Gerhard Leitner

A Functional Germline Variant in GLI1 Implicates Hedgehog Signaling in Clinical Outcome of Stage II and III Colon Carcinoma Patients

Purpose: Cumulating evidence indicates that germline variants in the Wnt, Notch, and Hedgehog pathways are involved in colon carcinoma progression and metastasis. We investigated germline polymorphisms in a comprehensive panel of Wnt, Notch, and Hedgehog pathway genes to predict time to recurrence (TTR) and overall survival in patients with stage II and III colon carcinoma. Experimental Design: A total of 742 consecutively collected patients with stage II and III colon carcinoma were included in this retrospective study. Genomic DNA was analyzed for 18 germline polymorphisms in Wnt, Notch, and Hedgehog pathway genes (SFRP, DKK 2 and 3, AXIN2, APC, MYC, TCF7L2, NOTCH2, and GLI1) by TaqMan 5′-exonuclease assays. Results: In univariate analysis, the homozygous mutant variant of GLI1 rs2228226 G>C was significantly associated with decreased TTR in a recessive genetic model after adjustment for multiple testing [HR = 2.35; confidence interval (95% CI), 1.48–3.74; P < 0.001] and remained significant in multivariate analysis including clinical stage, lymphovascular-, vascular-, and perineural-invasion (HR = 2.43; CI 95%, 1.52–3.87; P < 0.001). In subanalyses, the association was limited to patients with surgery alone (HR = 3.21; CI 95%, 1.59–6.49; P = 0.001), in contrast with patients with adjuvant chemotherapy (HR = 0.82; CI 95%, 0.35–1.95; P = 0.657). When the subgroup of patients with “high-risk” GLI1 rs2228226 C/C genotype was analyzed, no benefit of adjuvant 5-fluorouracil–based chemotherapy could be found. Conclusion: This is the first study identifying GLI1 rs2228226 G>C as an independent prognostic marker in patients with stage II and III colon carcinoma. Prospective studies are warranted to validate our findings. Clin Cancer Res; 20(6); 1687–97. ©2014 AACR.

Clinical epidemiology of invasive cutaneous malignant melanoma in the Austrian province Styria in the years 2001-2003 and its relationship with local geographical, meteorological and economic data.

Background:Melanoma incidence rates vary within Europe. The highest incidences are reported in Scandinavia, the lowest in the southern parts, but incidences themselves also vary within the different countries. Objective:We investigated the incidence of invasive cutaneous melanoma in Styria, a province of Austria, in the years 2001–2003. Methods:Data from 1,082 patients, 511 males and 571 females (mean age 58.2 years) with primary melanoma were collected. For each patient, information regarding residence was available, and therefore the geographic distribution of melanoma on district level was investigated with particular reference to the mean number of sun hours, mean altitude, number of companies with more than 200 employees and median income. Results:The mean annual incidence (age-standardized rate) was 24.5 per 100,000 (95% CI: 22.4–26.6), lifetime risk 1 in 52. Districts with a higher number of sun hours and higher altitude showed lower melanoma incidences. Higher median income was associated with higher melanoma incidence (p < 0.001). Conclusion:The high incidence of invasive melanoma in Styria is unclear and a causal relationship between higher income and melanoma incidence remains speculative. Further investigations, especially concerning lifestyle and environmental factors, may unravel additional causative factors.

Access recirculation in a native fistula in spite of a seemingly adequate access flow

True access recirculation (AR) measured by ultrasound dilution technique is usually absent in well-working shunts. It occurs with low access flows (Qa). High access flow rates are assumed to prevent AR. Two major exceptions to these rules are known: presence of intra-access strictures and inadvertently reversed blood lines. We present an additional exception in which true access recirculation occurred in a native arteriovenous (AV) fistula with correct placement of bloodlines. Surprisingly, access blood flow exceeded pump blood flow (Qb) almost threefold. The situation was clarified by a magnetic resonance angiogram showing a collateral forming a functional loop. This loop led to true access recirculation in one branch, although overall blood flow through both branches appeared to be adequate. The different findings in this shunt over time give insight into the often complex pathophysiology of native fistulae. This case proves that seemingly adequate access flow does not necessarily prevent access recirculation in native AV fistulae. We suggest monitoring both access flow and recirculation in hemodialysis accesses on a regular basis.

LGR5 rs17109924 is a predictive genetic biomarker for time to recurrence in patients with colon cancer treated with 5-fluorouracil-based adjuvant chemotherapy.

We recently found variants in cancer stem cell genes (CD44, ALCAM and LGR5) significantly associated with increased time to recurrence (TTR) in patients with stage III and high-risk stage II colon cancer treated with 5-fluorouracil (5-FU)-based chemotherapy. In this study, we validated these genetic biomarkers in a large and independent patient cohort (n=599). Patients who received 5-FU-based adjuvant chemotherapy (n=391) carrying at least one C allele in LGR5 rs17109924 had a significantly increased TTR compared with patients carrying the homozygous T/T variant (HR 0.38, 95%CI 0.19–0.79; P=0.006). In patients treated with surgery alone (n=208), no association between LGR rs17109924 and TTR was found (P=0.728). In the multivariate Cox-analysis, LGR5 rs17109924 remained statistically significant (HR 0.38, 95%CI 0.18–0.78; P=0.008) for patients who received adjuvant chemotherapy. We confirmed in a large and independent study cohort that LGR5 rs17109924 is a predictive genetic biomarker for TTR in patients with colon cancer treated with 5-FU-based adjuvant chemotherapy.

Prediction of clinical outcome in stage II and III colon cancer by a common gene variant in AXIN2.

387 Background: Recent evidence suggests that the Wnt and Notch signaling pathways are involved in colon cancer progression and tumor recurrence. There is substantial germline genetic variability in these pathways, including single nucleotide polymorphisms (SNPs). SNPs may alter transcription, translation or splicing, thereby causing inter-individual differences in a patient’s tumor recurrence capacity and chemoresistance. We hypothesized that SNPs analyzed in a comprehensive panel of Wnt and Notch pathway genes predict clinical outcome in patients with colon cancer. Methods: A total of 815 patients with stage II and III colon cancer treated at the Medical University of Graz were included in this retrospective study. FFPE tissue specimens from normal tissue adjacent to the tumor samples were available from 599 patients. 18 SNPs in Wnt and Notch pathway genes (SFRP, DKK2, DKK3, Axin2, APC, MYC, TCF7L2 and NOTCH-2) were determined by 5’-exonuclease assay (TaqMan). The primary endpoint of the study was disea...

Intraoperative radiation with external irradiation: an alternative for nonresectable non-small-cell lung cancer?

In 15 patients with nonresectable non-small-cell lung carcinoma (NSCLC) (10 squamous, 1 large cell, 4 adenocarcinomas; T1-T3, N0-N2, all M0), lymph node dissection and intraoperative irradiation of the tumour (IORT) with doses between 10 and 20 Gy (11-20 MeV electron beam) was performed. Four weeks postoperatively 46-56 Gy external irradiation (8 or 23 MeV photons) was delivered to the mediastinum and 46 Gy to the tumour-bearing area. Four weeks postoperatively, 8 minor responses (MR, tumour regression between 4% and 45%) and 6 partial responses (PR, 50%-84%) were found. In 1 case, CT was inconclusive. Eighteen weeks after IORT, volumetry showed 3 CR, 9 PR (62% to 94%) and 1 28% MR. One patient died from intrabronchial hemorrhage 7 weeks after IORT (50% PR). Two others (both CR) died from unrelated causes, 6 and 12 months, respectively, after IORT. One patient (62% PR) died after 14 months from an unknown cause. Another patient died at 15 months from local relapse after CR. The latest CT volume assessment between 7.5 and 21.5 months, respectively, yielded 8 CR, and 1 63% PR. One further case of local CR has developed contralateral pulmonary metastasis after 10 months. All these patients are alive and well. The median time elapsed since IORT is 12.5 months, 10 patients have survived more than 12 months.