Improving diagnostic accuracy of identifying gastric cancer patients with peritoneal metastases: tumor-guided cell-free DNA analysis of peritoneal fluid.

Detection of peritoneal dissemination (PD) in gastric cancer (GC) patients remains challenging. The feasibility of tumor-guided cell-free DNA (cfDNA) detection in prospectively collected peritoneal fluid (ascites and peritoneal lavage) was investigated and compared to conventional cytology in 28 patients. Besides conventional cytology, next generation sequencing was performed on primary tumor DNA and cell-free DNA from peritoneal fluid. Patients were retrospectively grouped into: a positive group (with PD) and a negative group (without PD). Detectable mutations were found in the primary tumor of 68% (n = 19). Sensitivity of PD detection by tumor-guided cfDNA analysis was 91%, compared to 64% by conventional cytology. Within the positive group (n = 11), tumor-guided cfDNA was detected in all patients with ascites samples (4/4, 100%) and in 86% (6/7) of the lavage samples, opposed to 4/4 (100%) patients with ascites and 43% (3/7) with lavage by conventional cytology. Within the negative group (n = 8), conventional cytology was negative for all samples. In two patients, tumor-guided cfDNA was detected in peritoneal lavage fluid. Interestingly, these 2 patients developed PD within 6 months, suggesting a prognostic value of tumor-guided cfDNA detection. This study showed that tumor-guided cfDNA detection in peritoneal fluids of GC patients is feasible and superior to conventional cytology in detecting PD.

Neoadjuvant atezolizumab plus chemotherapy in gastric and gastroesophageal junction adenocarcinoma: the phase 2 PANDA trial.

Gastric and gastroesophageal junction (G/GEJ) cancers carry a poor prognosis, and despite recent advancements, most patients die of their disease. Although immune checkpoint blockade became part of the standard-of-care for patients with metastatic G/GEJ cancers, its efficacy and impact on the tumor microenvironment (TME) in early disease remain largely unknown. We hypothesized higher efficacy of neoadjuvant immunotherapy plus chemotherapy in patients with nonmetastatic G/GEJ cancer. In the phase 2 PANDA trial, patients with previously untreated resectable G/GEJ tumors (n = 21) received neoadjuvant treatment with one cycle of atezolizumab monotherapy followed by four cycles of atezolizumab plus docetaxel, oxaliplatin and capecitabine. Treatment was well tolerated. There were grade 3 immune-related adverse events in two of 20 patients (10%) but no grade 4 or 5 immune-related adverse events, and all patients underwent resection without treatment-related delays, meeting the primary endpoint of safety and feasibility. Tissue was obtained at multiple time points, allowing analysis of the effects of single-agent anti-programmed cell death ligand 1 (PD-L1) and the subsequent combination with chemotherapy on the TME. Twenty of 21 patients underwent surgery and were evaluable for secondary pathologic response and survival endpoints, and 19 were evaluable for exploratory translational analyses. A major pathologic response (≤10% residual viable tumor) was observed in 14 of 20 (70%, 95% confidence interval 46-88%) patients, including 9 (45%, 95% confidence interval 23-68%) pathologic complete responses. At a median follow-up of 47 months, 13 of 14 responders were alive and disease-free, and five of six nonresponders had died as a result of recurrence. Notably, baseline anti-programmed cell death protein 1 (PD-1)+CD8+ T cell infiltration was significantly higher in responders versus nonresponders, and comparison of TME alterations following anti-PD-L1 monotherapy versus the subsequent combination with chemotherapy showed an increased immune activation on single-agent PD-1/L1 axis blockade. On the basis of these data, monotherapy anti-PD-L1 before its combination with chemotherapy warrants further exploration and validation in a larger cohort of patients with nonmetastatic G/GEJ cancer. ClinicalTrials.gov registration: NCT03448835 .

Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites.

Neuroendocrine neoplasms (NENs) comprise well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Treatment options for patients with NENs are limited, in part due to lack of accurate models. We establish patient-derived tumor organoids (PDTOs) from pulmonary NETs and derive PDTOs from an understudied subtype of NEC, large cell neuroendocrine carcinoma (LCNEC), arising from multiple body sites. PDTOs maintain the gene expression patterns, intra-tumoral heterogeneity, and evolutionary processes of parental tumors. Through hypothesis-driven drug sensitivity analyses, we identify ASCL1 as a potential biomarker for response of LCNEC to treatment with BCL-2 inhibitors. Additionally, we discover a dependency on EGF in pulmonary NET PDTOs. Consistent with these findings, we find that, in an independent cohort, approximately 50% of pulmonary NETs express EGFR. This study identifies an actionable vulnerability for a subset of pulmonary NETs, emphasizing the utility of these PDTO models.

Neoadjuvant Imatinib in Locally Advanced Gastrointestinal Stromal Tumors (GISTs) is Effective and Safe: Results from a Prospective Single-Center Study with 108 Patients.

BACKGROUND: Neoadjuvant imatinib is considered for gastrointestinal stromal tumors (GISTs) when decreased tumor size provides less extensive surgery and higher R0 resection rates. This study evaluates the effectivity and safety of neoadjuvant imatinib for large or locally advanced GIST. PATIENTS AND METHODS: From the prospective database of the Dutch GIST Consortium, all patients who underwent surgery after neoadjuvant imatinib at our center between 2009 and 2022 were selected. Independent and blinded assessment of surgical strategy was performed by two surgeons, based on anonymized computed tomography (CT) scans before and after neoadjuvant imatinib. RESULTS: Of 113 patients that received neoadjuvant imatinib, 108 (95%) [mean age 61.6, standard deviation (SD) 11.5, 54% male] underwent a GIST resection. Of all GISTs, 67% was localized in the stomach and 25% in the duodenum or small intestine. In 74% of the patients with GIST, a KIT exon 11 mutation was found. Decreased tumor size was seen in 95 (88%) patients. Having a KIT exon 11 mutation [odds ratio (OR) 5.64, 95% confidence interval (CI) 1.67-19.1, p < 0.01] or not having a mutation (OR 0.19, 95% CI 0.04-0.89, p = 0.04) were positive and negative predictive values for partial response, respectively. In 55 (51%) patients, there was deescalation of surgical strategy after neoadjuvant imatinib. Surgical complications were documented in 16 (15%) patients (n = 8, grade II; n = 5, grade IIIa; n = 3, grade IIIb) and R0 resection was accomplished in 95 (89%) patients. The 5-year disease-free and overall survival were 80% and 91%, respectively. CONCLUSION: This study shows that neoadjuvant imatinib is effective and safe for patients with large or locally advanced GIST.

Tumor-educated platelet blood tests for Non-Small Cell Lung Cancer detection and management.

Liquid biopsy approaches offer a promising technology for early and minimally invasive cancer detection. Tumor-educated platelets (TEPs) have emerged as a promising liquid biopsy biosource for the detection of various cancer types. In this study, we processed and analyzed the TEPs collected from 466 Non-small Cell Lung Carcinoma (NSCLC) patients and 410 asymptomatic individuals (controls) using the previously established thromboSeq protocol. We developed a novel particle-swarm optimization machine learning algorithm which enabled the selection of an 881 RNA biomarker panel (AUC 0.88). Herein we propose and validate in an independent cohort of samples (n = 558) two approaches for blood samples testing: one with high sensitivity (95% NSCLC detected) and another with high specificity (94% controls detected). Our data explain how TEP-derived spliced RNAs may serve as a biomarker for minimally-invasive clinical blood tests, complement existing imaging tests, and assist the detection and management of lung cancer patients.

The clinical impact of testing for biomarkers in gastric cancer patients: a real-world cohort.

BACKGROUND AND AIMS: In gastric cancer (GC), HER2 was the first biomarker for guided therapy registered for clinical use. Considering the recent approvals of immune check-point blockade (ICB) in gastro-oesophageal cancers, testing for mismatch repair deficiency (dMMR), Epstein-Barr virus (EBV) and PD-L1 combined positive score (CPS) is becoming increasingly important. Here we describe a real-world cohort on biomarker assessment in GC patients. METHODS: Patients diagnosed with GC between 2017 and 2021 were included. Biomarker results were retrieved from electronic patient files. PD-L1 CPS was determined retrospectively on dMMR and EBV-positive (EBV+) tumours. Data on genomic sequencing were analysed separately. RESULTS: Of 363 patients identified, 45% had metastatic disease. In 335 patients (92%) at least one biomarker was tested. The prevalence of HER2+, dMMR and EBV+ tumours was 10% (32 of 319), 7% (20 of 294) and 1% (three of 235), respectively. Of the dMMR and EBV+ tumours, 95% had a PD-L1 CPS ≥ 5. Therapeutic strategy was adjusted in 31 of 55 patients and consisted of anti-HER2 therapies as well as ICB in clinical trials. Genomic alterations were found in 44 of 60 tested patients. TP53 (73%) and PIK3CA (20%) mutations were most common, followed by KRAS mutations (11%) and amplifications (11%). CONCLUSIONS: In this real-world cohort, testing for HER2, dMMR and EBV status affected treatment decisions in 56% of the patients. Although most dMMR and EBV+ tumours had a PD-L1 CPS ≥ 5, not all patients with a high probability of treatment response are identified. Based on these results, a stepwise diagnostic strategy is proposed.

Identification of patient-specific CD4+ and CD8+ T cell neoantigens through HLA-unbiased genetic screens.

Cancer neoantigens that arise from tumor mutations are drivers of tumor-specific T cell responses, but identification of T cell-recognized neoantigens in individual patients is challenging. Previous methods have restricted antigen discovery to selected HLA alleles, thereby limiting the breadth of neoantigen repertoires that can be uncovered. Here, we develop a genetic neoantigen screening system that allows sensitive identification of CD4+ and CD8+ T cell-recognized neoantigens across patients' complete HLA genotypes.

Detection and localization of early- and late-stage cancers using platelet RNA.

Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I-IV cancer patients and in half of 352 stage I-III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening.

Combining variant detection and fragment length analysis improves detection of minimal residual disease in postsurgery circulating tumour DNA of stage II-IIIA NSCLC patients.

Stage II-IIIA nonsmall cell lung cancer (NSCLC) patients receive adjuvant chemotherapy after surgery as standard-of-care treatment, even though only approximately 5.8% of patients will benefit. Identifying patients with minimal residual disease (MRD) after surgery using tissue-informed testing of postoperative plasma circulating cell-free tumour DNA (ctDNA) may allow adjuvant therapy to be withheld from patients without MRD. However, the detection of MRD in the postoperative setting is challenging, and more sensitive methods are urgently needed. We developed a method that combines variant calling and a novel ctDNA fragment length analysis using hybrid capture sequencing data. Among 36 stage II-IIIA NSCLC patients, this method distinguished patients with and without recurrence of disease in a 20 times repeated 10-fold cross validation with 75% accuracy (P = 0.0029). In contrast, using only variant calling or only fragment length analysis, no signification distinction between patients was shown (P = 0.24 and P = 0.074 respectively). In addition, a variant-level fragmentation score was developed that was able to classify variants detected in plasma cfDNA into tumour-derived or white-blood-cell-derived variants with 84% accuracy. The findings in this study may help drive the integration of various types of information from the same data, eventually leading to cheaper and more sensitive techniques to be used in this challenging clinical setting.

Retrospective analysis of PSMA PET/CT thyroid incidental uptake in adults: incidence, diagnosis, and treatment/outcome in a tertiary cancer referral center and University Medical Center.

PURPOSE: A prostate-specific membrane antigen (PSMA) thyroid incidentaloma (PTI) is an unexpected, PSMA-avid thyroid lesion, newly detected during the investigation of an unrelated condition using PSMA PET/CT. The aim of this study is to examine the incidence and clinical significance of PTI and the associated management strategies since the implementation of the PSMA PET/CT scan. METHODS: This study involves a retrospective cohort study of 61 PTI cases depicted on PSMA PET/CT scans performed between January 2016 and July 2021, almost exclusively for (re)staging prostate cancer. The medical records of the included cases were retrospectively reviewed and data of the PSMA PET/CT scans, primary malignancy, thyroid diagnostics, treatment, and follow-up were collected. RESULTS: PTI was reported in 1.1% of the patients who underwent oncologic PSMA PET/CT scans included in this study. Two PTI cases had a histologically proven thyroid cancer: one a benign thyroid lesion and one a metastasis of a renal cell carcinoma. In none of the cases in whom any form of further thyroid workup was withheld, the PTI became clinically relevant during follow-up (median 1.8 years (1.1-3.3)). Six patients (10%) died due to their primary cancer. CONCLUSION: The incidence of thyroid incidentalomas on PSMA PET/CT was low (1.1%) in this large, two-center experience. Less than half of the PTI cases were analyzed and the risk of malignancy, despite being low, was not negligible. The clinical outcome was good using a standard diagnostic workup for PTI, while the prognosis of the patient was determined by the primary malignancy. The consideration to analyze and treat PTI cases should be part of the shared decision-making in cancer patients.

Detection of Circulating Tumor Cells Using the Attune NxT.

Circulating tumor cells (CTCs) have been detected in many patients with different solid malignancies. It has been reported that presence of CTCs correlates with worse survival in patients with multiple types of cancer. Several techniques have been developed to detect CTCs in liquid biopsies. Currently, the only method for CTC detection that is approved by the Food and Drug Administration is CellSearch. Due to low abundance of CTCs in certain cancer types and in early stages of disease, its clinical application is currently limited to metastatic colorectal cancer, breast cancer and prostate cancer. Therefore, we aimed to develop a new method for the detection of CTCs using the Attune NxT-a flow cytometry-based application that was specifically developed to detect rare events in biological samples without the need for enrichment. When healthy donor blood samples were spiked with variable amounts of different EpCAM+EGFR+ tumor cell lines, recovery yield was on average 75%. The detection range was between 1000 and 10 cells per sample. Cell morphology was confirmed with the Attune CytPix. Analysis of blood samples from metastatic colorectal cancer patients, as well as lung cancer patients, demonstrated that increased EpCAM+EGFR+ events were detected in more than half of the patient samples. However, most of these cells showed no (tumor) cell-like morphology. Notably, CellSearch analysis of blood samples from a subset of colorectal cancer patients did not detect CTCs either, suggesting that these blood samples were negative for CTCs. Therefore, we anticipate that the Attune NxT is not superior to CellSearch in detection of low amounts of CTCs, although handling and analysis of samples is easier. Moreover, morphological confirmation is essential to distinguish between CTCs and false positive events.

Importance of tumour volume and histology in trimodality treatment of patients with Stage IIIA non-small cell lung cancer-results from a retrospective analysis.

OBJECTIVES: Chemoradiotherapy (CRT) has been the backbone of guideline-recommended treatment for Stage IIIA non-small cell lung cancer (NSCLC). However, in selected operable patients with a resectable tumour, good results have been achieved with trimodality treatment (TT). The objective of this bi-institutional analysis of outcomes in patients treated for Stage IIIA NSCLC was to identify particular factors supporting the role of surgery after CRT. METHODS: In a 2-centre retrospective cohort study, patients with Stage III NSCLC (seventh edition TNM) were identified and those patients with Stage IIIA who were treated with CRT or TT between January 2007 and December 2013 were selected. Patient characteristics as well as tumour parameters were evaluated in relation to outcome and whether or not these variables were predictive for the influence of treatment (TT or CRT) on outcome [overall survival (OS) or progression-free survival (PFS)]. Estimation of treatment effect on PFS and OS was performed using propensity-weighted cox regression analysis based on inverse probability weighting. RESULTS: From a database of 725 Stage III NSCLC patients, 257 Stage IIIA NSCLC patients, treated with curative intent, were analysed; 186 (72%) with cIIIA-N2 and 71 (28%) with cT3N1/cT4N0 disease. One hundred and ninety-six (76.3%) patients were treated by CRT alone (high-dose radiation with daily low-dose cisplatin) and 61 (23.7%) by TT. The unweighted data showed that TT resulted in better PFS and OS. After weighting for factors predictive of treatment assignment, patients with a large gross tumour volume (>120 cc) had better PFS when treated with TT, and patients with an adenocarcinoma treated with TT had better OS, regardless of tumour volume. CONCLUSIONS: Patients with Stage IIIA NSCLC and large tumour volume, as well as patients with adenocarcinoma, who were selected for TT, had favourable outcome compared to patients receiving CRT. This information can be used to assist multidisciplinary team decision-making and for stratifying patients in studies comparing TT and definitive CRT.

Salvage Surgery for Patients With Local Recurrence or Persistent Disease After Treatment With Chemoradiotherapy for SCLC.

INTRODUCTION: The role of salvage surgery for patients with locoregional (LR) recurrence or persistent SCLC after radical chemoradiotherapy (CRT) for limited-stage disease is not well established. We evaluated our experience. METHODS: We conducted a retrospective study of consecutive patients who underwent salvage pulmonary resection for LR-recurrent or persistent SCLC between 2008 and 2020 at the Amsterdam University Medical Center. RESULTS: A total of 10 patients were identified. Median age at initial diagnosis of limited-stage SCLC was 58.5 years (48-71 y). All patients had radical-intent concurrent CRT. Of the 10 patients, 9 were diagnosed with LR-recurrent or persistent disease with a median of 18 months (3-78 y) after CRT. All patients underwent an anatomical radical resection and mediastinal lymph node dissection. No 90-day mortality was recorded. In addition, one patient developed a LR recurrence 7 months after resection. Distant progression was found in three patients at 6, 32, and 61 months after surgery, all of whom subsequently died of progressive SCLC. Median follow-up was 22.5 months (2-86 mos). Disease-free survival was 34 months; overall survival was not reached. CONCLUSIONS: For highly selected patients with LR-recurrent or persistent SCLC after CRT, salvage surgery is feasible and can result in clinically meaningful survival. Such patients should be presented to the multidisciplinary tumor board.

Variation in incidence, prevention and treatment of persistent air leak after lung cancer surgery.

OBJECTIVES: Persistent air leak (PAL; >5 days after surgery) is the most common complication after pulmonary resection and associated with prolonged hospital stay and increased morbidity. Literature is contradictory about the prevention and treatment of PAL. Variation is therefore hypothesized. The aim of this study is to understand the variation in the incidence, preventive management and treatment of PAL. METHODS: Data from the Dutch Lung Cancer Audit for Surgery were combined with results of an online survey among Dutch thoracic surgeons. The national incidence of PAL and case-mix corrected between-hospital variation were calculated in patients who underwent an oncological (bi)lobectomy or segmentectomy between January 2012 and December 2018. By multivariable logistic regression, factors associated with PAL were assessed. A survey was designed to assess variation in (preventive) management and analysed using descriptive statistics. Hospital-level associations between management strategies and PAL were assessed by univariable linear regression. RESULTS: Of 12 382 included patients, 9.0% had PAL, with a between-hospital range of 2.6-19.3%. Factors associated with PAL were male sex, poor lung function, low body mass index, high American Society of Anesthesiologists (ASA) score, pulmonary comorbidity, upper lobe resection, (bi)lobectomy (vs segmentectomy), right-sided tumour and robotic-assisted thoracic surgery. Perioperative (preventive) management of PAL differed widely between hospitals. When using water seal compared to suction drainage, the average incidence of PAL decreased 2.9%. CONCLUSIONS: In the Netherlands, incidence and perioperative (preventive) management of PAL vary widely. Using water seal instead of suction drainage and increasing awareness are potential measures to reduce this variation.

Well-Differentiated Bronchopulmonary Neuroendocrine Tumors: More Than One Entity.

INTRODUCTION: Until now, well-differentiated bronchopulmonary neuroendocrine tumors (bpNET) occurring either sporadically (sp-bpNET) or in the context of multiple endocrine neoplasia type 1 (MEN1) and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) are regarded as similar entities. However, in contrast to sp-bpNET: MEN1-related and DIPNECH-related bpNET rarely metastasize or lead to bpNET-related death. We aimed to describe and compare the course of the disease of sp-bpNET, DIPNECH- and MEN1-related bpNET. METHODS: All patients with histologically confirmed MEN1-related bpNET from the DutchMEN Study Group database (1990-2017), patients with resected sp-bpNET and DIPNECH patients referred to a Dutch European Neuroendocrine Tumor Society center between 2000 and 2018 were included. Fisher's exact test was used for comparison between groups. The primary end point was disease-specific mortality (DSM). Kaplan-Meier and logrank test were used to compare survival. Cox regression was used to identify risk factors for DSM in the sp-bpNET subgroup. RESULTS: We included 112 sp-bpNET, 29 MEN1, and 27 DIPNECH patients. Tumor classification was similar across subgroups. A total of 20 patients (18%) with sp-bpNET died because of bpNET, compared with none in the MEN1 group and DIPNECH group. Median disease-specific survival was 12.3 (confidence interval: 6.3-18.3) years for patients with sp-bpNET, and not estimable for the other subgroups (p < 0.001). Differences in baseline characteristics did not explain worse survival in sp-bpNET. Tumor classification and age at diagnosis were independent risk factors for DSM in sp-bpNET. CONCLUSIONS: Patients with sp-bpNET have a significantly higher DSM compared with MEN1 or DIPNECH-related bpNET, unexplained by differences in baseline characteristics. This implies that not all bpNET are similar entities.

Retrospective Analyses of 18FDG-PET/CT Thyroid Incidentaloma in Adults: Incidence, Treatment, and Outcome in a Tertiary Cancer Referral Center.

Background: A thyroid incidentaloma (TI) is an unexpected, asymptomatic thyroid lesion discovered during the investigation of an unrelated condition. The aim of the present study is to examine the incidence of 18Fluorodeoxyglucose (FDG)-positron emission tomography (PET) TI, the associated management strategies and the outcomes in a tertiary cancer referral center. Methods: This study involves a retrospective cohort study of 1003 patients with TI found on 18FDG-PET/CT scans performed between January 2010 and January 2020 for a nonthyroidal malignancy. The Kaplan-Meier method was used for survival analyses in patients concerning an underlying malignancy, with a prevalence of 5% or higher in this cohort. Logistic- and cox regression analyses were performed to analyze predictors of thyroid malignancy and mortality. A propensity score weighted method was used to control for baseline differences between the intervention (additional TI diagnostics) and control (no TI diagnostics) group. Results: FDG-positive TI occurred in 1.9% (1003/52,693) of the oncologic 18FDG-PET/CT scans performed in our center. Thyroid surgery was performed in 47 patients (6%) and a thyroid malignancy was detected in 31 of them, which is 66% of those who had an operation and 4% of all patients. During the follow-up (median 6 years), 334 deaths (42%) related to different types of cancer (38%) or other causes (4%) were observed. One patient died from medullary thyroid cancer. In multivariate analysis adjusted for age, gender and the type- and stage of nonthyroidal malignancy, were independent predictors of survival (P < .05). Conclusions: The incidence of TI in this tertiary cancer referral center was comparable to current literature. Further thyroid workup was performed in less than half of the patients, and only a minority of patients underwent thyroid surgery. Since only one patient died from thyroid cancer, the strategy to withhold from thyroid diagnostics and treatment seems valid for most TI. Active thyroid treatment might benefit a subgroup of patients in whom the primary nonthyroidal malignancy is successfully treated or presumably stable. A wait-and-see policy with ultrasound follow-up could be an alternative strategy. These considerations should be part of the shared decision making in cancer patients with a TI.

An ex vivo tumor fragment platform to dissect response to PD-1 blockade in cancer.

Inhibitors of the PD-1-PD-L1 axis have been approved as therapy for many human cancers. In spite of the evidence for their widespread clinical activity, little is known about the immunological alterations that occur in human cancer tissue after PD-1 blockade. We developed and employed a patient-derived tumor fragment platform to dissect the early immunological response of human tumor tissue to ex vivo PD-1 blockade. We observed that the capacity of immune cells to be reactivated ex vivo was predictive of clinical response, and perturbation analyses identified tumor-resident T cells as a key component of this immunological response. In addition, through combined analysis of baseline properties and immune response capacity, we identified a new subgroup of infiltrated tumors that lacks the capacity to respond to PD-1 blockade. Finally, the baseline presence of tertiary lymphoid structures and their components correlated with the capacity of cancers to undergo intratumoral immune cell reactivation.

Stage I non-small cell lung cancer: Treatment modalities, Dutch daily practice and future perspectives.

OBJECTIVES: Several treatment modalities are available for patients with stage I non-small cell lung cancer (NSCLC). Over the past decade, these treatment modalities have been further investigated and might have changed current treatment regimens. In this review we present an overview of the treatment options, developments and future perspectives for stage I NSCLC. Furthermore, we describe the current use of these treatment modalities in the Netherlands. MATERIALS AND METHODS: A bibliographical search was performed in PubMed and the Cochrane Library for publications concerning treatment modalities for stage I NSCLC. In addition, evidence-based guidelines of the European Society for Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN) were studied. RESULTS: The guideline-recommended treatment for operable stage I NSCLC patients is a lobectomy with systematic lymph node dissection. Inoperable patients or those refusing surgery are offered stereotactic ablative radiotherapy (SABR). Percutaneous ablation, such as radiofrequency ablation, is a non-surgical minimally invasive technique offered to those who are ineligible for surgery or SABR. The role of systemic therapy is currently limited. However, the efficacy of immunotherapy is being investigated in clinical trials. In the Netherlands, an increasing use of SABR and a relative decrease in resection rates have been observed. CONCLUSION: Surgery and SABR are currently the prevailing treatment modalities for stage I NSCLC patients. Despite optimization of treatment regimens, survival of patients with stage I NSCLC remains to be improved. Future studies are required to optimize treatment strategies, but also to investigate factors influencing treatment decision-making for patients with stage I NSCLC.

Prognostic Value of Deep Learning-Mediated Treatment Monitoring in Lung Cancer Patients Receiving Immunotherapy.

BACKGROUND: Checkpoint inhibitors provided sustained clinical benefit to metastatic lung cancer patients. Nonetheless, prognostic markers in metastatic settings are still under research. Imaging offers distinctive advantages, providing whole-body information non-invasively, while routinely available in most clinics. We hypothesized that more prognostic information can be extracted by employing artificial intelligence (AI) for treatment monitoring, superior to 2D tumor growth criteria. METHODS: A cohort of 152 stage-IV non-small-cell lung cancer patients (NSCLC) (73 discovery, 79 test, 903CTs), who received nivolumab were retrospectively collected. We trained a neural network to identify morphological changes on chest CT acquired during patients' follow-ups. A classifier was employed to link imaging features learned by the network with overall survival. RESULTS: Our results showed significant performance in the independent test set to predict 1-year overall survival from the date of image acquisition, with an average area under the curve (AUC) of 0.69 (p < 0.01), up to AUC 0.75 (p < 0.01) in the first 3 to 5 months of treatment, and 0.67 AUC (p = 0.01) for durable clinical benefit (6 months progression-free survival). We found the AI-derived survival score to be independent of clinical, radiological, PDL1, and histopathological factors. Visual analysis of AI-generated prognostic heatmaps revealed relative prognostic importance of morphological nodal changes in the mediastinum, supraclavicular, and hilar regions, lung and bone metastases, as well as pleural effusions, atelectasis, and consolidations. CONCLUSIONS: Our results demonstrate that deep learning can quantify tumor- and non-tumor-related morphological changes important for prognostication on serial imaging. Further investigation should focus on the implementation of this technique beyond thoracic imaging.