Ludger Bernd

Prognostic significance of drug-regulated genes in high-grade osteosarcoma

About 25–45% of patients with high-grade osteosarcoma poorly respond to chemotherapy with an increased risk of relapse and the development of metastasis. Therefore, the aim of this study was the evaluation of the prognostic value of eight previously identified drug-regulated candidate genes on osteosarcoma therapy outcome. Gene expression of 8 candidate genes was analyzed in 35 formalin-fixed, paraffin-embedded, laser-microdissected osteosarcoma biopsies. The prognostic value of these genes was evaluated by the correlation of gene expression with therapy outcome, overall survival and event-free survival in univariate and multivariate analysis. Upon univariate analysis, the expression of MALAT-1, IMPDH2, FTL and RHOA significantly correlated with response to chemotherapy. Expression of all four genes was increased in the poor responder group. Upon multivariate analysis, IMPDH2 maintained its independent prognostic value (P=0.025). Concerning the overall survival of the patients, we observed a significant association with the expression of FTL, PHB, ATAD2, ACTN1 and RRM2 as well as lactate dehydrogenase serum levels. In the subgroups of patients with high expression of these genes and those with elevated lactate dehydrogenase levels, the mean overall survival was decreased 1.7-, 1.9-, 2.2-, 2.4-, 1.5- and 4.5-fold, respectively. Except RRM2, all genes and lactate dehydrogenase serum levels remained significant in the multivariate analysis. In addition, the event-free survival was significantly decreased in the subgroups of patients with high FTL, ATAD2 and IMPDH2 expression (1.8-, 6.3- and 2.4-fold, respectively). These data demonstrate that among the identified genes are valuable markers for the prediction of osteosarcoma therapy outcome. Especially IMPDH2 and FTL are promising candidates for the stratification of osteosarcoma patients into low- and high-risk groups. Owing to their involvement in drug action these genes may further be potential targets for the modulation of drug sensitivity.

CORRELATION OF INTRAOPERATIVELY IRRADIATED VOLUME AND FIBROSIS IN PATIENTS WITH SOFT-TISSUE SARCOMA OF THE EXTREMITIES

PURPOSE To investigate the influence of intraoperatively irradiated volume on soft-tissue fibrosis. METHODS AND MATERIALS Fifty-three patients with soft-tissue sarcoma of the extremities were treated with intraoperative radiotherapy (IORT) (median dose 15 Gy) and postoperative fractionated therapy (median dose 46 Gy). The median follow-up was 41.5 months (range 18-94). Late toxicity was classified according to the LENT-SOMA criteria. A Cox regression model was calculated to identify the parameters that could influence soft-tissue fibrosis Grade 3 or 4. Five parameters were observed: extent of surgical procedure, IORT in case of recurrence, extent of IORT volume, extent of IORT dose, and extent of postoperative volume. In addition, a logistic regression model was calculated to demonstrate the relationship between the IORT volume and fibrosis development. RESULTS The overall survival rate after 5 years was 84%. The actuarial tumor control rate was 90% after 5 years. Eleven patients developed soft-tissue fibrosis. Five patients developed Grade 3 fibrosis and 1 patient developed Grade 4 fibrosis. Only the IORT volume had a significant influence on Grade 3 or 4 fibrosis development. An IORT volume of 210 cm(3) conveyed a 5% risk (confidence interval 1-20%) of the development of severe fibrosis. The risk of severe Grade 3 or 4 fibrosis increased to 50% (confidence interval 15-80%) if a volume of 420 cm(3) was irradiated. CONCLUSION The effect of volume in patients treated with IORT was remarkable. The ratio of side effects was relatively low. The risk of soft-tissue Grade 3 or 4 fibrosis increased with the extent of the IORT volume. Compared with the literature, IORT provides excellent local control in these patients.

Osteosarcoma of the Hand and Forearm: Experience of the Cooperative Osteosarcoma Study Group

BackgroundOsteosarcoma is extremely rare in the hand and forearm. Therefore, only limited data are available for planning treatment or predicting the outcome and prognosis of osteosarcoma in the peripheral upper extremity.MethodsEpidemiological, clinical, and histopathologic data were analyzed in 39 patients with osteosarcoma of the forearm or hand who were enrolled in studies of the Cooperative German-Austrian-Swiss Osteosarcoma Study Group from 1977 to December 2000. In patients with high-grade osteosarcoma, the treatment entailed surgical resection in combination with chemotherapy, whereas patients with low-grade osteosarcoma underwent only surgery.ResultsThe 5-year overall survival rate among the 33 patients with high-grade central osteosarcoma of the distal upper extremity was 86.2% ± 6.4%. The 5-year event-free survival rate was 65.4% ± 9.6%. Five of the eight patients with secondary metastases were in remission at the time of analysis. Four patients died of their disease, and two patients died of chemotherapy-related complications. The mean overall survival rate was 88.0% ± 6.5% in patients treated by wide or radical tumor resection and was 75.0% ± 21.7% in patients with nonwide margins of resection. Whether amputation or local resection was performed had no significant influence on the prognosis. All six patients whose osteosarcoma was not classified as high-grade central osteosarcoma were in remission at the time of analysis.ConclusionsThe results demonstrate a remarkably high survival rate for patients with high-grade osteosarcoma of the hand and forearm and confirm that multiagent chemotherapy in combination with wide excision is a highly effective treatment for this malignant tumor.

CD8+/FOXP3+-ratio in osteosarcoma microenvironment separates survivors from non-survivors: A multicenter validated retrospective study

Osteosarcoma is the most common primary bone tumor characterized by juvenile onset, tumor heterogeneity, and early pulmonary metastasis. Therapeutic improvement stagnates since more than two decades. Unlike major malignancies, biomarkers as prognostic factors at time of diagnosis are missing. Disease rareness hampers study recruitment of patient numbers sufficient to outweigh tumor heterogeneity. Here, we analyzed in a multicenter cohort the osteosarcoma microenvironment to reduce effects of tumor cell heterogeneity. We hypothesized that quantitative ratios of intratumoral CD8+T-cells to FOXP3+T-cells (CD8+/FOXP3+-ratios) provide strong prognostic information when analyzed by whole-slide imaging in diagnostic biopsies. We followed recommendations-for-tumor-marker-prognostic-studies (REMARK). From 150 included cases, patients with complete treatment were identified and assigned to the discovery (diagnosis before 2004) or the validation cohort (diagnosis 2004–2012). Highly standardized immunohistochemistry of CD8+ and FOXP3+, which was validated by methylation-specific gene analysis, was performed followed by whole-slide analysis and clinical outcome correlations. We observed improved estimated survival in patients with CD8+/FOXP3+-ratios above the median (3.08) compared to patients with lower CD8+/FOXP3+-ratios (p = 0.000001). No patients with a CD8+/FOXP3+-ratio above the third quartile died within the observation period (median follow-up 69 mo). Multivariate analysis demonstrated independence from current prognostic factors including metastasis and response to neoadjuvant chemotherapy. Data from an independent validation cohort confirmed improved survival (p = 0.001) in patients with CD8+/FOXP3+-ratios above 3.08. Multivariate analysis proofed that this observation was also independent from prognostic factors at diagnosis within the validation cohort. Intratumoral CD8+/FOXP3+-ratio in pretreatment biopsies separates patients with prolonged survival from non-survivors in osteosarcoma.

[Bone and soft-tissue tumors of the foot and ankle].

ZusammenfassungHintergrundDiese Studie berichtet über die Epidemiologie der Knochen- und Weichteiltumoren des Fußes und Sprunggelenkes, stellt eine differenzierte Therapieplanung vor und evaluiert mittelfristige klinisch-funktionelle Ergebnisse nach Operation der malignen Tumoren.Methode204 Patienten mit Tumoren des Fußes wurden analysiert (163 benigne und 41 maligne Tumoren). Epidemiologie und operative Versorgung werden dargestelltErgebnisseHäufigste benigne Tumoren waren Exostosen, Knochenzysten und Osteoidosteom, häufigste maligne Tumoren Metastasen, Chondrosarkom und Ewing-Sarkom. Bei benignen Tumoren konnte in über 90% eine lokale Resektion durchgeführt werden, während sich bei malignen Tumoren Amputation und Arthrodese einerseits und Extremitäten- oder Gelenkerhalt andererseits die Waage hielten. Klinisch ergaben sich nach operativer Versorgung der primär malignen Tumoren gute funktionelle Resultate und eine 5-Jahres-Überlebensrate von 84%.SchlussfolgerungTumoren des Fußes erfordern eine differenzierte Versorgungsstrategie. Trotz eines hohen Anteils an extremitäten- und gelenkopfernden Operationen sind die mittelfristigen funktionellen Ergebnisse und die Überlebensrate gut.AbstractBackgroundThis study reports the epidemiology of bone and soft-tissue tumors of the foot and ankle, presents therapy strategies, and evaluates mid-term clinicofunctional outcome after surgery for malignant tumors.MethodsTwo hundred four patients with tumors of the foot and ankle were analyzed (163 benign and 41 malignant). Epidemiology and surgical therapy are reported.ResultsThe most frequent tumors were exostosis, bone cyst, and osteoid osteoma for benign tumors and metastases and chondrosarcoma and Ewing’s sarcoma for malignant tumors. In more than 90% of the benign tumors, local resection could be carried out, whereas in malignant tumors, ablative procedures and arthrodeses were almost as common as limb- and joint-sparing techniques. However, follow-up revealed good functional results and a 5-year survival rate of 84% for patients with primary malignant tumors.ConclusionTumors of the foot and ankle require a thorough therapeutic strategy. Mid-term functional results and survival rate after surgical treatment are good, although a high percentage of ablative procedures or fusions could not be avoided in our patients.

Methods of biological reconstruction for bone sarcoma: indications and limits.

Therapy of bone sarcoma has dramatically changed over the past few decades. Several successful interdisciplinary treatment strategies have led to an increase of the survival rates from 20% to 60%-80%. Consequently new demands on the operative treatment of bone and soft tissue sarcoma have arisen. Nowadays limb salvage can be achieved in 80%-90% using tumour megaprostheses or biological reconstruction procedures. In this article we outline the indications and limitations of biological reconstruction procedures after bone tumour resection. We therefore introduce the different biological approaches such as free autologous bone grafting, reimplantation of extracorporeal devitalized autografts or distraction osteogenesis and summarize the currently available data on the individual procedures. Our analyses demonstrate a wide applicability of biological procedures in tumour situations. Although accompanied by considerable complications in the early postoperative phase, biological reconstructions clearly demonstrate the potential of having excellent long-term durability and functionality.

Verbesserung der lokalen Kontrolle bei Patienten mit aggressiver Fibromatose durch die Kombination von Chirurgie und Strahlentherapie

ZusammenfassungEinleitung. Ziel dieser retrospektiven Analyse ist es, Hinweise zu gewinnen, ob die Kombination aus Chirurgie und Strahlentherapie bei Patienten mit aggressiver Fibromatose die Behandlungsergebnisse beeinflusst. Methode. Klinische, radiologische und histopathologische Befunde von 23 Patienten mit histologisch gesicherter aggressiver Fibromatose wurden einer retrospektiven Analyse unterzogen. Die mediane Nachbeobachtungszeit betrug 59 Monate. Ergebnisse. Zwölf Patienten wurden bei der ersten Behandlung allein chirurgisch therapiert, 10 Patienten erhielten eine Kombination aus Chirurgie und Strahlentherapie und 1 Patient wurde mit einer Radiochemotherapie behandelt. Bei 14/23 (61%) Patienten traten ein oder mehrere Rezidive auf und 9/23 (39%) Patienten waren rezidivfrei. Insgesamt wurden 50 Behandlungen durchgeführt. In 29 von 50 Fällen (58%) kam es zu einem Rezidiv und 21 von 50 (42%) Behandlungen waren rezidivfrei. Bei den 29 Behandlungen mit Rezidiv handelte es sich bei 25/29 (86%) um chirurgische Eingriffe, bei 3/29 (10%) um eine Kombination aus chirurgischer Resektion mit Strahlentherapie und bei 1/29 (3%) um eine Radiochemotherapie. Bei den Patienten nach alleiniger chirurgischer erster Behandlung entwickelten nach 1 Jahr 8 von 12 (66%) und nach 5 Jahren alle ein Rezidiv. Die Patienten nach einer Kombination aus Chirurgie und Strahlentherapie waren hingegen nach 1 Jahr alle rezidivfrei, und nach 5 Jahren hatte einer ein Rezidiv entwickelt (10%) (p=0,0001). Schlussfolgerung. Wir empfehlen, wenn möglich, die chirurgische Resektion mit weiten Resektionsgrenzen, ohne dabei dem Patienten einen größeren Funktionsverlust zuzumuten. Die intra- und/oder postoperative Strahlentherapie als Ergänzung zur chirurgischen Resektion ist eine effektive, zusätzliche Behandlungsoption, um das Rezidivrisiko zu senken.AbstractIntroduction. The purpose of this retrospective analysis is to evaluate whether the combination of surgery and radiation therapy in patients with aggressive fibromatosis influences the therapeutic outcome. Method. Clinical, radiological and pathological results of 23 consecutive cases with histologically proven aggressive fibromatosis were retrospectively analyzed. The median follow-up was 59 months. Results. Twelve patients received surgery alone for their first treatment, 10 patients had a combination of surgery and radiotherapy and 1 patient had radiochemotherapy. Of 23 patients 14 (63%) had one or more local recurrences and 9 (39%) were recurrence-free. The patients received a total of 50 treatments: 29/50 (58%) treatments were followed by a local recurrence and 21/50 (42%) were without relapse. Twenty-nine treatments with local recurrence consisted of 25/29 (86%) surgical treatments, 3/29 (10%) combinations of surgery and radiation therapy, and 1/29 (3%) radiochemotherapy. Of the patients who had only surgery for their first treatment, after one year 8 of 12 (66%) and after 5 years all patients had a local recurrence. In the group with surgery and radiotherapy, there was no recurrence after 1 year and 1 recurrence after 5 years (p=0,0001). Conclusion. We recommend a complete tumor resection, without mutilating the patient. Radiation therapy in combination with surgery in contrast to surgery alone is an efficient treatment option for reducing local recurrence.