Efficacy of hyperthermic isolated limb perfusion in the treatment of locally recurrent high-grade soft tissue sarcoma of the extremities.

BACKGROUND: This novel study compared the use of tumor necrosis factor (TNF)-alpha and melphalan-based isolated limb perfusion (TM-ILP) to the standard treatment of locally recurrent soft tissue extremity sarcoma. The aim was to assess whether TM-ILP positively influences the recurrence-free survival of locally recurrent high-grade soft tissue sarcoma (STS) of the extremities. METHODS: We retrospectively analyzed our clinical database for patients with STS. Variables were analyzed using chi-square test or Mann-Whitney rank-sum test. Furthermore, Kaplan-Meier survival plots were calculated and a proportional hazard regression model was developed. RESULTS: Out of 448 patients with extraabdominal STS treated between August 2012 and December 2015, 52 cases involving 47 patients had locally recurrent STS. Twenty-eight of these patients were treated with TM-ILP prior to surgical resection (TM-ILP-group), and 24 were treated with standard therapy (without TM-ILP). The 3-year recurrence-free survival for the TM-ILP-group was estimated at 75% (95% confidence interval (CI), 71.5-78.5). Local recurrence-free survival in the standard group was significantly lower (LRFS: 43.4%, 95% CI 38.7-48.1, p = 0.026). Multivariable analysis revealed resection with negative margins, lower number of previous recurrences, and TM-ILP as positive predictors for recurrence-free survival. CONCLUSIONS: TM-ILP and consecutive resection of residual tumor with negative resection margins significantly improves local recurrence-free survival for patients with a first local recurrence of high-grade STS in the extremities.

Lower limb function and quality of life after ILP for soft-tissue sarcoma.

BACKGROUND: Isolated limb perfusion with TNF-alpha and melphalan (TM-ILP) in combination with complete tumor resection is an effective treatment option for non-resectable soft-tissue sarcoma of the extremities, with limb salvage rates greater than 80%. The aim of this study was to assess quality of life (QoL) after TM-ILP, also with regard to long-term survival. METHODS: We retrospectively examined 27 patients who had primarily non-resectable soft-tissue sarcoma of the leg and who had undergone TM-ILP and complete tumor resection (with limb-sparing intent) during their follow-up examinations using the Quality of Life Questionnaire (QLQ-C30) and the German Short Musculoskeletal Function Assessment (SMFA-D). The results from the QLQ-C30 were compared to the reference values for the general population, to the "all cancer patients" reference values (both reference values published by the European Organization for Research and Treatment of Cancer (EORTC)), and to the reference values of a historical amputation group from the literature. The results of the SMFA were compared with those from a reference group of healthy individuals. RESULTS: Surprisingly, we found that the global health status/QoL in the TM-ILP group was not significantly different from the general population or from patients with amputation, but it was higher than that of patients with cancer in general. Concerning the SMFA, we did find functional impairments in patients after TM-ILP compared to the reference group. With regard to long-term survival, we found no time-dependent deterioration in QoL for longer time intervals after treatment. CONCLUSIONS: These results support the use of TM-ILP in limb-sparing multimodal therapy settings from a quality-of-life perspective, but they also encourage further research on this matter.

Drug dosage in isolated limb perfusion: evaluation of a limb volume model for extremity volume calculation.

BACKGROUND: Exact drug dosing in isolated limb perfusion (ILP) and infusion (ILI) is essential. We developed and evaluated a model for calculating the volume of extremities and compared this model with body weight- and height-dependent parameters. METHODS: The extremity was modeled by a row of coupled truncated cones. The sizes of the truncated cone bases were derived from the circumference measurements of the extremity at predefined levels (5 cm). The resulting volumes were added. This extremity volume model was correlated to the computed tomography (CT) volume data of the extremity (total limb volume). The extremity volume was also correlated with the patient's body weight, body mass index (BMI) and ideal body weight (IBW). The no-fat CT limb volume was correlated with the circumference-measured limb volume corrected by the ideal-body-weight to actual-body-weight ratio (IBW corrected-limb-volume). RESULTS: The correlation between the CT volume and the volume measured by the circumference was high and significant. There was no correlation between the limb volume and the bare body weight, BMI or IBW. The correlation between the no-fat CT volume and IBW-corrected limb volume was high and significant. CONCLUSIONS: An appropriate drug dosing in ILP can be achieved by combining the limb volume with the simple circumference measurements and the IBW to body-weight ratio.

The pathologic response of resected synovial sarcomas to hyperthermic isolated limb perfusion with melphalan and TNF-α: a comparison with the whole group of resected soft tissue sarcomas.

BACKGROUND: Hyperthermic isolated limb perfusion with tumor necrosis factor-α and melphalan (TM-HILP) has been successfully used to treat limb soft tissue sarcomas (STSs) with high response rates. The data on the effectiveness of HILP-TM for the treatment of STSs are mainly based on various STS types. The aim of this study was to investigate the responses of synovial sarcomas (SS) to TM-HILP. METHODS: A total of 125 TM-HILP-treated tumors (STS all), including 14 SSs, were included in the study. The tumors were subdivided into proximal and distal limb localizations. Tumor typing (using the WHO classification), resection status (using the UICC classification), and response to therapy were assessed using light microscopy. The SSs were tested for the SYT-SSX translocation using RT-PCR. The following tests were applied: a chi-squared test, a t test, and the Mann-Whitney U test. RESULTS: The SSs were localized distally more often than were the STS cohort (STS(-SS)) (85.7% vs. 32.4%) and were smaller (5.8 cm vs. 10.7 cm). There were no differences in the responder/nonresponder ratios or the mean percentages of pathological regression between the SS and STS(-SS) cohorts (74.0% vs. 76.0%). A general localization-dependent difference in the tumor responses to TM-HILP could not be detected in the STS all cohort (distal, 72.0% vs. proximal, 78.0%); however, a UICC R0 status was more often observed in proximal tumors (distal, 50.0% vs. proximal, 71.4%). There was no association between the SYT-SSX type and SS responses to TM-HILP. CONCLUSIONS: Because of the high response rates, TM-HILP is recommended for the treatment of SSs. The distal limb localization of TM-HILP-treated STSs was generally (STS all cohort) associated with fewer R0 resections.

Trabectedin in metastatic soft tissue sarcomas: Role of pretreatment and age.

Trabectedin has mostly been studied in metastatic leiomyosarcoma and liposarcomas. Only limited data are available in other sarcoma subtypes, heavily pretreated and elderly patients. We retrospectively analyzed 101 consecutive sarcoma patients treated with trabectedin at our center. We recorded progression-free survival (PFS), clinical benefit rate (CBR, defined as complete or partial response or stable disease for at least 6 weeks) and toxicity. Covariates were sarcoma subtype, age and pretreatment. On average, trabectedin was administered for 2nd relapse/progression (range 1st to 12th line). A median of 2 cycles and a dose of 1.5 mg/m2 (range 1-21 cycles; 1.3-1.5 mg/m2) was administered. The median PFS under treatment with trabectedin was 2.1 months in the overall population. Different clinical outcomes were observed with respect to sarcoma subtypes: in patients with L-sarcoma [defined as leiosarcoma and liposarcoma (n=25)] the CBR was 55%. Notably, long lasting remissions were even observed in 7th-line treatment. In contrast, the majority of patients with non-L-sarcomas quickly progressed (median PFS 1.6 months). Nevertheless, a CBR of 34% was achieved, including long-lasting disease stabilization in subtypes such as rhabdomyosarcoma. Patients treated with trabectedin at 1st or 2nd line (n=16) achieved an improved PFS (median 5.7 months, range) and a CBR of 59%. No differences in terms of toxicity or efficacy were observed between patients older than 65 years (n=23) and younger patients (n=78). In this non-trial setting, port-associated complications were more frequent (14%) with trabectedin compared to other continuous infusion protocols administered at our outpatient therapy center. The majority of patients with relapsing L-sarcomas and a substantial fraction of patients with non-L-sarcomas derive a clinically meaningful benefit from trabectedin. Outpatient treatment is well tolerated also in elderly and heavily pretreated patients. Port-associated complications were observed at an unusually high rate. This suggests a drug-specific local toxicity that merits further investigation.

DOG1 regulates growth and IGFBP5 in gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GIST) are characterized by activating mutations of KIT or platelet-derived growth factor receptor α(PDGFRA), which can be therapeutically targeted by tyrosine kinase inhibitors (TKI) such as imatinib. Despite long-lasting responses, most patients eventually progress after TKI therapy. The calcium-dependent chloride channel DOG1 (ANO1/TMEM16A), which is strongly and specifically expressed in GIST, is used as a diagnostic marker to differentiate GIST from other sarcomas. Here, we report that loss of DOG1 expression occurs together with loss of KIT expression in a subset of GIST resistant to KIT inhibitors, and we illustrate the functional role of DOG1 in tumor growth, KIT expression, and imatinib response. Although DOG1 is a crucial regulator of chloride balance in GIST cells, we found that RNAi-mediated silencing or pharmacologic inhibition of DOG1 did not alter cell growth or KIT signaling in vitro. In contrast, DOG1 silencing delayed the growth of GIST xenografts in vivo. Expression profiling of explanted tumors after DOG1 blockade revealed a strong upregulation in the expression of insulin-like growth factor-binding protein 5 (IGFBP5), a potent antiangiogenic factor implicated in tumor suppression. Similar results were obtained after selection of imatinib-resistant DOG1- and KIT-negative cells derived from parental DOG1 and KIT-positive GIST cells, where a 5,000-fold increase in IGFBP5 mRNA transcripts were documented. In summary, our findings establish the oncogenic activity of DOG1 in GIST involving modulation of IGF/IGF receptor signaling in the tumor microenvironment through the antiangiogenic factor IGFBP5.

The two-incision, minimally invasive approach in the treatment of acetabular fractures.

OBJECTIVES: To present a novel two-incision minimally invasive (TIMI) method for the treatment of anterior acetabular fractures. DESIGN: Prospective consecutive case series. SETTING: Level I University Trauma Centre. PATIENTS: Twenty-six patients (mean age, 67 ± 19 years). INTERVENTION: The first TIMI-incision is performed by a pararectal approach at the level of the proximal third of the arcuate line of the ilium. After transection of the abdominal wall, the iliac vessels are mobilized medially and the neuromuscular bundle laterally. The second approach lies above the medial pubic bone. The soft tissue is held using a retraction system. After fracture reduction and fixation by isolated screws, a conventional reconstruction plate is inserted for fracture neutralization. MAIN OUTCOME MEASUREMENTS: Perioperative course, postoperative radiological evaluation, functional outcome Harris hip score, and quality of life (EQ 5D). RESULTS: Mean operative time was 109 ± 30 mins. All incisions healed primarily. Postoperative radiological exam revealed an anatomic reduction in 20 fractures and a satisfactory reduction in 6. There were no local soft-tissue complications, and no revisions were needed. Follow-up examinations were performed after a minimum of 12 months in 19 patients (73%). The Harris hip score was 86,6 ± 8. Quality of life was comparable to persons in the same age group. CONCLUSION: The TIMI approach represents a viable alternative to the ilioinguinal approach. Despite the limited incisions, a comparable quality of fracture reduction is achieved. The authors believe this technique would be most useful in those patients with a higher risk for postoperative soft-tissue complications. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

p53 modulation as a therapeutic strategy in gastrointestinal stromal tumors.

The KIT-inhibitor imatinib mesylate (IM) has greatly improved the treatment of metastatic gastrointestinal stromal tumors (GIST). IM exhibits strong antiproliferative effects but fails to induce sufficient levels of apoptosis resulting in low pathologic complete remission rates and a high rate of secondary progression in the metastatic setting. Upregulation of p53 by MDM2 inhibitors has been shown to induce apoptosis in p53 wildtype tumors. Analyzing a series of 62 mostly untreated, localized and metastatic GIST we detected a low rate (3%) of inactivating p53 mutations, thus providing a rationale for further exploration of p53-directed therapeutic strategies. To this end, we studied nutlin-3, an inhibitor of the p53 antagonist MDM2, and RITA, a putative p53 activator, in GIST cell lines. Nutlin-3 effectively induced p53 at therapeutically relevant levels, which resulted in moderate antiproliferative effects and cell cycle arrest in p53 wildtype GIST cell lines GIST430, GIST48 and GIST48B. P53 reactivation substantially improved the apoptotic response after effective KIT inhibition with sunitinib and 17-AAG in IM-resistant cell lines. The commonly used imatinib-sensitive cell lines GIST882 and GIST-T1 were shown to harbor defective p53 and therefore failed to respond to nutlin-3 treatment. RITA induced p53 in GIST48B, followed by antiproliferative effects and a strong induction of apoptosis. Surprisingly, GIST-T1 was also highly sensitive to RITA despite lacking functional p53. This suggested a more complex, p53-independent mechanism of action for the latter compound. No antagonistic effects from p53-activating drugs were seen with any drug combination. Our data provide first evidence that modulation of the MDM2/p53 pathway may be therapeutically useful to improve the apoptotic response of KIT-inhibitory drugs in the treatment of naïve GIST, with p53 mutation status being a predictive factor of response.

Size-based clinical response evaluation is insufficient to assess clinical response of sarcomas treated with isolated limb perfusion with TNF-α and melphalan.

BACKGROUND: The clinical assessment of the response of sarcomas to preoperative treatment is usually defined using size-based evaluation standards. For nonresectable sarcomas, hyperthermic isolated limb perfusion with TNF-α and melphalan (TM-ILP) yields high response rates. Based on our experience, we assume that anatomic radiological response criteria are insufficient to assess the degree of regression after TM-ILP. METHODS: The clinical response of 35 sarcomas to TM-ILP was assessed by unidimensional, bidimensional, and tridimensional size-based anatomical criteria, and responders were identified according to the established thresholds. The same tumors were investigated for pathological response according to the Salzer-Kuntschik regression scale (>90% devitalization) and reviewed for cystic degeneration, hemorrhage, and predominant necrotic or fibrosclerotic regression phenotype. RESULTS: None of the clinical response criteria were able to reliably identify the pathologic responders. The extent of size changes showed no association with the pathological degree of regression. The number of clinical responders was low compared with the number of pathological responders (RECIST N = 1, WHO N = 3, volumetry N = 3, pathology N = 19). The occurrence of hemorrhage and/or cystic degeneration was more frequently observed in predominant necrotic sarcomas and was associated with an increase in tumor size after TM-ILP. Furthermore, we identified the fibrosclerotic phenotype of regression to be more significantly strongly associated with posttherapeutic shrinkage than necrosis. CONCLUSIONS: Size-based clinical response evaluation is insufficient to assess clinical response in TM-ILP-treated sarcomas. The size changes of tumors after therapy reflect the type of regression rather than the extent of destruction.

Influence of prehospital fluid resuscitation on patients with multiple injuries in hemorrhagic shock in patients from the DGU trauma registry.

BACKGROUND: Severe bleeding as a result of trauma frequently leads to poor outcome by means of direct or delayed mechanisms. Prehospital fluid therapy is still regarded as the main option of primary treatment in many rescue situations. Our study aimed to assess the influence of prehospital fluid replacement on the posttraumatic course of severely injured patients in a retrospective analysis of matched pairs. MATERIALS AND METHODS: We reviewed data from 35,664 patients recorded in the Trauma Registry of the German Society for Trauma Surgery (DGU). The following patients were selected: patients having an Injury Severity Score >16 points, who were ≥16 years of age, with trauma, excluding those with craniocerebral injuries, who were admitted directly to the participating hospitals from the accident site. All patients had recorded values for replaced volume and blood pressure, hemoglobin concentration, and units of packed red blood cells given. The patients were matched based on similar blood pressure characteristics, age groups, and type of accident to create pairs. Pairs were subdivided into two groups based on the volumes infused prior to hospitalization: group 1: 0-1500 (low), group 2: ≥2000 mL (high) volume. RESULTS: We identified 1351 pairs consistent with the inclusion criteria. Patients in group 2 received significantly more packed red blood cells (group 1: 6.9 units, group 2: 9.2 units; P=0.001), they had a significantly reduced capacity of blood coagulation (prothrombin ratio: group 1: 72%, group 2: 61.4%; P≤0.001), and a lower hemoglobin value on arrival at hospital (group 1: 10.6 mg/dL, group 2: 9.1 mg/dL; P≤0.001). The number of ICU-free days concerning the first 30 days after trauma was significantly higher in group 1 (group 1: 11.5 d, group 2: 10.1 d; P≤0.001). By comparison, the rate of sepsis was significantly lower in the first group (group 1: 13.8%, group 2: 18.6%; P=0.002); the same applies to organ failure (group 1: 36.0%, group 2: 39.2%; P≤0.001). CONCLUSION: The high amounts of intravenous fluid replacement was related to early traumatic coagulopathy, organ failure, and sepsis rate.

Pancreatic injury in 284 patients with severe abdominal trauma: outcome, course, and treatment algorithm.

PURPOSE: The relevance of pancreatic trauma in severely injured patients within a large collective has not been thoroughly analyzed yet. This study aimed at assessing the prevalence of pancreatic trauma in relation to the outcome and the currently established algorithm of treatment. METHODS: Some 51,425 patients from the Trauma Register of the German Society of Trauma Surgery (TR DGU) (1993-2009) were retrospectively analyzed. All patients with an "injury severity score" ≥16, direct admission to a trauma center and subsequent treatment for at least 3 days, age ≥16, and an abdominal injury [abbreviated injury scale (AIS)(abdomen) ≥2] were included. Patients with abdominal trauma (AIS(abdomen) ≥2) were compared with patients with an additional pancreatic trauma (AIS(pancreas) 2-5). RESULTS: Of 51,425 patients, 9,268 (18%) had documented abdominal injuries. Two hundred eighty-four (3.1%) patients with abdominal injury additionally showed a pancreatic injury (AIS(abdomen) ≥2, AIS(pancreas) 2-5) and were analyzed in dependency of the classification of the American Association for the Surgery of Trauma (AAST) organ severity score. AAST-pancreas: II°, 1.9%; III°, 0.6%; IV°, 0.3%; and V°, 0.2%. Patients with leading pancreatic injury (grades IV and V) thereby showed a significant increase of mortality (IV°, 30.0% and V°, 33.3%) and an increase of the need for surgical intervention (IV°, 80.6% and V°: 81.8%). CONCLUSIONS: The results presented here show the prevalence and the outcome of pancreas injury in a large collective within the TR DGU for the first time. Based on the current literature and the findings, a treatment algorithm has been developed.

Tumor vascularization and histopathologic regression of soft tissue sarcomas treated with isolated limb perfusion with TNF-α and melphalan.

BACKGROUND: Isolated limb perfusion (TM-ILP) achieves high response rates in soft tissue sarcomas (STS). Some tumors show an insufficient association between radiological and pathological response. We investigated STS after TM-ILP with a primary emphasis on histologic regression patterns. METHODS: In 53 patients with STS, TM-ILP with subsequent tumor resection was performed. Regression was assessed by the Salzer-Kuntschik regression scale. Microvessel density (MVD) of primary biopsies of 37 patients was determined by immunohistochemistry. Tumor regression was correlated with MVD of primary biopsies and other clinico-pathological parameters. RESULTS: Regression presented mainly as necrosis or fibrosis/sclerosis upon histopathology. MFH, leiomyosarcoma, or clear cell sarcoma (CCS) responded well; whereas liposarcomas, synovial sarcomas, or MPNST were poor responders. MFH often had abundant necrosis; while other STS mainly presented with fibrosis/sclerosis. MVD had no influence on regression grade but modulated histologic regression patterns. Excellent regression demonstrated a trend toward an association with improved survival and local control. CONCLUSION: TM-ILP yielded high response rates in STS. Regression after TM-ILP exhibits MVD-dependent histopathologic patterns and variable efficacy in different sarcoma types. Complete regression seems to be a favorable prognostic factor. A concerted consideration of histopathology and clinical findings may contribute to a better clinical assessment of regression after TM-ILP.

Increased shedding of soluble TNF-receptor 1 during hyperthermic TNF-α-based isolated limb perfusion.

PURPOSE: Hyperthermic isolated limb perfusion (HILP) with TNF-α and melphalan has high response rates in patients with soft tissue sarcomas (STS) or melanomas of the limbs. Its effectiveness is based on the destructive effect of TNF-α on the blood supply of the tumours. Shedding of soluble TNF-receptor (sTNF-R) negatively modulates the effects of TNF-α, whereas hyperthermia (HT) induces shedding. Here, we investigated whether sTNF-R shedding in response to HT occurs during HILP. MATERIAL AND METHODS: The serum levels of sTNFR-1 were measured in 23 patients with HILP by obtaining serum from the extracorporeal and central circuits. The samples were taken from the patients under normothermic (37°C) and hyperthermic (39°C) conditions. Additionally, cell cultures of HUVEC, human fibrosarcoma cells and peripheral blood cells were used to confirm the effects of HT on sTNF-R1 shedding by ELISA and western blot. RESULTS: Under HT, levels of sTNF-R1 increased 23.5% in the extracorporeal circuit, but this increase was not observed in the systemic circuit. However, we could not confirm this effect using the cell culture model, where cellular TNF-R1 and sTNF-R1 of culture supernatants, respectively, were not significantly different between NT and HT conditions. CONCLUSIONS: HT is associated with an increase of sTNF-R1 in the extracorporeal circuit of perfused limbs. Interestingly, HT does not exhibit the same effect on cells cultured in vitro. Additional studies will be aimed at determining whether our findings have an impact in the clinic by analysing the relationship between TNF-R1 shedding and tumour response to HILP.

Overexpression of the drug resistance-associated protein metallothionein does not correlate with response of sarcomas to isolated limb perfusion treatment.

BACKGROUND AND OBJECTIVES: Hyperthermic isolated limb perfusion with TNF-alpha and melphalan (HILP-TM) achieves high response rates in sarcomas. Melphalan resistance was previously reported to be associated with overexpression of metallothioneins (MTs). Objective of this study was to investigate the influence of MT expression on tumor responses in HILP-TM-treated soft tissue (STSs) and bone sarcomas (BS). METHODS: In primary biopsies of 41 HILP-TM-treated sarcomas (37 STSs and 4 BS), MT expression was assessed by an immunoreactive score. The pathologic response to HILP-TM was quantified in the corresponding tumor resection specimens. We studied the association of MT-IRS between histological regression (responder >90%, or non-responder

Isolated closed minor-muscle injury of the lower leg did not cause an obvious systemic immune response.

OBJECTIVE: A common consequence in patients with blunt trauma is a deterioration of the immune system. The specific impacts of a frequently occurring isolated soft tissue trauma on the immune response are described. However, the dimension of trauma needed to cause systemic effects has not been definitely elucidated. METHODS: Mice were traumatized on the lower leg. The extent of soft tissue trauma was quantified by determination of the wet/dry ratio, magnetic resonance imaging (MRI), and serum content of muscle proteins. Five minutes, 3, 24, 36, 48, and 72 h after trauma (a.t.) the ex vivo cytokine-expression of immune-competent cells were measured. RESULTS: Trauma resulted in an early edema that could be quantified by MRI and wet/dry ration. Release of muscle-specific proteins was detected 5 min a.t. The trauma did not cause significant changes of TNF-alpha response of isolated cells to endotoxin. IL6-response of splenocytes to endotoxin was slightly increased 72 h a.t., while IL6-response of peritoneal macrophages to endotoxin was decreased 36 h a.t. CONCLUSION: We describe a standardized trauma model for minor soft tissue injury in mice. Systemic effects on the immune system by traumatized lower leg were not found on the level of circulating cytokines or cellular responses to endotoxin.

Inhibitors of deacetylases suppress oncogenic KIT signaling, acetylate HSP90, and induce apoptosis in gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GIST) are characterized by activating mutations of KIT or platelet-derived growth factor receptor A (PDGFRA), and treatment with the tyrosine kinase inhibitor imatinib yields responses in the majority of patients. However, most patients develop secondary resistance, which is associated with a dismal prognosis. Histone deacetylase inhibitors (HDACI) have been shown to enhance imatinib activity in imatinib-resistant chronic myelogenous leukemia. Against this background, we explored whether HDACI might provide an alternative therapeutic strategy to KIT/PDGFRA kinase inhibitors in GIST. Inhibition of cell proliferation by HDACI was seen in KIT-positive but not in KIT-negative GIST cell lines, suggesting that HDACI activity is mainly conferred by targeting oncogenic KIT. KIT activity, expression, and activation of downstream pathways were strongly inhibited by several HDACI (SAHA, LBH589, VPA, trichostatin A, and NaButyrate). SAHA and LBH589 induced apoptosis in KIT-positive GIST, and strong synergism with imatinib was observed at low concentrations of SAHA and LBH589. Mechanistically, treatment with HDACI reduced KIT mRNA transcript levels and led to strong acetylation of HSP90, interfering with its activity as KIT chaperone. These results provide preclinical evidence for a disease-specific effect of HDACI in KIT-positive GIST, which could translate into therapeutic activity.

Prognostic factors of liver injury in polytraumatic patients. Results from 895 severe abdominal trauma cases.

BACKGROUND AND AIMS: Prognosis of multiple injured patients is mainly limited by severe haemorrhage. Although mechanisms of altered immune response have been intensively investigated, little is known about the relevance of liver trauma as an independent predictive outcome factor in these patients. METHODS: 10,469 patients from the DGU Trauma Registry (1993-2005) were retrospectively analyzed. Primary admitted patients with an injury severity score > or = 16, without isolated head injury were included. Patients were analyzed according to the injury pattern as liver injury (Abbreviated Injury Scale--AIS abdomen < 3 and AIS liver 2-5; n = 321), non-liver abdominal trauma (AIS abdomen 2-5 or AIS liver < 3; n = 574) and control group without abdominal injuries (AIS abdomen or liver < 3; n = 9,574). RESULTS: Severe liver injury was associated with excessive demands for volume resuscitation and induced a significantly increased risk for sepsis and multi-organ failure (MOF) compared to both other groups (sepsis 19.9% vs. 11.0%; MOF 32.7% vs. 16.6%). Furthermore, deleterious outcome was more frequently associated with severe liver trauma (mortality 34.9%) compared to severe abdominal trauma (12.0%). CONCLUSION: Severe liver trauma is an independent predictor for severe haemorrhage with a substantially increased risk of sepsis, MOF and trauma-related death. While conservative treatment of patients with liver trauma but no haemorrhage is effective, patients with hemodynamic instability seem to be from a subgroup where contemporary treatment modalities are not yet sufficient.

Influence of head size on the development of metallic wear and on the characteristics of carbon layers in metal-on-metal hip joints.

BACKGROUND AND PURPOSE: Particles originating from the articulating surfaces of hip endoprostheses often induce an inflammatory response, which can be related to implant failure. We therefore analyzed the metal content in capsular tissue from 44 McKee-Farrar metal-on-metal hip prostheses (with 3 different head sizes) and we also analyzed the morphological structure of layers located on articulating surfaces. METHODS: Atomic absorption spectrometry (AAS) was used to analyze the metal content in capsular tissue. Visually detectable carbon layers located on the articulating surfaces were evaluated using scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), and X-ray photoelectron spectroscopy (XPS). RESULTS: Metallic debris was detected in all capsular tissue samples but no statistically significant differences in metal content were found in relation to implant head size. The morphological characteristics of the different layer zones allowed an exact analysis of contact and non-contact areas. Furthermore, surface layers appear to have a protective function because they can prevent sharp-edged particles from damaging the prostheses surface. INTERPRETATION: The implant head size does not appear to influence the amount of metallic debris. The layers obviously act like a lubricating agent because the protection function does not occur in regions without layers where the metal surface often shows numerous scratches. As layers are not generated immediately after the implantation of hip prostheses, these findings may at least partially explain the high amount of wear early after implantation.

Evaluation of 47 soft tissue sarcoma resection specimens after isolated limb perfusion with TNF-alpha and melphalan: histologically characterized improved margins correlate with absence of recurrences.

BACKGROUND: Isolated limb perfusion (TM-ILP) is an effective limb-sparing treatment for primarily nonresectable soft tissue sarcomas (STS). Surgical margins of STS after ILP were yet not systematically studied. METHODS: In 47 patients with nonresectable STS, TM-ILP with subsequent tumor resection was performed. Surgical margins were systematically analyzed by light microscopy using the TNM and the Enneking classification. Furthermore, margins were analyzed for tumor regression in terms of improved resectability. Results were correlated with clinical and pathological parameters. RESULTS: Of 47 STS, 44 were classified as high-grade (93.6%) with a median tumor size of 10.0 cm. Primary limb-salvage rate was 85.1%. According to TNM resection margins were complete in 70.2% (R0) and incomplete in 29.8% (R1=21.3%, R2=8.5%). According to Enneking, 27.7% intralesional, 42.6% marginal, 21.3% wide, 2.1% radical, and 6.4% unclassifiable margins were found. Prior surgery and/or radiotherapy significantly decreased margin quality. Ten patients with incomplete resection (three intralesional, seven marginal) had no viable tumor at the plane of dissection, which was designated as "improved margins." Whereas those patients remained relapse free, five patients with viable tumor (not improved margins) at the resection margin had local recurrences. Poor margins were associated with local and distant recurrences and limited disease-specific survival. CONCLUSION: TM-ILP is effective for achieving limb salvage. Histopathology of surgical margins demonstrates cases with so-called "improved margins" after TM-ILP, which are related to a better outcome even in intralesionally resected tumors. Improvement of margins should be further evaluated as a potential relevant prognostic parameter.

Recurrent high-grade leiomyosarcoma with heterologous osteosarcomatous differentiation.

Leiomyosarcomas (LM) of the soft tissue comprise approximately 5-10% of all soft tissue sarcomas. Besides the classic LM, several distinctly uncommon features of the cellular and growth patterns of LM have been described. The term "dedifferentiated LM" has rarely been used in the literature to describe soft tissue LM containing areas of undifferentiated, pleomorphic appearance or detectable heterologous differentiation. We report on a case of high-grade LM with almost entire transition to an osteosarcoma, which was classified as recurrent high-grade LM with heterologous osteosarcomatous differentiation. The identification of areas with osteosarcomatous dedifferentiation in soft tissue sarcomas can be of clinical importance because of a possible change in oncologic treatment strategies.