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.

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.

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.

Dose Reduction of Preoperative Radiotherapy in Myxoid Liposarcoma: A Nonrandomized Controlled Trial.

IMPORTANCE: Currently, preoperative radiotherapy for all soft-tissue sarcomas is identical at a 50-Gy dose level, which can be associated with morbidity, particularly wound complications. The observed clinical radiosensitivity of the myxoid liposarcoma subtype might offer the possibility to reduce morbidity. OBJECTIVE: To assess whether a dose reduction of preoperative radiotherapy for myxoid liposarcoma would result in comparable oncological outcome with less morbidity. DESIGN, SETTING, AND PARTICIPANTS: The Dose Reduction of Preoperative Radiotherapy in Myxoid Liposarcomas (DOREMY) trial is a prospective, single-group, phase 2 nonrandomized controlled trial being conducted in 9 tertiary sarcoma centers in Europe and the US. Participants include adults with nonmetastatic, biopsy-proven and translocation-confirmed myxoid liposarcoma of the extremity or trunk who were enrolled between November 24, 2010, and August 1, 2019. Data analyses, using both per-protocol and intention-to-treat approaches, were conducted from November 24, 2010, to January 31, 2020. INTERVENTIONS: The experimental preoperative radiotherapy regimen consisted of 36 Gy in once-daily 2-Gy fractions, with subsequent definitive surgical resection after an interval of 4 or more weeks. MAIN OUTCOMES AND MEASURES: As a short-term evaluable surrogate for local control, the primary end point was centrally reviewed pathologic treatment response. The experimental regimen was regarded as a success when 70% or more of the resection specimens showed extensive treatment response, defined as 50% or greater of the tumor volume containing treatment effects. Morbidity outcomes consisted of wound complications and late toxic effects. RESULTS: Among the 79 eligible patients, 44 (56%) were men and the median (interquartile range) age was 45 (39-56) years. Two patients did not undergo surgical resection because of intercurrent metastatic disease. Extensive pathological treatment response was observed in 70 of 77 patients (91%; posterior mean, 90.4%; 95% highest probability density interval, 83.8%-96.4%). The local control rate was 100%. The rate of wound complication requiring intervention was 17%, and the rate of grade 2 or higher toxic effects was 14%. CONCLUSIONS AND RELEVANCE: The findings of the DOREMY nonrandomized clinical trial suggest that deintensification of preoperative radiotherapy dose is effective and oncologically safe and is associated with less morbidity than historical controls, although differences in radiotherapy techniques and follow-up should be considered. A 36-Gy dose delivered in once-daily 2-Gy fractions is proposed as a dose-fractionation approach for myxoid liposarcoma, given that phase 3 trials are logistically impossible to execute in rare cancers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02106312.

Is pneumonectomy justifiable for patients with a locoregional recurrence or persistent disease after curative intent chemoradiotherapy for locally advanced non-small cell lung cancer?

OBJECTIVES: Locoregional recurrence and persistent/progressive disease after curative-intent definitive chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC) is challenging to manage, as salvage options are limited. Selected patients might be candidates for resection. This study evaluated the outcomes of patients after salvage surgery for locoregional recurrence, focusing specifically on morbidity and mortality after salvage pneumonectomy. MATERIALS AND METHODS: This retrospective study included patients from 2 tertiary referral hospitals who underwent salvage pulmonary resection for locoregional recurrence or disease persistence/progression >12 weeks after completion of curative intent high dose (>60 Gy) CRT. Disease-free (DFS) and overall survival (OS) were estimated and the influence of patient and treatment characteristics on these endpoints was assessed. RESULTS: A total of 30 patients treated between 2015-2017 were identified with a median age of 60 years (range 42-72 years), 67 % were male. Median follow-up was 47 months (95 % CI 46-NR). Pneumonectomy was performed in 13/30 (43 %) patients and lobectomy in 17/30 (57 %). Median DFS and OS after pneumonectomy/lobectomy were 14/6 and NR/17 months, respectively. 30 and 90-day mortality for pneumonectomy/lobectomy were 0/12 % and 0/24 % respectively. More favorable survival was seen after pathologically radical resection, i.e. R0, and when surgery was performed more than 12 months after completion of CRT. CONCLUSION: Salvage surgery, including pneumonectomy is associated with acceptable outcomes in selected patients with recurrent or persistent/progressive NSCLC after curative-intent high dose CRT. Patients should be assessed for the probability of an R0 resection, and patients with a locoregional recurrence more than 12 months after treatment with CRT may benefit most from salvage surgery.

Results of neoadjuvant chemo(radio)therapy and resection for stage IIIA non-small cell lung cancer in The Netherlands.

Introduction: Concurrent chemoradiotherapy remains the main treatment strategy for patients with stage IIIA non-small cell lung cancer (NSCLC); stage cT3N1 or cT4N0-1 may be eligible for surgery and potentially resectable stage IIIA (N2) NSCLC for neoadjuvant therapy followed by resection. We evaluated treatment patterns and outcomes of patients with stage IIIA NSCLC in The Netherlands.Material and Methods: Primary treatment data of patients with clinically staged IIIA NSCLC between 2010 and 2016 were extracted from The Netherlands Cancer Registry. Patient characteristics were tabulated and 5-year overall survival (OS) was calculated and reported.Results: In total, 9,591 patients were diagnosed with stage IIIA NSCLC. Of these patients, 41.3% were treated with chemoradiotherapy, 11.6% by upfront surgery and 428 patients (4.5%) received neoadjuvant treatment followed by resection. The 5-year OS was 26% after chemoradiotherapy, 40% after upfront surgery and 54% after neoadjuvant treatment followed by resection. Clinical over staging was seen in 42.3% of the patients that were operated without neoadjuvant therapy.Conclusion: In The Netherlands, between 2010 and 2016, 4.5% of patients with stage IIIA NSCLC were selected for treatment with neoadjuvant therapy followed by resection. The 5-year OS in these patients exceeded 50%. However, the outcome might be overestimated due to clinical over staging.

Pre- and postoperative care for stage I-III NSCLC: Which quality of care indicators are evidence-based?

Identification of evidenced-based Quality of Care (QoC) indicators for lung cancer care is essential to quality improvement. The aim of this review was to identify evidence-based quality indicators for the pre- and postoperative care of stage I-III Non Small Cell Lung Cancer (NSCLC) provided by the lung physician. To obtain these indicators, a search in PubMed, Embase and the Cochrane library database was performed. English literature published between 1980 and 2012 was included and search terms regarding 'lung neoplasms', 'quality of care', 'pathology', 'diagnostic methods', 'preoperative and postoperative treatment' were used. The potential indicators were categorized as structure, process or outcome measures and the indicators supported by literature with high evidence level were selected. Five QoC indicators were identified. The use of the positron emission tomography-computed tomography (PET-CT) results in more accurate mediastinal staging compared to the CT scan. Endoscopic Ultrasound-Fine Needle Aspiration and Endobronchial Ultrasound-Fine Needle Aspiration are sensitive diagnostic tools for mediastinal staging and reduce futile thoracotomies. Pathological conformation of lung cancer can best be obtained by a combination of cytological and histological diagnostics used during bronchoscopy. For patients with clinical stage III NSCLC, preoperative multimodality treatment (i.e. preoperative chemoradiation) results in superior survival and increased mediastinal downstaging compared to single modality treatment (i.e. preoperative chemotherapy or radiotherapy). After surgery, the addition of chemotherapy results in a significant survival benefit for patients with pathological stage II and III NSCLC. These five QoC indicators can be used for benchmarking and ultimately quality improvement of lung cancer care.

Peri- and postoperative management of stage I-III Non Small Cell Lung Cancer: Which quality of care indicators are evidence-based?

Quality of care (QoC) has a central role in our health care system. The aim of this review is to present a set of evidence-based quality indicators for the surgical treatment and postoperative management of lung cancer. A search was performed through PubMed, Embase and the Cochrane library database, including English literature, published between 1980 and 2012. Search terms regarding 'lung neoplasms', 'surgical treatment' and 'quality of care' were used. Potential QoC indicators were divided into structure, process or outcome measures and a final selection was made based upon the level of evidence. High hospital volume and surgery performed by a thoracic surgeon, were identified as important structure indicators. Sleeve resection instead of pneumonectomy and the importance of treatment within a clinical care path setting were identified as evidence-based process indicators. A symptom-based follow-up regime was identified as a new QoC indicator. These indicators can be used for registration, benchmarking and ultimately quality improvement in lung cancer surgery.

Management of large mediastinal masses: surgical and anesthesiological considerations.

Large mediastinal masses are rare, and encompass a wide variety of diseases. Regardless of the diagnosis, all large mediastinal masses may cause compression or invasion of vital structures, resulting in respiratory insufficiency or hemodynamic decompensation. Detailed preoperative preparation is a prerequisite for favorable surgical outcomes and should include preoperative multimodality imaging, with emphasis on vascular anatomy and invasive characteristics of the tumor. A multidisciplinary team should decide whether neoadjuvant therapy can be beneficial. Furthermore, the anesthesiologist has to evaluate the risk of intraoperative mediastinal mass syndrome (MMS). With adequate preoperative team planning, a safe anesthesiological and surgical strategy can be accomplished.

Tumor heterogeneity on (18)F-FDG-PET/CT for response monitoring in non-small cell lung cancer treated with erlotinib.

Response monitoring using fluorodeoxyglucose positron emission tomography acquired together with low dose computed tomography (FDG-PET/CT) textural features has potential in targeted treatment with erlotinib in non-small cell lung cancer (NSCLC) patients. Patients with substantial decrease of metabolic activity during erlotinib treatment will probably benefit from continued treatment. However, various aspects of the method (quantification tools, cut-off values, etc.) need to be standardized before the software becomes widely available in a similar manner as standardized uptake value (SUV) measurements. Heterogeneity on FDG-PET/CT opened an additional window for innovation but simultaneously a new challenge for molecular hybrid imaging.

Prognostic value of pre-operative glucose-corrected maximum standardized uptake value in patients with non-small cell lung cancer after complete surgical resection and 5-year follow-up.

INTRODUCTION: In this study we evaluated the value of pre-operative glucose corrected maximum standard uptake value (GC-SUVmax) as prognostic factor in patients with early stage non-small cell lung cancer (NSCLC) after complete surgical resection. METHODS: This study was designed as a retrospectively evaluated single center study with prospective data registry. Inclusion criteria were: histologically proven stage I NSCLC, 18F-FDG-PET/CT scan prior to surgery, complete resection (R0) and follow up in our outpatient department. Exclusion criteria were: history of malignancy other than NSCLC, diabetes and (neo) adjuvant therapy. Follow up period was 5 years. RESULTS: Between 2006 and 2008 a total of 33 patients (16 males, 17 females) met the inclusion criteria. SUVmax and GC-SUVmax were strongly correlated (Spearman's ρ = 0.97). Five-year overall survival (OS) rate was 70 % (95 % CI = 56-87 %). Patients who died within 5 years of follow up had significantly higher pre-operative GC-SUVmax (median = 10.6, IQR = 8.3-14.4) than patients who were alive at 5-year follow up (median = 6.4, IQR = 3.0-9.8), p = 0.04. SUVmax showed similar differences: 10.4 (8-12.9) vs. 6.6 (3.0-8.8), p = 0.047. The area under the receiver-operating characteristic (ROC) curve at 5 years was 0.70 (95 % CI = 0.50-0.90) for GC-SUVmax and 0.71 (95 % CI = 0.51-0.91) for SUVmax (p = 0.75). CONCLUSION: Pre-operative FDG tumor uptake in patients with NSCLC is predictive for survival after complete surgical resection. GC-SUVmax, as an additional value to SUVmax, may better approach competitive inhibition of FDG and glucose in tumors, however, in this study this potential advantage, if any, was very small.

Real-time In Vivo Tissue Characterization with Diffuse Reflectance Spectroscopy during Transthoracic Lung Biopsy: A Clinical Feasibility Study.

PURPOSE: This study presents the first in vivo real-time tissue characterization during image-guided percutaneous lung biopsies using diffuse reflectance spectroscopy (DRS) sensing at the tip of a biopsy needle with integrated optical fibers. EXPERIMENTAL DESIGN: Tissues from 21 consented patients undergoing lung cancer surgery were measured intraoperatively using the fiber-optic platform capable of assessing various physical tissue properties highly correlated to tissue architecture and composition. In addition, the method was tested for clinical use by performing DRS tissue sensing during 11 routine biopsy procedures in patients with suspected lung cancer. RESULTS: We found that water content and scattering amplitude are the primary discriminators for the transition from healthy lung tissue to tumor tissue and that the reliability of these parameters is not affected by the amount of blood at the needle tip. In the 21 patients measured intraoperatively, the water-to-scattering ratio yielded a 56% to 81% contrast difference between tumor and surrounding tissue. Analysis of the 11 image-guided lung biopsy procedures showed that the tissue diagnosis derived from DRS was diagnostically discriminant in each clinical case. CONCLUSIONS: DRS tissue sensing integrated into a biopsy needle may be a powerful new tool for biopsy guidance that can be readily used in routine diagnostic lung biopsy procedures. This approach may not only help to increase the successful biopsy yield for histopathologic analysis, but may also allow specific sampling of vital tumor tissue for genetic profiling.

Optimal surgical management of pulmonary metastases: VATS versus thoracotomy.

Survival benefit after pulmonary metastasectomy is under question and knowledge of functional recovery after pulmonary metastasectomy by thoracotomy and video-assisted thoracoscopic surgery (VATS) is of great importance. We analysed prospective data of 100 patients operated for pulmonary metastasis by either VATS or thoracotomy. VATS yielded a better physical performance 1 month postoperative, shorter hospital stay, a shorter duration of chest tube drainage and epidural analgesia. We concluded that VATS is the preferable approach due to superior functional outcome.

FDG-PET/CT response evaluation during EGFR-TKI treatment in patients with NSCLC.

Over recent years, [18F]-fluorodeoxyglucose positron emission tomography acquired together with low dose computed tomography (FDG-PET/CT) has proven its role as a staging modality in patients with non-small cell lung cancer (NSCLC). The purpose of this review was to present the evidence to use FDG-PET/CT for response evaluation in patients with NSCLC, treated with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI). All published articles from 1 November 2003 to 1 November 2013 reporting on 18F-FDG-PET response evaluation during EGFR-TKI treatment in patients with NSCLC were collected. In total 7 studies, including data of 210 patients were eligible for analyses. Our report shows that FDG-PET/CT response during EGFR-TKI therapy has potential in targeted treatment for NSCLC. FDG-PET/CT response is associated with clinical and radiologic response and with survival. Furthermore FDG-PET/CT response monitoring can be performed as early as 1-2 wk after initiation of EGFR-TKI treatment. Patients with substantial decrease of metabolic activity during EGFR-TKI treatment will probably benefit from continued treatment. If metabolic response does not occur within the first weeks of EGFR-TKI treatment, patients may be spared (further) unnecessary toxicity of ineffective treatment. Refining FDG-PET response criteria may help the clinician to decide on continuation or discontinuation of targeted treatment.

Timing of metabolic response monitoring during erlotinib treatment in non-small cell lung cancer.

UNLABELLED: The purpose of this study was to prospectively evaluate the timing of metabolic response monitoring with (18)F-FDG PET of (neoadjuvant) erlotinib treatment in patients with early-stage non-small cell lung cancer. METHODS: This study was designed as an open-label phase II trial performed in 4 hospitals in The Netherlands. Patients received preoperative erlotinib (150 mg) once daily for 3 wk. Response evaluation was performed after 4-7 d and at 3 wk with (18)F-FDG PET/CT scans. Tumor (18)F-FDG uptake and changes were measured as standardized uptake values (SUVs). The metabolic response was classified on the basis of European Organization for Research and Treatment of Cancer criteria (>25% decrease in the maximum SUV) and was compared with histopathologic regression as observed in the resection specimen. RESULTS: From December 2006 to November 2010, 60 patients with non-small cell lung cancer eligible for surgical resection were enrolled in this study. For 43 patients (18 men and 25 women), baseline (18)F-FDG PET/CT scans as well as both monitoring scans and histopathologic response monitoring were available. A partial metabolic response on (18)F-FDG PET/CT scans was observed for 10 patients (23%) after 1 wk and for 14 patients (33%) after 3 wk. Histopathologic examination revealed regression (necrosis of >50%) in 11 patients (26%). In these patients, the maximum SUV decreased by a mean of 17% within 1 wk and a mean of 31% at 3 wk. Seven patients were identified as responders within 1 wk. CONCLUSION: Response monitoring with (18)F-FDG PET/CT within 1 wk after the start of erlotinib treatment identified approximately 64% of histopathologic responders on the basis of European Organization for Research and Treatment of Cancer criteria.

(18)F-fluorodeoxyglucose positron emission tomography versus computed tomography in predicting histopathological response to epidermal growth factor receptor-tyrosine kinase inhibitor treatment in resectable non-small cell lung cancer.

PURPOSE: To prospectively evaluate diagnostic computed tomography (CT) and (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for identification of histopathologic response to neoadjuvant erlotinib, an epidermal growth factor receptor-tyrosine kinase inhibitor in patients with resectable non-small cell lung cancer (NSCLC). METHODS: This study was designed as an open-label phase 2 trial, performed in four hospitals in the Netherlands. Patients received preoperative erlotinib 150 mg once daily for 3 weeks. CT and FDG-PET/CT were performed at baseline and after 3 weeks of treatment. CT was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. FDG-PET/CT, tumor FDG uptake, and changes were measured by standardized uptake values (SUV). Radiologic and metabolic responses were compared to the histopathological response. RESULTS: Sixty patients were enrolled onto this study. In 53 patients (22 men, 31 women), the combination of CT, FDG-PET/CT, and histopathological evaluation was available for analysis. Three patients (6 %) had radiologic response. According to European Organisation for Research and Treatment of Cancer (EORTC) criteria, 15 patients (28 %) showed metabolic response. In 11 patients, histopathologic response (≥50 % necrosis) was seen. In predicting histopathologic response, relative FDG change in SUVmax showed more SUVmax decrease in the histopathologic response group (-32 %) versus the group with no pathologic response (-4 %) (p = 0.0132). Relative change in tumor size on diagnostic CT was similar in these groups with means close to 0. CONCLUSIONS: FDG-PET/CT has an advantage over CT as a predictive tool to identify histopathologic response after 3 weeks of EGFR-TKI treatment in NSCLC patients.

Complete pathological response is predictive for clinical outcome after tri-modality therapy for carcinomas of the superior pulmonary sulcus.

The objective was to define the relationship between histopathological changes after pre-operative chemo-radiotherapy (CRT) and clinical outcome following tri-modality therapy in patients with superior sulcus tumours. A retrospective analysis of tumour material was performed in a series of 46 patients who received tri-modality therapy between 1997 and 2007. Median follow-up was 34 months (5-154). Pathological complete response (pCR) was present in 20/46 tumours (43 %). The most common RECIST score after CRT in patients with pCR was a partial response (PR; 10/17, three unknown), whereas in patients without a pCR, stable disease was the most common (22/26) (p = 0.002). In 26 specimens with residual tumour, this was mainly located in the periphery of the lesion rather than the centre (Spearman's correlation = 0.67, p < 0.001). Prognosis was significantly better after a pCR compared to residual tumour (70 % 5-year overall survival vs. 20 %; p = 0.001) and in patients with fewer than 10 % vital tumour cells as compared to those with >10 % (65 % 5-year overall survival vs. 18 %; p < 0.001). A low mitotic count was associated with a longer disease-free survival (p = 0.02). Complete pathological response and the presence of fewer than 10 % vital tumour cells after pre-operative CRT are both associated with a more favourable prognosis. A modification of the pathological staging system after radiotherapy, incorporating the percentage of vital tumour cells, is proposed.