P Hohenberger

Universität Mannheim, Mannheim, Baden-Württemberg, Germany

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Publications (298)1142.36 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Gastrointestinal stromal tumors (GISTs) spread frequently to the peritoneum and the liver. If metastasectomy or tyrosine kinase inhibitors (TKIs) fail, interventional ablation techniques are considered. The purpose of this study is to assess the progression-free interval (PFI) of GIST liver metastases after radioembolization (RE). Eleven patients with progressive GIST liver metastases undergoing TKI therapy were referred for RE; one was excluded because of a large hepatopulmonary shunt, and one was lost to follow-up. Depending on intrahepatic tumor distribution, one or both liver lobes were treated with RE. Contrast-enhanced magnetic resonance imaging, contrast-enhanced computed tomography (CT), and [(18)F]fluorodeoxyglucose positron-emission tomography/CT were used for follow-up. In all, 16 liver lobes were treated with a mean activity of 1.06 GBq ± 0.37 (range, 0.55-1.88) per lobe. Three patients showed complete response, five showed partial response, and one showed stable disease. No patient showed progressive disease after RE. Median PFI was 15.9 months (range, 4-29 mo). Median survival was 29.8 months (range, 10-72 mo). No radiation-induced liver disease developed; however, one patient required surgery for persistent stomach ulcer. RE offers a safe and effective treatment for patients with GIST liver metastases who do not show a response to TKIs. RE could be an option for earlier phases of therapy in patients with mutational status. The results might also challenge the notion that GISTs are resistant to radiation therapy. Copyright © 2014 SIR. Published by Elsevier Inc. All rights reserved.
    Journal of vascular and interventional radiology: JVIR 11/2014; · 1.81 Impact Factor
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    ABSTRACT: To determine whether regional hyperthermia (RHT) in addition to chemotherapy improves local tumor control after macroscopically complete resection of abdominal or retroperitoneal high-risk sarcomas.
    Annals of surgery. 11/2014; 260(5):749-756.
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    ABSTRACT: The EORTC-STBSG coordinated two large trials of adjuvant chemotherapy(CT) in localized high grade soft tissue sarcoma(STS). Both studies failed to demonstrate any benefit on OS. The aim of the analysis of these two trials was to identify subgroups of patients who may benefit from adjuvant CT.
    Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 10/2014;
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    ABSTRACT: The use of potential surrogate endpoints for overall survival, such as disease-free-survival (DFS) or time-to-treatment failure (TTF) is increasingly common in randomized controlled trials (RCT) in cancer. However, the definition of time-to-event (TTE) endpoints is rarely precise and lacks uniformity across trials. Endpoint definition can impact trial results by affecting estimation of treatment effect and statistical power. The DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials) aims to provide recommendations for definitions of TTE endpoints. We report guidelines for RCT in sarcomas and gastro-intestinal-stromal tumors (GIST).
    Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 07/2014;
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    ABSTRACT: Background:Association studies have implicated the glycosaminoglycan hyaluronan (hyaluronic acid, HA) and its degrading enzymes the hyaluronidases in tumour progression and metastasis. Oligosaccharides of degraded HA have been ascribed a number of biological functions that are not exerted by high-molecular-weight HA (HMW-HA). However, whether these small HA oligosaccharides (sHA) have a role in tumour progression currently remains uncertain due to an inability to analyse their concentration in tumours.Methods:We report a novel method to determine the concentration of sHA ranging from 6 to 25 disaccharides in tumour interstitial fluid (TIF). Levels of sHA were measured in TIF from experimental rat tumours and human colorectal tumours.Results:While the majority of HA in TIF is HMW-HA, concentrations of sHA up to 6 μg ml(-1) were detected in a subset of tumours, but not in interstitial fluid from healthy tissues. In a cohort of 72 colorectal cancer patients we found that increased sHA concentrations in TIF are associated with lymphatic vessel invasion by tumour cells and the formation of lymph node metastasis.Conclusions:These data document for the first time the pathophysiological concentration of sHA in tumours, and provide evidence of a role for sHA in tumour progression.British Journal of Cancer advance online publication, 17 June 2014; doi:10.1038/bjc.2014.332 www.bjcancer.com.
    British journal of cancer. 06/2014;
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    ABSTRACT: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the digestive tract. The GIST differ substantially from gastrointestinal carcinomas regarding tumor biology, treatment strategies and indications for surgery. Every surgeon involved in the treatment of GIST should be acquainted with these aspects. The aims of this article are to discuss the value of positron emission tomography (PET) in the surgical treatment of patients with GIST and to provide an outlook on the development of molecular tracers specifically tailored for GIST. PET is an invaluable decision aid in the multimodal therapy of GIST and particularly for deciding on surgical indications. Specific scenarios in which PET is used are primary staging monitoring during neoadjuvant therapy and staging and response assessment in the metastatic setting. The routinely used tracer is 18F-fluorodeoxyglucose (18F-FDG) and uptake reliably correlates with the metabolism of GIST lesions. Compared to computed tomography and magnetic resonance imaging (CT/MRI), 18F-FDG-PET often allows a more timely and accurate response assessment. GIST-specific molecular tracers, which could provide a direct prognosis regarding response and development of resistance to treatment, are currently in preclinical development. However, pharmacokinetic and immunological issues still need to be resolved. A distant aim is the development of "theranostics", i.e. substances which serve both diagnostic and therapeutic purposes. PET has an established value in the multimodal treatment of GIST and is particularly useful for deciding on surgical indications.
    Der Chirurg 05/2014; · 0.52 Impact Factor
  • J Jakob, T Henzler, B Kasper, A Marx, P Hohenberger
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    ABSTRACT: Soft tissue sarcomas are a rare and heterogeneous group of tumors. Surgery clearly remains the standard therapy of non-metastatic soft tissue sarcoma. A pretreatment biopsy is necessary to determine the histology and grade of soft tissue sarcomas and to diagnose entities that can be treated by targeted therapies, such as dermatofibrosarcoma protuberans or alveolar soft tissue sarcoma once they are in a metastatic stage. Nevertheless, locally advanced disease requires multimodal treatment and interdisciplinary treatment decisions. Limb sarcoma of borderline resectability (encasement of vessels, invasion of joints or close proximity to motor nerves) may profit from isolated limb perfusion with recombinant tumor necrosis factor and melphalan. Preoperative chemotherapy may be applied in locally advanced high grade tumors when clear resection margins are difficult to achieve. Deep wave hyperthermia has proven to be a useful addition to systemic chemotherapy in such a neoadjuvant setting. Also preoperative radiation therapy has proven to be effective in controlling locally advanced sarcoma despite higher perioperative morbidity which pays off in the long run by better limb function. Postoperative adjuvant external beam irradiation therapy with the best available technique is recommended for any tumor larger than 5 cm with (FNLCC) grades 2 and 3 (American Joint Committee on Cancer stage IIb/III). Given all these therapeutic options, it is absolutely crucial that interdisciplinary decision-making starts early in the therapeutic process. Patients are often seen first by the surgeon. For an optimal treatment surgeons need to know the efficacy and toxicity of the multimodal treatment options described.
    Der Chirurg 04/2014; · 0.52 Impact Factor
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    ABSTRACT: Aim This randomised phase III trial evaluated first-line trabectedin versus doxorubicin-based chemotherapy (DXCT) in patients with advanced/metastatic translocation-related sarcomas (TRS). Methods Patients were randomly assigned (1:1) to receive trabectedin 1.5 mg/m2 24-h intravenous (i.v.) infusion every 3 weeks (q3wk) (Arm A), or doxorubicin 75 mg/m2 i.v. q3wk, or doxorubicin 60 mg/m2 i.v. plus ifosfamide (range, 6–9 g/m2) i.v. q3wk (Arm B). Progression-free survival (PFS) by independent review was the primary efficacy end-point. Results One hundred and twenty-one patients were randomised; 88 of them had TRS confirmed by central pathology review (efficacy population). Twenty-nine PFS events were assessed by independent review (16 with trabectedin; 13 with DXCT). PFS showed non-significant difference between arms (stratified log rank test, p = 0.9573; hazard ratio = 0.86, p = 0.6992). At the time of this analysis, 63.9% and 58.3% of patients were alive in trabectedin and DXCT arms, respectively. There was no statistically significant difference in survival curves. Response rate according to Response Evaluation Criteria in Solid Tumours (RECIST) v.1.0 was significantly higher in DXCT arm (27.0% versus 5.9%), but response according to Choi criteria showed fewer differences between treatment arms (45.9% versus 37.3%). Safety profile was as expected for both arms, with higher incidence of severe neutropenia, alopecia and mucositis in the DXCT arm. Conclusion Neither trabectedin nor doxorubicin-based chemotherapy showed significant superiority in the first-line treatment of patients with advanced translocation-related sarcoma.
    European journal of cancer (Oxford, England: 1990) 04/2014; · 4.12 Impact Factor
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    ABSTRACT: BACKGROUND Little is known about the factors that predict for gastrointestinal stromal tumor (GIST) recurrence in patients treated with adjuvant imatinib.METHODS Risk factors for GIST recurrence were identified, and 2 risk stratification scores were developed using the database of the Scandinavian Sarcoma Group (SSG) XVIII trial, where 358 patients with high-risk GIST with no overt metastases were randomly assigned to adjuvant imatinib 400 mg/day either for 12 or 36 months after surgery. The findings were validated in the imatinib arm of the American College of Surgeons Oncology Group Z9001 trial, where 359 patients with GIST were randomized to receive imatinib and 354 were to receive placebo for 12 months.RESULTSFive factors (high tumor mitotic count, nongastric location, large size, rupture, and adjuvant imatinib for 12 months) were independently associated with unfavorable recurrence-free survival (RFS) in a multivariable analysis in the SSGXVIII cohort. A risk score based on these 5 factors had a concordance index with GIST recurrence of 78.9%. When a simpler score consisting of the 2 strongest predictive factors (mitotic count and tumor site) was devised, the groups with the lowest, intermediate high, and the highest risk had 5-year RFS of 76.7%, 47.5%, and 8.4%, respectively. Both scores were strongly associated with RFS in the validation cohort (P < .001 for each comparison).CONCLUSIONS The scores generated were effective in stratifying the risk of GIST recurrence in patient populations treated with adjuvant imatinib. Patients with nongastric GIST with a high mitotic count are at a particularly high risk for recurrence. Cancer 2014 © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
    Cancer 04/2014; · 5.20 Impact Factor
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    ABSTRACT: Rationale and Objectives To compare in dual-energy CT (DECT) conventionally reconstructed polyenergetic images (PEI) at 120 kVp to virtual monoenergetic images (MEI) at different kiloelectron volt (keV) levels for evaluation of liver and gastrointestinal stromal tumor (GIST) hepatic metastases with regard to objective (IQob) and subjective image quality (IQsub) assessed by two readers of varying experience. Image quality was correlated to patient size and compared between PEI and MEI. Materials and Methods From 50 examinations of 17 GIST patients (12 with hepatic metastases) undergoing abdominal dual-source DECT for staging, therapy monitoring or follow-up, PEI and nine MEI in 10-keV intervals from 40 to 120 keV were reconstructed. Liver contrast-to-noise ratios (CNR) and metastasis-to-liver ratios were calculated. MEI reconstructions with the highest IQob were compared to PEI for IQsub by one experienced reader (ER) and one inexperienced reader (IR). Patients' diameters were correlated to IQob and IQsub ratings. Results MEI at 70 keV had the highest IQob with equal liver CNR and metastasis-to-liver ratio compared to PEI. The ER rated 70-keV MEI and PEI equally high (median 4), whereas the IR rated IQsub best in 70-keV MEI (median 5). Unlike in PEI, IQsub ratings in 70-keV MEI were not correlated to patient size. Conclusions MEI at 70 keV provided an IQob equivalent to PEI. Regarding the IR, IQsub was improved in 70-keV MEI compared to PEI and less dependent on patient size. Therefore, IRs might improve their diagnostic confidence in the assessment of hepatic GIST metastases by evaluating MEI reconstructions at 70 keV.
    Academic Radiology 04/2014; 21(4):514-522. · 1.91 Impact Factor
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    ABSTRACT: Isolated limb perfusion (ILP) is an effective limb salvage strategy in patients with advanced soft tissue sarcoma (STS) where surgery alone would result in significant functional morbidity or mandate an amputation. Most previous reports of patients undergoing ILP focus on limb salvage rates rather than local and distant relapse rates. Here, we report the oncological outcome of sarcoma patients treated by ILP and surgery. Data were retrieved from prospective ILP databases from two ILP centers following similar ILP techniques and surgical approaches. Only patients with primary, intermediate, or high grade non-metastatic STS were included. The cohort comprised 90 patients. Median follow-up was 39 months (range 3-165 months). Median tumor size was 11 cm (range 5-34). Twenty of 90 (22%) patients underwent prior debulking surgery outside the centers. Twenty-nine of 90 (32%) had postoperative irradiation. Four of 90 underwent amputation either related to local recurrence or irresectability, 4 of 90 underwent amputation for treatment-related complications. Fifteen of 83 (18%) patients had local recurrences after ILP and limb sparing surgery, 39 of 90 (43%) developed metastatic disease. Twenty-two of 90 (24%) died of disease. Preoperative ILP and tumor resection resulted in good local control in a cohort of high-risk STS patients. J. Surg. Oncol. © 2014 Wiley Periodicals, Inc.
    Journal of Surgical Oncology 03/2014; · 2.64 Impact Factor
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    ABSTRACT: Background Effective targeted treatment is unavailable for most sarcomas and doxorubicin and ifosfamide—which have been used to treat soft-tissue sarcoma for more than 30 years—still have an important role. Whether doxorubicin alone or the combination of doxorubicin and ifosfamide should be used routinely is still controversial. We assessed whether dose intensification of doxorubicin with ifosfamide improves survival of patients with advanced soft-tissue sarcoma compared with doxorubicin alone. Methods We did this phase 3 randomised controlled trial (EORTC 62012) at 38 hospitals in ten countries. We included patients with locally advanced, unresectable, or metastatic high-grade soft-tissue sarcoma, age 18–60 years with a WHO performance status of 0 or 1. They were randomly assigned (1:1) by the minimisation method to either doxorubicin (75 mg/m² by intravenous bolus on day 1 or 72 h continuous intravenous infusion) or intensified doxorubicin (75 mg/m²; 25 mg/m² per day, days 1–3) plus ifosfamide (10 g/m² over 4 days with mesna and pegfilgrastim) as first-line treatment. Randomisation was stratified by centre, performance status (0 vs 1), age (<50 vs ≥50 years), presence of liver metastases, and histopathological grade (2 vs 3). Patients were treated every 3 weeks till progression or unacceptable toxic effects for up to six cycles. The primary endpoint was overall survival in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT00061984. Findings Between April 30, 2003, and May 25, 2010, 228 patients were randomly assigned to receive doxorubicin and 227 to receive doxorubicin and ifosfamide. Median follow-up was 56 months (IQR 31–77) in the doxorubicin only group and 59 months (36–72) in the combination group. There was no significant difference in overall survival between groups (median overall survival 12·8 months [95·5% CI 10·5–14·3] in the doxorubicin group vs 14·3 months [12·5–16·5] in the doxorubicin and ifosfamide group; hazard ratio [HR] 0·83 [95·5% CI 0·67–1·03]; stratified logrank test p=0·076). Median progression-free survival was significantly higher for the doxorubicin and ifosfamide group (7·4 months [95% CI 6·6–8·3]) than for the doxorubicin group (4·6 months [2·9–5·6]; HR 0·74 [95% CI 0·60–0·90], stratified log-rank test p=0·003). More patients in the doxorubicin and ifosfamide group than in the doxorubicin group had an overall response (60 [26%] of 227 patients vs 31 [14%] of 228; p<0·0006). The most common grade 3 and 4 toxic effects—which were all more common with doxorubicin and ifosfamide than with doxorubicin alone—were leucopenia (97 [43%] of 224 patients vs 40 [18%] of 223 patients), neutropenia (93 [42%] vs 83 [37%]), febrile neutropenia (103 (46%) vs 30 [13%]), anaemia (78 [35%] vs 10 [5%]), and thrombocytopenia (75 [33%]) vs one [<1%]). Interpretation Our results do not support the use of intensified doxorubicin and ifosfamide for palliation of advanced soft-tissue sarcoma unless the specific goal is tumour shrinkage. These findings should help individualise the care of patients with this disease.
    The Lancet Oncology 03/2014; 15:415-423. · 25.12 Impact Factor
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    ABSTRACT: Effective targeted treatment is unavailable for most sarcomas and doxorubicin and ifosfamide-which have been used to treat soft-tissue sarcoma for more than 30 years-still have an important role. Whether doxorubicin alone or the combination of doxorubicin and ifosfamide should be used routinely is still controversial. We assessed whether dose intensification of doxorubicin with ifosfamide improves survival of patients with advanced soft-tissue sarcoma compared with doxorubicin alone. We did this phase 3 randomised controlled trial (EORTC 62012) at 38 hospitals in ten countries. We included patients with locally advanced, unresectable, or metastatic high-grade soft-tissue sarcoma, age 18-60 years with a WHO performance status of 0 or 1. They were randomly assigned (1:1) by the minimisation method to either doxorubicin (75 mg/m(2) by intravenous bolus on day 1 or 72 h continuous intravenous infusion) or intensified doxorubicin (75 mg/m(2); 25 mg/m(2) per day, days 1-3) plus ifosfamide (10 g/m(2) over 4 days with mesna and pegfilgrastim) as first-line treatment. Randomisation was stratified by centre, performance status (0 vs 1), age (<50 vs ≥50 years), presence of liver metastases, and histopathological grade (2 vs 3). Patients were treated every 3 weeks till progression or unacceptable toxic effects for up to six cycles. The primary endpoint was overall survival in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT00061984. Between April 30, 2003, and May 25, 2010, 228 patients were randomly assigned to receive doxorubicin and 227 to receive doxorubicin and ifosfamide. Median follow-up was 56 months (IQR 31-77) in the doxorubicin only group and 59 months (36-72) in the combination group. There was no significant difference in overall survival between groups (median overall survival 12·8 months [95·5% CI 10·5-14·3] in the doxorubicin group vs 14·3 months [12·5-16·5] in the doxorubicin and ifosfamide group; hazard ratio [HR] 0·83 [95·5% CI 0·67-1·03]; stratified log-rank test p=0·076). Median progression-free survival was significantly higher for the doxorubicin and ifosfamide group (7·4 months [95% CI 6·6-8·3]) than for the doxorubicin group (4·6 months [2·9-5·6]; HR 0·74 [95% CI 0·60-0·90], stratified log-rank test p=0·003). More patients in the doxorubicin and ifosfamide group than in the doxorubicin group had an overall response (60 [26%] of 227 patients vs 31 [14%] of 228; p<0·0006). The most common grade 3 and 4 toxic effects-which were all more common with doxorubicin and ifosfamide than with doxorubicin alone-were leucopenia (97 [43%] of 224 patients vs 40 [18%] of 223 patients), neutropenia (93 [42%] vs 83 [37%]), febrile neutropenia (103 (46%) vs 30 [13%]), anaemia (78 [35%] vs 10 [5%]), and thrombocytopenia (75 [33%]) vs one [<1%]). Our results do not support the use of intensified doxorubicin and ifosfamide for palliation of advanced soft-tissue sarcoma unless the specific goal is tumour shrinkage. These findings should help individualise the care of patients with this disease. Cancer Research UK, EORTC Charitable Trust, UK NHS, Canadian Cancer Society Research Institute, Amgen.
    The Lancet Oncology 03/2014; · 25.12 Impact Factor
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    ABSTRACT: The use of human acellular dermis (hAD) to close open abdomen in the treatment process of severe peritonitis might be an alternative to standard care. This paper describes an investigation of the effects of fluids simulating an open abdomen environment on the biomechanical properties of Epiflex(R) a cell-free human dermis transplant. hAD was incubated in Ringers solution, blood, urine, upper gastrointestinal (upper GI) secretion and a peritonitis-like bacterial solution in-vitro for 3 weeks. At day 0, 7, 14 and 21 breaking strength was measured, tensile strength was calculated and standard fluorescence microscopy was performed. hAD incubated in all five of the five fluids showed a decrease in mean breaking strength at day 21 when compared to day 0. However, upper GI secretion was the only incubation fluid that significantly reduced the mechanical strength of Epiflex after 21days of incubation when compared to incubation in Ringer's solution. hAD may be a suitable material for closure of the open abdomen in the absence of upper GI leakage and pancreatic fistulae.
    BMC Surgery 01/2014; 14(1):7. · 1.97 Impact Factor
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    ABSTRACT: Increased activity of Src has been found in several human cancers, and often is associated with poor clinical outcome. The present study aimed to determine whether Src activity is increased in gastrointestinal stromal tumors (GIST), and whether it correlates with established tumor or patient characteristics and prognosis. Tumor/normal tissues of 29 patients were analyzed for Src activity/protein with kinase assays, and for VEGF/VEGFR with immunohistochemical staining. Src activity was higher in tumor than in normal tissues (P = 0.093). However, when imatinib responders were excluded from the analyses, it was significantly higher in the tumor tissue (P = 0.017). Additionally, it was higher in primary compared to recurrent tumors or metastasis (P = 0.04). Univariate survival analysis showed a longer overall survival for patients with high Src activity (P = 0.038). In multivariate analysis, the response to imatinib treatment was the only survival-influencing factor (P = 0.072). Src activity is increased in GIST. In contrast to most other tumor entities, it does not correlate with poor clinical outcome, but decreases during the progression from primary tumor to recurrence and metastasis, especially under therapy with imatinib. Additionally, our results show that higher Src activity is associated with longer overall survival. J. Surg. Oncol. © 2014 Wiley Periodicals, Inc.
    Journal of Surgical Oncology 01/2014; · 2.64 Impact Factor
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    ABSTRACT: Background Long-term complete remissions remain a rare exception in patients with metastatic gastrointestinal stromal tumors (GIST) treated with IM (imatinib). To date the therapeutic relevance of surgical resection of metastatic disease remains unknown except for the use in palliative intent. Patients and methods We analyzed overall survival (OS) and progression-free survival (PFS) in consecutive patients with metastatic GIST who underwent metastasectomy and received IM therapy (n=239). Results Complete resection (R0+R1) was achieved in 177 patients. Median OS was 8.7y for R0/R1 and 5.3y in pts with R2 resection (p=0.0001). In the group who were in remission at time of resection median OS was not reached in the R0/R1 surgery and 5.1y in the R2-surgery (p=0.0001). Median time to relapse/progression after resection of residual disease was not reached in the R0/R1 and 1.9 years in the R2 group of patients, who were resected in response. No difference in mPFS was seen in patients progressing at time of surgery. Conclusions: Our analysis implicates possible long-term survival in patients in whom surgical complete remission can be achieved. Incomplete resection, including debulking surgery does not seem to prolong survival. Despite the retrospective character and likely selection bias, this analysis may help in decision making for surgical approaches in metastatic GIST.
    European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 01/2014; · 2.56 Impact Factor
  • Heikki Joensuu, Peter Hohenberger
    The Lancet 11/2013; 382(9906):1701-1702. · 39.21 Impact Factor
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    ABSTRACT: Brostallicin is a DNA minor groove binder that has shown activity in patients with soft tissue sarcoma (STS) failing first-line therapy. The present study assessed the safety and efficacy of first-line brostallicin in patients with advanced or metastatic STS>60years or not fit enough to receive combination chemotherapy. A prospective explorative pharmacogenetic analysis was undertaken in parallel. Patients were randomised in a 2:1 ratio between IV brostallicin 10mg/m(2) and doxorubicin 75mg/m(2) once every 3weeks for a maximum of six cycles. Disease stabilisation at 26weeks (primary end-point) was considered a 'success'. Further testing of brostallicin was warranted if ⩾35 'successes' were observed in the first 72 eligible patients treated with brostallicin. In addition, patients were genotyped for glutathione S transferase (GST) polymorphisms. One hundred and eighteen patients were included (79 brostallicin and 39 doxorubicin). Brostallicin was well tolerated in comparison to doxorubicin with less grade 3-4 neutropenia (67% versus 95%), grade 2-3 systolic dysfunction (0% versus 11%), alopecia (17% versus 61%) and grade 2-3 mucositis (0% versus 18%). For brostallicin versus doxorubicin, 'successes' were observed in 5/77 versus 10/36, progression free survival at 1year was 6.5% versus 15.6%, objective response rate was 3.9% versus 22.2% and overall survival at 1year was 50.5% versus 57.9%, respectively. Only GSTA1 genotype was significantly associated with success rate of doxorubicin treatment. Brostallicin cannot be recommended at this dose and schedule in this patient population as first-line therapy. GSTA1 genotype may be predictive for doxorubicin efficacy but warrants further study.
    European journal of cancer (Oxford, England: 1990) 11/2013; · 4.12 Impact Factor
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    ABSTRACT: KIT exon 9 mutations in gastrointestinal stromal tumors (GISTs) are highly relevant and have direct therapeutic implications. In this context, we established and validated a fast and sensitive high-resolution melting assay. Analyzing 126 primary and 18 metastatic KIT exon 9-mutated cases from our registry, we demonstrate that the mutational spectrum of exon 9 is broader than previously thought and describe 3 novel mutations. Including these cases and the common p.A502_Y503dup mutation, we provide a comprehensive list of all known KIT exon 9 mutations according to the Human Genome Variation Society nomenclature. Two of the newly described mutations were associated with an aggressive phenotype and tumor progression while being treated with 400 mg imatinib, indicating that also GIST with rare exon 9 mutations could be treated with increased imatinib dosage. On the basis of >1500 GISTs from our registry, we have determined the frequency of KIT exon 9 mutations to be 9.2% among all GISTs and 22.5% among small-bowel cases. We describe for the first time that nearly 20% of exon 9-mutated GIST occur in the stomach or rectum. Furthermore, we provide first evidence that exon 9-mutated GISTs metastasize significantly more often to the peritoneum than to the liver. Performing extensive statistical analyses on data from our registry and from the literature, we demonstrate that KIT exon 9 mutations are neither associated with intermediate-risk/high-risk status nor overrepresented among metastatic lesions. Thus, we conclude that exon 9 mutations per se do not have prognostic relevance.
    The American journal of surgical pathology 09/2013; · 4.06 Impact Factor
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    ABSTRACT: The combination of neoadjuvant radiochemotherapy and parenchyma-preserving sleeve resection for lung cancer remains controversial because of potentially increased rate of anastomotic breakdown. We analyzed the effects of applying a decellularized human dermis transplant seeded with autologous fibroblasts in a rodent sleeve resection model with neoadjuvant radiotherapy. A total of 64 male Fisher rats underwent a transsection and surgical anastomosis of the left main bronchus and were randomized to receive plus/minus radiation treatment and plus/minus augmentation of the anastomosis with a fibroblast-seeded dermis transplant (2 × 2 factorial design). A μCT scan was performed at postoperative days 7 and 14, and the animals were sacrificed on day 14. Anastomotic bursting pressure and hydroxyproline concentration were measured. In the irradiated groups, the anastomotic bursting pressure was significantly higher in the augmented group at day 7 (100.9 ± 18.3 vs 141.3 ± 18.0 kPa, p = 0.0005) but not at day 14. Hydroxyproline levels showed a similar pattern in the irradiated group with significant differences at day 7 (7 days postoperative 158 ± 11.6 vs 198.2 ± 10.9 nmol/mg, p < 0.0001) but not at day 14 postoperatively. Augmentation of a bronchial anastomosis by a dermal matrix, seeded with autologous, viable fibroblasts improves early wound breaking strength. Fibroblast-enhanced dermal matrices provide a new and easily usable tool to prevent early anastomotic leakage after neoadjuvant chemoradiation in locally advanced lung cancer.
    Annals of Surgical Oncology 08/2013; · 4.12 Impact Factor

Publication Stats

4k Citations
1,142.36 Total Impact Points

Institutions

  • 2008–2014
    • Universität Mannheim
      Mannheim, Baden-Württemberg, Germany
  • 2003–2014
    • Charité Universitätsmedizin Berlin
      Berlín, Berlin, Germany
  • 1987–2014
    • Universität Heidelberg
      • • Department of Spine Surgery
      • • Faculty of Medicine Mannheim and Clinic Mannheim
      • • Institute of Pathology (Mannheim)
      • • Surgical Hospital
      Heidelburg, Baden-Württemberg, Germany
  • 2013
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States
  • 2012–2013
    • Helsinki University Central Hospital
      • Department of Oncology
      Helsinki, Southern Finland Province, Finland
    • The University of Sheffield
      Sheffield, England, United Kingdom
    • Radboud University Nijmegen
      • Department of Medical Oncology
      Nijmegen, Provincie Gelderland, Netherlands
    • Erasmus MC
      • Department of Internal Oncology
      Rotterdam, South Holland, Netherlands
    • Centre Léon Bérard
      Lyons, Rhône-Alpes, France
    • University of Cologne
      • Institute of Pathology
      Köln, North Rhine-Westphalia, Germany
  • 2011–2013
    • Leiden University Medical Centre
      • Department of Clinical Oncology
      Leyden, South Holland, Netherlands
    • KU Leuven
      • Department of Oncology
      Leuven, VLG, Belgium
    • Centre Hospitalier Régional Universitaire de Lille
      Lille, Nord-Pas-de-Calais, France
    • CRO Centro di Riferimento Oncologico di Aviano
      • Department of Surgery
      Aviano, Friuli Venezia Giulia, Italy
  • 1998–2012
    • German Cancer Research Center
      • • Division of Clinical Cooperation Unit Radiation Oncology
      • • Division of Radiology
      Heidelberg, Baden-Wuerttemberg, Germany
  • 2010
    • University Hospital München
      München, Bavaria, Germany
    • University of Bonn
      • Institut für Pathologie
      Bonn, North Rhine-Westphalia, Germany
    • Universitätsmedizin Mannheim
      Mannheim, Baden-Württemberg, Germany
    • European Organisation for Research and Treatment of Cancer
      • Department of Biostatistics
      Bruxelles, Brussels Capital Region, Belgium
    • HELIOS Klinikum Bad Saarow
      Bad Saarow, Brandenburg, Germany
  • 2005–2006
    • University of Bonn - Medical Center
      Bonn, North Rhine-Westphalia, Germany
  • 2002–2004
    • HELIOS Klinikum Berlin-Buch
      Berlín, Berlin, Germany
  • 1996–2004
    • Humboldt-Universität zu Berlin
      • Department of Psychology
      Berlín, Berlin, Germany
    • University of Groningen
      • Department of Surgical Oncology
      Groningen, Province of Groningen, Netherlands
  • 1992–2004
    • Max-Delbrück-Centrum für Molekulare Medizin
      Berlín, Berlin, Germany
  • 1993–2000
    • Freie Universität Berlin
      • Department of Hematology
      Berlin, Land Berlin, Germany