Ten recommendations for sarcoma surgery: consensus of the surgical societies based on the German S3 guideline "Adult Soft Tissue Sarcomas".

PURPOSE: The evidence-based (S3) guideline "Adult Soft Tissue Sarcomas" (AWMF Registry No. 032/044OL) published by the German Guideline Program in Oncology (GGPO) covers all aspects of sarcoma treatment with 229 recommendations. Representatives of all medical specialties involved in sarcoma treatment contributed to the guideline. This paper compiles the most important recommendations for surgeons selected by delegates from the surgical societies. METHODS: A Delphi process was used. Delegates from the surgical societies involved in guideline process selected the 15 recommendations that were most important to them. Votes for similar recommendations were tallied. From the resulting ranked list, the 10 most frequently voted recommendations were selected and confirmed by consensus in the next step. RESULTS: The statement "Resection of primary soft tissue sarcomas of the extremities should be performed as a wide resection. The goal is an R0 resection" was selected as the most important term. The next highest ranked recommendations were the need for a preoperative biopsy, performing preoperative MRI imaging with contrast, and discussing all cases before surgery in a multidisciplinary sarcoma committee. CONCLUSION: The evidence-based guideline "Adult Soft Tissue Sarcomas" is a milestone to improve the care of sarcoma patients in Germany. The selection of the top ten recommendations by surgeons for surgeons has the potential to improve the dissemination and acceptance of the guideline and thus improve the overall outcome of sarcoma patients.

Endoscopic Lung Volume Reduction Using Endobronchial Valves in Patients with Severe Emphysema and Very Low FEV1.

BACKGROUND: Patients with a forced expiratory volume in 1 s (FEV1) below 20% of the predicted normal values (pred.) and either homogeneous emphysema or low diffusing capacity for carbon monoxide (DLCO) have a high risk for adverse events including death when undergoing surgical lung volume reduction. OBJECTIVES: We hypothesized that selected patients can benefit from endoscopic lung volume reduction (eLVR) despite a very low FEV1. METHODS: This study is a retrospective analysis of consecutive patients with severe airflow obstruction, an FEV1 ≤20% of pred., and low DLCO who were treated by eLVR with endobronchial valves (EBV) between June 2012 and January 2015. Pre- and postinterventional lung function parameters, the 6-min walking test (6-MWT) distance, adverse events, and follow-up were recorded. RESULTS: In 20 patients, there was an overall improvement in lung function with an increase in FEV1 (16.97-21.03% of pred.) and a decrease in residual volume (322-270% of pred.) and total lung capacity (144-129.06% of pred.). The 6-MWT distance improved (from 239 ± 77 to 267± 97 m overall, and from 184 ± 50 to 237 ± 101 m if patients developed an atelectasis of the target lobe). Pneumothorax occurred in 5 of the 20 patients (25%). 30-day mortality was 0%, and all patients survived to discharge. CONCLUSIONS: The patients benefitted moderately from EBV treatment despite an initially low FEV1. Some patients improved remarkably. EBV treatment in patients with an FEV1 ≤20% of pred. is generally feasible and safe. The greatest risk is pneumothorax with prolonged chest tube duration.

Analysis of Patients Unable to Undergo Adjuvant Chemotherapy after Surgery in Stage IIIA/B Non-Small Cell Lung Cancer: Will They Benefit from Mediastinal Radiotherapy?

Objectives The role of postoperative mediastinal radiotherapy in completely resected non-small cell lung cancer (NSCLC) and pathological N2 disease is controversial. In clinical practice, not all lung cancer patients with histologically confirmed N2 disease and a high risk for local recurrence are able to undergo postoperative concurrent radio/chemotherapy due to their physical condition or postoperative morbidities. Mediastinal radiotherapy is less compromising than a combination of radio/chemotherapy and seems likely to be tolerable for limited patients to achieve better local tumor control. Materials and Methods All patients included in this retrospective analysis were excluded from postoperative adjuvant combination chemo/radiotherapy due to their comorbidity, advanced age, or a complicated postoperative course. Three-dimensional conformal radiotherapy of the mediastinal lymph node stations (mean dose: 50 Gy; range: 50-54 Gy) in patients with R0 resection, additional boost of 10 Gy in patients with R1 or R2 resection, was performed postoperatively. Results A total of 110 patients were included in this analysis. Mean survival was 25.5 ± 19.2 months. The 1-, 3-, and 5-year survival was 75.4, 38.7, and 26.2%, respectively. Postoperative complications and the development of distant metastases did not correlate (p = 0.7). Distant metastases proved to be a significant prognostic factor of survival (p < 0.0001). Local recurrence was seen in a total of three patients (2.7%). Five-year survival of patients developing major postoperative complications was significantly inferior (p = 0.04) to those without postoperative complications. The extent of surgery had a significant impact on survival-5-year survival after lobectomy was significantly longer than after pneumonectomy (p = 0.029). R1 resection had no significant impact on the survival rates (p = 0.67). Discussion Stage III-N2 NSCLC patients with multiple comorbidities or a complicated postoperative course after surgery may benefit from modern mediastinal radiotherapy. Surgery and postoperative mediastinal radiotherapy can achieve local tumor control. Distant metastases have the highest impact on the prognosis. Pneumonectomy, however, should be avoided in stage III NSCLC, when possible.

Laser assisted pulmonary metastasectomy promises a low local recurrence rate.

Pulmonary metastasectomy (PM) is consensually performed in a parenchyma-sparing manner to preserve functionally healthy lung tissue. However, this may increase the risk of local recurrence at the surgical margin. Laser assisted pulmonary metastasectomy (LPM) is a relatively recent innovation that is especially useful to resect multiple metastatic pulmonary nodules. In this study we investigated the rate of local recurrence after LPM and evaluated the influence of various clinical and pathological factors on local recurrence. Retrospectively, a total of 280 metastatic nodules with different histopathological entities were studied LPM from 2010 till 2018. All nodules were resected via diode-pumped neodymium: yttrium-aluminum-garnet (Nd:YAG) 1,318 nm laser maintaining a safety margin of 5 mm. Patients included were observed on average for 44 ± 17 months postoperatively. Local recurrence at the surgical margin following LPM was found in 9 nodules out of 280 nodules (3.21%). Local recurrence at the surgical margin occurred after 20 ± 8.5 months post operation. Incomplete resection (p = < 0.01) and size of the nodule (p = < 0.01) were associated with significantly increased risk of local recurrence at the surgical margin. Histology of the primary disease showed no impact on local recurrence. Three and five-year survival rates were 84% and 49% respectively. Following LPM, the rate of local recurrence is low. This is influenced by the size of the metastatic nodules and completeness of the resection. Obtaining a safety margin of 5 mm seems to be sufficient, larger nodules require larger safety margins.

WNT4 overexpression and secretion in thymic epithelial tumors drive an autocrine loop in tumor cells in vitro.

Background: WNT4-driven non-canonical signaling is crucial for homeostasis and age-related involution of the thymus. Abnormal WNT signaling is important in many cancers, but the role of WNT signaling in thymic tumors is largely unknown. Materials & Methods: Expression and function of WNT4 and FZD6 were analyzed using qRT-PCR, Western blot, ELISA, in biopsies of non-neoplastic thymi (NT), thymoma and thymic carcinomas. ShRNA techniques and functional assays were used in primary thymic epithelial cells (pTECs) and TC cell line 1889c. Cells were conventionally (2D) grown and in three-dimensional (3D) spheroids. Results: In biopsy, WHO classified B3 thymomas and TCs showed increased WNT4 expression compared with NTs. During short-term 2D culture, WNT4 expression and secretion declined in neoplastic pTECs but not in 3D spheroids or medium supplemented with recombinant WNT4 cultures. Under the latter condition, the growth of pTECs was accompanied by increased expression of non-canonical targets RAC1 and JNK. Down-regulation of WNT4 by shRNA induced cell death in pTECs derived from B3 thymomas and led to decreased RAC1, but not JNK protein phosphorylation. Pharmacological inhibition of NF-κB decreased both RAC1 and JNK phosphorylation in neoplastic pTECs. Conclusions: Lack of the age-related decline of non-canonical WNT4 expression in TETs and restoration of declining WNT4 expression through exogeneous WNT4 or 3D culture of pTECs hints at an oncogenic role of WNT4 in TETs and is compatible with the WNT4 autocrine loop model. Crosstalk between WNT4 and NF-κB signaling may present a promising target for combined interventions in TETs.

Metabolic Profiling of Thymic Epithelial Tumors Hints to a Strong Warburg Effect, Glutaminolysis and Precarious Redox Homeostasis as Potential Therapeutic Targets.

Thymomas and thymic carcinomas (TC) are malignant thymic epithelial tumors (TETs) with poor outcome, if non-resectable. Metabolic signatures of TETs have not yet been studied and may offer new therapeutic options. Metabolic profiles of snap-frozen thymomas (WHO types A, AB, B1, B2, B3, n = 12) and TCs (n = 3) were determined by high resolution magic angle spinning 1H nuclear magnetic resonance (HRMAS 1H-NMR) spectroscopy. Metabolite-based prediction of active KEGG metabolic pathways was achieved with MetPA. In relation to metabolite-based metabolic pathways, gene expression signatures of TETs (n = 115) were investigated in the public "The Cancer Genome Atlas" (TCGA) dataset using gene set enrichment analysis. Overall, thirty-seven metabolites were quantified in TETs, including acetylcholine that was not previously detected in other non-endocrine cancers. Metabolite-based cluster analysis distinguished clinically indolent (A, AB, B1) and aggressive TETs (B2, B3, TCs). Using MetPA, six KEGG metabolic pathways were predicted to be activated, including proline/arginine, glycolysis and glutathione pathways. The activated pathways as predicted by metabolite-profiling were generally enriched transcriptionally in the independent TCGA dataset. Shared high lactic acid and glutamine levels, together with associated gene expression signatures suggested a strong "Warburg effect", glutaminolysis and redox homeostasis as potential vulnerabilities that need validation in a large, independent cohort of aggressive TETs. If confirmed, targeting metabolic pathways may eventually prove as adjunct therapeutic options in TETs, since the metabolic features identified here are known to confer resistance to cisplatin-based chemotherapy, kinase inhibitors and immune checkpoint blockers, i.e., currently used therapies for non-resectable TETs.

Pulmonary cancers across different histotypes share hybrid tuft cell/ionocyte-like molecular features and potentially druggable vulnerabilities.

Tuft cells are chemosensory epithelial cells in the respiratory tract and several other organs. Recent studies revealed tuft cell-like gene expression signatures in some pulmonary adenocarcinomas, squamous cell carcinomas (SQCC), small cell carcinomas (SCLC), and large cell neuroendocrine carcinomas (LCNEC). Identification of their similarities could inform shared druggable vulnerabilities. Clinicopathological features of tuft cell-like (tcl) subsets in various lung cancer histotypes were studied in two independent tumor cohorts using immunohistochemistry (n = 674 and 70). Findings were confirmed, and additional characteristics were explored using public datasets (RNA seq and immunohistochemical data) (n = 555). Drug susceptibilities of tuft cell-like SCLC cell lines were also investigated. By immunohistochemistry, 10-20% of SCLC and LCNEC, and approximately 2% of SQCC expressed POU2F3, the master regulator of tuft cells. These tuft cell-like tumors exhibited "lineage ambiguity" as they co-expressed NCAM1, a marker for neuroendocrine differentiation, and KRT5, a marker for squamous differentiation. In addition, tuft cell-like tumors co-expressed BCL2 and KIT, and tuft cell-like SCLC and LCNEC, but not SQCC, also highly expressed MYC. Data from public datasets confirmed these features and revealed that tuft cell-like SCLC and LCNEC co-clustered on hierarchical clustering. Furthermore, only tuft cell-like subsets among pulmonary cancers significantly expressed FOXI1, the master regulator of ionocytes, suggesting their bidirectional but immature differentiation status. Clinically, tuft cell-like SCLC and LCNEC had a similar prognosis. Experimentally, tuft cell-like SCLC cell lines were susceptible to PARP and BCL2 co-inhibition, indicating synergistic effects. Taken together, pulmonary tuft cell-like cancers maintain histotype-related clinicopathologic characteristics despite overlapping unique molecular features. From a therapeutic perspective, identification of tuft cell-like LCNECs might be crucial given their close kinship with tuft cell-like SCLC.

Surgical Morbidity and Lung Function Changes After Laser-Assisted Pulmonary Metastasectomy: A Prospective Bicentric Study.

Objective: The surgical resection of pulmonary metastases is associated with a survival benefit in selected patients. The use of laser devices for pulmonary metastasectomy (PM) is believed to facilitate the complete resection of metastases while preserving a maximum of healthy parenchyma. This is a prospective study to evaluate surgical outcome including the changes of lung function after laser-assisted surgery (LAS). Methods: A total of 77 operations in 61 patients in which PM was carried out in a curative intent were analyzed. A 1.320 nm diode-pumped Nd: YAG-Laser was used for resection of the metastases. Surgical and clinical data were collected using a standardized form and postoperative lung function changes 3 and 6 months after surgery were assessed using whole body plethysmography and diffusion capacity for carbon monoxide (DLCO). Size and distance of metastases to the pleural surface were measured radiologically. Results: A median of two metastases were resected per operation (range 1-13). The median duration of postoperative air leak was 1 day (range 0-11). LAS associated postoperative minor and major complications were observed in 4 (5%) cases and 1 (1%) case, respectively; there were no mortalities. The analysis of perioperative lung function showed that mean VC 3 months after surgery was reduced by 11 %, FEV1 by 11% and median DLCO by 11% (all p < 0.0001). There was almost no recovery of lung function between 3 and 6 months in the whole cohort. Patients with two or less metastases showed a recovery of lung function after 3 months regarding DLCO (p = 0.003). Decline of DLCO in the whole cohort correlated with the number of resected metastases at 3 months (r = 0.45, p = 0.006) and at 6 months (r = 0.42, p = 0.02) as well as depth of metastases in the parenchyma at 6 months (r = 0.48, p = 0.001). Conclusions: LAS is a safe and effective method for PM even for higher numbers of metastases, with short duration of postoperative air leak and little morbidity. Number and depth, but not size of metastases affect lung function changes after resection.

A Tuft Cell-Like Signature Is Highly Prevalent in Thymic Squamous Cell Carcinoma and Delineates New Molecular Subsets Among the Major Lung Cancer Histotypes.

INTRODUCTION: In-depth genomic characterization of thymic epithelial tumors (TETs), comprising thymomas and thymic carcinomas (TCs), failed to identify targetable mutations and suggested unique biology of TETs, including KIT expression in most TCs. Recently, tuft cell-like medullary thymic epithelial cells were identified in the murine thymus, and our reanalysis of the published gene expression data revealed that these cells express KIT. In addition, recently, a minor subset of SCLCs with tuft cell-like features was described. METHODS: We interrogated mRNA expression data from our tumor cohorts (N = 60) and publicly available, independent data sets from TETs and NSCLC (N = 1199) for expression of tuft cell genes and KIT. Expression of KIT and of POU2F3 protein, the master regulator of tuft cells, was analyzed in cancer tissue (N = 344) by immunohistochemistry. RESULTS: Normal human thymic tuft cells and most TCs coexpressed KIT and known tuft cell genes, particularly POU2F3 and GFI1B. Unexpectedly, small subsets of tuft cell-like tumors coexpressing POU2F3, GFI1B, and KIT were also identified among pulmonary squamous cell carcinomas, adenocarcinomas, and large cell neuroendocrine carcinoma and clustered together in each histologic cohort. In addition to the tuft cell-like signature, both thymic and lung tuft cell-like carcinomas had distinct genetic, pathologic, and clinical features in each cohort. CONCLUSIONS: We suggest that the tuft cell-like phenotype defines novel subsets of thymic and pulmonary carcinoma. Its high prevalence in thymic squamous cell carcinomas that have no known toxic or viral etiologies suggests a new mechanism of carcinogenesis that may lead to specific drug susceptibilities.

Thymic Hyperplasia with Lymphoepithelial Sialadenitis (LESA)-Like Features: Strong Association with Lymphomas and Non-Myasthenic Autoimmune Diseases.

Thymic hyperplasia (TH) with lymphoepithelial sialadenitis (LESA)-like features (LESA-like TH) has been described as a tumor-like, benign proliferation of thymic epithelial cells and lymphoid follicles. We aimed to determine the frequency of lymphoma and autoimmunity in LESA-like TH and performed retrospective analysis of cases with LESA-like TH and/or thymic MALT-lymphoma. Among 36 patients (21 males) with LESA-like TH (age 52 years, 32-80; lesion diameter 7.0 cm, 1-14.5; median, range), five (14%) showed associated lymphomas, including four (11%) thymic MALT lymphomas and one (3%) diffuse large B-cell lymphoma. One additional case showed a clonal B-cell-receptor rearrangement without evidence of lymphoma. Twelve (33%) patients (7 women) suffered from partially overlapping autoimmune diseases: systemic lupus erythematosus (n = 4, 11%), rheumatoid arthritis (n = 3, 8%), myasthenia gravis (n = 2, 6%), asthma (n = 2, 6%), scleroderma, Sjögren syndrome, pure red cell aplasia, Grave's disease and anti-IgLON5 syndrome (each n = 1, 3%). Among 11 primary thymic MALT lymphomas, remnants of LESA-like TH were found in two cases (18%). In summary, LESA-like TH shows a striking association with autoimmunity and predisposes to lymphomas. Thus, a hematologic and rheumatologic workup should become standard in patients diagnosed with LESA-like TH. Radiologists and clinicians should be aware of LESA-like TH as a differential diagnosis for mediastinal mass lesions in patients with autoimmune diseases.

Prognostic value and therapeutic consequences of vascular invasion in non-small cell lung carcinoma.

The prognostic relevance of blood vessel invasion (BVI) in non-small cell lung carcinoma (NSCLC) remains controversial, as is the question of whether its finding should influence therapeutic decisions after an R0 resection. One hundred and twelve cases of NSCLC were included in the study. All had been treated by potentially curative surgical resection of the primary tumor and systematic lymphadenectomy. In all cases, lymphatic metastatic spread was at its earliest stage and only one regional lymph node was involved, 27.0+/-8.9 nodes per patient being examined histologically. Most of the cases were pT2 (75.9%) and pN1 (81.3%), and all were MX/M0 and R0. 62.5% were at stage IIB, 25.9% at stage IIIA, and 9.8% at stage IIA. BVI was found in 45.5% of the tumors (V1), and 18.8% exhibited both lymphatic invasion and BVI (L1V1). Local recurrence occurred in 10.7% of the patients, distant metastasis in 24.1%, and both forms of tumor progression simultaneously in a further 7.1%. Thus 31.2% of the patients developed distant metastases by hematogenous spread (to the brain, bones, lung, adrenal, and liver, in descending order of frequency), mostly within two years of surgery. Late metastasis is not typical of NSCLC. Adenocarcinomas showed a strong tendency to be associated with a poorer prognosis than squamous cell carcinomas, probably because of their more frequent involvement of blood vessels. Five-year survival (Kaplan-Meier method) was significantly lower in V1 cases (37.2%) than in V0 cases (56.0%; p = 0.0249). Adjuvant mediastinal radiation in node-positive cases of NSCLC may prevent local recurrence but is unlikely to influence the development of distant metastases. The histological detection of BVI is of prognostic relevance and should be considered for inclusion in the staging criteria and indications for adjuvant chemotherapy.

18F-FDG PET for mediastinal staging of lung cancer: which SUV threshold makes sense?

UNLABELLED: (18)F-FDG PET is the most accurate noninvasive modality for staging mediastinal lymph nodes in lung cancer. Besides using visual image interpretation, some institutions use standardized uptake value (SUV) measurements in lymph nodes. Mostly, an SUV of 2.5 is used as the cutoff, but this choice was never deduced from respective studies. Receiver operating characteristic (ROC) analyses demonstrated that SUV thresholds of more than 4 resulted in the highest accuracy. But these high cutoffs imply high false-negative rates (FNRs). The aim of our evaluation was to determine an optimal SUV threshold and to compare its diagnostic performance with the results of visual interpretation. METHODS: This retrospective study included 95 patients with suspected lung cancer who underwent mediastinoscopy/mediastinal lymphadenectomy after (18)F-FDG PET (90-150 min after 250 MBq of (18)F-FDG). Maximum SUV was measured in 371 lymph node regions biopsied afterward and visually interpreted using a 6-level score (- - - through + + +). Diagnostic performance was assessed by ROC analysis. FNR and false-positive rate (FPR), the sum of both error rates (FNR + FPR), and diagnostic accuracy were plotted against a hypothetical SUV threshold to determine the optimum SUV threshold. RESULTS: SUVs in metastatic lymph nodes were higher (mean +/- SD, 7.1 +/- 4.5; range, 1.4-26.9; n = 70) than in tumor-free lymph node stations (2.4 +/- 1.7; range, 0.6-14.9; n = 301; P < 0.01). Inflammatory lymph nodes exhibited slightly increased SUVs (2.7 +/- 2.0; range, 0.8-14.9; n = 146). The plot of error rates featured a minimum of the sum FNR + FPR for an SUV of 2.5. With increasing SUV threshold, the FPR decreased most prominently up to that value whereas a continuous rise of FNR was noticed. Highest diagnostic accuracy was achieved with an SUV of 4.5. The areas under the ROC curves demonstrated that visual interpretation tends to be more accurate than SUV quantification (visual, 0.930 +/- 0.022; SUV, 0.899 +/- 0.025; P = 0.241). Using an SUV of 2.5 as the threshold, the resulting sensitivity, specificity, and negative predictive value were 89%, 84%, and 96%, respectively. CONCLUSION: For mediastinal staging, the choice of an SUV of 2.5 as the threshold is justified because FNR + FPR is minimized. The resulting high negative predictive value of 96% allows the omission of mediastinoscopy in patients with negative mediastinal findings on (18)F-FDG PET images. For the experienced observer, visual analysis should be relied on primarily, with calculation of the SUV used, at most, as a secondary aid. For the less experienced observer, the SUV may be of greater value.

In-vitro comparison of aortic valve hemodynamics between aortic root remodeling and aortic valve reimplantation.

BACKGROUND AND AIM OF THE STUDY: Valve-preserving aortic replacement has become an accepted option for patients with aortic valve regurgitation and aortic dilatation. The relative role of root remodeling versus valve reimplantation inside a vascular graft has been discussed, albeit controversially. In the present study, an in-vitro model was used to investigate the aortic valve hemodynamics of root remodeling and valve reimplantation; roots with supracommissural aortic replacement served as controls. METHODS: Aortic roots with aortoventricular diameter 21 mm were obtained from pigs. Root remodeling was performed using a 22-mm graft (group I, n = 6), or valve reimplantation with a 24-mm graft (group II, n = 7). Control roots were treated by supracommissural aortic replacement (22-mm graft; group III, n = 7). Using an electrohydraulic, computer-controlled pulse duplicator, the valves were tested at flows of 2, 4, 5, 7, and 9 I/min at a heart rate of 70 /min and a mean arterial pressure of 100 mmHg. Parameters assessed included: mean pressure gradient, effective orifice area, valve closure and regurgitant volume, and energy loss due to ejection, valve closure and regurgitation. Data were compared using ANOVA. RESULTS: There were no differences between the three groups in terms of regurgitant volume, energy loss due to valve regurgitation, or valve closure. The aortic valve orifice area was largest and systolic gradient lowest in group I at all flow rates (p < 0.001). Ejection energy loss was lowest in group I at all flow rates (9 l/min: group I, 128 +/- 21 mJ; group II, 399 +/- 46 mJ; group III, 312 +/- 27 mJ; p < 0.001). Valve closure volumes were similar in groups I and III, but significantly lower in group II at all flow rates (p = 0.047). CONCLUSION: In this standardized experimental setting, root remodeling--but not valve reimplantation--resulted in physiologic hemodynamic performance of the aortic valve with regard to orifice area, pressure gradient, and systolic energy loss.

Increased lymphangiogenesis in lung metastases from colorectal cancer is associated with early lymph node recurrence and decreased overall survival.

Pulmonary metastasectomy (PM) is an accepted treatment modality in colorectal cancer (CRC) patients with pulmonary tumor spread. Positive intrathoracic lymph nodes at the time of PM are associated with a poor prognosis and 5-year survival rates of <20 %. Increased lymphangiogenesis in pulmonary metastases might represent an initial step for a subsequent lymphangiogenic spreading. We aimed to evaluate the presence of lymphangiogenesis in clinically lymph node negative patients undergoing PM and its impact on outcome parameters. 71 patients who underwent PM for CRC metastases were included in this dual-center study. Tissue specimens of pulmonary metastases and available corresponding primary tumors were assessed by immunohistochemistry for lymphatic microvessel density (LMVD) and lymphovascular invasion (LVI). Results were correlated with clinical outcome parameters. LMVD was 13.9 ± 8.1 and 13.3 ± 8.5 microvessels/field (mean ± SD) in metastases and corresponding primary CRC; LVI was evident in 46.5 and 58.6 % of metastases and corresponding primary CRC, respectively. Samples with high LMVD had a higher likelihood of LVI. LVI was associated with early tumor recurrence in intrathoracic lymph nodes and a decreased overall survival (p < 0.001 and p = 0.029). Herein, we present first evidence in a well-defined patient collective that increased lymphangiogenesis is already present in a subtype of pulmonary metastases of patients staged as N0 at the time of PM. This lymphangiogenic phenotype has a strong impact on patients' prognosis. Our findings may have impact on the post-surgical therapeutic management of CRC patients with pulmonary spreading.

Three-Year Follow-Up of a Randomized Phase II Trial on Refinement of Early-Stage NSCLC Adjuvant Chemotherapy with Cisplatin and Pemetrexed versus Cisplatin and Vinorelbine (the TREAT Study).

INTRODUCTION: Adjuvant chemotherapy in non-small cell lung cancer (NSCLC) improves survival but is associated with significant toxicity. The Randomized Phase II Trial on Refinement of Early-Stage NSCLC Adjuvant Chemotherapy with Cisplatin and Pemetrexed versus Cisplatin and Vinorelbine (TREAT study) was designed to test the hypothesis that a protocol with reduced toxicity might improve feasibility of postoperative delivery of adjuvant chemotherapy drugs to patients with NSCLC, thereby improving compliance and, potentially, survival. METHODS: Two adjuvant regimens were evaluated for feasibility in 132 patients with NSCLC: the standard regimen of cisplatin and vinorelbine (CVb) (cisplatin 50 mg/m(2) on day 1 and day 8 and vinorelbine 25 mg/m(2) on days 1, 8, 15, and 22 every 4 weeks) and a regimen consisting of cisplatin and pemetrexed (CPx) (cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 every 3 weeks). The primary end-point analysis showing that CPx is safe and feasible with dose delivery superior to that of CVb has already been published. Here we report the 3-year follow-up results of the secondary efficacy end points-overall, relapse-free, distant metastasis-free, and local relapse-free survival-also with regard to histologic diagnosis. RESULTS: After a median of 39 months, no significant differences in any of the outcome parameters between CVb and CPx were observed. Also, histologic diagnosis and tumor size in stage IB did not influence survival in the CPx-treated patients. Yet, Cox regression analyses showed that overall survival at 3 years was significantly correlated with feasibility and the occurrence of dose-limiting toxicity. CONCLUSIONS: Although adjuvant chemotherapy with CPx is safe and characterized by less toxicity and better dose delivery than CVb, overall survival was not influenced by treatment arm in the context of this phase II trial.

Unexpected lymph node disease in resections for pulmonary metastases.

BACKGROUND: Pulmonary metastasectomy is widely accepted for different malignant diseases. The role of mediastinal lymph node (LN) dissection in these procedures is discussed controversially. We evaluated our results of LN removal at the time of pulmonary metastasectomy with respect to the frequency of unexpected LN disease. METHODS: This was a retrospective analysis of 313 resections performed in 209 patients. Operations were performed in curative intention. Patients with known thoracic LN involvement and those without lymphadenectomy (n = 43) were excluded. Patients were analyzed according the type of LN dissection. Subgroups of different primary cancers were evaluated separately. RESULTS: Sublobar resections were performed in 256 procedures with lymphadenectomy, and 14 patients underwent lobectomy. Patients underwent radical lymphadenectomy (n = 158) or LN sampling (n = 112). The overall incidence of unexpected tumor in LN was 17% (radical lymphadenectomy, 15.8%; sampling, 18.8%). Unexpected LN involvement was found in 17 patients (35.5%) with breast cancer, in 120 (9.2%) with colorectal cancer, and in 53 (20.8%) with renal cell carcinoma. The 5-year survival was 30.2% if LN were tumor negative and 25% if positive (p = 0.19). LN sampling vs radical removal had no significant effect on 5-year survival (23.6% vs 30.9%; p = 0.29). CONCLUSIONS: Dissection of mediastinal LN in resection of lung metastases will reveal unexpected LN involvement in a relevant proportion of patients, in particular in breast and renal cancer. Routine LN dissection appears necessary and may become important for further therapeutic decisions. On the basis of our data, LN sampling seems to be sufficient.

Value of F-18-fluorodeoxyglucose positron emission tomography after induction therapy of locally advanced bronchogenic carcinoma.

OBJECTIVES: Induction therapy is an important treatment option in locally advanced non-small cell lung cancer. F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) has an important role in initial staging. The aim of this study was to assess the value of FDG-PET in restaging after induction therapy and in analyzing tumor viability, nodal status, distant metastases, and prognosis. METHODS: Forty-seven patients with locally advanced non-small cell lung cancer accepted for resection after induction therapy underwent FDG-PET. Images were interpreted visually for mediastinal nodal status and metastatic spread. The FDG accumulation in the tumor site was measured by using the maximum standardized uptake value. RESULTS: Unexpected metastases were detected by means of FDG-PET in 9 patients. Surgical intervention was not performed in 8 patients with confirmed metastases. The rate of unexpected findings increased from complete radiologic remission (0%) over partial remission (9%) to no change (67%). The standardized uptake value was higher in tumors with (n = 26) than in those without (n = 11) histologic proof of viability (6.4 +/- 5.3 vs 2.9 +/- 1.6, P = .006). All patients with standardized uptake values of greater than 5.8 had viable tumors. Sensitivity, specificity, and negative predictive value were 81%, 64%, and 58% for tumor viability and 50%, 88%, and 85% for persistent mediastinal disease. Median survival after resection was greater than 56 months for patients with tumor standardized uptake values of less than 4 and 19 months for patients with standardized uptake values of 4 or greater ( P < .001). CONCLUSION: FDG-PET helps in the selection of patients for resection after induction therapy. It can be used to detect unexpected distant metastases, especially after poor response to induction therapy. Its high negative predictive value in mediastinal restaging allows for omission of repeat mediastinoscopy. Tumor standardized uptake value after induction is a prognostic factor.

Mediastinal lymph node staging in suspected lung cancer: comparison of positron emission tomography with F-18-fluorodeoxyglucose and mediastinoscopy.

BACKGROUND: In patients with bronchogenic carcinoma, mediastinal lymph node staging is essential for determining treatment options. In this retrospective analysis we compared the results of positron emission tomography (PET) using F-18 fluorodeoxyglucose with those of mediastinoscopy in nodal staging for suspected bronchogenic carcinoma. METHODS: From March 1997 to June 2001, 102 patients (86 male,16 female, age 62 +/- 9 years) underwent both PET and mediastinoscopy for radiologically suspected mediastinal lymph node disease in bronchogenic carcinoma. Total body emission scans were acquired 90 to 150 minutes after injection of 230 MBq of F-18 fluorodeoxyglucose. Mediastinoscopic evaluation of lymph node stations was performed according to the method of Mountain and Dresler (1R, 1L, 2L, 2R, 4L, 4R,7). Patients were eligible if surgical staging was performed within 6 weeks after the PET scan. RESULTS. Of the 102 patients, benign lesions were diagnosed in 15. In 87 patients malignant disease was proven by histology, and bronchogenic carcinoma was found in 82. Of 469 nodal stations analyzed, malignancy was documented by histology in 84. In PET analysis 79 true-positive and 304 true-negative samples were found. Five lymph node stations were false negative, and 81 samples were false positive. False-positive findings in PET frequently were seen in inflammatory lung disease. The sensitivity of PET was 94.1%, specificity was 79% with a diagnostic accuracy of 81.6%. The positive predictive value of PET was 49.3%, and the negative predictive value was 98.4%. CONCLUSIONS: In patients with positive PET scan results histologic verification appears necessary for exact lymph node staging. In view of the negative predictive value mediastinoscopy can be omitted in patients with bronchogenic carcinoma whose PET scan results were negative.