Diagnosis of sarcopenia on thoracic computed tomography and its association with postoperative survival after anatomic lung cancer resection

Computer tomography-derived skeletal muscle index normalized for height in conjunction with muscle density enables single modality-based sarcopenia assessment that accounts for all diagnostic criteria and cutoff recommendations as per the widely accepted European consensus. Yet, the standard approach to quantify skeletal musculature at the third lumbar vertebra is limited for certain patient groups, such as lung cancer patients who receive chest CT for tumor staging that does not encompass this lumbar level. As an alternative, this retrospective study assessed sarcopenia in lung cancer patients treated with curative intent at the tenth thoracic vertebral level using appropriate cutoffs. We showed that skeletal muscle index and radiation attenuation at level T10 correlate well with those at level L3 (Pearson’s R = 0.82 and 0.66, p < 0.001). During a median follow-up period of 55.7 months, sarcopenia was independently associated with worse overall (hazard ratio (HR) = 2.11, 95%-confidence interval (95%-CI) = 1.38–3.23, p < 0.001) and cancer-specific survival (HR = 2.00, 95%-CI = 1.19–3.36, p = 0.009) of lung cancer patients following anatomic resection. This study highlights feasibility to diagnose sarcopenia solely by thoracic CT in accordance with the European consensus recommendations. The straightforward methodology offers easy translation into routine clinical care and potential to improve preoperative risk stratification of lung cancer patients scheduled for surgery

Disseminated cancer cells detected by immunocytology in lymph nodes of NSCLC patients are highly prognostic and undergo parallel molecular evolution

In melanoma, immunocytology (IC) after sentinel lymph node disaggregation not only enables better quantification of disseminated cancer cells (DCCs) than routine histopathology (HP) but also provides a unique opportunity to detect, isolate, and analyse these earliest harbingers of metachronous metastasis. Here, we explored lymph node IC in non-small cell lung cancer (NSCLC). For 122 NSCLC patients, 220 lymph nodes (LNs) were split in half and prepared for IC and HP. When both methods were compared, IC identified 22% positive patients as opposed to 4.5% by HP, revealing a much higher sensitivity of IC (p < 0.001). Assessment of all available 2,952 LNs of the same patients by HP uncovered additional patients escaping detection of lymphatic tumour spread by IC alone, consistent with the concept of skip metastasis. A combined lymph node status of IC and complete HP on a larger cohort of patients outperformed all risk factors in multivariable analysis for prognosis (p < 0.001; RR = 2.290; CI 1.407–3.728). Moreover, isolation of DCCs and single-cell molecular characterization revealed that (1) LN-DCCs differ from primary tumours in terms of copy number alterations and selected mutations and (2) critical alterations are acquired during colony formation within LNs. We conclude that LN-IC in NSCLC patients when combined with HP improves diagnostic precision, has the potential to reduce total workload, and facilitates molecular characterization of lymphatically spread cancer cells, which may become key for the selection and development of novel systemic therapies. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

Disseminated cancer cells detected by immunocytology in lymph nodes of NSCLC patients are highly prognostic and undergo parallel molecular evolution

Abstract In melanoma, immunocytology (IC) after sentinel lymph node disaggregation not only enables better quantification of disseminated cancer cells (DCCs) than routine histopathology (HP) but also provides a unique opportunity to detect, isolate, and analyse these earliest harbingers of metachronous metastasis. Here, we explored lymph node IC in non‐small cell lung cancer (NSCLC). For 122 NSCLC patients, 220 lymph nodes (LNs) were split in half and prepared for IC and HP. When both methods were compared, IC identified 22% positive patients as opposed to 4.5% by HP, revealing a much higher sensitivity of IC (p < 0.001). Assessment of all available 2,952 LNs of the same patients by HP uncovered additional patients escaping detection of lymphatic tumour spread by IC alone, consistent with the concept of skip metastasis. A combined lymph node status of IC and complete HP on a larger cohort of patients outperformed all risk factors in multivariable analysis for prognosis (p < 0.001; RR = 2.290; CI 1.407–3.728). Moreover, isolation of DCCs and single‐cell molecular characterization revealed that (1) LN‐DCCs differ from primary tumours in terms of copy number alterations and selected mutations and (2) critical alterations are acquired during colony formation within LNs. We conclude that LN‐IC in NSCLC patients when combined with HP improves diagnostic precision, has the potential to reduce total workload, and facilitates molecular characterization of lymphatically spread cancer cells, which may become key for the selection and development of novel systemic therapies. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

Mindestmengen in der chirurgischen Behandlung des Lungenkarzinoms: Ein Meinungsbild von in Deutschland aktiven Thoraxchirurgen zur Einführung einer Mindestmengenregelung für die chirurgische Therapie des Lungenkarzinoms

Background The Federal Joint Committee (G-BA) is currently discussing the introduction of new minimum volume regulations (MVR) in Germany. The present study examined the current opinions of active thoracic surgeons regarding minimum volumes (MV) for the surgical treatment of lung cancer. Methods The participating centers for the online survey were identified on the basis of the thoracic surgery departments in the 2017 hospital directory (Federal Statistical Office), lung cancer centers (German Cancer Society), certified centers of excellence for thoracic surgery (German Society for Thoracic Surgery), hospitals with a focus on lung surgery and German university hospitals. They were asked about the potential effects of MVR on the quality of results and quality of care, economic aspects and the structure of care. Furthermore, a recommendation for MV was requested and possible provisions for exemption were evaluated. Results A total of 145 hospitals (response rate 85%) with 454 thoracic surgeons (response rate 54%) were surveyed. The results showed a high degree of approval for MV to improve the quality of results and 78.4% of the surgeons surveyed expected it to result in centralization of surgical care, although this would not lead to a deterioration in care according to 70.1% of the participants. Approximately 46.1% of the participants expected care to become more economical and 83.3% supported the introduction of an MVR, with the average recommended MV being 67 anatomical lung resections per center per year. Conclusion An MVR for the surgical treatment of lung cancer met with a high degree of approval among active thoracic surgeons. The MV that was called for (n & x202f;=& x202f;67) was slightly below the prerequisite for primary surgical cases at a certified lung cancer center

Mindestmengen in der chirurgischen Behandlung des Lungenkarzinoms

Zusammenfassung Hintergrund Im Rahmen der aktuellen Diskussion des G‑BA zur Einführung neuer Mindestmengenregelungen (MMR) in Deutschland untersucht die vorliegende Studie das Meinungsbild aktiver Thoraxchirurgen zu Mindestmengen (MM) bei der operativen Behandlung des Lungenkarzinoms. Methoden Die Auswahl der thoraxchirurgischen Zentren für die Onlinebefragung erfolgte auf Basis des Krankenhausverzeichnisses 2017 (Bundesamt für Statistik), der Lungenkrebszentren (Deutsche Krebsgesellschaft), der zertifizierten Kompetenzzentren Thoraxchirurgie (Deutsche Gesellschaft für Thoraxchirurgie), der Kliniken mit thoraxchirurgischem Schwerpunkt und der deutschen Universitätskliniken. Abgefragt wurde der potenzielle Einfluss einer MMR auf die Ergebnisqualität, Versorgungsqualität, ökonomische Aspekte und auf die Versorgungsstruktur. Des Weiteren wurde eine Empfehlung für eine MM gefordert und aktuelle Ausnahmeregelungen bewertet. Ergebnisse Es wurden 145 Kliniken (Rücklaufquote 85 %) mit 454 Thoraxchirurgen (Rücklaufquote 54 %) kontaktiert. Bei hoher Akzeptanz von MM zur Verbesserung der Ergebnisqualität erwarten 78,4 % der befragten Operateure eine Zentralisierung der chirurgischen Versorgung, welche jedoch nach Aussage von 70,1  % zu keiner Verschlechterung der Versorgung von Lungenkrebspatienten führen würde. Etwa 46,1 % der Teilnehmer rechnen mit einer ökonomischeren Versorgung und 83,3 % sprachen sich für die Einführung einer MMR mit einer durchschnittlichen MM von 67 anatomischen Lungenresektionen pro Jahr und pro Zentrum aus. Schlussfolgerung Eine MMR zur chirurgischen Therapie des Lungenkarzinoms findet unter aktiven Thoraxchirurgen eine hohe Akzeptanz. Die geforderte MM (n = 67) liegt etwas unter der Vorgabe für chirurgische Primärfälle eines zertifizierten Lungenkrebszentrums. </jats:sec

Ergeben sich durch die Einführung der 8. Auflage der TNM-Klassifikation Änderungen für eine leitliniengerechte, chirurgische Therapiestrategie des Lungenkarzinoms?

Zusammenfassung Einleitung Durch die 8. Auflage der TNM-Klassifikation und die aktualisierte S3-Leitlinie ergaben sich in den letzten beiden Jahren Neuerungen in der Stadieneinteilung und Behandlung des Lungenkarzinoms. Ziel dieser Arbeit ist es, die Stadiendifferenzierungen und -wechsel von der 7. hin zur 8. Auflage zu identifizieren und mögliche therapeutische, insbesondere chirurgische Konsequenzen darzustellen. Methoden Prospektive Datenerhebung aller Lungenkrebsprimärfälle vom 01.01.2016 bis 31.12.2016 an 2 thoraxchirurgischen Zentren und Nachuntersuchung im März 2019. Vergleich der 7. Auflage der Tumorklassifikation für das Lungenkarzinom mit der 8. Auflage in Hinblick auf Veränderungen des Stadiums, Auswirkungen auf die leitliniengerechte, insbesondere chirurgische Therapie des Lungenkarzinoms und das Gesamtüberleben. Ergebnisse Es konnten 432 Primärfälle einer Lungenkrebserkrankung ermittelt werden. Davon konnten entsprechend der 8. Auflage 82 Patienten (7. Auflage: n = 85) dem Stadium I, 43 (n = 49) Patienten dem Stadium II, 100 (n = 91) Patienten dem Stadium III und 207 (n = 207) Patienten dem Stadium IV zugeordnet werden. Es wurden 81 (18,7%) Veränderungen des Tumorstadiums mit einer deutlichen Tendenz zur Höherstufung (77 Aufwertungen vs. 4 Abwertungen) detektiert. Bei 63 Patienten (14,6%) zeigte sich ein Stadienwechsel innerhalb eines Stadiums (z. B. IIA → IIB), für 18 Patienten (4,1%) ergab die Auswertung einen übergreifenden Stadienwechsel (z. B. IIB → IIIA) mit einer formalen Änderung in der Therapieempfehlung ohne primär operative Therapieindikation bei 12 Patienten (2,8%). Die neu eingeführten Subgruppen (IA1–3, IIIC und IVA/B) ergaben für 290 Patienten (67,1%) eine spezifischere Stadiendifferenzierung. Für die neuen Stadien IVA/B konnte ein signifikanter Unterschied im 2-Jahres-Überleben dargestellt werden (IVA = 25,2%; IVB = 13,0%; p &lt; 0,05). Schlussfolgerung Die Weiterentwicklung der TNM-Klassifikation für das Bronchialkarzinom zur aktuellen 8. Auflage zeichnet sich durch eine differenziertere Einteilung aus. Im untersuchten Kollektiv zeigte sich eine deutliche Tendenz zur Höherstufung des Tumorstadiums. Unter Berücksichtigung der aktuellen Empfehlungen aus der S3-Leitlinie reduziert sich daher die Anzahl der Patienten mit formal primärer OP-Empfehlung im Stadium I – IIIA. Vor allem die Veränderungen des T-Status bei gleichbleibendem N-Status und die Aufwertung einzelner Tumorformeln in ein höheres Tumorstadium verursachen diese Dynamik. Das signifikant bessere 2-Jahres-Überleben im Stadium IVA bei singulärer Fernmetastasierung (M1b) und M1a-Metastasierung im Vergleich zum Stadium IVB unterstützt die differenzierte Betrachtung der unterschiedlichen Metastasierungsgrade.</jats:p

Ergeben sich durch die Einführung der 8. Auflage der TNM-Klassifikation Änderungen für eine leitliniengerechte, chirurgische Therapiestrategie des Lungenkarzinoms?

Study Aim The 8th edition of the TNM classification combined with the latest update of the S3-guideline (by AWMF/Scientific Medical Societies in Germany) on prevention, diagnosis, therapy and follow-up of lung cancer led to several changes in staging and treatment of lung cancer. The aim of this study was to identify differences in the distribution of patients due to changes from the 7th to the 8th edition that affected staging. The influence on surgical therapy will be discussed by using the recommendations of the latest S3 guideline. Methods Prospective analysis of all primary cases at two thoracic surgical centres in the year 2016 and follow-up in March 2019. Comparison of the 7th edition of tumour classification for lung cancer with the 8th edition, focused on changes in tumour staging and its effects on the appropriate surgical therapy according to the latest S3 guideline. Results A total of 432 primary cases comprised the study population. According to the 8th edition, 82 patients (7th edition: n = 85) in stage I, 43 (n = 49) patients in stage II, 100 (n = 91) patients in stage III and 207 (n = 207) patients are assigned to stage IV. 81 changes (18.7%) were detected (77 upgrades vs. 4 downgrades). 63 patients (14.6%) exhibited a different graduation within the stages. 18 patients (4.1%) were classified in different tumour stages. As a result, fewer patients (n = 12; 2.8%) should have surgery according to the latest S3 guidelines. 290 patients (67.1%) were classified to new subgroups (IA1-3, IIIC and IVA/B). Two-year survival was significantly higher in IVA (25.2%) vs. IVB (13.0%) patients (p < 0.05). Conclusion The 8th edition of the TNM-classification affords a higher level of differentiation. In this study, the new TNM classification led to a shift in the distribution, with a tendency to increase the tumour stage. This is mainly caused by changes in the T-descriptor and stage grouping. As a result, fewer patients in stage I-IIIA should have surgery according to the latest S3 guidelines. A significantly higher two-year survival rate was detected in stage IVA (M1a and M1b) compared to IVB and justifies the new differentiation due to the metastatic pattern

EpCAM-positive disseminated cancer cells in bone marrow impact on survival of early-stage NSCLC patients

Introduction Detection of disseminated cancer cells (DCC) in bone marrow (BM) of patients with early-stage NSCLC has been associated with poor outcome. However, the phenotype, and hence relevant therapy targets, of DCCs in BM are unknown. We therefore compared a classical pan-Cytokeratin (CK) antibody for DCC detection with an anti-EpCAM antibody that may also detect more stem-like cells and tested whether assay positivity impacts on the survival of NSCLC patients. Materials and methods We prospectively collected BM aspirates from 104 non-metastasized NSCLC patients that underwent potentially curative tumor resection from 2011 to 2016 at the Department of Thoracic Surgery of the University Hospital and Hospital Barmherzige Brüder in Regensburg. DCCs were detected by staining with the pan anti-CK antibody A45-B/B3 and the anti-EpCAM antibody HEA-125. We analyzed the association between detection of DCCs and clinicopathological characteristic and patient outcome. Results CK-positive and EpCAM-positive DCCs were detected in 45.2% and 52.9% of patients, respectively. Correlation between the two markers was low and neither of them was associated with sex, age, histology, T or N classification, resection status, grading or smoking habit. No significant association with tumor specific survival (TSS) and progression-free survival (PFS) was observed in patients with CK-positive DCCs. In contrast, detection of EpCAM-positive DCCs significantly correlated with reduced PFS (P=0.017) and TSS (P=0.017) and remained an independent prognostic variable for PFS and TSS upon multivariate testing (hazard ratio: 7.506 and 3.551, respectively). Detection of EpCAM-positive DCCs was the only prognostic marker for PFS. Conclusions EpCAM-positive, but not CK-positive DCCs in BM predict reduced PFS and TSS. This finding suggests that EpCAM-positive DCCs in the BM comprise metastatic founder cells necessitating their in-depth molecular analysis for detection of novel therapy targets

Ex vivo expansion of lung cancer‐derived disseminated cancer cells from lymph nodes identifies cells associated with metastatic progression

The cellular basis of the apparent aggressiveness in lung cancer is poorly understood but likely associated with functional or molecular features of disseminated cancer cells (DCCs). DCCs from epithelial cancers are mostly detected by antibodies directed against histogenetic markers such as cytokeratin or EpCAM. It has been argued that marker-negative metastatic founder cells might escape detection. We therefore used ex vivo sphere formation for functional detection of candidate metastasis founders. We generated cell suspensions from 199 LN samples of 131 lung cancer patients and placed them into non-adherent cell culture. Sphere formation was associated with detection of DCCs using EpCAM immunocytology and with significantly poorer prognosis. The prognostic impact of sphere formation was strongly associated with high numbers of EpCAM-positive DCCs and aberrant genotypes of expanded spheres. We also noted sphere formation in patients with no evidence of lymphatic spread, however such spheres showed infrequent expression of signature genes associated with spheres from EpCAM-positive samples and displayed neither typical lung cancer mutations (KRAS, TP53, ERBB1) nor copy number variations, but might be linked to disease progression >5 years post curative surgery. We conclude that EpCAM identifies relevant disease-driving DCCs, that such cells can be expanded for model generation and that further research is needed to clarify the functional and prognostic role of rare EpCAM-negative sphere forming cells