Dietmar Öfner

Prostate-specific membrane antigen expression in the neovasculature of gastric and colorectal cancers

Prostate-specific membrane antigen (PSMA), a type II transmembrane metallo-peptidase highly overexpressed in prostate cancer cells, has been studied as a targeting molecule in prostate cancer. Recently, PSMA has also been found to be expressed in the neovasculature of multiple nonprostatic solid tumors. Because of its unique expression pattern limited to tumor-associated endothelial cells, PSMA may also be an interesting molecule for vascular targeting. In this study, PSMA expression was determined by immunohistochemistry in 119 cases of primary gastric adenocarcinoma, 130 cases of primary colorectal adenocarcinoma, and 24 metastasis of colorectal adenocarcinoma. Expression data were correlated with clinicopathologic information. PSMA expression was detected in tumor-associated neovasculature of 79 (66%) of 119 gastric and 110 (85%) of 130 colorectal carcinomas. Furthermore, the neovasculatures of 16 (84%) of 19 liver and 4 (80%) of 5 nodal metastases from colorectal carcinomas were prostate-specific membrane antigen positive. There was a trend for high-grade tumors to higher PSMA expression (Spearman r = 0.18, P = .046) in colorectal cancers. No association between PSMA expression and overall- or disease-free survival was observed in gastric or colorectal cancers. This study provides the first in-depth look at PSMA expression in gastric and colorectal cancer. Because of its highly tumor-restricted expression and its accessibility to targeted therapy, PSMA represents a promising therapeutic and diagnostic target in colorectal and gastric cancer.

SFRP2 methylation in fecal DNA—a marker for colorectal polyps

IntroductionDNA methylation of secreted frizzled-related proteins (SFRPs) can be detected in colorectal cancer (CRC) tissue, in tissue of adenomas, and in aberrant crypt foci, whereas in normal colorectal mucosa tissue, SFRP genes are unmethylated. Recently, our study group was able to demonstrate SFRP2 methylation as the most sensitive single DNA-based marker in stool for identification of CRC. The purpose of this study was to clarify whether SFRP2 methylation in fecal DNA can be found in stool of individuals with hyperplastic and adenomatous colorectal polyps.Materials and methodsPatients who were diagnosed with colorectal polyps or showed negative colonoscopy were included in this study. DNA from stool samples was isolated. SFRP2 methylation was assessed by means of MethyLight.ResultsStool samples from 68 individuals were checked for DNA content; 23% of the samples (6 of 26) from healthy controls, 46% of the samples (6 of 13) from patients with hyperplastic polyps, and 45% of the samples (13 of 29) from patients with adenomas were positive for human DNA. SFRP2 methylation in stool samples was found in none of the healthy controls, in 33% (2 of 6) patients with hyperplastic polyps, and in 46% (6 of 13) patients with adenomas. Statistical analysis revealed that the frequency of SFRP2 methylation increased significantly (Pu2009=u20090.028) from healthy controls to patients with hyperplastic polyps and to patients with adenomas.ConclusionsIn the current study, we report for the first time that SFRP2 methylation in fecal DNA increases significantly from healthy controls to patients with hyperplastic polyps and to patients with adenomas. SFRP2 methylation may serve as a marker for molecular stool-based adenoma and CRC screening.

Preoperative treatment with capecitabine, bevacizumab and radiotherapy for primary locally advanced rectal cancer – A two stage phase II clinical trial

BACKGROUND AND PURPOSEnThe aim of this single-arm multicenter phase II clinical trial was to assess the feasibility and tolerability of preoperative radiotherapy and simultaneous capecitabine and bevacizumab. Secondary endpoints were downstaging-rate and induction of complete pathological response.nnnMATERIAL AND METHODSnPatients with cT3 rectal cancer were eligible. Capecitabine (825 mg/sqm twice daily on radiotherapy-days weeks 1-4) and bevacizumab (5 mg/kg on days 1, 15 and 29) were administered concurrently to pelvic radiotherapy (1.8 Gy daily up to 45 Gy in 5 weeks). Surgery followed 6-8 weeks later. A two-stage trial was designed with early termination at eight patients if more than three patients had experienced a common toxicity criteria ≥grade 3 according to the NCI CTC guidelines.nnnRESULTSnIn the first stage eight patients were enrolled. Median age was 70 years (range 55-76) and ECOG PS 0/1 (%) was 87.5/12.5. Major side effects were mostly intestinal bleeding (grade 3, 25%), diarrhea (grade 3, 25%), perianal and abdominal pain (grades 3 and 4, 25%) followed by anemia (grade 3, 12.5%). Tumor downstaging was observed in 37.5% of patients with complete pathological response in two patients (25%).nnnCONCLUSIONSnAfter interim analysis of feasibility and tolerability, accrual was terminated according to protocol due to ≥grade 3 toxicities in 50% of patients. Complete pathological response was seen in 25% of patients but was accompanied by considerable toxicity. Further clinical trials are needed to clarify the role of bevacizumab in this setting.

Cumulative incidence of permanent stoma after sphincter preserving low anterior resection of mid and low rectal cancer.

BACKGROUND: Changes in the treatment of rectal cancer during the past decades have led to an increase in sphincter preservation with a consecutive decline in abdominoperineal resection rates. OBJECTIVE: The aim of this study was to analyze the cumulative incidence of permanent stoma in patients undergoing sphincter-preserving resection of mid and low rectal cancer. DESIGN: This study is a retrospective analysis of prospectively collected data. SETTINGS: This study was conducted at a tertiary referral cancer hospital. PATIENTS: From 2003 to 2010, 125 patients with primary mid and low rectal cancer who underwent sphincter-preserving low anterior resection were included. MAIN OUTCOME MEASURES: The occurrence of a permanent stoma over time was investigated by using a Cox proportional hazards regression model and competing-risk models, with death as a competing risk. The risk factors were assessed by computing HRs and a Cox proportional hazards regression. RESULTS: After a median follow-up time of 61 months (range, 22–113), 15 of 125 patients ended up with a permanent stoma, accounting for a 5-year cumulative incidence of 6% (95% CI, 4%–11%). The reasons for obtaining a permanent stoma were anastomotic leakage (60%, 9/15), intractable fecal incontinence (27%, 4/15), and local recurrence (13%, 2/15). The Cox proportional hazards regression identified anastomotic leakage (HR, 6.10; 95% CI, 2.23–16.71; p = 0.0004) and coloanal anastomosis (HR, 4.31; 95% CI, 1.49–12.47; p = 0.007) as statistically significant risk factors. LIMITATIONS: Because of the small number of events in this sample, further investigations with a larger number of patients are required. Fecal incontinence was assessed by patient self-reported data without the use of a validated score. CONCLUSION: The 5-year cumulative incidence of a permanent stoma was 6%. Anastomotic leakage and coloanal anastomosis were identified as risk factors. These details should be considered before sphincter-preserving surgery.

Preoperative Oxaliplatin, Capecitabine, and External Beam Radiotherapy in Patients with Newly Diagnosed, Primary Operable, cT3NxM0, Low Rectal Cancer

AbstractPurpose:In patients with locally advanced rectal cancer (LARC), preoperative chemoradiation is known to improve local control,nand down-staging of the tumor serves as a surrogate for survival. Intensification of the systemic therapy may lead to higher downstagingnrates and, thus, enhance survival. This phase II study investigated the efficacy and safety of preoperative capecitabinenand oxaliplatin in combination with radiotherapy.Patients and Methods:Patients with LARC of the mid and lower rectum, T3NxM0 staged by MRI received radiotherapy (totalndose 45 Gy) in combination with oral capecitabine (825 mg/m2 twice a day on radiotherapy days; weeks 1–4) and oxaliplatin 50nmg/m2 intravenously (days 1, 8, 15, and 22). Efficacy was evaluated as rate of tumor down-categorization at the T level.Results:A total of 59 patients were enrolled (19 women, 40 men; median age of 61 years) and all were evaluable for efficacy andntoxicity. Down-categorization at the T level was observed in 53% with pathological complete response in 6 patients (10%). Actualntotal radiotherapy, oxaliplatin and capecitabine doses received were 97%, 90%, and 93% of the protocol-specified preplannedndoses, respectively. Grade 3/4 toxicity was observed in 15 patients (25%). The most frequent was diarrhea (12%).Conclusions:Preoperative chemoradiation with capecitabine and oxaliplatin is feasible in patients with MRI-proven cT3 LARC.nThe only clinically relevant toxicity was diarrhea. Overall, efficacy of the multimodality treatment was good, but not markedlynexceeding that of 5-FU- or capecitabine-based chemoradiation approaches.ZusammenfassungZiel:Eine präoperative Radiochemotherapie verbessert bei Patienten mit einem tief sitzenden Rektumkarzinom (LARC) die lokalenTumorkontrolle und ein so genanntes „down-staging“ dient als Überlebenssurrogatparameter. Von einer Dosisintensivierung dernsystemischen Therapie kann man sich höhere Down-Staging-Raten erwarten und damit das Überleben verbessern. Diese multizentrischenPhase-II-Studie soll die Wirksamkeit und Toxizität einer neoadjuvanten durch Capecitabin und Oxaliplatin intensiviertennRadiochemotherapie prüfen.Patienten und Methodik:Patienten mit einem LARC, das mittels MRI als cT3NxM0 klassifizierten wurde, erhielten eine Radiotherapien(45 Gy in konventioneller Fraktionierung) mit konkomitanter Gabe von Capecitabin (oral 2 x täglich 825 mg an dennBestrahlungstagen, Woche 1–4) und Oxaliplatin intravenös 50mg/m2 (an den Tagen 1, 8, 15 und 22). Die Rate an Tumor-Down-nCategorization dient als Parameter der Wirksamkeit.Ergebnisse:59 Patienten (davon 68% männlich, mittleres Alter 61 Jahre) wurden in die Studie eingeschlossen. Eine Down-nCategorization in der T-Kategorie wurde in 53% der Patienten beobachtet, wobei 6 Patienten (10%) eine komplette pathologischenRemission zeigten. Die tatsächlich verabreichte Strahlendosis betrug 97%, die Capecitabindosis 93% und die Oxaliplatindosisn90% der im Protokoll festgelegten Gesamtdosis. Akute Nebenwirkungen CTC-Grad ≥3 (Common Toxicity Criteria) wurden in 15nPatienten (25%) registriert, wobei mit 12% eine Diarrhoe am häufigsten vorkam.Schlussfolgerung:Eine präoperative Radiochemotherapie mit Capecitabin und Oxaliplatin ist bei Patienten mit mittels MRIndiagnostiziertem cT3 LARC gut durchführbar. Die einzige klinisch relevante Nebenwirkung war eine Diarrhoe. Allerdings übertrifftndie Wirksamkeit nicht wesentlich die bisherigen Erkenntnisse von Studien mit kontinuierlicher 5-Fluorouracil- oder alleinigernCapecitabingabe.

The C allele of the GNB3 C825T polymorphism of the G protein β3-subunit is associated with an increased risk for the development of oncocytic thyroid tumours

Carriers of the C allele of the common C825T polymorphism in the GNB3 gene of the G protein have been associated with the development of follicular thyroid adenomas. Since the C allele of this polymorphism is related to a lower signalling capacity, it was speculated whether the C825T polymorphism may play a particular role in oncocytic thyroid tumours, which are recognized for their reduced ability to synthesize thyroid‐specific proteins and hormones, although they possess an intact thyroid‐stimulating hormone receptor–adenylyl cyclase system. Using pyrosequencing, both the genotype distribution and the allele frequency of the C825T polymorphism were investigated in a series of 104 patients with oncocytic thyroid tumours of follicular cell origin [58 adenomas, 41 follicular thyroid carcinomas (FTCs), and five papillary thyroid carcinomas (PTCs)]; the results were compared with those obtained from 321 age and gender‐matched healthy blood donors and a series of 327 non‐oncocytic thyroid tumours of follicular cell origin (119 adenomas, 80 FTCs, and 186 PTCs). Analysis of the genotype distribution (comparing oncocytic with non‐oncocytic tumours of the present series) revealed a significantly increased odds ratio (OR) for CC versus TT (OR = 4.22; p = 0.011) and CC versus CT (OR = 1.62; p = 0.049) carriers to develop an oncocytic thyroid tumour; ORs to develop an oncocytic thyroid tumour were also increased comparing the genotype distribution between the group of oncocytic tumours and healthy controls for CC versus TT (OR = 3.73; p = 0.017) and CC versus all T carriers (OR = 1.56; p = 0.034). Oncocytic thyroid tumours as a group showed a statistically significant increase of the C‐allele frequency when compared with all non‐oncocytic tumours (p = 0.0039) as well as healthy blood donors (p = 0.017). The results strongly suggest that the C allele of the GNB3 C825T polymorphism of the G protein β3‐subunit is associated with an increased risk for the development of oncocytic thyroid tumours. This polymorphism may thus be considered a (co)factor favouring the development of oncocytic thyroid tumours, although the biological mechanism(s) underlying this association remain obscure. Copyright

Evolution of surgical microwave ablation for the treatment of colorectal cancer liver metastasis: review of the literature and a single centre experience

Surgical resection is the gold standard treatment for colorectal liver metastasis, with reported five-year survival rates of 40xa0%. Unfortunately, despite progress in systemic therapies and surgical techniques, only 20–30xa0% of patients can be offered this potentially curative treatment modality. Ablative therapies have recently been suggested to treat unresectable lesions or to extend the margins of resectability. Additionally, cases of local recurrence after hepatic surgery might require alternative strategies and options for re-intervention. Microwave ablation (MWA) has recently become a matter of particular interest for such indications. We, herein, present a review of the literature published between January 1999 and June 2013 from a database search with the following keywords: microwave, ablation, liver metastases, colorectal neoplasm, resection, hepatectomy, colonic neoplasm, cancer. Furthermore, we provide insight based on our own data for 28 consecutive patients who underwent hepatic resection combined with MWA from 2005 to 2012 in a single centre.

Different genotype distribution of the GNB3 C825T polymorphism of the G protein β3 subunit in adenomas and differentiated thyroid carcinomas of follicular cell origin

A C825T polymorphism has been demonstrated in the GNB3 gene that encodes the Gβ3 subunit of heterotrimeric G proteins. Due to enhanced G protein activation, the GNB3 825T allele is associated with an increased signal transduction activity. To elucidate a possible role in the development and course of thyroid tumours of follicular cell origin, C825T polymorphism genotypes and allele frequencies were investigated in a series of adenomas and differentiated carcinomas. Genotypes and the allele frequency of the Gβ3 polymorphism were investigated in samples from 361 patients (all white Caucasians) with differentiated thyroid tumours of follicular cell origin [80 adenomas and 95 follicular (FTCs) and 186 papillary carcinomas (PTCs)]. The results were compared with those of 1859 healthy controls. Both the genotype distribution (p = 0.029) and the allele frequency (p = 0.028) of the adenoma group were statistically significantly different from those of the control group. Thyroid adenomas also differed for both parameters significantly from FTCs (p = 0.042 and 0.033, respectively) and PTCs (0.0018 and 0.0081, respectively), whereas no statistical difference was noted between the FTC and PTC groups. Although the biological significance of these observations remains obscure, the results are suggestive of a putative role for the GNB3 polymorphism in thyroid tumour development and/or progression. Further research has to elucidate if, and to what extent, this common germ‐line variation influences the TSH‐triggered signalling pathways responsible for thyroid function and proliferation. Copyright

Postoperative Morbidity Following Chemoradiation for Locally Advanced Low Rectal Cancer

BackgroundPostoperative morbidity remains a significant clinical problem and may alter long-term outcome particularly after neoadjuvant chemoradiation in patients with locally advanced low rectal cancer. The aim of the present study was to identify a potential long-term effect of postoperative morbidity.MethodsAnalysis of prospectively collected data of 90 consecutive patients who underwent neoadjuvant chemoradiation and curative mesorectal excision for locally advanced (cT3/4, Nx, M0/1) adenocarcinoma of the mid and lower third of the rectum during a 7-year period (1996–2002).ResultsMajor postoperative complications occurred in 17.8% and minor complications in 26.6% of patients. Hospital mortality and 30-day mortality was 0%. Infectious complications were seen in 34.5%. The leading causes of infectious complications were anastomotic leakage and perineal wound infection. Postoperative morbidity was statistically significantly associated with gender (Pu2009<u20090.05), pre-therapeutic haemoglobin level (Pu2009<u20090.05), ASA score (Pu2009<u20090.05), hospitalisation (Pu2009<u20090.001) and clinical long-time course (Pu2009<u20090.01). Moreover, early postoperative morbidity was proven as an independent prognostic factor concerning disease-free (Pu2009<u20090.05) and overall survival (Pu2009<u20090.05).ConclusionEarly postoperative morbidity in patients with preoperative chemoradiation due to locally advanced low rectal cancer is demonstrated as an independent prognosticator. Gender, pre-therapeutic haemoglobin level and ASA score indicate patients at risk for early postoperative complications and may therefore serve as predictive features.

Are gender-associated differences in quality of life in colorectal cancer patients disease-specific?

PurposeThe purpose of this study was to investigate gender-associated differences in quality of life in colorectal cancer patients and compare such differences to the general population.MethodsColorectal cancer patients attending three oncological centres in Austria were consecutively recruited and assessed with the EORTC QLQ-C30. For the purpose of comparison, a gender- and age-matched healthy control group was drawn from a representative sample of the Austrian general population.ResultsAbout 206 patients (47.1% women; mean age 64.8xa0years) with colorectal cancer were included and compared with 206 persons from the general population. A two-way analysis of variance showed significant main effects (gender and colorectal cancer vs. healthy) for most EORTC QLQ-C30 scales, but a significant interaction effect was only found for diarrhea. This means that gender-associated differences specific for colorectal cancer patients were only found for diarrhea.ConclusionThe vast majority of studies on gender-associated differences in quality of life compare male and female oncological patients and neglect the issue of the disease-specificity of such differences. Our study revealed that women and men suffering from colorectal cancer scored differently across many aspects of quality of life, but with the exception of diarrhea, these differences were also found in the general population, i.e. they indicated no gender-specific reaction to disease.