 1.49, 4.46, p < 0.01), retreatments (OR 3.13, 1.6, 6.41, p < 0.001). Subgroup analyses revealed that dentists were more successful in mitigating risks than undergraduate students. Prediction of RFL on a separate testset was limitedly possible regardless of the machine learning approach.
Achieving RFL is depending on the operator and several risk factors. The predictive performance on the technical outcome of a root canal treatment utilizing ML algorithms was insufficient.
Preoperative risk assessment is a relevant step in endodontic treatment planning. Single radiographic risk factors were significantly associated with achieving (or not achieving) optimal RFL and showed higher predictive value than a more complex risk assessment form.
Lung adenocarcinomas (LUADs) lead to the majority of deaths attributable to lung cancer. We performed whole-exome sequencing (WES) and immune profiling analyses of a unique set of clinically ...annotated early-stage LUADs to better understand the pathogenesis of this disease and identify clinically relevant molecular markers.
We performed WES of 108 paired stage I-III LUADs and normal lung tissues using the Illumina HiSeq 2000 platform. Ten immune markers (PD-L1, PD-1, CD3, CD4, CD8, CD45ro, CD57, CD68, FOXP3 and Granzyme B) were profiled by imaging-based immunohistochemistry (IHC) in a subset of LUADs (n=92). Associations among mutations, immune markers and clinicopathological variables were analyzed using ANOVA and Fisher’s exact test. Cox proportional hazards regression models were used for multivariate analysis of clinical outcome.
LUADs in this cohort exhibited an average of 243 coding mutations. We identified 28 genes with significant enrichment for mutation. SETD2-mutated LUADs exhibited relatively poor recurrence- free survival (RFS) and mutations in STK11 and ATM were associated with poor RFS among KRAS-mutant tumors. EGFR, KEAP1 and PIK3CA mutations were predictive of poor response to adjuvant therapy. Immune marker analysis revealed that LUADs in smokers and with relatively high mutation burdens exhibited increased levels of immune markers. Analysis of immunophenotypes revealed that LUADs with STK11 mutations exhibited relatively low levels of infiltrating CD4+/CD8+T-cells indicative of a muted immune response. Tumoral PD-L1 was significantly elevated in TP53 mutant LUADs whereas PIK3CA mutant LUADs exhibited markedly down-regulated PD-L1 expression. LUADs with TP53 or KEAP1 mutations displayed relatively increased CD57 and Granzyme B levels indicative of augmented natural killer (NK) cell infiltration.
Our study highlights molecular and immune phenotypes that warrant further analysis for their roles in clinical outcomes and personalized immune-based therapy of LUAD.
In KEYNOTE-010, pembrolizumab versus docetaxel improved overall survival (OS) in patients with programmed death-1 protein (PD)-L1-positive advanced non-small-cell lung cancer (NSCLC). A prespecified ...exploratory analysis compared outcomes in patients based on PD-L1 expression in archival versus newly collected tumor samples using recently updated survival data.
PD-L1 was assessed centrally by immunohistochemistry (22C3 antibody) in archival or newly collected tumor samples. Patients received pembrolizumab 2 or 10 mg/kg Q3W or docetaxel 75 mg/m2 Q3W for 24 months or until progression/intolerable toxicity/other reason. Response was assessed by RECIST v1.1 every 9 weeks, survival every 2 months. Primary end points were OS and progression-free survival (PFS) in tumor proportion score (TPS) ≥50% and ≥1%; pembrolizumab doses were pooled in this analysis.
At date cut-off of 24 March 2017, median follow-up was 31 months (range 23–41) representing 18 additional months of follow-up from the primary analysis. Pembrolizumab versus docetaxel continued to improve OS in patients with previously treated, PD-L1-expressing advanced NSCLC; hazard ratio (HR) was 0.66 95% confidence interval (CI): 0.57, 0.77. Of 1033 patients analyzed, 455(44%) were enrolled based on archival samples and 578 (56%) on newly collected tumor samples. Approximately 40% of archival samples and 45% of newly collected tumor samples were PD-L1 TPS ≥50%. For TPS ≥50%, the OS HRs were 0.64 (95% CI: 0.45, 0.91) and 0.40 (95% CI: 0.28, 0.56) for archival and newly collected samples, respectively. In patients with TPS ≥1%, OS HRs were 0.74 (95% CI: 0.59, 0.93) and 0.59 (95% CI: 0.48, 0.73) for archival and newly collected samples, respectively. In TPS ≥50%, PFS HRs were similar across archival 0.63 (95% CI: 0.45, 0.89) and newly collected samples 0.53 (95% CI: 0.38, 0.72). In patients with TPS ≥1%, PFS HRs were similar across archival 0.82 (95% CI: 0.66, 1.02) and newly collected samples 0.83 (95% CI: 0.68, 1.02).
Pembrolizumab continued to improve OS over docetaxel in intention to treat population and in subsets of patients with newly collected and archival samples.
ClinicalTrials.gov: NCT01905657.
The European Society for Medical Oncology (ESMO) held a virtual consensus-building process on epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer in 2021. The consensus included ...a multidisciplinary panel of 34 leading experts in the management of lung cancer. The aim of the consensus was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where the available evidence is either limited or conflicting. The main topics identified for discussion were: (i) tissue and biomarkers analyses; (ii) early and locally advanced disease; (iii) metastatic disease and (iv) clinical trial design, patient’s perspective and miscellaneous. The expert panel was divided into four working groups to address questions relating to one of the four topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the recommendations developed, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation.
•A virtual consensus on the management of EGFR-mutant NSCLC was organized by the ESMO, including 34 experts from 18 countries.•The experts compiled recommendations with supporting evidence on controversial topics about the EGFR-mutant lung cancer.•Recommendations were formulated for tissue and biomarkers analyses; early, locally advanced and metastatic disease; miscellaneous.
It is unknown, why only a minority of chronic myeloid leukemia (CML) patients sustains treatment free remission (TFR) after discontinuation of tyrosine kinase inhibitor (TKI) therapy in deep ...molecular remission (MR). Here we studied, whether expression of the T-cell inhibitory receptor (CTLA-4)-ligand CD86 (B7.2) on plasmacytoid dendritic cells (pDC) affects relapse risk after TKI cessation. CML patients in MR displayed significantly higher CD86
pDC frequencies than normal donors (P<0.0024), whereas TFR patients had consistently low CD86
pDC (n=12). This suggested that low CD86
pDC might be predictive of TFR. Indeed, in a prospective analysis of 122 patients discontinuing their TKI within the EURO-SKI trial, the one-year relapse-free survival (RFS) was 30.1% (95% CI 15.6-47.9) for patients with >95 CD86
pDC per 10
lymphocytes, but 70.0% (95% CI 59.3-78.3) for patients with <95 CD86
pDC (hazard ratio (HR) 3.4, 95%
CI: 1.9-6.0; P<0.0001). Moreover, only patients with <95 CD86
pDC derived a significant benefit from longer (>8 years) TKI exposure before discontinuation (HR 0.3, 95% CI 0.1-0.8; P=0.0263). High CD86
pDC counts significantly correlated with leukemia-specific CD8
T
cell exhaustion (Spearman correlation: 0.74, 95%-CI: 0.21-0.92; P=0.0098). Our data demonstrate that CML patients with high CD86
pDC counts have a higher risk of relapse after TKI discontinuation.
Personal similarities to a transgressor makes one view the transgression as less immoral. We investigated whether personal relevance might also affect the perceived immorality of politically-charged ...threats. We hypothesized that increasing the personal relevance of a threat would lead participants to report the threat as more immoral, even for threats the participant might otherwise view indifferently. U.S. participants recruited online (N = 488) were randomly assigned to write about the personal relevance of either a liberal threat (pollution), conservative threat (disrespecting an elder), neutral threat (romantic infidelity), or given a control filler task. Participants then rated how immoral and personally relevant each political threat was, as well as reported their political ideology. Partial support for our hypothesis emerged: when primed with conservative writing prompts, liberal-leaning participants rated the conservative threat as more immoral, compared with the same threat after a liberal writing prompt. We did not find these results for conservative-leaning participants, perhaps because all participants cared relatively equally about the liberal threat.
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