Reconstruction of long-segment tracheal defects requires a vascularized allograft. We report successful tracheal allotransplantation after indirect revascularization of the graft in a heterotopic ...position. Immunosuppressive therapy was administered before the operation, and the tracheal allograft was wrapped in the recipient's forearm fascia. Once revascularization was achieved, the mucosal lining was replaced progressively with buccal mucosa from the recipient. At 4 months, the tracheal chimera was fully lined with mucosa, which consisted of respiratory epithelium from the donor and buccal mucosa from the recipient. After withdrawal of immunosuppressive therapy, the tracheal allograft was moved to its correct anatomical position with an intact blood supply. No treatment-limiting adverse effects occurred.
Cancer cells are embedded in the tumor microenvironment (TME), a complex ecosystem of stromal cells. Here, we present a 52,698-cell catalog of the TME transcriptome in human lung tumors at ...single-cell resolution, validated in independent samples where 40,250 additional cells were sequenced. By comparing with matching non-malignant lung samples, we reveal a highly complex TME that profoundly molds stromal cells. We identify 52 stromal cell subtypes, including novel subpopulations in cell types hitherto considered to be homogeneous, as well as transcription factors underlying their heterogeneity. For instance, we discover fibroblasts expressing different collagen sets, endothelial cells downregulating immune cell homing and genes coregulated with established immune checkpoint transcripts and correlating with T-cell activity. By assessing marker genes for these cell subtypes in bulk RNA-sequencing data from 1,572 patients, we illustrate how these correlate with survival, while immunohistochemistry for selected markers validates them as separate cellular entities in an independent series of lung tumors. Hence, in providing a comprehensive catalog of stromal cells types and by characterizing their phenotype and co-optive behavior, this resource provides deeper insights into lung cancer biology that will be helpful in advancing lung cancer diagnosis and therapy.
Abstract
OBJECTIVES
The role of segmentectomy in early-stage non-small-cell lung cancer (NSCLC) remains a matter of debate. We performed a meta-analysis to evaluate the oncological outcomes following ...segmentectomy versus lobectomy for stage I, stage IA only and stage IA <2 cm only.
METHODS
We systematically searched the literature for articles reporting on overall survival (OS), cancer-specific survival (CSS) or recurrence-free survival (RFS). The hazard ratios (HRs) were retrieved and pooled using an inverse variance-weighted approach.
RESULTS
Twenty-eight studies were included in the analysis. In stage I, segmentectomy was found to be inferior to lobectomy for all 3 outcomes with HR: 1.25 (P = 0.01) for OS, 1.59 (P = 0.02) for CSS and 1.40 (P < 0.001) for RFS. In stage IA, the differences were significant for OS and CSS, though not for RFS with HR: 1.31 (P = 0.04), 1.56 (P = 0.02) and 1.22 (P = 0.11), respectively. In stage IA <2 cm, no significant differences were found between segmentectomy and lobectomy with HR: 1.13 (P = 0.37) for OS, 1.02 (P = 0.95) for CSS and 1.24 (P = 0.11) for RFS.
CONCLUSIONS
For stages I and IA, lobectomy showed superior results whereas for tumours <2 cm, our study did not find significant differences in oncological outcomes between both groups. These results suggest that segmentectomy might be a valuable alternative to lobectomy for NSCLC in tumours <2 cm.
A quarter of patients with clinical N1 (cN1) non-small cell lung cancer (NSCLC) based on positron emission tomography-computed tomography (PET-CT) imaging have occult mediastinal nodal involvement ...(N2 disease). In a prospective study, endosonography alone had an unsatisfactory sensitivity (38%) in detecting N2 disease. The current prospective multicentre trial investigated the sensitivity of preoperative mediastinal staging by video-assisted mediastinoscopy (VAM) or VAM-lymphadenectomy (VAMLA).Consecutive patients with operable and resectable (suspected) NSCLC and cN1 after PET-CT imaging underwent VAM(LA). The primary study outcome was sensitivity to detect N2 disease. Secondary endpoints were the prevalence of N2 disease, negative predictive value (NPV) and accuracy of VAM(LA).Out of 105 patients with cN1 on imaging, 26% eventually developed N2 disease. Invasive mediastinal staging with VAM(LA) had a sensitivity of 73% to detect N2 disease. The NPV was 92% and accuracy 93%. Median number of assessed lymph node stations during VAM(LA) was 4 (IQR 3-5), and in 96%, at least three stations were assessed.VAM(LA) has a satisfactory sensitivity of 73% to detect mediastinal nodal disease in cN1 lung cancer, and could be the technique of choice for pre-resection mediastinal lymph node assessment in this patient group with a one in four chance of occult-positive mediastinal nodes after negative PET-CT.
Non-small cell lung cancer (NSCLC) is a heterogeneous disorder consisting of distinct molecular subtypes each characterised by specific genetic and epigenetic profiles. Here, we aimed to identify ...novel NSCLC subtypes based on genome-wide methylation data, assess their relationship with smoking behaviour, age, COPD, emphysema and tumour histopathology, and identify the molecular pathways underlying each subtype.
Methylation profiling was performed on 49 pairs of tumour and adjacent lung tissue using Illumina 450 K arrays. Transcriptome sequencing was performed using Illumina HiSeq2000 and validated using expression data from The Cancer Genome Atlas (TCGA). Tumour immune cell infiltration was investigated by immunohistochemistry.
Unsupervised hierarchical clustering of tumour methylation data revealed two subgroups characterised by a significant association between cluster membership and presence of COPD (p=0.024). Ontology analysis of genes containing differentially methylated CpGs (false discovery rate, FDR-adjusted p<0.05) revealed that immune genes were strongly enriched in COPD tumours, but not in non-COPD tumours. This COPD-specific immune signature was attributable to methylation changes in immune genes expressed either by tumour cells or tumour-infiltrating immune cells. No such differences were observed in adjacent tissue. Transcriptome profiling similarly revealed that genes involved in the immune response were differentially expressed in COPD tumours (FDR-adjusted p<0.05), an observation that was independently replicated using TCGA data. Immunohistochemistry validated these findings, revealing fewer CD4-positive T lymphocytes in tumours derived from patients with COPD.
Lung tumours of patients with COPD differ from those of patients without COPD, with differentially methylated and expressed genes being mainly involved in the immune response.
Lung transplantation is an effective and safe therapy for carefully selected patients suffering from a variety of end-stage pulmonary diseases. Lung cancer negatively affects prognosis, particularly ...in patients who are no longer candidates for complete resection. Lung transplantation can be considered for carefully selected and well staged lung cancer patients with proven, lung-limited, multifocal, (minimally invasive) adenocarcinoma in situ (AIS) (previously called bronchioloalveolar cell carcinoma) causing respiratory failure. Despite a substantial risk of tumour recurrence (33-75%), lung transplantation may offer a survival benefit (50% at 5 years) with best palliation of their disease. Reports on lung transplantation for other low-grade malignancies are rare. Lung transplant candidates at higher risk for developing lung cancer mainly previous smokers with chronic obstructive lung disease (COPD) and idiopathic pulmonary fibrosis (IPF) or older patients should be thoroughly and repeatedly screened for lung cancer prior to listing, and preferably also during waiting list time if longer than 1 year, including the use of PET-CT scan and EBUS-assisted bronchoscopy in case of undefined, but suspicious pulmonary abnormalities. Double-lung transplantation should now replace single-lung transplantation in these high-risk patients because of a 6-9% prevalence of lung cancer developing in the remaining native lung. Patients with unexpected, early stage bronchial carcinoma in the explanted lung may have favourable survival without recurrence. Early PET-CT (at 3-6 months) following lung transplantation is advisable to detect early, subclinical disease progression. Donor lungs from (former) smokers should be well examined at retrieval. Suspicious nodules should be biopsied to avoid grafting cancer in the recipient. Close follow-up with regular visits and screening test in all recipients is needed because of the increased risk of developing a primary or secondary cancer in the allograft from either donor or recipient origin.
To clarify the biologic behavior of esophageal signet ring cell (SRC) carcinomas of the esophagus and gastroesophageal junction (GEJ). To evaluate the accuracy of pretreatment biopsies in diagnosing ...true SRC carcinoma.
In contrast with gastric cancer, little is known about the biologic behavior and prognosis of SRC.
All adenocarcinomas (ADC) of the esophagus and GEJ-patients undergoing primary resection between 1990 and 2009 were included (n = 920). Specimens containing SRCs (n = 114) were classified according to World Health Organization criteria (>50% SRC or <50% SRC).
Thirty-two patients showed more than 50% SRC and 71 patients showed less than 50% SRC. Overall cancer-specific 5-year survival was worse for SRC (22.4%, P < 0.0001) and for SRC > 50% (13.6%, P = 0.0001) compared with ADC. Complete resection was achieved in 86.5% of patients (n = 697) in ADC, 69.5% (n = 57) in SRC < 50%, and 78.1% (n = 25) in SRC > 50% (vs ADC, respectively, P < 0.0001 and P = 0.1801). In 379 pN + R0 patients, the median number of positive lymph nodes was comparable between ADC and SRC < 50% (4 vs 5, P = 0.207) or SRC > 50% (4 vs 8, P = 0.077). Compared with ADC, SRC > 50% showed more pN3's (30% vs 61%, P = 0.006), higher recurrence (56% vs 42% for ADC, P = 0.003), and local-regional recurrences (29% vs 16%, P = 0.002). Pretreatment biopsies were unreliable to define the presence of SRC > 50% (sensitivity = 56.3%, positive predictive value = 43.9%).
SRCs are aggressive neoplasms associated with poorer prognosis than other ADCs after primary esophagectomy. Because our data suggest that pretreatment biopsies failed to reliably define presence of SRC > 50%, presence of SRCs in pretreatment biopsies seems to be of no use to define treatment strategy or prognosis.
Abstract Background We hypothesized that modern postoperative radiotherapy (PORT) could decrease local recurrence (LR) and improve overall survival (OS) in patients with stage IIIA-N2 non-small-cell ...lung cancer (NSCLC). Methods To investigate the effect of modern PORT on LR and OS, we identified published phase III trials for PORT and stratified them according to use or non-use of linear accelerators. Non-individual patient data were used to model the potential benefit of modern PORT in stage IIIA-N2 NSCLC treated with induction chemotherapy and resection. Results Of the PORT phase III studies, eleven trials (2387 patients) were included for OS analysis and eight (1677 patients) for LR. PORT decreased LR, whether given with cobalt, cobalt and linear accelerators, or with linear accelerators only. An increase in OS was only seen when PORT was given with linear accelerators, along with the most significant effect on LR (relative risk for LR and OS 0.31 ( p = 0.01) and 0.76 ( p = 0.02) for PORT vs. controls, respectively). Four trials (357 patients) were suitable to assess LR rates in stage III NSCLC treated with surgery, in most cases after induction chemotherapy. LR as first relapse was 30% (105/357) after 5 years. In the modeling part, PORT with linear accelerators was estimated to reduce LR rates to 10% as first relapse and to increase the absolute 5-year OS by 13%. Conclusions This modeling study generates the hypothesis that modern PORT may increase both LR and OS in stage IIIA-N2 NSCLC even in patients being treated with induction chemotherapy and surgery.
Background
Although most guidelines suggest performing a positron emission tomography/computed tomography (PET/CT) with somatostatin receptor (SSTR) ligands for staging of pulmonary carcinoid tumours ...(PC), only a limited number of studies have evaluated the role of this imaging tool in this specific patient population. The preoperative differentiation between typical carcinoid (TC) and atypical carcinoid (AC) and the extent of dissemination (N/M status) are crucial factors for treatment allocation and prognosis of these patients. Therefore, we performed a pathology-based retrospective analysis of the value of SSTR PET/CT in tumour grading and detection of nodal and metastatic involvement of PC and compared this with the previous literature and with
18
FFDG PET/CT in a subgroup of patients.
Methods
SSTR PET/CT scans performed between January 2007 and May 2020 in the context of PC were included. If available,
18
FFDG PET/CT images were also evaluated. The maximum standardized uptake (SUV
max
) values of the primary tumour, of the pathologically examined hilar and mediastinal lymph node stations, as well as of the distant metastases, were recorded. Tumoural SUV
max
values were related to the tumour type (TC versus AC) for both SSTR and
18
FFDG PET/CT in diagnosing and differentiating both tumour types. Nodal SUV
max
values were compared to the pathological status (N
+
versus N
−
) to evaluate the diagnostic accuracy of SSTR PET/CT in detecting lymph node involvement. Finally, a mixed model analysis of all pathologically proven distant metastatic lesions was performed.
Results
A total of 86 SSTR PET/CT scans performed in 86 patients with PC were retrospectively analysed.
18
FFDG PET/CT was available in 46 patients. Analysis of the SUV
max
values in the primary tumour showed significantly higher SSTR uptake in TC compared with AC (median SUV
max
18.4 vs 3.8;
p
= 0.003) and significantly higher
18
FFDG uptake in AC compared to TC (median SUV
max
5.4 vs 3.5;
p
= 0.038). Receiver operating characteristic (ROC) curve analysis resulted in an area under the curve (AUC) of 0.78 for the detection of TC on SSTR PET/CT and of 0.73 for the detection of AC on
18
FFDG PET/CT. A total of 267 pathologically evaluated hilar and mediastinal lymph node stations were analysed. ROC analysis of paired SSTR/
18
FFDG SUV
max
values for the detection of metastasis of TC in 83 lymph node stations revealed an AUC of 0.91 for SSTR PET/CT and of 0.74 for
18
FFDG PET/CT (difference 0.17; 95% confidence interval − 0.03 to 0.38;
p
= 0.10). In a sub-cohort of 10 patients with 12 distant lesions that were pathologically examined due to a suspicious aspect on SSTR PET/CT, a positive predictive value (PPV) of 100% was observed.
Conclusion
Our findings confirm the higher SSTR ligand uptake in TC compared to AC and vice versa for
18
FFDG uptake. More importantly, we found a good diagnostic performance of SSTR PET/CT for the detection of hilar and mediastinal lymph node metastases of TC. Finally, a PPV of 100% for SSTR PET/CT was found in a small sub-cohort of patients with pathologically investigated distant metastatic lesions. Taken together, SSTR PET/CT has a very high diagnostic value in the TNM assessment of pulmonary carcinoids, particularly in TC, which underscores its position in European guidelines.
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