Survivorship program including long-term toxicities and quality-of-life development over 10 years in a randomized trial in operable stage III non-small-cell lung cancer (ESPATUE).

Over 40% stage-III non-small-cell lung cancer (NSCLC) patients (pts) experience 5-year survival following multimodality treatment. Nevertheless, little is known about relevant late toxicities and quality-of-life (QoL) in the further long-term follow-up. Therefore, we invited pts from our randomized phase-III trial (Eberhardt et al., Journal of Clinical Oncology 2015) after 10 years from diagnosis to participate within a structured survivorship program (SSP) including follow-up imaging, laboratory parameters, cardio-pulmonary investigations, long-term toxicity evaluations and QoL questionnaires. Of 246 pts initially accrued, 161 were considered potentially resectable following the induction therapy and were randomized (80 to arm A: definitive chemoradiation; 81 to arm B: definitive surgery; 85 not randomized for different reasons; group C). 31 from 37 pts still alive after 10 years agreed to the SSP (13 in A; 12 in B; 6 in C). Clinically relevant long-term toxicities (grade 3 and 4) were rarely observed with no signal favoring any of the randomization arms. Furthermore, available data from the global QoL analysis did not show a signal favoring any definitive locoregional approach (Mean QoL in SSP A pts: 56.41/100, B pts: 64.39/100) and no late decline in comparison to baseline and early 1-year follow-up. This is the first comprehensive SSP of very late survival follow-up reported in stage-III NSCLC treated within a randomized multimodality trial and it may serve as important baseline information for physicians and pts deciding for a locoregional treatment option.

Primary osteosarcoma of the ribs: A report from the Cooperative Osteosarcoma Study Group.

PURPOSE: Primary rib osteosarcoma has not been investigated extensively, and clinical characteristics and optimal therapeutic strategies have not been defined. The authors used the database of the Cooperative Osteosarcoma Study Group (COSS) to analyze this tumor-site in depth. METHODS: The COSS database was searched for treatment-naive, high-grade osteosarcomas of the rib. Affected patients were analyzed for demographic and tumor-related factors, treatments, and outcomes. RESULTS: A total of 44 patients (23 males, 21 females; median age, 23 years [range, 6-59]) were identified. Primary metastases were detected in six of 44 (14%) patients. Surgery was performed in 40 of 44 (91%) patients and rendered 35 of 44 (80%) patients macroscopically disease-free. Chemotherapy was known to have been administered in 43 of 44 (98%) patients and radiotherapy in seven of 42 (17%) (no data for two patients). A good response to chemotherapy was only noted in five (33%) of those 15 evaluable patients who had received any preoperative chemotherapy. After a median follow-up of 2.49 (0.22-40.35) years for all patients and 6.61 (0.25-40.35) years for 26 survivors (21 of these in first complete remission), 5-year actuarial overall and event-free survival were 53.0% (8.5%) and 42.2% (8.1%), respectively. Incomplete tumor surgery was the most notable negative prognostic factor. Osteoblastic histology and a poor response to chemotherapy may have contributed. CONCLUSION: This large series provides evidence that patients with costal primaries are older than the average osteosarcoma patient, but appear to share the similar tumor biology and-if treated according to standard protocols-prognostic factors with tumors of other sites. Early, preoperative diagnosis and permanent, definitive local control remain major challenges and should contribute to improved outcomes.

Corticomedullary differentiation and maturational arrest in thymomas.

AIMS: Morphological complexity hampers the histological classification of thymomas. Our aim was to determine whether the use of novel differentiation and maturation markers of cortical and medullary thymic epithelial cells (cTECs and mTECs) might provide an approach to understanding the underlying biology of these tumours. METHODS AND RESULTS: Fifty-seven thymomas were studied by immunohistochemistry. The cortical markers used were B5T, PRSS16, and cathepsin V. The medullary markers used were CD40, claudin-4, AIRE, and desmin. Involucrin and cytokeratin 10 were used to study terminal mTEC maturation. Irrespective of histological subtype, most thymomas contained distinct areas with cortical and medullary differentiation. Type B1, type B2 and type AB thymomas showed marked bi-lineage differentiation, with lack of terminal mTEC maturation in type AB. Type AB thymomas were unique in showing areas where cells with either cortical or medullary differentiation were intimately 'mixed' at the single-cell level. Type B3 and type A thymomas showed only abortive lineage differentiation and maturation. CONCLUSIONS: Thymomas show highly characteristic patterns of bi-lineage TEC differentiation that reflect the histological subtypes recognized by the WHO classification. We hypothesize that thymomas arise from thymic precursor cells with different cortical and/or medullary maturation defects.

Primary pulmonary synovial sarcoma: a rare primary pulmonary tumor.

INTRODUCTION: Pulmonary sarcomas overall are very uncommon and comprise only 0.5 % of all primary lung malignancies. The diagnosis is established only after sarcoma-like primary lung malignancies and a metastatic extrathoracic sarcoma have been excluded. Synovial sarcoma accounts for ~8 % of soft-tissue sarcomas. Synovial sarcoma arising from the pleura has rarely been reported. METHODS: We report a case of a 58-year-old woman who complained of right-sided chest pain and shortness of breath. Chest CT scan revealed a large heterogeneous mass, occupying most of the right hemithorax. Histologic diagnosis was supplemented by interphase cytogenetic (FISH) analysis. RESULTS: Computed tomography guided Tru-cut biopsy was suspicious for a sarcomatous or fibrous malignancy. However, intraoperative frozen-section diagnostics confirmed the diagnosis of a sarcoma. Immunohistochemistry showed that tumor cells expressed epithelial membrane antigen, CD99 and BCL2. Based on immunohistochemistry, the diagnosis of synovial sarcoma was suspected and was confirmed by FISH analysis. The patient was treated with right upper bilobectomy. Due to R1-resection status, postsurgical systemic chemotherapy was administered. CONCLUSIONS: Primary pulmonary synovial sarcoma is a rare primary lung tumor. Due to extensive size of the tumor with pleural and mediastinal invasion only a R1-resection status could be achieved by thoracic surgery.

Primary Multi-Systemic Metastases in Osteosarcoma: Presentation, Treatment, and Survival of 83 Patients of the Cooperative Osteosarcoma Study Group.

BACKGROUND: To evaluate patient and tumour characteristics, treatment, and their impact on survival in patients with multi-systemic metastases at initial diagnosis of high-grade osteosarcoma. Precedure: Eighty-three consecutive patients who presented with multi-systemic metastases at initial diagnosis of high-grade osteosarcoma were retrospectively reviewed. In cases of curative intent, the Cooperative Osteosarcoma Study Group recommended surgical removal of all detectable metastases in addition to complete resection of the primary tumour and chemotherapy. RESULTS: Eighty-three eligible patients (1.8%) were identified among a total of 4605 individuals with high-grade osteosarcoma. Nine (10.8%) of these achieved complete surgical remission, of whom seven later had recurrences. The median follow-up time was 12 (range, 1-165) months for all patients. Actuarial event-free survival after 1, 2, and 5 years was 9.6 ± 3.2%, 1.4 ± 1.4%, and 1.4 ± 1.4%, and overall survival was 54.0 ± 5.6%, 23.2 ± 4.9%, and 8.7 ± 3.3%. In univariate analyses, elevated alkaline phosphatase before chemotherapy, pleural effusion, distant bones as metastatic sites, and more than one bone metastasis were negative prognostic factors. Among treatment-related factors, the microscopically complete resection of the primary tumour, a good response to first-line chemotherapy, the macroscopically complete resection of all affected tumour sites, and local treatment (surgery ± radiotherapy) of all bone metastases were associated with better outcomes. Tumour progression under first-line treatment significantly correlated with shorter survival times. CONCLUSION: The outlook for patients with multi-systemic primary metastases from osteosarcoma remains very poor. The utmost importance of surgical resection of all tumour sites was confirmed. For unresectable bone metastases, radiotherapy might be considered. In the patient group studied, standard chemotherapy was often insufficiently effective. In the case of such advanced disease, alternative treatment options are urgently required.

Does dose matter? Effect of two different neoadjuvant protocols in advanced NSCLC.

BACKGROUND: For stage III, NSCLC neoadjuvant protocols have been intensified up to full dose protocols but up till now the effect of more intensive protocols in a trimodal setting could not be compared directly because of different selection criteria or experience of involved facilities in different studies or multicenter studies. We analyzed our experience with two different neoadjuvant protocols, consistent selection criteria, and surgical teams over 17-year time period. METHOD: Single-center retrospective study in 159 patients concerning survival, recurrence, and downstaging effect. RESULTS: Overall median survival was 32 months, with 26 months for protocol 1, and 35 months for protocol 2, respectively. Hospital mortality was 5%. Log-rank test showed significant difference between the protocols for UICC-downstaging-effect, ypT-stage, ypN-stage, and ypUICC-stage, respectively, but only ypN-stage and ypUICC-stage were significant risk factors for survival using Cox regression. CONCLUSION: The median survival benefit of 9 months is evident but (probably still) not significant. The more aggressive protocol 2 shows a significant better downstaging effect concerning N- and UICC-stage if R0-resection can be achieved. Insofar dose does matter!

Solitary pulmonary metastases at first recurrence of osteosarcoma: Presentation, treatment, and survival of 219 patients of the Cooperative Osteosarcoma Study Group.

BACKGROUND: To evaluate patient and tumour characteristics, treatment and their impact on survival in patients with a solitary pulmonary metastasis at first relapse of high-grade osteosarcoma. PROCEDURE: Two-hundred and nineteen consecutive patients who had achieved a complete surgical remission and then developed a solitary pulmonary metastasis at first recurrence of high-grade osteosarcoma were retrospectively reviewed. RESULTS: Two hundred and three (94.9%) of 214 patients achieved a second complete remission. After a median time from initial diagnosis of osteosarcoma to first relapse of 2.3 years (range, 0.3-18.8 years), actuarial post-relapse overall survival after 2 and 5 years was 72.0% and 51.2%. Post-relapse event-free survival was 39.1% and 31.1%. Median follow-up time was 3.2 years (range, 0.1-29.4 years). A longer time until first relapse and diagnosis due to imaging were positive prognostic factors in uni- and multivariate analyses, as were a second complete surgical remission and, in regard to death, the absence of a subsequent relapse. The use of salvage chemotherapy and radiotherapy were not associated with patient outcomes, nor was the surgical approach (thoracoscopy vs. thoracotomy) nor the exploration (uni- vs. bilateral). CONCLUSION: Approximately half of the patients who experience a solitary pulmonary relapse at first recurrence of osteosarcoma remain alive 5 years after this first relapse. Only one third will remain disease-free. A complete surgical resection of the lesion is essential for long-term survival while relapse chemotherapy does not seem to improve survival. Innovative therapies are required to improve outcomes.

Ultra-Late Osteosarcoma Recurrences: An Analysis of 17 Cooperative Osteosarcoma Study Group Patients with a First Recurrence Detected More Than 10 Years After Primary Tumor Diagnosis.

Purpose: Osteosarcoma is a typical malignancy of childhood and adolescence. Recurrences usually occur early, but rarely may arise after decades of remission. Little is known about these very late events and we set out to fill this knowledge gap. Methods: The database of the Cooperative Osteosarcoma Study Group (COSS) was searched for patients with a first recurrence of a high-grade central osteosarcoma occurring >10 years after diagnosis of the primary disease. Identified patients were analyzed for demographic, tumor-, and treatment-related factors as well as outcomes. Results: Among a total of 1,178 10-year relapse-free survivors, 17 affected patients were identified. Only five of these had a documented good response to initial chemotherapy. No presenting factor was identified to predict these very late events. Prognosis was generally very poor despite intensive multimodal therapy. Inoperability of the recurrences seems to have constituted a major limiting factor. Conclusion: Osteosarcoma patients should be followed for potential recurrences for well >10 years from initial diagnosis. Only through such an extended truly long-term follow-up and a structured transition of young patients can these be detected while they are still operable and, hence, potentially curable.

Methacholine delays pulmonary absorption of inhaled ß(2)-agonists due to competition for organic cation/carnitine transporters.

BACKGROUND: The aim of the present investigation was to compare the pulmonary absorption of the novel long-acting ß(2)-agonist GW597901 with salbutamol and to determine the influence of an induced bronchoconstriction on the pharmacokinetics of the compounds using a human lung reperfusion model. METHODS: In an initial study with six lung perfusions the pharmacokinetic properties of the ß(2)-agonists were determined. We then investigated the influence of an induced bronchoconstriction on the pulmonary absorption in six lung lobes for each drug. Therefore, methacholine (MCh) challenge agent was nebulised prior to administration of the ß(2)-agonists. RESULTS: As expected, the extent of pulmonary absorption of salbutamol into the perfusate was more pronounced than for the more lipophilic GW597901. Although the observed differences were not statistically significant they were further supported by analysis of tissue concentrations. In contrast, we observed a statistically significant influence of the bronchoprovocation with MCh on the pulmonary absorption of both ß(2)-agonists, but this effect was not limited to a successfully induced bronchoconstriction. A prominent decline of salbutamol distribution into perfusion fluid was also observed when the organic cation transporter substrate carnitine was nebulised prior to the bronchodilator. CONCLUSIONS: Nebulised methacholine had a significant influence on the pharmacokinetics of bronchodilators. Since we observed this effect independently of a successfully induced bronchoconstriction and also after nebulisation of carnitine we suggest a significant delay of pulmonary absorption of inhaled salbutamol and GW597901 due to competition for a cation/carnitine drug transporter, most likely OCTN2.

Thoracoscopic mesh implantation as a definitive treatment approach for peritoneal dialysis-associated hydrothorax.

Pleuroperitoneal leakage with the formation of hydrothorax is a rare complication of peritoneal dialysis, usually necessitating termination of peritoneal dialysis. We hypothesized that implantation of a polypropylene mesh on the diaphragm using video-assisted thoracoscopic surgery might induce permanent closure of pleuroperitoneal leakage. We report a case series of n = 12 peritoneal dialysis patients with pleuroperitoneal leakage and right-sided hydrothorax who underwent video-assisted thoracoscopy with mesh implantation from 2011 to 2020. Pleuroperitoneal leakage had been confirmed before surgery by intraperitoneal administration of toluidine blue, contrast-enhanced computer tomography or glucose determination from the pleural effusion. Median time from the start of peritoneal dialysis to manifestation of pleuroperitoneal leakage was 52 days. Video-assisted thoracoscopic surgery revealed multiple penetration points in the tendinous part of the diaphragm in all patients, which appeared as blebs. These were closed by covering the whole diaphragm with a polypropylene mesh. In all patients, peritoneal dialysis was paused for three months and bridged by hemodialysis. After restarting peritoneal dialysis and a median follow-up time of 1.9 years, none of the patients experienced a recurrence of pleuroperitoneal leakage. This case series demonstrates that pleuroperitoneal leakage in peritoneal dialysis patients can be permanently closed using thoracoscopic mesh implantation and allows peritoneal dialysis to be continued as renal replacement therapy.