G. Taeger

Resection of residual disease in patients with metastatic gastrointestinal stromal tumors responding to treatment with imatinib

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Long‐term survival of patients with metastatic disease has only been observed in patients with completely resected disease. Recently, the tyrosine kinase inhibitor imatinib has been found to yield responses in the majority of patients with metastatic GIST suggesting improved resectability in responding patients. Combined treatment approaches including resective surgery after imatinib treatment in patients with advanced metastatic disease have rarely been explored. We report a series of 90 patients with metastatic GIST in whom treatment with imatinib enabled 12 patients with mostly recurrent and extensive disease to be considered for resection of residual disease. In 11 of these patients, complete resection could be achieved. Viable tumor cells were found in all but one resected specimens suggesting that despite favorable radiological or clinical responses, imatinib is unlikely to induce pathological complete responses. Until more mature data from prospective trials are available, these data suggest that an early aggressive surgical approach should be considered for all patients with metastatic GIST. Further trials investigating a combined surgical and pre/postoperative treatment with imatinib in patients with advanced metastatic GIST are warranted.

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.

Damage Control Orthopedics

ZusammenfassungHintergrundIm Rahmen der Polytraumaversorgung wird das „Damage-control-orthopedics- (DCO-)Konzept“ weiterhin kontrovers diskutiert. Damit erhebt sich die Frage nach dem Stellenwert dieses Verfahrens.ErgebnisseIn einem Review der Vielzahl von Publikationen werden die schweregradabhängige unfallbedingte inflammatorische Reaktion sowie deren prognostische Bedeutung für den weiteren Verlauf herausgestellt. Neben eigenen Ergebnissen zeigen weitere aktuelle Literaturberichte, dass Operationen eine additive Entzündungsreaktion verursachen und dass diese nach primären Oberschenkelmarknagelungen wesentlich stärker ausgeprägt sind als nach Fixateur-externe-Stabilisierungen. Dagegen ist die inflammatorische Reaktion nach sekundären Marknagelungen wesentlich geringer ausgeprägt als bei der primären Marknagelung. In 3 retrospektiven Kohortenstudien konnte nachgewiesen werden, dass DCO zu einer Reduzierung von Organfunktionsstörungen und zu einer verbesserten Überlebensrate führte. Gleichzeitig konnte in weiteren Untersuchungen aufgezeigt werden, dass die Wechseloperationen vom Fixateur externe auf die definitiven Stabilisierungen zu keiner erhöhten Rate an lokalen und systemischen Komplikationen führte.SchlussfolgerungDie Autoren der dargestellten DCO-Kollektive argumentieren, dass schwer Polytraumatisierte mit schwerem Schädel-Hirn- bzw. Thoraxtrauma, instabiler Kreislaufsituation und ausgeprägter systemischer Entzündungsreaktion durch eine primäre definitive Frakturversorgung gefährdet sind. In diesen Fällen sollte deshalb eine primäre minimal-invasive externe Frakturstabilisierung ohne additivem inflammatorischem Trauma und sekundärer definitiver Versorgung nach intensivmedizinischer Stabilisierung erfolgen.AbstractBackgroundIn the management of patients with multiple injuries, the concept of damage control orthopedics (DCO) is still a matter of controversy. Thus, the clinical value of DCO remains unclear and should be evaluated on an evidence-based level by a review of the current literature.ResultsThe work of various authors has demonstrated an association between injury severity and the clinical immunoinflammatory response and its prognostic relevance regarding organ dysfunction or organ failure and clinical outcome. Research data published by the authors and other investigators have clearly demonstrated an additional inflammatory response caused by surgical trauma which is significantly higher after primary intramedullary fracture treatment than after external fracture stabilization. In contrast, a generally minor inflammatory response seems to be associated with intramedullary nailing for secondary conversion osteosynthesis. Three retrospective cohort studies have shown a reduction of organ dysfunction and an improvement of survival with the DCO approach. Simultaneously, it was demonstrated that primary external fracture fixation and secondary conversion to definite osteosynthesis is not associated with an increased rate of local or systemic complications.ConclusionsThe advocates of DCO claim that patients with multiple injuries including severe brain and chest injuries as well as those with an unstable cardiopulmonary or circulatory condition are at high risk of developing a severe systemic immunoinflammatory reaction during early total fracture care. Therefore, they recommend primary minimally invasive external fracture stabilization in these patients to avoid additional surgical trauma and that definitive secondary fracture care should be performed after medical stabilization of the patient in intensive care.

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.

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.

Effectiveness of regional chemotherapy with TNF-α/Melphalan in advanced soft tissue sarcoma of the extremities

Hyperthermic isolated limb perfusion with tumour necrosis factor alpha (TNF-α) and melphalan was repeatedly reported to achieve extraordinarily high clinical remission rates in advanced and non-resectable soft tissue sarcoma of the limbs, thus avoiding imminent mutilation or amputation for most of those patients. With the limb being isolated throughout the extracorporal perfusion, high doses of recombinant TNF-α as well as melphalan can be applied. Basically, TNF-α directly affects the vasculature of the tumour and induces a severe inflammation with consecutive deterioration of the tumour capillaries. Furthermore, TNF-α increases the tumour-selective uptake of melphalan into the tumour cells thus leading to synergy of antivascular targeted treatment and antineoplastic effects of highest dose chemotherapy supplemented by hyperthermia. Meanwhile, a lot of sarcoma centres in Europe adopted this technique and established referral programmes for patients with non-resectable soft tissue sarcomas of the limbs. Despite these programmes many patients still do not get offered hyperthermic ILP with TNF-α and melphalan as a treatment option and modality. This article summarizes multimodality in treatment of soft tissue sarcoma of the limbs and reviews the current status of melphalan-based ILP with TNF-α (TM-ILP) and its results, to enable comparison and critical consideration of other treatment options.

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.

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

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.

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 Mesurements: 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.

Management of polytrauma

ZusammenfassungDie ersten Stunden nach Trauma sind entscheidend für die Prognose. Das Behandlungsvorgehen erfordert daher ein stringentes zeit- und prioritätenorientiertes Konzept unter dem Gesichtspunkt eines modernen Qualitätsmanagements. Dies beginnt bereits mit der schnellstmöglichen und zielgerichteten Einlieferung Schwerverletzter in eine geeignete Klinik, welche über ständige Schockraumbereitschaft, alle notwendigen diagnostischen Möglichkeiten, eventuell erforderliche chirurgische Disziplinen sowie operative und intensivmedizinische Kapazitäten verfügen sollte. Effizientes Schockraummanagement bedeutet standardisierte Maßnahmenabfolgen mit einem Nebeneinander diagnostischer und therapeutischer Maßnahmen. An die Erfassung und Therapie unmittelbar lebensbedrohender Verletzungen (Sofortmaßnahmen/Notoperationen/“damage control surgery“) schließen sich in der Frühphase weitere Operationen an (Weichteilverletzungen/Frakturen). Dabei setzt sich wegen der potenziellen Gefährdung der Vitalfunktionen durch traumabedingte pro- und antiinflammatorische Reaktionen und durch operationsbedingte additive Traumata die Damage-control-orthopedics-Strategie immer mehr durch. Die zunächst mit Fixateur externe stabilisierten Frakturen können dann sekundär gefahrlos definitiv versorgt werden. Durch die Implementierung von Therapieprotokollen, die von allen beteiligten Disziplinen erarbeitet und akzeptiert wurden, sowie durch standardisierte Systeme des Qualitätsmanagement mit internen und externen Rückkopplungsmechanismen konnte zudem eine erhebliche Verbesserung der Behandlungsqualität erreicht werden.AbstractThe first hours after trauma are decisive. Therefore the treatment chosen demands very strict planning according to concepts of modern quality management. This begins with the fastest possible and most efficient delivery of injured patients to the applicable clinic. Such institutions are permanently ready and have at their service all the necessary diagnostic techniques and surgical and intensive care methods. Effective shock treatment entails standardized procedures accompanied by up-to-date diagnostic and therapeutic measures. After admittance and therapy of life-threatening injuries (immediate measures, damage control surgery), early-stage surgery will follow (soft tissue injuries and fractures). Strategy of damage control orthopedics is growing in acceptance because of the potential danger to life functions due to pro- and anti-inflammatory response induced additional trauma caused by following surgery. Fractures initially stabilized by external fixation can consecutively be treated safely by secondary conversion osteosynthesis. A considerable improvement in quality can be attained through therapeutic procedures approved by all concomitant disciplines and standardized systems with internal and external control methods.