Comparative study of short-and long-term results in patients with perihilar cholangiocarcinoma undergoing surgical resection: does the extent and side of resection really affect outcome?

BACKGROUND: The surgical management of perihilar carcinoma (pCCA) is still subject of ongoing debate. To provide more clarity, this study was conducted to evaluate outcomes related to the side and extent of heatectomy in patients with pCAA. METHODS: A total of 32 patients with curative resection for pCCA were identified from our prospective database. Short-and long-term clinical outcome data and histopathological results were compared between right-sided (R-H) and left-sided (L-H) hepatectomy. RESULTS: Nine patients (28.13%) underwent left-sided hepatectomy while a right-sided hepatectomy was accomplished in 23 patients (71.87%). In the R-H group hepatic conditioning of the future liver remnant (FLR) prior to extended resection was necessary in 13 cases (56.52%), and simultaneous pancreaticoduodenectomy was performed in 5 patients (21.74%). The arterial and portal venous reconstruction rates were 17.39% and 11.11% (P=1.00), and 60.87% and 33.33% (P=0.243) in the R-H and L-H groups, respectively. No statistically significant differences in short-term morbidity and mortality between both groups were observed. The rate of R0 resections was comparable (R-H: 78.26% versus L-H: 66.67%; P=0.654) resulting in similar long-term overall and disease-free survival rates after right-and left hepatectomy. CONCLUSIONS: In patients with pCCA, both right- and left-sided resections appear to be safe and feasible options with similar postoperative morbidity and oncologic outcomes. Consecutively, the ideal surgical approach should be patient-tailored based on anatomical considerations and the functional future liver capacity.

Predictive factors of 90-day mortality after curative hepatic resection for hepatocellular carcinoma: a western single-center observational study.

PURPOSE: The aim of this study was to identify predictive risk factors associated with 90-day mortality after hepatic resection (HR) in hepatocellular carcinoma (HCC). METHODS: All patients undergoing elective resection for HCC from a single- institutional and prospectively maintained database were included. Multivariate regression analysis was conducted to identify pre- and intraoperative as well as histopathological predictive factors of 90-day mortality after elective HR. RESULTS: Between August 2004 and October 2021, 196 patients were enrolled (148 male /48 female). The median age of the study cohort was 68.5 years (range19-84 years). The rate of major hepatectomy (≥ 3 segments) was 43.88%. Multivariate analysis revealed patient age ≥ 70 years [HR 2.798; (95% CI 1.263-6.198); p = 0.011], preoperative chronic renal insufficiency [HR 3.673; (95% CI 1.598-8.443); p = 0.002], Child-Pugh Score [HR 2.240; (95% CI 1.188-4.224); p = 0.013], V-Stage [HR 2.420; (95% CI 1.187-4.936); p = 0.015], and resected segments ≥ 3 [HR 4.700; (95% 1.926-11.467); p = 0.001] as the major significant determinants of the 90-day mortality. CONCLUSION: Advanced patient age, pre-existing chronic renal insufficiency, Child-Pugh Score, extended hepatic resection, and vascular tumor involvement were identified as significant predictive factors of 90-day mortality. Proper patient selection and adjustment of treatment strategies could potentially reduce short-term mortality.

Which factors predict tumor recurrence and survival after curative hepatectomy in hepatocellular carcinoma? Results from a European institution.

BACKGROUND: High tumor recurrence and dismal survival rates after curative intended resection for hepatocellular carcinoma (HCC) are still concerning. The primary goal was to assess predictive factors associated with disease-free (DFS) and overall survival (OS) in a subset of patients with HCC undergoing hepatic resection (HR). METHODS: Between 08/2004-7/2021, HR for HCC was performed in 188 patients at our institution. Data allocation was conducted from a prospectively maintained database. The prognostic impact of clinico-pathological factors on DFS and OS was assessed by using uni- and multivariate Cox regression analyses. Survival curves were generated with the Kaplan Meier method. RESULTS: The postoperative 1-, 3- and 5- year overall DFS and OS rates were 77.9%, 49.7%, 41% and 72.7%, 54.7%, 38.8%, respectively. Tumor diameter ≥ 45 mm [HR 1.725; (95% CI 1.091-2.727); p = 0.020], intra-abdominal abscess [HR 3.812; (95% CI 1.859-7.815); p < 0.0001], and preoperative chronic alcohol abuse [HR 1.831; (95% CI 1.102-3.042); p = 0.020] were independently predictive for DFS while diabetes mellitus [HR 1.714; (95% CI 1.147-2.561); p = 0.009), M-Stage [HR 2.656; (95% CI 1.034-6.826); p = 0.042], V-Stage [HR 1.946; (95% CI 1.299-2.915); p = 0.001, Sepsis [HR 10.999; (95% CI 5.167-23.412); p < 0.0001], and ISGLS B/C [HR 2.008; (95% CI 1.273-3.168); p = 0.003] were significant determinants of OS. CONCLUSIONS: Despite high postoperative recurrence rates, an acceptable long-term survival in patients after curative HR could be achieved. The Identification of parameters related to OS and DFS improves patient-centered treatment and surveillance strategies.

Optimizing Growth of the Future Liver Remnant and Making In-Situ Liver Transsection Safe-A Standardized Approach to ISLT or ALPPS.

In-situ splitting of the liver before extended resection has gained broad attention. This two-step procedure requires several measures to make an effective and safe procedure. Although the procedure is performed in many institutions, there is no consensus on a uniform technique. The two steps can be divided into different parts and a standardized technique may render the procedure safer and the results will be easier to evaluate. In this paper, we describe a detailed approach to in-situ splitting that allows making both procedures safe, avoids liver necrosis, and is easily reproducible. In the first procedure the portal branches to segments I and IV to VIII are divided, the arterial branches and bile ducts to these segments are preserved and encircled and the parenchyma between segments II/III and IVa/b is divided. This avoids necrosis and bile leaks of segments I and IV and avoids urgent completion operations. In particular, the handling of vital structures close to the dissection line seems important to us. Complete splitting and securing the right and middle hepatic vein will make the second step of this procedure a minimal-risk procedure at a stage where the patient is still recovering from the more demanding first step.

Clinicopathological and Prognostic Value of Survivin Expression in Surgically Resected Pancreatic Ductal Adenocarcinoma.

Background: Survival after surgery for pancreatic ductal adenocarcinoma (PDAC) remains poor. Thus, novel therapeutic concepts focus on the development of targeted therapies. In this context, inhibitor of apoptosis protein (IAP) survivin is regarded as a promising oncotherapeutic target. However, its expression and prognostic value in different tumour compartments of PDAC have not been studied. Methods: Immunohistochemical analysis of survivin in different PDAC tumour compartments from 236 consecutive patients was correlated with clinicopathological variables and survival. Results: In comparison to healthy pancreatic tissue high nuclear (p < 0.001) and high cytoplasmic (p < 0.01) survivin expression became evident in the tumour centre, along the invasion front and in lymph node metastases. Cytoplasmic overexpression of survivin in tumour centres was related to the presence of distant metastasis (p = 0.016) and UICC III/IV stages (p = 0.009), while high cytoplasmic expression at the invasion front grouped with venous infiltration (p = 0.022). Increased nuclear survivin along the invasion front correlated with perineural invasion (p = 0.035). High nuclear survivin in tumour centres represented an independent prognostic factor for overall survival of pancreatic tail carcinomas (HR 13.5 95%CI (1.4−129.7)) and correlated with a limited disease-free survival in PDAC (HR 1.80 95%CI (1.04−3.12)). Conclusion: Survivin is associated with advanced disease stages and poor prognosis. Therefore, survivin will help to identify patients with aggressive tumour phenotypes that could benefit from the inclusion in clinical trials incorporating survivin inhibitors in PDAC.

Effectiveness of Video-Assisted Thoracoscopic Surgery with Bullectomy and Partial Pleurectomy in the Treatment of Primary Spontaneous Pneumothorax-A Retrospective Long-Term Single-Center Analysis.

Background: Video-assisted thoracoscopic surgery (VATS) with bullectomy and partial pleurectomy (VBPP) is an increasingly used and well-established surgical treatment for primary spontaneous pneumothorax (PSP). However, reports on its effectiveness and long-term outcomes are limited. The aim of this study was to assess and compare long-term recurrence rates following VBPP and chest tube (CT) treatment and to identify potential risk factors for disease recurrence in patients with PSP. Methods: A total of 116 patients treated either by VBPP or CT were included in this study. Long-term recurrence rates and associations between clinical parameters and recurrence of pneumothorax were analyzed. Results: Sixty-two patients (53.4%) underwent VBPP, whereas 54 (46.6%) patients underwent CT treatment only. During a median follow-up period of 76.5 months, VBPP patients experienced a significantly lower recurrence rate compared to CT patients (6/62 vs. 35/54; p < 0.0001). CT treatment (VBPP vs. CT; p < 0.001) and a large initial pneumothorax size (Collins < 4 vs. Collins ≥ 4; p = 0.018) were independent risk factors for pneumothorax recurrence. Conclusion: VBPP is an effective and safe surgical treatment for PSP. Therefore, patients with a large pneumothorax size might benefit from VBPP, as they are at high risk for disease recurrence.

Video-Assisted Thoracoscopic Surgery with Bullectomy and Partial Pleurectomy versus Chest Tube Drainage for Treatment of Secondary Spontaneous Pneumothorax-A Retrospective Single-Center Analysis.

Background and objective: Current guidelines recommend chest tube (CT) drainage as the initial treatment of secondary spontaneous pneumothorax (SSP). Surgery should be considered in cases of persistent air leak or recurrent disease. Video-assisted thoracoscopic surgery (VATS) is nowadays an established surgical treatment for complicated spontaneous pneumothorax. However, reports on VATS-bullectomy with partial pleurectomy (VBPP) for treatment of secondary spontaneous pneumothorax (SSP) are limited. The primary aim of this study was to evaluate and compare the clinical outcomes of patients with secondary pneumothorax treated either by VBPP or CT drainage in our institution. Secondly, we assessed underlying clinical parameters to identify potential risk factors for SSP recurrence. Materials and Methods: Eighty-two patients were included in this study. Long-term recurrence rates and potential risk factors for SSP recurrence were analyzed. Results: Thirty-six patients (43.9%) underwent VBPP, whereas 46 (56.1%) patients subsequently underwent CT treatment. During a median follow-up period of 76.5 months, VBPP patients experienced a significantly low recurrence rate compared to CT patients (VBPP vs. CT: 16.7% vs. 41.3%; p = 0.016). However, VBPP was associated with a higher complication rate and significantly longer length of hospital stay (LOS). Male sex (male vs. female: p = 0.021) and CT treatment (VBPP vs. CT: p < 0.001) were identified as potential risk factors for SSP recurrence. Conclusions: VBPP is a suitable surgical treatment for SSP. However, prolonged LOS and possible complications should be discussed prior to VBPP.

Postoperative Pain and Clinical Outcome Following Two- and Three-Port Video-Assisted Thoracoscopic Surgery for Secondary Spontaneous Pneumothorax.

BACKGROUND: Two-port (2P) and three-port (3P) video-assisted thoracoscopic surgery (VATS) are well-established surgical methods for the treatment of complicated spontaneous pneumothorax (SP). However, a comparison between both techniques, in terms of clinical outcomes in patients with secondary spontaneous pneumothorax (SSP), is unreported. The aim of this study was to evaluate and compare postoperative pain, as well as clinical outcome, following 2P and 3P VATS for SSP in our institution. METHODS: Between January 2008 and December 2020, we retrospectively analyzed the data of 115 SSP patients treated by VATS in our institution. Fifty-two patients underwent 2P-VATS, while 63 patients were treated by 3P-VATS. The total dose of analgesic use per stay (opioid and non-opioid), length of hospital stay (LOS), operation time, total area of pleurectomy, recurrence rates and postoperative complications were compared between both groups. RESULTS: The 3P-VATS group had a significantly higher total dose of analgesic use compared with the 2P-VATS patients. The LOS and mean operation time were significantly shorter in the 2P-VATS group. A larger area of pleurectomy was resected using 3P-VATS compared to 2P-VATS. The postoperative complications and recurrence of SSP during a median follow-up period of 76.5 months were similar in both groups. CONCLUSION: 2P-VATS is a safe surgical technique. It is associated with a short LOS and less postoperative pain, and, thus, low analgesic use.

Targeting abundant survivin expression in liposarcoma: subtype dependent therapy responses to YM155 treatment.

PURPOSE: Liposarcoma (LPS) represent the largest group of malignant soft tissue tumours comprising a heterogeneous group of subtypes in which the degrees of chemoresistance and radiosensitivity strongly vary. Consequently, it is of utmost interest to establish novel therapeutic regimens based on molecular targets. METHODS: Immunohistochemical staining of survivin was performed in tissue microarrays comprising 49 primary LPS specimens. LPS cell lines were treated with survivin antagonist YM155 and doxorubicin or etoposide alone as well as in combination. Changes in cell viability were investigated and the synergistic effect of a combined therapy analysed. RESULTS: Immunohistochemistry revealed an abundant expression of survivin in LPS that significantly concurred with less-differentiated tumour subtypes and grading. In vitro, we demonstrated the impact of the survivin inhibitor YM155 on dedifferentiated LPS (DDLPS) and, even more imposing, pleomorphic LPS (PLS) tumour cell viability with a strong induction of apoptosis. A combined treatment of doxorubicin or etoposide with YM155 augmented the cytotoxic effects on DDLPS and PLS cells. CONCLUSION: These findings support the significant role of survivin in the oncogenesis and progression of LPS subtypes providing a rationale to target survivin in eligible in-vivo models and to pioneer clinical applications of survivin-specific substances unfolding their therapeutic potential in LPS patients prospectively.

Two-port versus three-port video-assisted thoracoscopic surgery for primary spontaneous pneumothorax: feasibility, postoperative outcome and long-term recurrence rates.

BACKGROUND: Two-port VATS (2-P-VATS) and three-port VATS (3-P-VATS) are well-established techniques for surgical therapy of primary spontaneous pneumothorax (PSP). However, comparisons of both techniques in terms of postoperative outcome and recurrence are limited. METHODS: From January 2010 to March 2020, we retrospectively reviewed data of 58 PSP patients who underwent VATS in our institution. For statistical analysis, categorical and continuous variables were compared by chi-square test or Fisher's exact test and the Student´s t-test, respectively. Twenty-eight patients underwent 2-P-VATS and 30 were treated with 3-P-VATS. Operation time, length of hospital stay (LOS), total dose of analgesics per stay (opioids and non-opioids), duration of chest tube drainage, pleurectomy volume (PV), postoperative complications and recurrence rates were compared between both groups. RESULTS: Clinical and surgical characteristics including mean age, gender, Body-Mass-Index (BMI), pneumothorax size, smoking behaviour, history of contralateral pneumothorax, side of pneumothorax, pleurectomy volume and number of resected segments were similar in both groups. The mean operation time, LOS and total postoperative opioid and non-opioid dose was significantly higher in the 3-P-VATS group compared with the 2-P-VATS group. Despite not being statistically significant, duration of chest tube was longer in the 3-P-VATS group compared with the 2-P-VATS group. In terms of postoperative complications, the occurrence of hemothorax was significantly higher in the 3-P-VATS group (3-P-VATS vs. 2-P-VATS; p = 0.001). During a median follow-up period of 61.6 months, there was no significant statistical difference in recurrence rates in both groups (2/28 (16.7%) vs. 5/30 (7.1%); p = 0.274). CONCLUSION: Our data demonstrate that 2-P-VATS is safer and effective. It is associated with reduced length of hospital stay and decreased postoperative pain resulting in less analgesic use.

Does Video-Assisted Thoracoscopic Surgery with Bullectomy and Partial Pleurectomy for Primary Spontaneous Pneumothorax Impair Health-Related Quality of Life and Pulmonary Function?

BACKGROUND: Video-assisted thoracoscopic surgery (VATS) with partial pleurectomy is an established treatment for primary spontaneous pneumothorax (PSP). However, postoperative pulmonary function and health-related quality of life (HR-QoL) after VATS-bullectomy with partial pleurectomy (VBPP) have not been elucidated. METHODS: Eligible patients were assessed for HR-QoL using the Short-Form 36 (SF-36) health survey. Pulmonary function (PF) was evaluated by spirometry. We compared the results of the VBPP cohort with the German national norms, and with a similar cohort of patients successfully treated by chest tube (CT) only. RESULTS: A total of 25 VBPP patients completed the SF-36 health survey, of whom 15 presented for PF assessment. Between the VBPP and CT groups, the mean forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and FEV1/FVC ratio were not statistically significantly different. However, in both groups, FVC, FEV1, and FEV1/FVC were above the lower limit of normal (LLN), suggesting no restrictive or obstructive patterns. Compared with the sex- and age-matched normal German population, patients who underwent VBPP displayed a similar physical component summary score and a significantly decreased mental component summary score. Interestingly, comparison of the SF-36 domains between the VBPP and CT groups showed no statistical difference. CONCLUSION: VBPP is a suitable surgical treatment for PSP, with no apparent adverse impacts on pulmonary or physical function. However, psychological distress and measures to counteract its impact should be considered.

Socioeconomic Impact of Recurrent Primary Spontaneous Pneumothorax: Should Video-Assisted Thoracoscopic Surgery Be Considered at First Episode of Primary Spontaneous Pneumothorax?

BACKGROUND: Current guidelines recommend video-assisted thoracoscopic surgery (VATS) for recurrent primary spontaneous pneumothorax (PSP) and for cases with persistent air leak after chest tube treatment. The socioeconomic impact of recurrent PSP on the healthcare system is insufficiently reported. METHODS: Ninety-six patients treated for PSP between 01/2010 and 01/2020 were included. Forty-eight patients underwent primary VATS, while the second group received chest tube (CT) treatment only. Length of hospital stay (LOS), duration of chest tube, prolonged air leak, postoperative complications, recurrences and treatment costs were analyzed. RESULTS: Prolonged air leaks were evident in 12.5% and 22.9% patients of the VATS and CT group, respectively. Ten (20.8%) patients in the CT group underwent VATS for persistent air leakage. During follow-up, the VATS group recurred at 8.3% compared to 52.1% in the CT group. The total cost of treatment per patient, including treatment cost due to recurrence, was EUR 1.501 in the VATS group and EUR 2.233 in the CT group. CONCLUSIONS: Primary treatment of PSP by CT is associated with an increased socioeconomic burden for patients and the healthcare system due to high recurrence rates. This burden may be reduced if VATS is considered at the first episode of PSP.

FGF Signalling in the Self-Renewal of Colon Cancer Organoids.

The progression of colorectal cancer (CRC) is supposedly driven by cancer stem cells (CSC) which are able to self-renew and simultaneously fuel bulk tumour mass with highly proliferative and differentiated tumour cells. However, the CSC-phenotype in CRC is unstable and dependent on environmental cues. Fibroblast growth factor 2 (FGF2) is essential and necessary for the maintenance of self-renewal in adult and embryonic stem cells. Investigating its role in self-renewal in advanced CRC patient-derived organoids, we unveiled that FGF-receptor (FGFR) inhibition prevents organoid formation in very early expanding cells but induces cyst formation when applied to pre-established organoids. Comprehensive transcriptome analyses revealed that the induction of the transcription factor activator-protein-1 (AP-1) together with MAPK activation was most prominent after FGFR-inhibition. These effects resemble mechanisms of an acquired resistance against other described tyrosine kinase inhibitors such as EGF-receptor targeted therapies. Furthermore, we detected elevated expression levels of several self-renewal and stemness-associated genes in organoid cultures with active FGF2 signalling. The combined data assume that CSCs are a heterogeneous population while self-renewal is a common feature regulated by distinct but converging pathways. Finally, we highlight FGF2 signalling as one of numerous components of the complex regulation of stemness in cancer.

Detection of circulating tumor cells in colorectal cancer patients using the GILUPI CellCollector: results from a prospective, single-center study.

The GILUPI CellCollector (CC) is a novel in vivo circulating tumor cell (CTC) detection device reported to overcome the limitations of small blood sample volumes. The aim of this prospective, blinded study was to evaluate the clinical application of the CC and to compare its performance to the CellSearch (CS) system in M0 and M1 colorectal cancer (CRC) patients. A total of 80 patients (31 M0, 49 M1) with CRC were enrolled. CTCs were simultaneously measured in the peripheral blood using CS and the CC, and the results of both assays were correlated to clinicopathological variables and overall survival. The total number of detected CTCs and CTC-positive patients did not significantly differ between both assays. In the M0 patients, the CC detected CTCs more frequently than CS. There was no significant difference in total CTC numbers detected with the CC between M0 and M1 patients. In addition, no significant correlation with clinicopathological parameters or overall survival was observed with CC CTCs. In contrast, detection of CTCs with CS was significantly correlated with Union for International Cancer Control stage and reduced overall survival. There was no correlation between CTCs detected by the CC and the CS system. Using in silico analysis, we estimate that CC screens a volume of 0.33-18 mL during in vivo application, in contrast to much higher volumes reported elsewhere. In conclusion, while being safe and easy to use, the CC did not outperform CS in terms of CTC yield or sensitivity. While CTC detection in M0 CRC patients was significantly increased with the CC, the clinical relevance of these CTCs appears inferior to the cells identified by the CS system.

BRAFV600E mutation: A promising target in colorectal neuroendocrine carcinoma.

To determine the role of BRAFV600E mutation and MAPK signaling as well as the effects of BRAF and MEK directed therapy in gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN), with a focus on highly aggressive gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC). Using Sanger sequencing of BRAF exon 15 we determined the frequency of BRAFV600E mutations in 71 primary GEP-NENs. MEK phosphorylation was examined by immunohistochemistry in corresponding tissue samples. To evaluate the biological relevance of BRAFV600E mutation and MAPK signaling in GEP-NECs, effects of a pharmacological BRAF and MEK inhibition were analyzed in NEC cell lines both in vitro and in vivo. BRAFV600E mutation was detected in 9.9% of all GEP-NENs. Interestingly, only NECs of the colon harbored BRAFV600E mutations, leading to a mutation frequency of 46.7% in this subgroup of patients. In addition, a BRAFV600E mutation was significantly associated with high levels of MEK phosphorylation (pMEK) and advanced tumor stages. Pharmacological inhibition of BRAF and MEK abrogated NEC cell growth, inducing G1 cell cycle arrest and apoptosis only in BRAFV600E mutated cells. BRAF inhibitor dabrafenib and MEK inhibitor trametinib prevented growth of BRAFV600E positive NEC xenografts. High frequencies of BRAFV600E mutation and elevated expression levels of pMEK were detected in biologically aggressive and highly proliferative colorectal NECs. We provide evidence that targeting BRAF oncogene may represent a therapeutic strategy for patients with BRAF mutant colorectal NECs.

Establishment and Characterization of a Novel Cell Line Derived from a Small Cell Neuroendocrine Carcinoma of the Anal Canal.

BACKGROUND: Gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) are biologically aggressive tumors, associated with a very poor survival. Due to their rarity, our knowledge on GEP-NEC biology is very limited. The aim of this study was to establish a GEP-NEC cell line model that might contribute to a better understanding of this rare malignant disease to further develop novel therapeutic approaches in preclinical studies. METHODS: Small cell neuroendocrine cancer cell line NEC-DUE3 was derived from a lymph node metastasis of a neuroendocrine carcinoma (NEC) located at the anal canal. Morphological characteristics and the expression of neuroendocrine markers were comprehensively investigated. For genetic profiling, NEC-DUE3 cells were analyzed by DNA fingerprinting. Chromosomal aberrations were mapped by array comparative genomic hybridization. NEC-DUE3 cell tumorigenicity was evaluated in vivo and the sensitivity to chemotherapeutic agents was assessed in vitro. RESULTS: NEC-DUE3 cells were characterized by the expression of molecular markers that are commonly observed in GEP-NECs, were sensitive to treatment with cisplatin, and able to form tumors in immunodeficient mice. CONCLUSION: We established and characterized the first small cell GEP-NEC cell line that may serve as a valuable tool to create a better understanding of the biology of these rare tumors and to develop novel treatment strategies.

CXCR4/CXCR7/CXCL12-Axis in Follicular Thyroid Carcinoma.

Background: Follicular thyroid carcinoma's (FTC) often benign course is partially due to adjuvant radioactive iodine (RAI) treatment. However, once the tumour has spread and fails to retain RAI, the therapeutic options are limited and the outcome is poor. In this subset of patients, the identification of novel druggable biomarkers appears invaluable. Here, we investigated the stage dependent expression and functional role of the C-X-C chemokine receptors type 4 and 7 (CXCR4/7) in FTC. Methods: CXCR4/7 expression was examined in 44 FTC and corresponding non-neoplastic thyroid specimens as well as 10 FTC distant metastases and 18 follicular adenomas using tissue microarray technology. Expression levels were correlated with clinicopathological variables as well as overall and recurrence free survival. Changes regarding cell cycle activation, tumour cell invasiveness and mRNA expression of genes related to epithelial-mesenchymal transition (EMT) were investigated after treatment with recombinant human SDF1α/CXCL12 (rh-SDF1α) and CXCR4 antagonists AMD3100 and WZ811. Results: CXCR4/7 expression was associated with large tumour size, advanced UICC stage as well as shorter overall and recurrence free survival. CXCR4 was significantly higher expressed in distant metastases than in primary tumour cores. In addition, rh-SDF1α induced invasive growth, cell cycle activation and EMT, while CXCR4 antagonists significantly reduced FTC invasiveness in vitro. Conclusion: Here we provide first evidence of the biological importance of the CXCR4/CXCR7/CXCL12 axis in FTC. Our findings underscore the therapeutic potential of this chemokine receptor family in advanced FTC and offer new valuable insight into the oncogenesis of metastatic FTC.

Clinicopathological and functional implications of the inhibitor of apoptosis proteins survivin and XIAP in esophageal cancer.

Based on their overexpression and important roles in progression and therapy-resistance in malignant diseases, the inhibitor of apoptosis protein family (IAP) members, survivin and X-linked inhibitor of apoptosis protein (XIAP), represent attractive candidates for targeted therapy. The present study investigated the prognostic and biological relevance of survivin and XIAP in esophageal squamous-cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Survivin and XIAP expression was analyzed by immunohistochemistry using tissue microarrays containing 120 ESCC and 90 EAC samples as well as the corresponding non-neoplastic esophageal mucosa samples. IAP expression levels were then correlated to clinicopathological parameters and overall survival to identify any associations. In addition, esophageal cancer cell lines were treated with the survivin inhibitor YM155, and the XIAP inhibitors Birinapant and GDC-0152 in vitro. Survivin and XIAP expression were significantly increased in EAC and ESCC when compared with tumor-adjacent mucosa. In patients with ESCC XIAP expression was associated with female gender and advanced tumor stages, and nuclear survivin expression was associated with poor grading. High XIAP expression was identified as an independent negative prognostic marker in ESCC. By contrast, XIAP inhibitors did not affect cancer cell viability in vitro, and the small molecule survivin inhibitor YM155 significantly reduced cell viability and proliferation in esophageal cancer cell lines. Western blot analysis revealed a dose dependent decrease of survivin accompanied by an increased poly (adenosine diphosphate-ribose) polymerase cleavage following YM155 treatment. These findings underline the potential role of survivin and XIAP in the oncogenesis of esophageal cancer and provide a rationale for future clinical studies investigating the therapeutic efficacy of IAP directed therapies in patients with esophageal cancer.

IAPs cause resistance to TRAIL-dependent apoptosis in follicular thyroid cancer.

Follicular thyroid cancer's (FTC) excellent long-term prognosis is mainly dependent on postoperative radioactive iodine (RAI) treatment. However, once the tumour becomes refractory, the 10-year disease-specific survival rate drops below 10%. The aim of our study was to evaluate the prognostic and biological role of the TRAIL system in FTC and to elucidate the influence of small-molecule-mediated antagonisation of inhibitor of apoptosis proteins (IAPs) on TRAIL sensitivity in vitro Tissue microarrays were constructed from forty-four patients with histologically confirmed FTC. Expression levels of TRAIL and its receptors were correlated with clinicopathological data and overall as well as recurrence-free survival. Non-iodine-retaining FTC cell lines TT2609-bib2 and FTC133 were treated with recombinant human TRAIL alone and in combination with Smac mimetics GDC-0152 or Birinapant. TRAIL-R2/DR5 as well as TRAIL-R3/DcR1 and TRAIL-R4/DcR2 were significantly higher expressed in advanced tumour stages. Both decoy receptors were negatively associated with recurrence-free and overall survival. TRAIL-R4/DcR2 additionally proved to be an independent negative prognostic marker in FTC (HR = 1.446, 95% CI: 1.144-1.826; P < 0.001). In vitro, the co-incubation of Birinapant or GDC-0152 with rh-TRAIL-sensitised FTC cell lines for TRAIL-induced apoptosis, through degradation of cIAP1/2. The TRAIL system plays an important role in FTC tumour biology. Its decoy receptors are associated with poor prognosis as well as earlier recurrence. The specific degradation of cIAP1/2 sensitises FTC cells to TRAIL-induced apoptosis and might highlight a new point of attack in patients with RAI refractory disease.

CXCR4/CXCR7/CXCL12 axis promotes an invasive phenotype in medullary thyroid carcinoma.

BACKGROUND: Medullary thyroid carcinoma (MTC) is a rare and challenging endocrine malignancy. Once spread, the therapeutic options are limited and the outcome poor. For these patients, the identification of new druggable biological markers is of great importance. Here, we investigated the prognostic and biological role of the C-X-C chemokine receptors type 4 and 7 (CXCR4/7) in MTC. METHODS: Eighty-six MTC and corresponding non-neoplastic thyroid specimens were immunohistochemically stained for CXCR4/7 using tissue microarray technology and expression levels correlated with clinicopathological variables. Medullary thyroid carcinoma cell line TT was treated with recombinant human SDF1α/CXCL12 (rh-SDF1α) and CXCR4 antagonists AMD3100 and WZ811. Changes in cell cycle activation, tumour cell invasiveness as well as changes in mRNA expression levels of genes associated with epithelial-mesenchymal transition (EMT) were investigated. RESULTS: High CXCR4 expression was associated with large tumour size and metastatic disease. CXCR4 antagonists significantly reduced tumour cell invasiveness, while the treatment with rh-SDF1α stimulated invasive growth, caused cell cycle activation and induced EMT. CONCLUSIONS: The CXCR4/CXCR7/CXCL12 axis plays an important role in MTC. We provide first evidence that the chemokine receptors might serve as potential therapeutic targets in patients with advanced MTC and offer new valuable insight into the underlying molecular machinery of metastatic MTC.