Lung cancer among outpatients with COPD: a 7-year cohort study.

Introduction: Lung cancer (LC) is the most common cause of cancer-related deaths worldwide, and its prognosis upon metastasis remains poor. Patients with COPD face a significantly elevated LC risk, up to six times greater than those with normal lung function. We aimed to investigate LC prevalence and stage distribution among COPD outpatients. Furthermore, we aimed to outline the COPD-related variables associated with referral for LC examination. Methods: We conducted a retrospective analysis encompassing the period from 1 January 2012 to 31 December 2018 on all outpatients with COPD and LC and individuals referred for LC examinations. Results: Among all COPD outpatients, 2231 patients (18%) were referred for LC examinations and 565 (4.6%) were diagnosed with LC. LC patients with COPD were more likely to be stage I-II, in contrast to the non-COPD LC population (46% versus 26%, p<0.001 for all). Patients referred for LC examinations exhibited higher use of COPD-related medications, reported more severe dyspnoea (69% versus 66% with Medical Research Council dyspnoea score >2) and experienced a greater frequency of exacerbations (30% versus 24% with two or more exacerbations). Conclusion: Our study revealed a notably high LC incidence among COPD outpatients. LC patients with COPD were diagnosed at earlier stages, and outpatients with more pronounced COPD symptoms were more inclined to undergo LC diagnostics. The overrepresentation of LC cases among COPD outpatients emphasises the importance of tailoring specific screening initiatives for this demographic.

Identification of patients' smoking status using an explainable AI approach: a Danish electronic health records case study.

BACKGROUND: Smoking is a critical risk factor responsible for over eight million annual deaths worldwide. It is essential to obtain information on smoking habits to advance research and implement preventive measures such as screening of high-risk individuals. In most countries, including Denmark, smoking habits are not systematically recorded and at best documented within unstructured free-text segments of electronic health records (EHRs). This would require researchers and clinicians to manually navigate through extensive amounts of unstructured data, which is one of the main reasons that smoking habits are rarely integrated into larger studies. Our aim is to develop machine learning models to classify patients' smoking status from their EHRs. METHODS: This study proposes an efficient natural language processing (NLP) pipeline capable of classifying patients' smoking status and providing explanations for the decisions. The proposed NLP pipeline comprises four distinct components, which are; (1) considering preprocessing techniques to address abbreviations, punctuation, and other textual irregularities, (2) four cutting-edge feature extraction techniques, i.e. Embedding, BERT, Word2Vec, and Count Vectorizer, employed to extract the optimal features, (3) utilization of a Stacking-based Ensemble (SE) model and a Convolutional Long Short-Term Memory Neural Network (CNN-LSTM) for the identification of smoking status, and (4) application of a local interpretable model-agnostic explanation to explain the decisions rendered by the detection models. The EHRs of 23,132 patients with suspected lung cancer were collected from the Region of Southern Denmark during the period 1/1/2009-31/12/2018. A medical professional annotated the data into 'Smoker' and 'Non-Smoker' with further classifications as 'Active-Smoker', 'Former-Smoker', and 'Never-Smoker'. Subsequently, the annotated dataset was used for the development of binary and multiclass classification models. An extensive comparison was conducted of the detection performance across various model architectures. RESULTS: The results of experimental validation confirm the consistency among the models. However, for binary classification, BERT method with CNN-LSTM architecture outperformed other models by achieving precision, recall, and F1-scores between 97% and 99% for both Never-Smokers and Active-Smokers. In multiclass classification, the Embedding technique with CNN-LSTM architecture yielded the most favorable results in class-specific evaluations, with equal performance measures of 97% for Never-Smoker and measures in the range of 86 to 89% for Active-Smoker and 91-92% for Never-Smoker. CONCLUSION: Our proposed NLP pipeline achieved a high level of classification performance. In addition, we presented the explanation of the decision made by the best performing detection model. Future work will expand the model's capabilities to analyze longer notes and a broader range of categories to maximize its utility in further research and screening applications.

Missingness mechanisms and generalizability of patient reported outcome measures in colorectal cancer survivors - assessing the reasonableness of the "missing completely at random" assumption.

BACKGROUND: Patient-Reported Outcome Measures (PROM) provide important information, however, missing PROM data threaten the interpretability and generalizability of findings by introducing potential bias. This study aims to provide insight into missingness mechanisms and inform future researchers on generalizability and possible methodological solutions to overcome missing PROM data problems during data collection and statistical analyses. METHODS: We identified 10,236 colorectal cancer survivors (CRCs) above 18y, diagnosed between 2014 and 2018 through the Danish Clinical Registries. We invited a random 20% (2,097) to participate in a national survey in May 2023. We distributed reminder e-mails at day 10 and day 20, and compared Initial Responders (response day 0-9), Subsequent Responders (response day 10-28) and Non-responders (no response after 28 days) in demographic and cancer-related characteristics and PROM-scores using linear regression. RESULTS: Of the 2,097 CRCs, 1,188 responded (57%). Of these, 142 (7%) were excluded leaving 1,955 eligible CRCs. 628 (32%) were categorized as initial responders, 418 (21%) as subsequent responders, and 909 (47%) as non-responders. Differences in demographic and cancer-related characteristics between the three groups were minor and PROM-scores only marginally differed between initial and subsequent responders. CONCLUSION: In this study of long-term colorectal cancer survivors, we showed that initial responders, subsequent responders, and non-responders exhibit comparable demographic and cancer-related characteristics. Among respondents, Patient-Reported Outcome Measures were also similar, indicating generalizability. Assuming Patient-Reported Outcome Measures of subsequent responders represent answers by the non-responders (would they be available), it may be reasonable to judge the missingness mechanism as Missing Completely At Random.

Early integration of basic palliative care in cancer: scoping review of cross-sectorial models - components, facilitators, barriers.

BACKGROUND: Shared care between oncology specialists and general practice regarding the delivery of palliative care (PC) is necessary to meet the demands for a cohesive PC. The primary objective of this study is to investigate models of cross-sectorial integration between primary care and oncology specialists that have been developed to promote early and basic PC and factors influencing the process. METHOD: A scoping review was conducted using publications dated up until April 2023. Searches were conducted in MEDLINE, CINAHL, Embase, Web of Science and ProQuest Dissertations and Theses. Complementary searches were performed via reference lists and grey literature. Explicit early PC models aimed at patients with cancer aged ≥18 years with healthcare professionals from primary care and oncology constituted the inclusion criteria. The screening of the papers was performed independently by two reviewers. The reporting adheres to the extension for scoping reviews of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. RESULTS: The search provided 5630 articles of which six met the eligibility criteria, each describing a different model of early and cross-sectorial, integrated PC. 12 active components were identified. Education of staff as well as good communication and cooperation skills are essential factors to succeed with integrated, early PC. CONCLUSION: Integration of PC between general practice and oncology specialists has potential. The components of basic PC have been established. Factors known to influence the process are trust, communication and a common goal. Further research is required into strategies for approaching different levels of integration.

Soluble programmed death ligand 1 as prognostic biomarker in non-small cell lung cancer patients receiving nivolumab, pembrolizumab or atezolizumab therapy.

Many studies have focused on the prognostic role of soluble programmed death ligand 1 (sPD-L1) in non-small cell lung cancer (NSCLC), but outcomes are ambiguous and further investigations are needed. We addressed the matter by studying sPD-L1 in baseline samples and in longitudinal samples taken prior to three subsequent cycles of anti-PD-1/anti-PD-L1 treatments. Eighty patients with NSCLC were enrolled. Median sPD-L1 level at baseline was 52 pg/mL [95% confidence interval (CI) 49-57]. In patients treated with pembrolizumab and nivolumab, the concentration of sPD-L1 remained rather stable throughout treatment. In contrast, sPD-L1 rose by 50-fold following the first cycle of atezolizumab therapy. We found the baseline level of sPD-L1 to be related to overall survival (OS) after two years of follow-up in simple Cox analysis (p = 0.006) and multiple Cox Regression, hazard ratio 1.02 (95% CI 1.00-1.03) (p = 0.033). There was no association between sPD-L1 and tissue PD-L1 expression, overall response rate, or progression free survival. In conclusion, sPD-L1 measured in baseline serum samples may be associated with OS in NSCLC patients receiving anti-PD1/anti-PD-L1 treatment. Importantly, the results signify that further research is warranted to explore the clinical utility of sPD-L1 in patients treated with anti-PD-L1.

The prognostic value of tumor budding in a thoroughly characterized stage II colon cancer population in the context of a national screening program.

Tumor budding as a prognostic marker in colorectal cancer has not previously been investigated in a cohort of screened stage II colon cancer patients. We assessed the prognostic significance of tumor budding in a thoroughly characterized stage II colon cancer population comprising surgically resected patients in the Region of Southern Denmark from 2014 to 2016. Tumors were re-staged according to the 8th edition of UICC TNM Classification, undergoing detailed histopathological evaluation and tumor budding assessment following guidelines from the International Tumor Budding Consensus Conference. Prognostic evaluation utilized Kaplan-Meier curves, log-rank tests, and Cox proportional hazard models for time to recurrence (TTR), recurrence-free survival (RFS), and overall survival (OS). Out of 497 patients, 20% were diagnosed through the national colorectal cancer screening program. High-grade tumor budding (Bd3) was found in 19% of tumors and was associated with glandular subtype, perineural invasion, mismatch repair proficient tumors, and tumor recurrence (p < 0.001, p < 0.001, p = 0.045, and p = 0.007 respectively). In multivariable Cox regression, high-grade budding was a significant prognostic factor for TTR compared to low-grade (Bd3 HR 2.617; p = 0.007). An association between tumor budding groups and RFS was observed, and the difference was significant in univariable analysis for high-grade compared to low-grade tumor budding (Bd3 HR 1.461; p = 0.041). No significant differences were observed between tumor budding groups and OS. High-grade tumor budding is a predictor of recurrence in a screened population of patients with stage II colon cancer and should be considered a high-risk factor in a shared decision-making process when stratifying patients to adjuvant chemotherapy.

Methylated Cell-Free Tumor DNA in Sputum as a Tool for Diagnosing Lung Cancer-A Systematic Review and Meta-Analysis.

Lung cancer is the leading cause of cancer-related mortality worldwide. Early diagnosis is pivotal for the prognosis. There is a notable overlap between lung cancer and chronic bronchitis, and the potential use of methylated tumor DNA in sputum as a biomarker for lung cancer detection is appealing. This systematic review and meta-analysis followed the PRISMA 2020 statement. A comprehensive search was conducted in Embase, Medline, Web of Science, and the Cochrane Library, using these search strings: Lung cancer, sputum, and methylated tumor DNA. A total of 15 studies met the eligibility criteria. Studies predominantly utilized a case-control design, with sensitivity ranging from 10 to 93% and specificity from 8 to 100%. A meta-analysis of all genes across studies resulted in a summary sensitivity of 54.3% (95% CI 49.4-59.2%) and specificity of 79.7% (95% CI 75.0-83.7%). Notably, two less explored genes (TAC1, SOX17) demonstrated sensitivity levels surpassing 85%. The study's findings highlight substantial variations in the sensitivity and specificity of methylated tumor DNA in sputum for lung cancer detection. Challenges in reproducibility could stem from differences in tumor site, sample acquisition, extraction methods, and methylation measurement techniques. This meta-analysis provides a foundation for prioritizing high-performing genes, calling for a standardization and refinement of methodologies before potential application in clinical trials.

Study protocol: fish oil supplement in prevention of oxaliplatin-induced peripheral neuropathy in adjuvant colorectal cancer patients - a randomized controlled trial. (OxaNeuro).

BACKGROUND: Oxaliplatin-induced peripheral neuropathy (OIPN) in general and painful OIPN in particular is a debilitating late effect that severely affects cancer survivors' quality of life and causes premature cessation of potentially lifesaving treatment. No preventive treatments and no effective treatment for chronic OIPN exist despite many attempts. One of several suggested mechanisms includes neuroinflammation as a contributing factor to OIPN. Fish oil containing long-chain n-3 polyunsaturated fatty acids (n-3 LCPUFAs) are precursors to specialized proresolving mediators that mediate the resolution of inflammation. Our primary hypothesis is that a high supplementation of n-3 LCPUFAs will lower the prevalence and severity of OIPN. METHODS: The OxaNeuro project is an investigator-initiated, multicenter, double-blinded, randomized, placebo-controlled clinical study. We will include 120 patients eligible to receive adjuvant oxaliplatin after colorectal cancer surgery. Patients will receive fish oil capsules containing n-3 LCPUFAs or corn oil daily for 8 months. The primary endpoint is the prevalence of OIPN at 8 months defined as relevant symptoms, including one of the following: abnormal nerve conduction screening, abnormal vibration threshold test, abnormal skin biopsy, or abnormal pinprick test. Additional endpoints include the intensity and severity of OIPN-related neuropathic pain, patient-reported OIPN symptoms, quality of life, mental health symptoms, body composition, and cognitive evaluation. Furthermore, we will evaluate inflammatory biomarkers in blood samples and skin biopsies, including the potential OIPN biomarker neurofilament light protein (NfL) which will be measured before each cycle of chemotherapy. DISCUSSION: If readily available fish oil supplementation alleviates OIPN prevalence and severity, it will significantly improve the lives of both cancer survivors and palliative cancer patients receiving oxaliplatin; it will improve their quality of life, optimize chemotherapeutic treatment plans by lowering the need for dose reduction or premature cessation, and potentially increase survival. TRIAL REGISTRATION: ClinicalTrial.gov identifier: NCT05404230 Protocol version: 1.2, April 25th. 2023.

International Validation of the Immunoscore Biopsy in Patients With Rectal Cancer Managed by a Watch-and-Wait Strategy.

PURPOSE: No biomarker capable of improving selection and monitoring of patients with rectal cancer managed by watch-and-wait (W&W) strategy is currently available. Prognostic performance of the Immunoscore biopsy (ISB) was recently suggested in a preliminary study. METHODS: This international validation study included 249 patients with clinical complete response (cCR) managed by W&W strategy. Intratumoral CD3+ and CD8+ T cells were quantified on pretreatment rectal biopsies by digital pathology and converted to ISB. The primary end point was time to recurrence (TTR; the time from the end of neoadjuvant treatment to the date of local regrowth or distant metastasis). Associations between ISB and outcomes were analyzed by stratified Cox regression adjusted for confounders. Immune status of tumor-draining lymph nodes (n = 161) of 17 additional patients treated by neoadjuvant chemoradiotherapy and surgery was investigated by 3'RNA-Seq and immunofluorescence. RESULTS: Recurrence-free rates at 5 years were 91.3% (82.4%-100.0%), 62.5% (53.2%-73.3%), and 53.1% (42.4%-66.5%) with ISB High, ISB Intermediate, and ISB Low, respectively (hazard ratio [HR; Low v High], 6.51; 95% CI, 1.99 to 21.28; log-rank P = .0004). ISB was also significantly associated with disease-free survival (log-rank P = .0002), and predicted both local regrowth and distant metastasis. In multivariate analysis, ISB was independent of patient age, sex, tumor location, cT stage (T, primary tumor; c, clinical), cN stage (N, regional lymph node; c, clinical), and was the strongest predictor for TTR (HR [ISB High v Low], 6.93; 95% CI, 2.08 to 23.15; P = .0017). The addition of ISB to a clinical-based model significantly improved the prediction of recurrence. Finally, B-cell proliferation and memory in draining lymph nodes was evidenced in the draining lymph nodes of patients with cCR. CONCLUSION: The ISB is validated as a biomarker to predict both local regrowth and distant metastasis, with a gradual scaling of the risk of pejorative outcome.

Prognostic impact of early ctDNA dynamics during chemotherapy of metastatic cancer.

Aim: Clinical utility of the dynamics of ctDNA is sparse. This study aimed at evaluating the prognostic impact of early ctDNA dynamics in patients with metastatic cancer treated with chemotherapy. Materials & methods: The ctDNA dynamics were evaluated in 595 patients with metastatic cancer using droplet digital PCR. Results: Patients with an increase in ctDNA after one treatment cycle (n = 73; 12.2%) had an overall survival of 5.6 months compared with 8.6 months in patients with stable or decreasing ctDNA (n = 328; 55.1%) and 21.0 months in patients with undetectable ctDNA (p < 0.001; hazard ratio: 0.47; 95% CI: 0.41-0.53). Conclusion: Early ctDNA dynamics hold important prognostic information and have great implications for evaluation with the perspective of a more individualized treatment strategy.

ctDNA-guided adjuvant treatment after radical-intent treatment of metastatic spread from colorectal cancer-the first interim results from the OPTIMISE study.

BACKGROUND: Patients with detectable ctDNA after radical-intent treatment of metastatic spread from colorectal cancer (mCRC) have a very high risk of recurrence, which may be prevented with intensified adjuvant chemotherapy (aCTh). In the OPTIMISE study, we investigate ctDNA-guided aCTh after radical-intent treatment of mCRC. Here we present results from the preplanned interim analysis. MATERIAL AND METHODS: The study is an open-label 1:1 randomized clinical trial comparing ctDNA-guided aCTh against standard of care (SOC), with a run-in phase investigating feasibility measures. Key inclusion criteria; radical-intent treatment for mCRC and clinically eligible for triple-agent chemotherapy. Patients underwent a PET-CT scan before randomization. ctDNA analyses of plasma samples were done by ddPCR, detecting CRC-specific mutations and methylation of the NPY gene. In the ctDNA-guided arm, ctDNA positivity led to an escalation strategy with triple-agent chemotherapy, and conversely ctDNA negativity led to a de-escalation strategy by shared-decision making. Patients randomized to the standard arm were treated according to SOC. Feasibility measures for the run-in phase were; the inclusion of 30 patients over 12 months in two Danish hospitals, compliance with randomization >80%, rate of PET-CT-positive findings <20%, and eligibility for triple-agent chemotherapy >80%. RESULTS: Thirty-two patients were included. The rate of PET-CT-positive cases was 22% (n = 7/32). Ninety-seven percent of the patients were randomized. Fourteen patients were randomly assigned to SOC and sixteen to ctDNA-guided adjuvant treatment and follow-up. All analyses of baseline plasma samples in the ctDNA-guided arm passed the quality control, and 19% were ctDNA positive. The median time to result was three working days. All ctDNA-positive patients were eligible for triple-agent chemotherapy. CONCLUSION: The study was proven to be feasible and continues in the planned large-scale phase II trial. Results from the OPTIMISE study will potentially optimize the adjuvant treatment of patients undergoing radical-intent treatment of mCRC, thereby improving survival and reducing chemotherapy-related toxicity.

Delta tocotrienol as a supplement to FOLFOXIRI in first-line treatment of metastatic colorectal cancer. A randomized, double-blind, placebo-controlled phase II study.

PURPOSE: Triplet chemotherapy might be more effective than doublet chemotherapy in metastatic colorectal cancer (mCRC), but it may also be marked by increased toxicity. To investigate whether δ-tocotrienol, a vitamin E analogue, with possible neuroprotective and anti-inflammatory effects, reduces the toxicity of triplet chemotherapy, we conducted a randomized, double-blind, placebo-controlled trial in mCRC patients receiving first-line 5-fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI). MATERIAL AND METHODS: Seventy patients with mCRC were randomly assigned (1:1) to receive FOLFOXIRI plus either δ-tocotrienol or placebo at the Department of Oncology, Vejle Hospital, Denmark. Eligibility criteria were adenocarcinoma in the colon or rectum, age 18-75 years and ECOG performance status 0-1. FOLFOXIRI was given in eight cycles followed by four cycles of 5-fluorouracil. δ-tocotrienol 300 mg or placebo × 3 daily was added during chemotherapy and for a maximum of two years. The primary endpoint was time to hospitalization or death during treatment with chemotherapy. RESULTS: Median time to first hospitalization or death was 3.7 months in the placebo group (95% CI 1.93-not reached (NR)), and was NR in the δ-tocotrienol group (95% CI 1.87-NR) with a hazard ratio of 0.70 (95% CI 0.36-1.36). Grade 3-4 toxicities were uncommon in both groups, except for neutropenia, which occurred in 19 patients (58%) in the placebo group and 17 patients (50%) in the δ-tocotrienol group. There were no grade 3 or 4 peripheral sensory neuropathy. In the placebo group, 24 patients (71%) had oxaliplatin dose reductions compared to 17 patients (47%) in the δ-tocotrienol group (p = 0.047). CONCLUSION: The addition of δ-tocotrienol to FOLFOXIRI did not statistically significant prolong the time to first hospitalization or death compared to FOLFOXIRI plus placebo. Toxicity was manageable and not statistically different. There was a statistically significant difference in dose reductions of oxaliplatin pointing to a possible neuroprotective effect of δ-tocotrienol.

Methylated Circulating Tumor DNA in Blood as a Tool for Diagnosing Lung Cancer: A Systematic Review and Meta-Analysis.

Lung cancer is the leading cause of cancer-related deaths, and early detection is crucial for improving patient outcomes. Current screening methods using computed tomography have limitations, prompting interest in non-invasive diagnostic tools such as methylated circulating tumor DNA (ctDNA). The PRISMA guidelines for systematic reviews were followed. The electronic databases MEDLINE, Embase, Web of Science, and Cochrane Library were systematically searched for articles. The search string contained three main topics: Lung cancer, blood, and methylated ctDNA. The extraction of data and quality assessment were carried out independently by the reviewers. In total, 33 studies were eligible for inclusion in this systematic review and meta-analysis. The most frequently studied genes were SHOX2, RASSF1A, and APC. The sensitivity and specificity of methylated ctDNA varied across studies, with a summary sensitivity estimate of 46.9% and a summary specificity estimate of 92.9%. The area under the hierarchical summary receiver operating characteristics curve was 0.81. The included studies were generally of acceptable quality, although they lacked information in certain areas. The risk of publication bias was not significant. Based on the findings, methylated ctDNA in blood shows potential as a rule-in tool for lung cancer diagnosis but requires further research, possibly in combination with other biomarkers.

Precision medicine applied to metastatic colorectal cancer using tumor-derived organoids and in-vitro sensitivity testing: a phase 2, single-center, open-label, and non-comparative study.

BACKGROUND: Patients with colorectal metastatic disease have a poor prognosis, limited therapeutic options, and frequent development of resistance. Strategies based on tumor-derived organoids are a powerful tool to assess drug sensitivity at an individual level and to suggest new treatment options or re-challenge. Here, we evaluated the method's feasibility and clinical outcome as applied to patients with no satisfactory treatment options. METHODS: In this phase 2, single-center, open-label, non-comparative study (ClinicalTrials.gov, register NCT03251612), we enrolled 90 patients with metastatic colorectal cancer following progression on or after standard therapy. Participants were 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2, adequate organ function, and metastasis available for biopsy. Biopsies from the metastatic site were cultured using organoids model. Sensitivity testing was performed with a panel of drugs with proven activity in phase II or III trials. At the discretion of the investigator considering toxicity, the drug with the highest relative activity was offered. The primary endpoint was the proportion of patients alive without disease progression at two months per local assessment. RESULTS: Biopsies available from 82 to 90 patients were processed for cell culture, of which 44 successfully generated organoids with at least one treatment suggested. The precision cohort of 34 patients started treatment and the primary endpoint, progression-free survival (PFS) at two months was met in 17 patients (50%, 95% CI 32-68), exceeding the pre-defined level (14 of 45; 31%). The median PFS was 67 days (95% CI 51-108), and the median overall survival was 189 days (95% CI 103-277). CONCLUSIONS: Patient-derived organoids and in-vitro sensitivity testing were feasible in a cohort of metastatic colorectal cancer. The primary endpoint was met, as half of the patients were without progression at two months. Cancer patients may benefit from functional testing using tumor-derived organoids. TRIAL REGISTRATION: ClinicalTrials.gov, register NCT03251612.

NK cell activity and methylated HOXA9 ctDNA as prognostic biomarkers in patients with non-small cell lung cancer treated with PD-1/PD-L1 inhibitors.

BACKGROUND: PD-1/PD-L1 inhibitors have improved survival for patients with non-small cell lung cancer (NSCLC). We evaluated natural killer cell activity (NKA) and methylated HOXA9 circulating tumor DNA (ctDNA) as prognostic biomarkers in NSCLC patients treated with PD-1/PD-L1 inhibitors. METHODS: Plasma was prospectively collected from 71 NSCLC patients before treatment with PD-1/PD-L1 inhibitors and before cycles 2-4. We used the NK Vue® assay to measure the level of interferon gamma (IFNγ) as a surrogate for NKA. Methylated HOXA9 was measured by droplet digital PCR. RESULTS: A score combining NKA and ctDNA status measured after one treatment cycle had a strong prognostic impact. Group 1 had IFNγ < 250 pg/ml and detectable ctDNA (n = 27), group 2 consisted of patients with either low levels of IFNγ and undetectable ctDNA or high levels of IFNγ and detectable ctDNA (n = 29), group 3 had IFNγ ≥250 pg/ml and undetectable ctDNA (n = 15). Median OS was 221 days (95% CI 121-539 days), 419 days (95% CI 235-650 days), and 1158 days (95% CI 250 days-not reached), respectively (P = 0.002). Group 1 had a poor prognosis with a hazard ratio of 5.560 (95% CI 2.359-13.101, n = 71, P < 0.001) adjusting for PD-L1 status, histology, and performance status. CONCLUSIONS: Combining NKA and ctDNA status after one cycle of treatment was prognostic in patients with NSCLC treated with PD-1/PD-L1 inhibitors.

Assessment of circulating biomarkers for detection of lung cancer in a high-risk cohort.

BACKGROUND: There is an urgent need for early detection of lung cancer. Screening with low-dose computed tomography (LDCT) is now implemented in the US. Supplementary use of a lung cancer biomarker with high specificity is desirable. OBJECTIVE: To assess the diagnostic properties of a biomarker panel consisting of cytokeratin 19 fragment (CYFRA 21-1), carcinoembryonic antigen (CEA) and cancer antigen 125 (CA125). METHODS: A cohort of 250 high-risk patients was investigated on suspicion of lung cancer. Ahead of diagnostic work-up, blood samples taken. Cross-validated prediction models were computed to assess lung cancer detection properties. RESULTS: In total 32% (79/250) of patients were diagnosed with lung cancer. Area under the curve (AUC) for the three biomarkers was of 0.795, with sensitivity/specificity of 57%/93% and negative predictive value of 83%. When combining the biomarkers with US screening criteria, the AUC was 0.809, while applying only US screening criteria on the cohort, yielded an AUC of 0.62. The ability of the biomarkers to detect stage I-II lung cancer was substantially lower; AUC 0.54. CONCLUSIONS: In a high-risk cohort, the detection properties of the three biomarkers were acceptable compared to current LDCT screening criteria. However, the ability to detect early stage lung cancer was low.

A collection of multiregistry data on patients at high risk of lung cancer-a Danish retrospective cohort study of nearly 40,000 patients.

Background: Lung cancer (LC) is the leading cause of cancer related deaths, and several countries are implementing screening programs. Risk models have been introduced to refine the LC screening criteria, but the use of real-world data for this task demands a robust data infrastructure and quality. In this retrospective cohort study, we aim to address the different relevant risk factors in terms of data sources, descriptive statistics, completeness and quality. Methods: Data on comorbidity, prescription medication, smoking history, consultations, symptoms, familial predispositions, exposures, laboratory data among others were collected for all patients examined on a risk of LC over a 10-year period in the Region of Southern Denmark. Data were delivered from the regional data warehouse as well as the Danish Lung Cancer Registry. Associations between LC and non-LC groups were examined through Chi-squared test (categorical variables) and Wilcoxon signed-rank test (continuous variables that were non-parametric). These associations were investigated on both the original datasets and the subset of patients with complete data. Results: The number of examined individuals increased over the study period and more patients were diagnosed with LC in stage I-II, from 18% in 2009 to 31% in 2018. LC patients were more likely to be older, smoker, with a registered prescription of the included medication. They also exhibited differences in laboratory analysis indicating inflammation and hyponatremia. Weight loss, fatigue and pain were more prevalent in the LC group, while hemoptysis and fever were more common among the non-LC patients. Advanced-stage LC patients experienced a higher rate of symptoms compared to those in the low stages. Within the sub-cohort with complete dataset results, most observed trends persisted, although data on comorbidities were susceptibility to change. Conclusions: This study provides key insights into LC risk assessment using a robust dataset of patients examined for suspected LC. A consistent positive trend in early-stage LC diagnosis was observed throughout the study period. LC patients exhibited distinct smoking behaviors, medication patterns, variations in lab results, and specific symptoms. These discoveries have the potential to enhance discrimination in machine learning-based prediction models, particularly those capable of handling complex distributions. Serving as a detailed account of real-world data collection and processing, the study establishes a foundation for future development of prediction models aimed at facilitating the early referral of LC patients.

NPY Gene Methylation in Circulating Tumor DNA as an Early Biomarker for Treatment Effect in Metastatic Colorectal Cancer.

Despite several limitations, the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) are still the gold standard in response evaluation of metastatic colorectal cancer (mCRC). The aim of the present study was to investigate hypermethylated neuropeptide Y circulating tumor DNA (meth-NPY) as an early biomarker for treatment effect and monitoring in 70 mCRC patients receiving first-line treatment in the FOLFOXIRI-Toco trial. Meth-NPY was analyzed using droplet digital PCR, and the response rate was defined as the fraction of patients converting from a baseline detectable level to an undetectable level after the first treatment cycle (responders). A significant increase in meth-NPY was defined as a value with no overlap between the 95% CI of the current and preceding measurement. Progression-free survival (PFS) was significantly longer in meth-NPY responders compared to non-responders, 10.1 and 7.6 months, respectively (p = 0.02, HR = 0.43). Patients with response according to RECIST 1.1 had a PFS of 10.1 compared to 7.3 months for non-responders (p = 0.17, HR = 0.65). A significant increase in meth-NPY was found with a median of 49 days before radiological progression. In conclusion, early meth-NPY response proved superior to response according to RECIST 1.1 with respect to predicting improved PFS. Meth-NPY is an early indicator of progression, allowing treatment reorientation at an earlier timepoint.

Natural killer cell activity as a biomarker for the diagnosis of lung cancer in high-risk patients.

OBJECTIVE: Natural killer (NK) cells play an essential role in the immune response against cancer. However, immune escape mechanisms may cause inferior NK cell activity (NKA) in patients with cancer. This prospective study examined the relationship between NKA and lung cancer in a high-risk cohort. METHODS: In a cohort study, 250 participants referred by their general practitioner for suspicion of lung cancer were included. Before clinical investigation, blood was collected into NK Vue tubes, and the level of interferon gamma after 24 hours served as a surrogate marker for NKA. RESULTS: Among 250 patients, 79 were diagnosed with lung cancer. No difference in NKA was found between patients with lung cancer and control participants in which lung cancer was ruled out (median 226 pg/mL vs. 450 pg/mL). However, there was a significant difference in NKA between patients with late-stage lung cancer and controls (median 161 pg/mL vs. 450 pg/mL). A linear regression model showed that NKA was not influenced by age, sex or smoking status. CONCLUSIONS: The significantly lower NKA in patients with late-stage lung cancer warrants further investigation combining NKA with other biomarkers and examining the potential role of NKA as a marker of disseminated disease.