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Nature 01/2013; 493(7434):608. · 36.28 Impact Factor
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ABSTRACT: The presence of tumor budding (TuB) at the invasive front of rectal cancers is a valuable indicator of tumor aggressiveness. Tumor buds, typically identified as single cells or small tumor cell clusters detached from the main tumor body, are characterized by loss of cell adhesion, increased migratory, and invasion potential and have been referred to as malignant stem cells. The adverse clinical outcome of patients with a high-grade TuB phenotype has consistently been demonstrated. TuB is a category IIB prognostic factor; it has yet to be investigated in the prospective setting. The value of TuB in oncological and pathological practice goes beyond its use as a simple histomorphological marker of tumor aggressiveness. In this paper, we outline three situations in which the assessment of TuB may have direct implications on treatment within the multidisciplinary management of patients with rectal cancer: (a) patients with TNM stage II (i.e., T3/T4, N0) disease potentially benefitting from adjuvant therapy, (b) patients with early submucosally invasive (T1, sm1-sm3) carcinomas at a high risk of nodal positivity and (c) the role of intratumoral budding assessed in preoperative biopsies as a marker for lymph node and distant metastasis thus potentially aiding the identification of patients suitable for neoadjuvant therapy.
International journal of surgical oncology. 01/2012; 2012:795945.
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Andrew P Dobson, Markus Borner,
Anthony R E Sinclair,
Peter J Hudson,
T Michael Anderson,
Gerald Bigurube,
Tim B B Davenport,
James Deutsch,
Sarah M Durant,
Richard D Estes, [......],
Robert D Holt,
J Grant C Hopcraft,
Ray Hilborn,
George L K Jambiya,
M Karen Laurenson,
Lota Melamari,
Alais Ole Morindat,
Joseph O Ogutu,
George Schaller,
Eric Wolanski
Nature 09/2010; 467(7313):272-3. · 36.28 Impact Factor
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ABSTRACT: Pancreatic cancer is an aggressive tumour following a multistep progression model through precursors called pancreatic intraepithelial neoplasia (PanIN). Identification of reliable prognostic markers would help in improving survival. The aim of this study was to investigate the role as well as the prognostic significance of different cell cycle and proliferation markers, namely p21, p27, p53 and Ki-67, in pancreatic carcinogenesis.
We analysed the expression of p21, p27, p53 and Ki-67, in 210 ductal pancreatic adenocarcinomas, 40 PanIN-3 cases and 40 normal controls combined in a tissue microarray. The results were correlated with clinicopathological and follow-up data.
Our study revealed a differential p27, p21, p53, and Ki-67 expression between ductal adenocarcinoma, PanIN-3 and normal pancreas. p27 expression progressively decreased from normal pancreas to PanIN and to pancreatic cancer. Decreased p27 and increased p53 expression showed a significant association with the T stage. A Ki-67 >5% correlated with reduced survival.
In pancreatic cancer, loss of p27 and increased p53 expression is associated with a more aggressive phenotype. p27 may play an important role in pancreatic carcinogenesis. A Ki-67 >5% independently predicted poor outcome.
Pathology 04/2010; 42(3):229-34. · 2.38 Impact Factor
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Dieter Koeberle,
Michael Montemurro,
Panagiotis Samaras,
Pietro Majno,
Mathew Simcock,
Andreas Limacher,
Stefanie Lerch,
Katalin Kovàcs,
Roman Inauen,
Vivianne Hess,
Piercarlo Saletti, Markus Borner,
Arnaud Roth,
György Bodoky
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ABSTRACT: Sunitinib (SU) is a multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity. The objective of this trial was to demonstrate antitumor activity of continuous SU treatment in patients with hepatocellular carcinoma (HCC).
Key eligibility criteria included unresectable or metastatic HCC, no prior systemic anticancer treatment, measurable disease, and Child-Pugh class A or mild Child-Pugh class B liver dysfunction. Patients received 37.5 mg SU daily until progression or unacceptable toxicity. The primary endpoint was progression-free survival at 12 weeks (PFS12).
Forty-five patients were enrolled. The median age was 63 years; 89% had Child-Pugh class A disease and 47% had distant metastases. PFS12 was rated successful in 15 patients (33%; 95% confidence interval, 20%-47%). Over the whole trial period, one complete response and a 40% rate of stable disease as the best response were achieved. The median PFS duration, disease stabilization duration, time to progression, and overall survival time were 1.5, 2.9, 1.5, and 9.3 months, respectively. Grade 3 and 4 adverse events were infrequent. None of the 33 deaths were considered drug related.
Continuous SU treatment with 37.5 mg daily is feasible and has moderate activity in patients with advanced HCC and mild to moderately impaired liver dysfunction. Under this trial design (>13 PFS12 successes), the therapy is considered promising. This is the first trial describing the clinical effects of continuous dosing of SU in HCC patients on a schedule that is used in an ongoing, randomized, phase III trial in comparison with the current treatment standard, sorafenib (ClinicalTrials.gov identifier, NCT00699374).
The Oncologist 03/2010; 15(3):285-92. · 3.91 Impact Factor
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Eva Karamitopoulou,
Pierlorenzo Pallante,
Inti Zlobec,
Luigi Tornillo,
Vincenza Carafa,
Thomas Schaffner, Markus Borner,
Ioannis Diamantis,
Francesco Esposito,
Thomas Brunner,
Arthur Zimmermann,
Antonella Federico,
Luigi Terracciano,
Alfredo Fusco
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ABSTRACT: Polycomb group (PcG) proteins function as multiprotein complexes and are part of a gene regulatory mechanism that determines cell fate during normal and pathogenic development. Several studies have implicated the deregulation of different PcG proteins in neoplastic progression. Pancreatic ductal adenocarcinoma is an aggressive neoplasm that follows a multistep model of progression through precursor lesions called pancreatic intraepithelial neoplasia (PanIN). Aim of this study was to investigate the role of PcG protein CBX7 in pancreatic carcinogenesis and to evaluate its possible diagnostic and prognostic significance. We analysed by immunohistochemistry the expression of CBX7 in 210 ductal pancreatic adenocarcinomas from resection specimens, combined on a tissue microarray (TMA) including additional 40 PanIN cases and 40 normal controls. The results were evaluated by using receiver operating characteristic (ROC) curve analysis for the selection of cut-off scores and correlated to the clinicopathological parameters of the tumours and the outcome of the patients. Expression of E-cadherin, a protein positively regulated by CBX7, was also assessed. A significantly differential, and progressively decreasing CBX7 protein expression was found between normal pancreatic tissue, PanINs and invasive ductal adenocarcinoma. Loss of CBX7 expression was associated with increasing malignancy grade in pancreatic adenocarcinoma, whereas the maintenance of CBX7 expression showed a trend toward a longer survival. Moreover, loss of E-cadherin expression was associated with loss of CBX7 and with a trend towards worse patient survival. These results suggest that CBX7 plays a role in pancreatic carcinogenesis and that its loss of expression correlates to a more aggressive phenotype.
European journal of cancer (Oxford, England: 1990) 02/2010; 46(8):1438-44. · 4.12 Impact Factor
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Thomas Ruhstaller,
Arnoud Templeton,
Karin Ribi,
Jan C Schuller, Markus Borner,
Sandra Thierstein,
Roger von Moos,
Stefanie Pederiva,
Andreas Lohri,
Norbert Lombriser,
Christian von Briel,
Dieter Koeberle,
Razvan Popescu
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ABSTRACT: There is no standard treatment for patients with locally advanced esophageal carcinoma without systemic metastasis in whom surgery is no longer considered a reasonable option.
Patients with cervical esophageal tumors, locally very advanced stage (T4 and/or M1a) or locally advanced (T3 and/or N+) with comorbidities were included. Therapy: 2 cycles of induction chemotherapy (cisplatin and docetaxel, both 75 mg/m(2) 3-weekly) followed by chemoradiation therapy (CRT) comprising a total radiation dose of 59.4 Gy together with docetaxel 15 mg/m(2) and cisplatin 25 mg/m(2) (5 weekly doses). Primary endpoint: Histologically proven freedom from local failure 6 months after CRT completion.
21 patients were included: 12 had locally very advanced tumors, 3 had cervical esophagus tumors, and 6 were medically unfit for surgery. 18 patients completed therapy per protocol. Grade 3/4 toxicities during CRT were thrombopenia (10%) and dysphagia (15%). 1 patient died due to herpes simplex infection. The primary endpoint was achieved by 4 patients, 6 were alive after median follow-up of 34 months, and median survival was 16 months. Most patients experienced lasting improvement of dysphagia following induction chemotherapy.
This regimen is feasible, showed clinically meaningful, long-lasting improvements in quality of life and resulted in long-term survival in 29% of the patients.
Onkologie 01/2010; 33(5):222-8. · 0.87 Impact Factor
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Karin Ribi,
Dieter Koeberle,
Jan C Schuller,
Hanspeter Honegger,
Arnaud Roth,
Viviane Hess,
Peter Moosmann,
Roger von Moos, Markus Borner,
Norbert Lombriser,
Bernhard Pestalozzi,
Thomas Ruhstaller
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ABSTRACT: In patients with locally advanced esophageal cancer, only those responding to the treatment ultimately benefit from preoperative chemoradiation. We investigated whether changes in subjective dysphagia or eating restrictions after two cycles of induction chemotherapy can predict histopathological tumor response observed after chemoradiation. In addition, we examined general long-term quality of life (QoL) and, in particular, eating restrictions after esophagectomy.
Patients with resectable, locally advanced squamous cell- or adenocarcinoma of the esophagus were treated with two cycles of chemotherapy followed by chemoradiation and surgery. They were asked to complete the EORTC oesophageal-specific QoL module (EORTC QLQ-OES24), and linear analogue self-assessment QoL indicators, before and during neoadjuvant therapy and quarterly until 1 year postoperatively. A median change of at least eight points was considered as clinically meaningful.
Clinically meaningful improvements in the median scores for dysphagia and eating restrictions were found during induction chemotherapy. These improvements were not associated with a histopathological response observed after chemoradiation, but enhanced treatment compliance. Postoperatively, dysphagia scores remained low at 1 year, while eating restrictions persisted more frequently in patients with extended transthoracic resection compared to those with limited transhiatal resection.
The improvement of dysphagia and eating restrictions after induction chemotherapy did not predict tumor response observed after chemoradiation. One year after esophagectomy, dysphagia was a minor problem, and global QoL was rather good. Eating restrictions persisted depending on the surgical technique used.
Supportive Care in Cancer 03/2009; 17(8):1109-16. · 2.09 Impact Factor
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Eva Karamitopoulou,
Luigi Tornillo,
Inti Zlobec,
Lukas Cioccari,
Vincenza Carafa, Markus Borner,
Thomas Schaffner,
Thomas Brunner,
Ioannis Diamantis,
Arthur Zimmermann,
Luigi Terracciano
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ABSTRACT: Cholangiocarcinoma is the second most common malignant tumor of the liver. We analyzed, immunohistochemically, the significance of cell cycle- and apoptosis-related markers in 128 cholangiocarcinomas (42 intrahepatic, 70 extrahepatic, and 16 gallbladder carcinomas) combined in a tissue microarray. Follow-up was available for 57 patients (44.5%). In comparison with normal tissue (29 specimens), cholangiocarcinomas expressed significantly more frequently p53, bcl-2, bax, and COX-2 (P.05 <). Intrahepatic tumors were significantly more frequently bcl-2+ and p16+, whereas extrahepatic tumors were more often p53+ (P < .05). Loss of p16 expression was associated with reduced survival of patients. Our data show that p53, bcl-2, bax, and COX-2 have an important role in the pathogenesis of cholangiocarcinomas. The differential expression of p16, bcl-2, and p53 between intrahepatic and extrahepatic tumors demonstrates that there are location-related differences in the phenotype and the genetic profiles of these tumors. Moreover, p16 was identified as an important prognostic marker in cholangiocarcinomas.
American Journal of Clinical Pathology 11/2008; 130(5):780-6. · 2.60 Impact Factor
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Dieter Koeberle,
Piercarlo Saletti, Markus Borner,
Daniela Gerber,
Daniel Dietrich,
Clemens B Caspar,
Walter Mingrone,
Kurt Beretta,
Florian Strasser,
Thomas Ruhstaller,
Oreste Mora,
Richard Herrmann
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ABSTRACT: To evaluate the effects of palliative chemotherapy with gemcitabine plus capecitabine (GemCap) on patient-reported outcomes measured using clinical benefit response (CBR) and quality-of-life (QOL) measures in patients with advanced biliary tract cancer.
Patients had to manifest symptoms of advanced biliary tract cancer and have at least one of the following: impaired Karnofsky performance score (60 to 80), average analgesic consumption >or= 10 mg of morphine equivalents per day, and average pain intensity score of >or= 20 mm out of 100 mm. Treatment consisted of oral capecitabine 650 mg/m(2) twice daily on days 1 through 14 plus gemcitabine 1,000 mg/m(2) as a 30-minute infusion on days 1 and 8 every 3 weeks until progression. The primary end point was the number of patients categorized as having a CBR or stable CBR (SCBR) during the first three treatment cycles.
Forty-four patients were enrolled (bile duct cancer, n = 36; gallbladder cancers, n = 8). The main grade 3 or 4 adverse events included hematologic toxicity and fatigue. After three cycles, 36% of patients achieved a CBR, and 34% achieved an SCBR. Over the full course of treatment, 57% of patients achieved a CBR, and 18% achieved an SCBR. Improved QOL was observed in patients with a CBR or SCBR. The objective response rate was 25%. Median time to progression and overall survival times were 7.2 months and 13.2 months, respectively.
Chemotherapy with GemCap is well tolerated and effective and leads to a high CBR rate. Patient-reported outcomes are useful for evaluating the effects of palliative chemotherapy in patients with biliary tract cancer.
Journal of Clinical Oncology 08/2008; 26(22):3702-8. · 18.37 Impact Factor
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ABSTRACT: Prostate cancer is the most common type of cancer in men, however, therapeutic options are limited. 50-90% of hormone-refractory prostate cancer cells show an overexpression of epidermal growth factor receptor (EGFR), which may contribute to uncontrolled proliferation and resistance to chemotherapy. In vitro, gefitinib, an orally administered tyrosine kinase inhibitor, has shown a significant increase in antitumor activity when combined with chemotherapy.
In this phase II study, the safety and efficacy of gefitinib in combination with docetaxel, a chemotherapeutic agent commonly used for prostate cancer, was investigated in patients with hormone-refractory prostate cancer (HRPC). 37 patients with HRPC were treated continuously with gefitinib 250 mg once daily and docetaxel 35 mg/m2 i.v. for up to 6 cycles. PSA response, defined as a =50% decrease in serum PSA compared with trial entry, was the primary efficacy parameter. PSA levels were measured at prescribed intervals.
The response rate and duration of response were consistent with those seen with docetaxel monotherapy. The combination of docetaxel and gefitinib was reasonably well tolerated in this study.
Future studies should investigate whether patients with specific tumor characteristics, e.g. EGFR protein overexpression, respond better to gefitinib than patients without, leading to a more customized therapy option.
Onkologie 08/2007; 30(7):355-60. · 0.87 Impact Factor
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ABSTRACT: Considerable controversy surrounds the effectiveness of strictly protected areas that prohibit consumptive resource use. For Tanzania we compared temporal changes in densities of large herbivores among heavily protected national parks and game reserves, partially protected game-controlled areas, and areas with little or no protection. Comparisons based on surveys conducted in the late 1980s and early 1990s versus the late 1990s and early 2000s showed three consistent patterns across the country. First, significant declines in the densities of large herbivores between these two snapshots in time overwhelmingly outnumbered significant increases in all protection categories. Second, more species fared well (increased significantly or showed no significant change) in strictly protected national parks than in areas with partial or no protection and in heavily protected game reserves relative to areas with no protection. Third, significantly more species fared poorly (densities declined or were too low to detect a decline) than fared well in areas with partial or no protection. Our results show that although heavy protection was generally more effective in maintaining large herbivore populations than partial or no protection, continued long-term monitoring is needed in Tanzania to inform managers whether large herbivores are experiencing declining population trends even within heavily protected areas.
Conservation Biology 07/2007; 21(3):635-46. · 4.69 Impact Factor
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ABSTRACT: Wildlife within protected areas is under increasing threat from bushmeat and illegal trophy trades, and many argue that enforcement within protected areas is not sufficient to protect wildlife. We examined 50 years of records from Serengeti National Park in Tanzania and calculated the history of illegal harvest and enforcement by park authorities. We show that a precipitous decline in enforcement in 1977 resulted in a large increase in poaching and decline of many species. Conversely, expanded budgets and antipoaching patrols since the mid-1980s have greatly reduced poaching and allowed populations of buffalo, elephants, and rhinoceros to rebuild.
Science 12/2006; 314(5803):1266. · 31.20 Impact Factor
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ABSTRACT: We collated aerial census data collected during the late 1980s to early 2000s for large herbivore populations in eight large census zones in Tanzania. Of the ungulate populations that showed significant changes in densities at the start versus end of this decade, most declined; very few populations increased significantly. Thomson's gazelle, Grant's gazelle, hartebeest, reedbuck, roan antelope, sable antelope, warthog and zebra, for example, declined in over 50% of the zones where they were surveyed. Interestingly, small-bodied species fared particularly poorly in many census zones, whereas elephant and giraffe generally fared well across the country. Most populations of all herbivores declined in some portions of the country (e.g. Burigi-Biharamulo, Katavi, Greater Ruaha and Tarangire census zones). These surveys suggest that, even in a country renowned for its protected areas and conservation commitment, some large herbivore populations need more conservation attention in order to remain stable.RésuméNous avons rassemblé les données récoltées entre la fin des années 1980 et le début des années 2000 lors de recensements des populations de grands herbivores dans huit vastes zones de Tanzanie. La plupart des populations d'ongulés qui présentaient des changements de densité significatifs entre le début et la fin de ces recensements avaient diminué; très peu avaient augmenté significativement. La gazelle de Thomson, la gazelle de Grant, le bubale, le cobe des roseaux, l'antilope rouanne, l'antilope sable, le phacochère et le zèbre, par exemple, avaient décliné dans plusieurs zones. Il est intéressant de remarquer que les espèces de petite taille avaient des résultats plutôt médiocres dans de nombreuses zones de recensement alors que les éléphants et les girafes s'en sortaient bien dans tout le pays. La plupart des populations de tous les herbivores ont baissé dans certaines parties du pays (ex. les zones de recensement de Burigi-Biharamulo, Katavi, le Grand Ruaha et Tarangire). Ces études montrent que, même dans un pays renommé pour son engagement envers ses aires protégées et la conservation, certaines populations de grands herbivores ont besoin d'une attention de conservation plus grande pour rester stables.
African Journal of Ecology 11/2006; 45(2):202 - 215. · 0.65 Impact Factor
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European Journal of Cancer 11/2006; 42(15):2660-1. · 5.54 Impact Factor
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Onkologie 11/2005; 28 Suppl 4:35-9. · 0.87 Impact Factor
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Stephen Chan,
Max E Scheulen,
Stephen Johnston,
Klaus Mross,
Fatima Cardoso,
Christian Dittrich,
Wolfgang Eiermann,
Dagmar Hess,
Rudolph Morant,
Vladimir Semiglazov, Markus Borner,
Marc Salzberg,
Valerijus Ostapenko,
Hans-Joachim Illiger,
Dirk Behringer,
Nathalie Bardy-Bouxin,
Joseph Boni,
Steven Kong,
Maria Cincotta,
Laurence Moore
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ABSTRACT: In this study, two doses of temsirolimus (CCI-779), a novel inhibitor of the mammalian target of rapamycin, were evaluated for efficacy, safety, and pharmacokinetics in patients with locally advanced or metastatic breast cancer who had been heavily pretreated.
Patients (n = 109) were randomly assigned to receive 75 or 250 mg of temsirolimus weekly as a 30-minute intravenous infusion. Patients were evaluated for tumor response, time to tumor progression, adverse events, and pharmacokinetics of temsirolimus.
Temsirolimus produced an objective response rate of 9.2% (10 partial responses) in the intent-to-treat population. Median time to tumor progression was 12.0 weeks. Efficacy was similar for both dose levels but toxicity was more common with the higher dose level, especially grade 3 or 4 depression (10% of patients at the 250-mg dose level, 0% at the 75-mg dose level). The most common temsirolimus-related adverse events of all grades were mucositis (70%), maculopapular rash (51%), and nausea (43%). The most common, clinically important grade 3 or 4 adverse events were mucositis (9%), leukopenia (7%), hyperglycemia (7%), somnolence (6%), thrombocytopenia (5%), and depression (5%).
In heavily pretreated patients with locally advanced or metastatic breast cancer, 75 and 250 mg temsirolimus showed antitumor activity and 75 mg temsirolimus showed a generally tolerable safety profile.
Journal of Clinical Oncology 09/2005; 23(23):5314-22. · 18.37 Impact Factor
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ABSTRACT: Territorial behavior is expected to buffer populations against short-term environmental perturbations, but we have found that group living in African lions causes a complex response to long-term ecological change. Despite numerous gradual changes in prey availability and vegetative cover, regional populations of Serengeti lions remained stable for 10- to 20-year periods and only shifted to new equilibria in sudden leaps. Although gradually improving environmental conditions provided sufficient resources to permit the subdivision of preexisting territories, regional lion populations did not expand until short-term conditions supplied enough prey to generate large cohorts of surviving young. The results of a simulation model show that the observed pattern of "saltatory equilibria" results from the lions' grouping behavior.
Science 02/2005; 307(5708):390-3. · 31.20 Impact Factor
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ABSTRACT: The conservation of migratory species can be problematic because of their requirements for large protected areas. We investigated this issue by examining the annual movements of the migratory wildebeest, Connochaetes taurinus, in the 25 000 km 2 Serengeti-Mara Ecosystem of Tanzania and Kenya. We used Global Positioning System telemetry to track eight wildebeest during 1999–2000 in relation to protected area status in different parts of the ecosystem. The collared wildebeest spent 90% of their time within well-protected core areas. However, two sections of the wildebeest migration route – the Ikoma Open Area and the Mara Group Ranches – currently receive limited protection and are threatened by poaching or agriculture. Comparison of current wildebeest migration routes to those recorded during 1971–73 indicates that the western buffer zones appear to be used more extensively than in the past. This tentative conclusion has important repercussions for management and needs further study. The current development of community-run Wildlife Management Areas as additional buffer zones around the Serengeti represents an important step in the conservation of this UNESCO World Heritage Site. This study demonstrates that detailed knowledge of movement of migratory species is required to plan effective conservation action.
Animal Conservation. 01/2004; 7.
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ABSTRACT: Preclinical studies indicate positive interactions between capecitabine, an oral fluorouracil precursor, and gemcitabine, the current standard treatment for advanced pancreatic carcinoma (APC). In this study, we investigated the addition of capecitabine to gemcitabine treatment for patients with APC.
This multicenter study included patients naïve to chemotherapy who had histologically or cytologically confirmed, nonresectable or metastatic pancreatic carcinoma. Gemcitabine was given at a fixed dose of 1,000 mg/m(2) on days 1 and 8 of a 21-day cycle. Capecitabine was given in increasing doses orally bid for 14 days followed by a 1-week rest. The maximum-tolerated dose (MTD) was defined as one dose level below the dose causing dose-limiting toxicity (DLT) in >or= one third of a cohort of six patients. We included an additional 15 patients at the MTD.
Thirty-six patients were included. DLT occurred at a dose of 800 mg/m(2) bid of capecitabine and consisted of myelotoxicity and mucositis. Hand-foot syndrome was not observed, and other toxic effects were mild. Thus, in this regimen, the recommended dose of capecitabine is 650 mg/m(2) bid. In 27 patients with measurable disease, we observed one complete and four partial remissions. In addition, significant drops (> 50% from baseline value) of the tumor marker CA 19-9 occurred in 14 of 24 assessable patients.
The combination of capecitabine and gemcitabine is well tolerated, with apparent efficacy in patients with APC. Therefore, it is currently being compared with gemcitabine monotherapy in a phase III study.
Journal of Clinical Oncology 01/2003; 21(1):66-8. · 18.37 Impact Factor
