Planning Benchmark Study for Stereotactic Body Radiation Therapy of Pancreas Carcinomas with Simultaneously Integrated Boost and Protection: Results of the DEGRO/DGMP Working Group on Stereotactic Radiation Therapy and Radiosurgery.

PURPOSE/OBJECTIVE: The proximity or overlap of PTV and OAR poses a major challenge in SBRT of pancreatic cancer (PACA). This international treatment planning benchmark study investigates whether Simultaneously Integrated Boost (SIB) and Protection (SIP) concepts in PACA SBRT can lead to improved and harmonized plan quality. MATERIALS/METHODS: A multiparametric specification of desired target doses (GTVD50%, GTVD99%, PTVD95%, PTV0.5cc) with two prescription doses of GTVD50%=5×9.2Gy (46Gy) and GTVD50%=8×8.25Gy (66Gy) and OAR limits were distributed with planning CT and contours from 3 PACA patients. In phase 1, plans were ranked using a scoring system for comparison of trade-offs between GTV/PTV and OAR. In phase 2, re-planning was performed for the most challenging case and prescription with dedicated SIB and SIP contours provided for optimization after group discussion. RESULTS: For all 3 cases and both phases combined, 292 plans were generated from 42 institutions in 5 countries using commonly available treatment planning systems. The GTVD50% prescription was performed by only 76% and 74% of planners within 2% for 5 and 8 fractions, respectively. The GTVD99% goal was mostly reached, while the balance between OAR and target dose showed initial SIB/SIP-like optimization strategies in about 50% of plans. For plan ranking, 149 and 217 score penalties were given for 5 and 8 fractions, pointing to improvement possibilities. For phase 2, the GTVD50% prescription was performed by 95% of planners within 2% and GTVD99% as well as OAR doses were better harmonized with notable less score penalties. Fourteen of 19 planners improved their plan rank, 9 of them by at least 2 ranks. CONCLUSION: Dedicated SIB/SIP concepts in combination with multiparametric prescriptions and constraints can lead to overall harmonized and high treatment plan quality for PACA SBRT. Standardized SIB/SIP treatment planning in multicenter clinical trials appears feasible after group consensus and training.

Interobserver agreement on definition of the target volume in stereotactic radiotherapy for pancreatic adenocarcinoma using different imaging modalities.

PURPOSE: The aim of this study was to evaluate interobserver agreement (IOA) on target volume definition for pancreatic cancer (PACA) within the Radiosurgery and Stereotactic Radiotherapy Working Group of the German Society of Radiation Oncology (DEGRO) and to identify the influence of imaging modalities on the definition of the target volumes. METHODS: Two cases of locally advanced PACA and one local recurrence were selected from a large SBRT database. Delineation was based on either a planning 4D CT with or without (w/wo) IV contrast, w/wo PET/CT, and w/wo diagnostic MRI. Novel compared to other studies, a combination of four metrics was used to integrate several aspects of target volume segmentation: the Dice coefficient (DSC), the Hausdorff distance (HD), the probabilistic distance (PBD), and the volumetric similarity (VS). RESULTS: For all three GTVs, the median DSC was 0.75 (range 0.17-0.95), the median HD 15 (range 3.22-67.11) mm, the median PBD 0.33 (range 0.06-4.86), and the median VS was 0.88 (range 0.31-1). For ITVs and PTVs the results were similar. When comparing the imaging modalities for delineation, the best agreement for the GTV was achieved using PET/CT, and for the ITV and PTV using 4D PET/CT, in treatment position with abdominal compression. CONCLUSION: Overall, there was good GTV agreement (DSC). Combined metrics appeared to allow a more valid detection of interobserver variation. For SBRT, either 4D PET/CT or 3D PET/CT in treatment position with abdominal compression leads to better agreement and should be considered as a very useful imaging modality for the definition of treatment volumes in pancreatic SBRT. Contouring does not appear to be the weakest link in the treatment planning chain of SBRT for PACA.

Vestibular Schwannoma Hypofractionated Stereotactic Radiation Therapy in Five Fractions.

AIM: To retrospectively analyse the long-term results of hypofractionated stereotactic radiation therapy (HSRT) applied in five fractions for vestibular schwannomas. MATERIALS AND METHODS: One hundred and thirty-four patients with vestibular schwannomas underwent medical treatment of HSRT. The median follow-up time interval was 54 months (range 6-121 months). All patients had a prescribed dose of 22 Gy in five fractions to D90. Restaging was carried out by thin-slice contrast-enhanced T1 magnetic resonance imaging. Progression was defined as 2 mm post-treatment tumour enlargement. Progression or death for any reason was counted as an event in progression-free survival rates. Acute toxicity was defined as adverse events occurring within 3 months of HSRT; long-term toxicity was defined as such events occurring after 3 months. RESULTS: In 74/128 patients who had >6 months of follow-up (54%), the HSRT resulted in a partial or a complete response. The mean time interval for response in 50% of these was 4 years, whereas in 49 patients (38%) vestibular schwannomas failed to show any response, resulting in stable disease. Five of 128 patients (4%) showed marked progressive vestibular schwannomas after treatment in the first 3 years; two of them received conventionally fractionated radiation therapy. Local control at 3, 5 and 7 years was 96%, 95% and 94%, respectively. Seven were lost to follow-up. The median planning target volume was 2.1 ml (range 0.78-8.66). The 3- and 5-year progression-free survival rates were 95% and 94%, respectively. Seven patients reported a marked deterioration in hearing ability. Post-radiation therapy magnetic resonance imaging showed variability in oedema collection, but no patient suffered from radio-necrosis. Grade 2 temporary facial nerve disorders were observed in 10 patients (8%) 3-6 months after HSRT. CONCLUSION: Delivering HSRT in five fractions for vestibular schwannoma appears safe and efficient, combining both efficiency and short treatment time while optimising neurological function preservation.

F18-FDG PET/CT imaging early predicts pathologic complete response to induction chemoimmunotherapy of locally advanced head and neck cancer: preliminary single-center analysis of the checkrad-cd8 trial.

AIM: In the CheckRad-CD8 trial patients with locally advanced head and neck squamous cell cancer are treated with a single cycle of induction chemo-immunotherapy (ICIT). Patients with pathological complete response (pCR) in the re-biopsy enter radioimmunotherapy. Our goal was to study the value of F-18-FDG PET/CT in the prediction of pCR after induction therapy. METHODS: Patients treated within the CheckRad-CD8 trial that additionally received FDG- PET/CT imaging at the following two time points were included: 3-14 days before (pre-ICIT) and 21-28 days after (post-ICIT) receiving ICIT. Tracer uptake in primary tumors (PT) and suspicious cervical lymph nodes (LN +) was measured using different quantitative parameters on EANM Research Ltd (EARL) accredited PET reconstructions. In addition, mean FDG uptake levels in lymphatic and hematopoietic organs were examined. Percent decrease (Δ) in FDG uptake was calculated for all parameters. Biopsy of the PT post-ICIT acquired after FDG-PET/CT served as reference. The cohort was divided in patients with pCR and residual tumor (ReTu). RESULTS: Thirty-one patients were included. In ROC analysis, ΔSUVmax PT performed best (AUC = 0.89) in predicting pCR (n = 17), with a decline of at least 60% (sensitivity, 0.77; specificity, 0.93). Residual SUVmax PT post-ICIT performed best in predicting ReTu (n = 14), at a cutpoint of 6.0 (AUC = 0.91; sensitivity, 0.86; specificity, 0.88). Combining two quantitative parameters (ΔSUVmax ≥ 50% and SUVmax PT post-ICIT ≤ 6.0) conferred a sensitivity of 0.81 and a specificity of 0.93 for determining pCR. Background activity in lymphatic organs or uptake in suspected cervical lymph node metastases lacked significant predictive value. CONCLUSION: FDG-PET/CT can identify patients with pCR after ICIT via residual FDG uptake levels in primary tumors and the related changes compared to baseline. FDG-uptake in LN + had no predictive value. TRIAL REGISTRY: ClinicalTrials.gov identifier: NCT03426657.

Thiazolides promote G1 cell cycle arrest in colorectal cancer cells by targeting the mitochondrial respiratory chain.

Systemic toxicity and tumor cell resistance still limit the efficacy of chemotherapy in colorectal cancer. Therefore, alternative treatments are desperately needed. The thiazolide Nitazoxanide (NTZ) is an FDA-approved drug for the treatment of parasite-mediated infectious diarrhea with a favorable safety profile. Interestingly, NTZ and the thiazolide RM4819-its bromo-derivative lacking antibiotic activity-are also promising candidates for cancer treatment. Yet the exact anticancer mechanism(s) of these compounds still remains unclear. In this study, we systematically investigated RM4819 and NTZ in 2D and 3D colorectal cancer culture systems. Both compounds strongly inhibited proliferation of colon carcinoma cell lines by promoting G1 phase cell cycle arrest. Thiazolide-induced cell cycle arrest was independent of the p53/p21 axis, but was mediated by inhibition of protein translation via the mTOR/c-Myc/p27 pathway, likely caused by inhibition of mitochondrial respiration. While both thiazolides demonstrated mitochondrial uncoupling activity, only RM4819 inhibited the mitochondrial respiratory chain complex III. Interestingly, thiazolides also potently inhibited the growth of murine colonic tumoroids in a comparable manner with cisplatin, while in contrast to cisplatin thiazolides did not affect the growth of primary intestinal organoids. Thus, thiazolides appear to have a tumor-selective antiproliferative activity, which offers new perspectives in the treatment of colorectal cancer.

The impact of local control on overall survival after stereotactic body radiotherapy for liver and lung metastases from colorectal cancer: a combined analysis of 388 patients with 500 metastases.

BACKGROUND: The aim of this analysis was to model the effect of local control (LC) on overall survival (OS) in patients treated with stereotactic body radiotherapy (SBRT) for liver or lung metastases from colorectal cancer. METHODS: The analysis is based on pooled data from two retrospective SBRT databases for pulmonary and hepatic metastases from 27 centers from Germany and Switzerland. Only patients with metastases from colorectal cancer were considered to avoid histology as a confounding factor. An illness-death model was employed to model the relationship between LC and OS. RESULTS: Three hundred eighty-eight patients with 500 metastatic lesions (lung n = 209, liver n = 291) were included and analyzed. Median follow-up time for local recurrence assessment was 12.1 months. Ninety-nine patients with 112 lesions experienced local failure. Seventy-one of these patients died after local failure. Median survival time was 27.9 months in all patients and 25.4 months versus 30.6 months in patients with and without local failure after SBRT. The baseline risk of death after local failure exceeds the baseline risk of death without local failure at 10 months indicating better survival with LC. CONCLUSION: In CRC patients with lung or liver metastases, our findings suggest improved long-term OS by achieving metastatic disease control using SBRT in patients with a projected OS estimate of > 12 months.

Combination of stereotactic radiotherapy and targeted therapy: patterns-of-care survey in German-speaking countries.

INTRODUCTION: Stereotactic body radiotherapy (SBRT) is increasingly used in metastasized patients receiving targeted/immunotherapy. Information on safety and effectivity of concurrent SBRT and targeted/immunotherapy remains limited, resulting in a lack of consensus on treatment strategies. This study aimed to investigate how SBRT-experienced centers in German-speaking countries combine both therapies. MATERIALS AND METHODS: Patterns-of-care of combined treatment with SBRT and targeted/immunotherapy were assessed in 27 radiation oncology centers (19 German, 1 Austrian and 7 Swiss centers). A survey was performed to analyze the details of SBRT, SBRT planning and combined modality treatment. Consensus was defined as ≥75% agreement among participants. RESULTS: Most participants (60%) were university centers. SBRT for oligometastases has been performed since the year 2008 (median, range 1997-2016), since then a median of 140 cases (5-1100) of SBRT have been performed. In all, 67% performed concurrent SBRT and targeted agents. BRAF inhibitors and VEGF/EGFR inhibitors (bevacizumab [90%], erlotinib [11%], sorafenib [19%], lapatinib [4%]) were considered a contraindication. Bevacizumab was never given simultaneously with SBRT; other agents were given concurrently in 7-52% of centers. A majority (59%) paused targeted agents 1 week before/after SBRT. Only 1 center reduced SBRT dose when combined with targeted agents. CONCLUSION: Although evidence for safety and efficacy of concurrent SBRT and targeted agents is limited, it is regularly performed outside of clinical trials. The survey showed consensus not to combine SBRT with antiangiogenic agents, especially bevacizumab. Furthermore, SBRT with concurrent BRAF inhibitors should be practiced with caution and BRAF inhibitors should be paused at least 1 week before SBRT.

[Clinical target volume : Principles and limits]. / Klinisches Zielvolumen : Grundsätze und Grenzen.

BACKGROUND: The clinical target volume (CTV) is regarded fundamental for radiotherapy planning by the International Commission on Radiation Units and Measurements (ICRU). OBJECTIVES: The aim of this article is to give an overview on the basics and problems of defining the CTV for radiotherapy planning. MATERIALS AND METHODS: After briefly defining CTV, a short description of the process to homogenize CTV in intraindividual comparisons is given, where special attention is paid to radiological requirements. This information is summarized in a number of tables. RESULTS: CTV is the most complex volume among the target volumes that have been defined by the ICRU. A survey of the determinants of the definition of CTV is given. CONCLUSIONS: This overview on the basic rules of how to define CTVs can help to increase the understanding of the radiological requirements for optimum imaging to support radiotherapy planning regardless of the specialty of the physician.

[Small renal cell carcinoma-active surveillance and ablation]. / Kleines Nierenzellkarzinom ­ Aktive Überwachung und Ablation.

The incidence of renal cell carcinoma has been rising for years. At the same time there is an increasing prevalence of chronic renal failure with subsequent higher morbidity and shorter life expectancy in those affected. In the last decades the gold standard has thus shifted from radical to partial nephrectomy or tumor enucleation. A treatment alternative can be advantageous for selected patients with high morbidity and an increased risk of complications in anesthesia or surgery. Active surveillance represents a controlled delay in the initiation of treatment with a curative intention. Percutaneous radiofrequency ablation and laparoscopic cryoablation are currently the most commonly used treatment alternatives. Newer ablation procedures, such as high-intensity focused ultrasound, irreversible electroporation, microwave ablation, stereotactic ablative radiotherapy and high-dose brachytherapy have a high potential in some cases but are still considered experimental for the treatment.

The SBRT database initiative of the German Society for Radiation Oncology (DEGRO): patterns of care and outcome analysis of stereotactic body radiotherapy (SBRT) for liver oligometastases in 474 patients with 623 metastases.

BACKGROUND: The intent of this pooled analysis as part of the German society for radiation oncology (DEGRO) stereotactic body radiotherapy (SBRT) initiative was to analyze the patterns of care of SBRT for liver oligometastases and to derive factors influencing treated metastases control and overall survival in a large patient cohort. METHODS: From 17 German and Swiss centers, data on all patients treated for liver oligometastases with SBRT since its introduction in 1997 has been collected and entered into a centralized database. In addition to patient and tumor characteristics, data on immobilization, image guidance and motion management as well as dose prescription and fractionation has been gathered. Besides dose response and survival statistics, time trends of the aforementioned variables have been investigated. RESULTS: In total, 474 patients with 623 liver oligometastases (median 1 lesion/patient; range 1­4) have been collected from 1997 until 2015. Predominant histologies were colorectal cancer (n = 213 pts.; 300 lesions) and breast cancer (n = 57; 81 lesions). All centers employed an SBRT specific setup. Initially, stereotactic coordinates and CT simulation were used for treatment set-up (55%), but eventually were replaced by CBCT guidance (28%) or more recently robotic tracking (17%). High variance in fraction (fx) number (median 1 fx; range 1­13) and dose per fraction (median: 18.5 Gy; range 3­37.5 Gy) was observed, although median BED remained consistently high after an initial learning curve. Median follow-up time was 15 months; median overall survival after SBRT was 24 months. One- and 2-year treated metastases control rate of treated lesions was 77% and 64%; if maximum isocenter biological equivalent dose (BED) was greater than 150 Gy EQD2Gy, it increased to 83% and 70%, respectively. Besides radiation dose colorectal and breast histology and motion management methods were associated with improved treated metastases control. CONCLUSION: After an initial learning curve with regards to total cumulative doses, consistently high biologically effective doses have been employed translating into high local tumor control at 1 and 2 years. The true impact of histology and motion management method on treated metastases control deserve deeper analysis. Overall survival is mainly influenced by histology and metastatic tumor burden.

Interobserver variability in target volume delineation of hepatocellular carcinoma : An analysis of the working group "Stereotactic Radiotherapy" of the German Society for Radiation Oncology (DEGRO).

BACKGROUND: Definition of gross tumor volume (GTV) in hepatocellular carcinoma (HCC) requires dedicated imaging in multiple contrast medium phases. The aim of this study was to evaluate the interobserver agreement (IOA) in gross tumor delineation of HCC in a multicenter panel. METHODS: The analysis was performed within the "Stereotactic Radiotherapy" working group of the German Society for Radiation Oncology (DEGRO). The GTVs of three anonymized HCC cases were delineated by 16 physicians from nine centers using multiphasic CT scans. In the first case the tumor was well defined. The second patient had multifocal HCC (one conglomerate and one peripheral tumor) and was previously treated with transarterial chemoembolization (TACE). The peripheral lesion was adjacent to the previous TACE site. The last patient had an extensive HCC with a portal vein thrombosis (PVT) and an inhomogeneous liver parenchyma due to cirrhosis. The IOA was evaluated according to Landis and Koch. RESULTS: The IOA for the first case was excellent (kappa: 0.85); for the second case moderate (kappa: 0.48) for the peripheral tumor and substantial (kappa: 0.73) for the conglomerate. In the case of the peripheral tumor the inconsistency is most likely explained by the necrotic tumor cavity after TACE caudal to the viable tumor. In the last case the IOA was fair, with a kappa of 0.34, with significant heterogeneity concerning the borders of the tumor and the PVT. CONCLUSION: The IOA was very good among the cases were the tumor was well defined. In complex cases, where the tumor did not show the typical characteristics, or in cases with Lipiodol (Guerbet, Paris, France) deposits, IOA agreement was compromised.

Pancreatic stellate cells in pancreatic cancer: In focus.

Pancreatic stellate cells are stromal cells that have multiple physiological functions such as the production of extracellular matrix, stimulation of amylase secretion, phagocytosis and immunity. In pancreatic cancer, stellate cells exhibit a different myofibroblastic-like morphology with the expression of alpha-smooth muscle actin, the activated form is engaged in several mechanisms that support tumorigenesis and cancer invasion and progression. In contrast to the aforementioned observations, eliminating the stromal cells that are positive for alpha-smooth muscle actin resulted in immune-evasion of the cancer cells and resulted in worse prognosis in animal models. Understanding the cancer-stromal signaling in pancreatic adenocarcinoma will provide novel strategies for therapy. Here we provide an updated review of studies that handle the topic "pancreatic stellate cells in cancer" and recent experimental approaches that can be the base for future directions in therapy.

Stereotactic body radiotherapy for oligo-metastatic liver disease - Influence of pre-treatment chemotherapy and histology on local tumor control.

INTRODUCTION: Stereotactic body radiation therapy (SBRT) is applied in the oligometastatic setting to treat liver metastases. However, factors influencing tumor control probability (TCP) other than radiation dose have not been thoroughly investigated. Here we set out to investigate such factors with a focus on the influence of histology and chemotherapy prior to SBRT using a large multi-center database from the German Society of Radiation Oncology. METHODS: 452 SBRT treatments in 363 patients were analyzed after collection of patient, tumor and treatment data in a multi-center database. Histology was considered through random effects in semi-parametric and parametric frailty models. Dose prescriptions were parametrized by conversion to the maximum biologically effective dose using alpha/beta of 10Gy (BEDmax). RESULTS: After adjusting for histology, BEDmax was the strongest predictor of TCP. Larger PTV volumes, chemotherapy prior to SBRT and simple motion management techniques predicted significantly lower TCP. The model predicted a BED of 209±67Gy10 necessary for 90% TCP at 2years with no prior chemotherapy, but 286±78Gy10 when chemotherapy had been given. Breast cancer metastases were significantly more responsive to SBRT compared to other histologies with 90% TCP at 2years achievable with BEDmax of 157±80Gy10 or 80±62Gy10 with and without prior chemotherapy, respectively. CONCLUSIONS: Besides dose, histology and pretreatment chemotherapy were important factors influencing local TCP in this large cohort of liver metastases. After adjusting for prior chemotherapy, our data add to the emerging evidence that breast cancer metastases do respond better to hypofractionated SBRT compared to other histologies.

Correlation of 18F-Fluorodeoxyglucose Positron Emission Tomography Parameters with Patterns of Disease Progression in Locally Advanced Pancreatic Cancer after Definitive Chemoradiotherapy.

AIMS: A proportion of patients with pancreatic cancer never develop metastatic disease. We evaluated a role for 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in identifying a subset of patients with locally advanced pancreatic cancer (LAPC) who never develop metastatic disease and only experience local disease and may therefore benefit from local treatment intensification. MATERIAL AND METHODS: Patients with histologically confirmed LAPC entered a single-centre phase II study of definitive upfront chemoradiotherapy (CRT). All patients underwent FDG-PET/CT before and 6 weeks after CRT. Tumour volume, standardised uptake values (SUVmax, SUVpeak, SUVmean, SUVmedian) and total lesion glycolysis (TLG) were measured on each scan and the response in each parameter was evaluated. The presence or absence of metastatic disease was noted on contrast-enhanced CT carried out every 3 months for 1 year and then at clinician discretion. RESULTS: Twenty-three patients with LAPC were recruited; 17/23 completed treatment and had interpretable sequential imaging. Twenty-four per cent of patients only ever experienced local disease. Median pre-CRT FDG-PET parameters were significantly lower in patients with local disease only during follow-up compared with those who developed metastatic disease: SUVmax 3.8 versus 8.6 (P=0.006), SUVpeak 2.5 versus 7.5 (P=0.002), SUVmean 1.8 versus 3.3 (P=0.001), SUVmedian 1.7 versus 3.0 (P=0.002), TLG 26.9 versus 115.9 (P=0.006). Tumour volume, post-CRT FDG-PET values and their relative change were not statistically different between local disease and metastatic disease groups. Receiver operating characteristic curves for pre-CRT FDG-PET parameters to predict those who never develop metastatic disease all had areas under the curve (AUCs) ≥ 0.932. Pre-CRT FDG-PET SUVmax < 6.2 predicted patients with local disease only during follow-up with 100.0% sensitivity and 92.3% specificity, 80.0% positive predictive value and 100% negative predictive value. CONCLUSIONS: Our findings suggest that patients with less FDG-avid tumours are less likely to metastasise and may therefore benefit from upfront local treatment intensification.

Stereotactic body radiotherapy (SBRT) in recurrent or oligometastatic pancreatic cancer : A toxicity review of simultaneous integrated protection (SIP) versus conventional SBRT.

BACKGROUND: Stereotactic body radiotherapy (SBRT) in pancreatic cancer can be limited by its proximity to organs at risk (OAR). In this analysis, we evaluated the toxicity and efficacy of two different treatment approaches in patients with locally recurrent or oligometastatic pancreatic cancer. MATERIALS AND METHODS: According to the prescription method, patients were divided in two cohorts (C1 and C2). The planning target volume (PTV) was created through a 4 mm expansion of the internal target volume. In C2, a subvolume was additionally created, a simultaneous integrated protection (SIP), which is the overlap of the PTV with the planning risk volume of an OAR to which we prescribed a reduced dose. RESULTS: In all, 18 patients were treated (7 with local recurrences, 9 for oligometastases, 2 for both). Twelve of 23 lesions were treated without SIP (C1) and 11 with SIP (C2). The median follow-up was 12.8 months. Median overall survival (OS) was 13.2 (95% confidence interval [CI] 9.8-14.6) months. The OS rates at 6 and 12 months were 87 and 58%, respectively. Freedom from local progression for combined cohorts at 6 and 12 months was 93 and 67% (95% CI 15-36), respectively. Local control was not statistically different between the two groups. One patient in C2 experienced grade ≥3 acute toxicities and 1 patient in C1 experienced a grade ≥3 late toxicity. CONCLUSION: The SIP approach is a useful prescription method for abdominal SBRT with a favorable toxicity profile which does not compromise local control and overall survival despite dose sacrifices in small subvolumes.

Thiazolides promote apoptosis in colorectal tumor cells via MAP kinase-induced Bim and Puma activation.

While many anticancer therapies aim to target the death of tumor cells, sophisticated resistance mechanisms in the tumor cells prevent cell death induction. In particular enzymes of the glutathion-S-transferase (GST) family represent a well-known detoxification mechanism, which limit the effect of chemotherapeutic drugs in tumor cells. Specifically, GST of the class P1 (GSTP1-1) is overexpressed in colorectal tumor cells and renders them resistant to various drugs. Thus, GSTP1-1 has become an important therapeutic target. We have recently shown that thiazolides, a novel class of anti-infectious drugs, induce apoptosis in colorectal tumor cells in a GSTP1-1-dependent manner, thereby bypassing this GSTP1-1-mediated drug resistance. In this study we investigated in detail the underlying mechanism of thiazolide-induced apoptosis induction in colorectal tumor cells. Thiazolides induce the activation of p38 and Jun kinase, which is required for thiazolide-induced cell death. Activation of these MAP kinases results in increased expression of the pro-apoptotic Bcl-2 homologs Bim and Puma, which inducibly bind and sequester Mcl-1 and Bcl-xL leading to the induction of the mitochondrial apoptosis pathway. Of interest, while an increase in intracellular glutathione levels resulted in increased resistance to cisplatin, it sensitized colorectal tumor cells to thiazolide-induced apoptosis by promoting increased Jun kinase activation and Bim induction. Thus, thiazolides may represent an interesting novel class of anti-tumor agents by specifically targeting tumor resistance mechanisms, such as GSTP1-1.

[Surgical treatment of esophageal cancer : Evolution of management and prognosis over the last 3 decades]. / Chirurgische Therapie des Ösophaguskarzinoms : Entwicklung von Management und Prognose über die letzten drei Jahrzehnte.

BACKGROUND: An increasing incidence of adenocarcinoma, a modified surgical strategy and the increasing use of multimodal therapeutic protocols have had a major impact on the surgical treatment of esophageal cancer during the last 3 decades. OBJECTIVES: This study analyzed the development of these factors and their impact on the short and long-term prognosis of esophageal cancer over the last 25 years. PATIENTS AND METHODS: The study included 366 patients with esophageal cancer treated by esophagectomy at the University Hospital in Freiburg from 1988 to 2012. The study period was split into four time periods for further comparisons, i.e. 1988-1994, 1995-2001, 2001-2006 and 2007-2012. RESULTS: Within the time periods analyzed a marked increase in adenocarcinoma was found (time periods1988-1994, 1995-2001, 2001-2006 and 2007-2012: 21%, 37%, 61% and 64%, respectively, p<0.001). The initially commonly used transhiatal approach and reconstruction with cervical anastomosis was gradually replaced by the thoracoabdominal procedure with intrathoracic reconstruction (i.e. Ivor Lewis esophagectomy, 2007-2012: 98 %). During the study period increasingly more patients received multimodal therapy (13%, 85%, 72% and 84%, p<0.001), the overall rate of perioperative complications (70%, 88%, 73% and 56%, p<0.001) and perioperative mortality (16%, 18%, 8% and 2.5%, p<0.001) were significantly reduced, while the overall 5-year survival (12%, 34%, 41% and 62%, p<0.001) improved. An early tumor stage (p=0.002), N0 status (p<0.001) and histological type of adenocarcinoma (p=0.011) were identified as independent predictors of improved survival. CONCLUSION: During the period from 1988 to 2012 a significant improvement of long-term survival as well as a marked reduction of perioperative mortality after esophagectomy were observed. The improved outcome was associated with an increased use of multimodal therapeutic protocols, the preferred use of thoracoabdominal esophagectomy and epidemiological changes in histology over the study period.