Repeated adjuvant anti-CEA radioimmunotherapy after resection of colorectal liver metastases: Safety, feasibility, and long-term efficacy results of a prospective phase 2 study.

BACKGROUND: In previous work, a single administration of anticarcinoembryonic antigen (anti-CEA) 131 I-labetuzumab radioimmunotherapy (RIT) after complete resection of colorectal liver metastases was well tolerated and significantly improved survival compared with controls. In the current phase 2 trial, the authors studied repeated RIT in the same setting, examining safety, feasibility, and efficacy. METHODS: Sixty-three patients (median age, 64.5 years) received RIT at 40 to 50 millicuries/m2 per dose. Before the receipt of RIT, restaging was performed with computed tomography/magnetic resonance imaging and 18 F-fluorodeoxyglucose-positron emission to confirm that patients were "truly adjuvant." Patients who had elevated serum CEA levels or radiographically inconclusive new lesions were classified as "possibly nonadjuvant," but they also received RIT. Time to progression (TTP), overall survival (OS), and cause-specific survival (CSS) were calculated. The median follow-up was 54 months. RESULTS: After the first course of RIT, 14 of 63 patients experienced National Cancer Institute Common Toxicity Criteria grade 4 hematotoxicity; 19 patients did not receive the second course of RIT because of impaired performance status (N = 5) or relapse (N = 14). After the second course of RIT, 9 of 44 patients experienced National Cancer Institute Common Toxicity Criteria grade 4 hematotoxicity. Five patients developed myelodysplastic syndrome (MDS) from 22 to 55 months after their last RIT. The median TTP, OS, and CSS for all patients were 16, 55, and 60 months, respectively. The "truly adjuvant" patients (N = 39) had an improved median TTP (not reached vs 6.1 months; hazard ratio, 0.12; P < .001), OS (75.6 vs 33.4 months; hazard ratio, 0.44; P = .014), and CSS (not reached vs 41.4 months; hazard ratio,0.42; P = .014) compared with "possibly nonadjuvant" patients (N = 24). CONCLUSIONS: Repeated RIT with 131 I-labetuzumab is feasible but is associated with hematotoxicity. Survival is very encouraging, especially for "truly adjuvant" patients. However, the maximum safe dose of 131 I-labetuzumab is a single administration of 50 millicuries/m2 . Cancer 2017;123:638-649. © 2016 American Cancer Society.

The utilization of multidisciplinary tumor boards (MDT) in clinical routine: results of a health care research study focusing on patients with metastasized colorectal cancer.

PURPOSE: Multidisciplinary tumor boards (MDT) have been advocated as standard of care in modern oncology. German guidelines for metastasized colorectal cancer (mCRC) recommend MDT discussion of colon cancer patients after completion of primary tumor therapy but stage IV colon cancer as well as rectal cancer patients prior to any therapy. In this health care research study, we evaluated application and decisional consequences of this approach in clinical routine. METHODS: All major institutions providing oncological care in southern Lower Saxony and Northern Hesse (N = 11) were invited. Patients with mCRC diagnosed between 01/2011 and 12/2013 were eligible. Data were collected using a standardized patient report form and stored in a GCP-conform EDC-system (secuTrial®). RESULTS: A university medical center, four teaching hospitals, one communal hospital, and three oncological focus practices participated in the study. In total, 470 patients with a median age of 70 years were enrolled. Guideline conform MDT discussion was performed in 63% of operated colon cancer patients, 38% of stage IV colon cancer patients and 47% of rectal cancer patients, respectively. Resection of metastases was performed in 41% of cases. Patients ≥70 years (n = 250) received significantly more often treatment following MDT discussion (86 versus 64%, p = 0.0002). Not the resection rate (48 versus 57%, p = 0.1574) but indication for preoperative chemotherapy (57 versus 33%, p = 0.0056) significantly differed when patients with single organ metastases experienced MDT discussion. CONCLUSIONS: MDT discussion is not as established as advocated by national guidelines. Treatment decisions differ especially in older patients and those with single organ metastases.

Stage-Dependent Frequency of Lymph Node Metastases in Patients With Rectal Carcinoma After Preoperative Chemoradiation: Results from the CAO/ARO/AIO-94 Trial and From a Comparative Prospective Evaluation With Extensive Pathological Workup.

BACKGROUND: For patients with ycT1/2 rectal carcinomas after neoadjuvant chemoradiotherapy, local excision instead of radical surgery has increasingly been discussed as a way to avoid postoperative morbidity associated with radical surgery. OBJECTIVE: The purpose of this study was to determine the incidence of lymph node metastases in total mesorectal excision specimens with ypT0, ypT1/2, and ypT3/4 rectal cancers. DESIGN: This is a prospective and retrospective cohort study. SETTINGS: This study was conducted in tertiary referral hospitals that are part of the German Rectal Cancer Study Group. PATIENTS: A total of 479 patients with stage II and III rectal cancers treated within phase III trials of the German Rectal Cancer Study Group were evaluated. Specimens from 81 patients treated in the Working Group of Surgical Oncology/Working Group of Radiation Oncology/Working Group of Medical Oncology of the Germany Cancer Society (CAO/ARO/AIO-04) trial were prospectively studied with extensive microscopic screening of the entire mesorectum. The frequency and localization of nodal metastases were specified and compared with those of 398 patients having received neoadjuvant chemoradiation within the CAO/ARO/AIO-94 trial. MAIN OUTCOME MEASURES: Frequency and localization of mesorectal lymph node metastases in patients with ypT0, ypT1/2, or ypT3/4 cancer were measured. RESULTS: A mean number of 28.0 ± 13.7 nodes were detected per specimen within the prospective group. A total of 25% of patients in the ypT1/2 group had nodal metastases compared with 40% in the ypT3/4 group. Patients with node-positive ypT1/2 had a mean number of 2.2 metastases, and 55% of these metastases were located far from the primary lesion in the proximal mesorectum. Within the CAO/ARO/AIO-94 cohort (n = 398), 19% of patients with ypT1/2 (ypT1 = 22%; ypT2 = 18%) had ypN+ status compared with 43% with ypT3/4 cancers (ypT3 = 40%; ypT4 = 73%). LIMITATIONS: Low numbers of patients with ypT0 limited the evaluation of nodal metastases in pathologic complete responders. CONCLUSIONS: Even in good responders (ypT1/2), >20% of rectal carcinomas still harbored residual lymph node metastases. Local excision for patients with ycT1/2 rectal cancers would, thus, miss metastases in a considerable percentage and might involve the risk of significant undertreatment in a number of patients.

Enrichment of CD133-expressing cells in rectal cancers treated with preoperative radiochemotherapy is an independent marker for metastasis and survival.

BACKGROUND: The transmembrane glycoprotein CD133 (cluster of differentiation 133; also known as Prominin or PROM1) has been described as a potential stem cell marker in colorectal cancer and is associated with higher tumorigenic potential and resistance to radiochemotherapy (RCT). In this study, CD133 expression was evaluated in pre-RCT tumor biopsies and the corresponding post-RCT surgical specimens from patients with locally advanced rectal adenocarcinoma, and expression levels were correlated with histopathologic features and clinical follow-up. METHODS: One hundred twenty-six patients with International Union Against Cancer (UICC) stage II/III rectal cancer who received preoperative 5-fluorouracil (5-FU)-based RCT within the German Rectal Cancer Trials were investigated. Pre-RCT and post-RCT CD133 expression levels were determined using immunohistochemistry and were correlated with histopathologic parameters, tumor regression grade, cancer recurrence, and patient survival. RESULTS: Compared with pre-RCT biopsies, significantly higher CD133 expression was observed in tumor specimens (P = .01). However, no correlations were observed for either biopsies or tumor specimens between CD133 expression levels, histopathologic characteristics, or survival. In matched analyses of corresponding biopsy/tumor pairs, patients who had an increased fraction of CD133-expressing (CD133+) cells after preoperative RCT had significantly higher residual tumor stages (P = .02) and lower histopathologic tumor regression (P < .01). Moreover, these patients had significantly reduced disease-free survival and cancer-specific overall survival in univariate analysis (P < .001 and P = .004, respectively) and multivariate analysis (P = .003 and P = .024, respectively). CONCLUSIONS: The enrichment of CD133+ cancer cells during preoperative RCT was correlated with minor local tumor response, increased distant cancer recurrence, and decreased survival. The current results indicate that the up-regulation of intratumoral CD133 expression, in contrast to absolute pre-RCT and post-RCT CD133 levels, plays an important role in tumor progression and metastasis in patients with rectal cancer who are receiving neoadjuvant RCT.

Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.

OBJECTIVE: The purpose of this study was to assess outcomes and indications in a large cohort of patients who underwent liver transplantation (LT) for liver metastases (LM) from neuroendocrine tumors (NET) over a 27-year period. BACKGROUND: LT for NET remains controversial due to the absence of clear selection criteria and the scarcity and heterogeneity of reported cases. METHODS: This retrospective multicentric study included 213 patients who underwent LT for NET performed in 35 centers in 11 European countries between 1982 and 2009. One hundred seven patients underwent transplantation before 2000 and 106 after 2000. Mean age at the time of LT was 46 years. Half of the patients presented hormone secretion and 55% had hepatomegaly. Before LT, 83% of patients had undergone surgical treatment of the primary tumor and/or LM and 76% had received chemotherapy. The median interval between diagnosis of LM and LT was 25 months (range, 1-149 months). In addition to LT, 24 patients underwent major resection procedures and 30 patients underwent minor resection procedures. RESULTS: Three-month postoperative mortality was 10%. At 5 years after LT, overall survival (OS) was 52% and disease-free survival was 30%. At 5 years from diagnosis of LM, OS was 73%. Multivariate analysis identified 3 predictors of poor outcome, that is, major resection in addition to LT, poor tumor differentiation, and hepatomegaly. Since 2000, 5-year OS has increased to 59% in relation with fewer patients presenting poor prognostic factors. Multivariate analysis of the 106 cases treated since 2000 identified the following predictors of poor outcome: hepatomegaly, age more than 45 years, and any amount of resection concurrent with LT. CONCLUSIONS: LT is an effective treatment of unresectable LM from NET. Patient selection based on the aforementioned predictors can achieve a 5-year OS between 60% and 80%. However, use of overly restrictive criteria may deny LT to some patients who could benefit. Optimal timing for LT in patients with stable versus progressive disease remains unclear.

Pyloric gland adenoma of the cystic duct with malignant transformation: report of a case with a review of the literature.

BACKGROUND: Pyloric gland adenoma consists of closely packed pyloric-type glands lined by mucus-secreting cells. To date, approximately 230 cases have been reported, mostly of gastric localization with a tumour size up to 3.5 cm and a mean age of occurrence around 70 years. Adenocarcinoma develops in about 40% of cases and may be difficult to detect due to relatively mild nuclear atypia. CASE PRESENTATION: We present the first case of a pyloric gland adenoma of the cystic duct in a 62-year-old male patient and demonstrate the clinicopathologic characteristics, including radiographic, molecular, and cytogenetic findings. The 2 cm-tumour developed in the cystic duct and protruded into the hepatic and common bile duct. On microscopic examination, it displayed closely packed pyloric-type glands, and focal architectural distortion with mild nuclear atypia. Immunohistochemically, it expressed MUC1, MUC5AC, MUC6 and p53, but not MUC2 and CD10. The Ki67-proliferation index was 25%. Furthermore, high-grade intraepithelial neoplasia was observed in the surrounding bile duct. We detected chromosomal gains at 7p, 7q11q21, 15q, 16p, 20, losses at 6p23pter, 6q, 18, and amplifications at 1q and 6p21p22 in the pyloric gland adenoma by comparative genomic hybridization. A KRAS codon 12 mutation (c.35G>T; p.G12V) was detected in the pyloric gland adenoma and in the adjacent dysplasia by sequencing analysis. The diagnosis of pyloric gland adenoma was established with transition into well-differentiated adenocarcinoma and high-grade biliary intraepithelial neoplasia. CONCLUSION: Pyloric gland adenoma evolving in the cystic duct is a rare differential diagnosis of obstructive bile duct tumours. Other premalignant bile duct lesions may be associated. Due to the risk of developing adenocarcinoma, surgical resection should be performed.

Ultrasonic scalpel causes greater depth of soft tissue necrosis compared to monopolar electrocautery at standard power level settings in a pig model.

BACKGROUND: Ultrasonic scalpel (UC) and monopolar electrocautery (ME) are common tools for soft tissue dissection. However, morphological data on the related tissue alteration are discordant. We developed an automatic device for standardized sample excision and compared quality and depth of morphological changes caused by UC and ME in a pig model. METHODS: 100 tissue samples (5 × 3 cm) of the abdominal wall were excised in 16 pigs. Excisions were randomly performed manually or by using the self-constructed automatic device at standard power levels (60 W cutting in ME, level 5 in UC) for abdominal surgery. Quality of tissue alteration and depth of coagulation necrosis were examined histopathologically. Device (UC vs. ME) and mode (manually vs. automatic) effects were studied by two-way analysis of variance at a significance level of 5%. RESULTS: At the investigated power level settings UC and ME induced qualitatively similar coagulation necroses. Mean depth of necrosis was 450.4 ± 457.8 µm for manual UC and 553.5 ± 326.9 µm for automatic UC versus 149.0 ± 74.3 µm for manual ME and 257.6 ± 119.4 µm for automatic ME. Coagulation necrosis was significantly deeper (p < 0.01) when UC was used compared to ME. The mode of excision (manual versus automatic) did not influence the depth of necrosis (p = 0.85). There was no significant interaction between dissection tool and mode of excision (p = 0.93). CONCLUSIONS: Thermal injury caused by UC and ME results in qualitatively similar coagulation necrosis. The depth of necrosis is significantly greater in UC compared to ME at investigated standard power levels.

The impact of preferences for clinical and managerial leadership roles on the willingness to apply for a medical leadership position: Analysis of gender differences among a sample of German senior physicians.

BACKGROUND: The hybrid role (clinical and managerial leadership tasks) of physicians in medical leadership positions (MLPs) is a driver of the attractiveness of these positions. The increasing feminization of the medical profession makes gender-related preferences for hybrid roles relevant. PURPOSE: The current study uses the (EPL) career aspirations framework to analyze the (gender-related) effects that efficacy beliefs, motivations, and preferences for clinical leadership and managerial leadership have on the willingness of chief physicians to apply for an MLP.Methodology: A survey of senior physicians in German university hospitals yielded a sample size of N = 496. The resulting data were analyzed using a structural equation modeling approach. FINDINGS: The results confirm the low preference for MLPs among senior physicians, which is mainly affected by preferences for managerial leadership tasks. Female senior physicians perceive the position of an MLP to be less attractive than their male counterparts do, and female physicians' willingness to apply for an MLP is concurrently driven by their preferences for clinical leadership and managerial leadership tasks.Practical implications: Mentoring programs could boost female senior physicians' preparedness for MLPs. Further, flexibility in fulfilling managerial leadership tasks could be promoted to make MLPs more attractive to women.

High-Throughput Profiling of Colorectal Cancer Liver Metastases Reveals Intra- and Inter-Patient Heterogeneity in the EGFR and WNT Pathways Associated with Clinical Outcome.

Seventy percent of patients with colorectal cancer develop liver metastases (CRLM), which are a decisive factor in cancer progression. Therapy outcome is largely influenced by tumor heterogeneity, but the intra- and inter-patient heterogeneity of CRLM has been poorly studied. In particular, the contribution of the WNT and EGFR pathways, which are both frequently deregulated in colorectal cancer, has not yet been addressed in this context. To this end, we comprehensively characterized normal liver tissue and eight CRLM from two patients by standardized histopathological, molecular, and proteomic subtyping. Suitable fresh-frozen tissue samples were profiled by transcriptome sequencing (RNA-Seq) and proteomic profiling with reverse phase protein arrays (RPPA) combined with bioinformatic analyses to assess tumor heterogeneity and identify WNT- and EGFR-related master regulators and metastatic effectors. A standardized data analysis pipeline for integrating RNA-Seq with clinical, proteomic, and genetic data was established. Dimensionality reduction of the transcriptome data revealed a distinct signature for CRLM differing from normal liver tissue and indicated a high degree of tumor heterogeneity. WNT and EGFR signaling were highly active in CRLM and the genes of both pathways were heterogeneously expressed between the two patients as well as between the synchronous metastases of a single patient. An analysis of the master regulators and metastatic effectors implicated in the regulation of these genes revealed a set of four genes (SFN, IGF2BP1, STAT1, PIK3CG) that were differentially expressed in CRLM and were associated with clinical outcome in a large cohort of colorectal cancer patients as well as CRLM samples. In conclusion, high-throughput profiling enabled us to define a CRLM-specific signature and revealed the genes of the WNT and EGFR pathways associated with inter- and intra-patient heterogeneity, which were validated as prognostic biomarkers in CRC primary tumors as well as liver metastases.

Thymidylate synthase as a prognostic biomarker for locally advanced rectal cancer after multimodal treatment.

PURPOSE: For years, 5-fluorouracil (5-FU) has been the backbone of radiochemotherapy (RCT) of locally advanced rectal cancer. Its main target, thymidylate synthase (TS), is speculated to be an important biomarker for response prediction and long-term prognosis. In this study, we analyzed TS expression in the rectal cancer tissue of 208 patients to evaluate its predictive/prognostic potential. METHODS: All patients included were diagnosed with locally advanced adenocarcinoma of the rectum (UICC II and III) and were treated within randomized clinical trials of the German Rectal Cancer Study Group. Preoperative RCT (50.4 Gy and concomitant either 5-FU or 5-FU and oxaliplatin) was administered in 167 patients followed by surgical resection with total mesorectal excision (TME). Another 41 patients received postoperative RCT. TS levels and further clinicopathological parameters were assessed in univariate and multivariate analyses. Additionally, a TS gene polymorphism was analyzed with respect to the intratumoral protein levels. RESULTS: Low TS expression in pretreatment biopsies correlated with impaired patient survival (p = 0.015). Analysis of a 28-bp repeat revealed a correlation between the *3/*3 genotype and high TS expression in pretherapeutic biopsies. In this study, a correlation of TS expression and grade of RCT-induced tumor regression was not found. Histopathological examination confirmed a complete tumor remission in 16 patients (9.6%). Analyses of the resection specimen indicated an unfavorable prognosis for patients with low intratumoral TS expression in case of detected lymph node metastases (p = 0.04). CONCLUSIONS: TS can serve as a prognostic biomarker indicating an unfavorable prognosis for patients with low TS expression.

Multimodal treatment options for bilobar colorectal liver metastases.

PURPOSE: We evaluated individualized multimodal oncological strategies in patients with bilobular colorectal liver metastases (biCRC-LM) as well as their effect on R0 resection rates, disease-free survival (DFS), and overall survival (OS). METHODS: Between January 2001 and December 2008, 64 patients were assigned to straightforward or two-stage liver resection +/- preoperative 5-fluorouracil (5FU)-based chemotherapy (CTx). Postoperative strategy after R0-resection was either "wait and see" or "adjuvant" therapy (3 cycles of CTx or anti-carcinoembryonic antigen (CEA)-radioimmunotherapy with (131)I-labetuzumab in a dose of 40-50 mCi/m(2)). RESULTS: Forty-three initially unresectable patients received preoperative CTx for downsizing of their biCRC-LM. Straightforward or two-stage liver resection was intended in 40 and 24 patients, respectively. Histopathologically confirmed R0-liver resection could be achieved in 47 patients. Surgical morbidity and mortality rates were 33% and 1.5%, respectively. Postoperatively, 26 patients received anti-cancer therapy (5 x CTx, 21 x anti-CEA-radioimmunotherapy). After R0-liver resection, median OS was significantly better compared to R1/R2 resections followed by palliative 5FU-CTx (38 versus 19 months, p = 0.035). There was no significant difference in DFS (p = 0.650) and OS (p = 0.435) between straightforward and two-stage liver resection. Compared to "wait and see" strategy, the application of postoperative therapy in adjuvant intent was associated with a better OS (p = 0.048). CONCLUSION: Extensive liver resection within multimodal treatment concepts is justified in patients with biCRC-LM when complete resection of all metastases seems to be achievable.

Digital Affinity in Medical Students Influences Learning Outcome: A Cluster Analytical Design Comparing Vodcast With Traditional Lecture.

BACKGROUND/OBJECTIVE: Undergraduate medical education still relies on lectures as the core teaching activity. However, e-learning and new media have begun to augment learning and information gathering over the last few years. The aim of this study was to investigate the effect of 2 teaching formats in surgical education, a classic lecture and a video podcast (vodcast), on knowledge gain, in particular with respect to the participants' characteristics and preferences. DESIGN: A prospective study was conducted over 2 consecutive semesters. A traditional lecture on goitre was given to the first of the 2 semesters and replaced by a matching vodcast made available to the second. An untaught subject (cholelithiasis) served as control. Knowledge gain was calculated as the difference in point scores between entry and mid-module examinations. Furthermore, participants completed a postintervention survey, in which they specifically rated their digital affinity and learning preferences. A cluster analysis was conducted pooling both semesters to evaluate differences between individuals affecting their performance. RESULTS: Both teaching formats resulted in a significant knowledge gain. Two clusters could be identified across both semesters: Cluster 2 (Digital natives) proved to be significantly different from Cluster 1 (Traditional) with respect to the 4 variables: "technically interested," the "use of smartphones," "activity in social networks," and "reading in digital formats." The knowledge gain differences between formats for students in the "Traditional" cluster were statistically insignificant. However, students in the cluster "Digital natives" performed significantly worse when exposed to the lecture format. CONCLUSIONS: Cluster analysis revealed that the students with an obvious affinity to information communication technology were found to be at a significant disadvantage in the lecture. In future, we recommend offering some form of pretest to determine an individual's profile and empower students to plan their learning activities accordingly.

Using RNA-Seq Data for the Detection of a Panel of Clinically Relevant Mutations.

Somatic single nucleotide variants (SNVs) are genomic events with increasing implications in cancer treatment. The clinical standard for SNVs detection is whole genome/exome sequencing (WGS/WES) in matched tumor-normal samples. Yet, this is a very costly approach both economically and biologically and very often only tumor samples are sequenced. On the other hand, RNA sequencing (RNA-Seq) is the most popular technology to study gene expression, and has also the potential for a cost-effective identification of SNVs as an alternative to tumor-only WES. Here we present a method for the identification of SNVs in tumor-only RNA-Seq data putting a special focus on a small panel of clinically relevant SNVs. For evaluation purposeswe analyzed matched tumor-normal WEStumor-only RNA-Seq data from 14 cancer patients. We compared SNVs detected in i) RNA-Seq by our method, ii) WES tumor-only by Mutect2 and iii) WES matched tumor-normal by Mutect2. We did a detailed evaluation for a reduced panel of clinically relevant SNVs and reliably identified in RNA-Seq data a subset of mutations for which we had pathological annotation. Hence, RNA-Seq rises as a cost-effective option to detect in parallel gene expression as well as a small panel of clinically relevant SNVs in research.

FGFR3 mRNA overexpression defines a subset of oligometastatic colorectal cancers with worse prognosis.

OBJECTIVES: Metastatic colorectal cancer (CRC) remains a leading cause of cancer related deaths. Patients with oligometastatic liver disease represent a clinical subgroup with heterogeneous course. Until now, biomarkers to characterize outcome and therapeutic options have not been fully established. METHODS: We investigated the prevalence of FGFR alterations in a total of 140 primary colorectal tumors and 63 liver metastases of 55 oligometastatic CRC patients. FGF receptors (FGFR1-4) and their ligands (FGF3, 4 and 19) were analyzed for gene amplifications and rearrangements as well as for RNA overexpression in situ. Results were correlated with clinico-pathologic data and molecular subtypes. RESULTS: Primary tumors showed FGFR1 (6.3%) and FGF3,4,19 (2.2%) amplifications as well as FGFR1 (10.1%), FGFR2 (5.5%) and FGFR3 (16.2%) overexpression. In metastases, we observed FGFR1 amplifications (4.8%) as well as FGFR1 (8.5%) and FGFR3 (14.9%) overexpression. Neither FGFR2-4 amplifications nor gene rearrangements were observed. FGFR3 overexpression was significantly associated with shorter overall survival in metastases (mOS 19.9 vs. 47.4 months, HR=3.14, p=0.0152), but not in primary CRC (HR=1.01, p=0.985). Although rare, also FGFR1 amplification was indicative of worse outcome (mOS 12.6 vs. 47.4 months, HR=8.83, p=0.00111). CONCLUSIONS: We provide the so far most comprehensive analysis of FGFR alterations in primary and metastatic CRC. We describe FGFR3 overexpression in 15% of CRC patients with oligometastatic liver disease as a prognosticator for poor outcome. Recently FGFR3 overexpression has been shown to be a potential therapeutic target. Therefore, we suggest focusing on this subgroup in upcoming clinical trials with FGFR-targeted therapies.

The Prognostic Value of Tyrosine Kinase SRC Expression in Locally Advanced Rectal Cancer.

The cellular sarcoma gene (SRC) is a proto-oncogene encoding for a tyrosine kinase. SRC expression was determined in locally advanced rectal adenocarcinoma tissue from pretreatment biopsies and resection specimens. The expression level was correlated with clinicopathological parameters to evaluate the predictive and prognostic capacity. For this monocentric analysis 186 patients with locally advanced rectal cancer (median: 63.7 years; 130 men (69.9%), 56 women (30.1%)) were included. Patients with a carcinoma of the upper third of the rectum were treated with primary tumor resection (n=27; 14.5%). All other patients received a preoperative chemoradiotherapy (CRT) with 50.4 Gy and concomitant 5-fluorouracil (5-FU) or 5-FU+oxaliplatin followed by postoperative chemotherapy with 5-FU or 5-FU+oxaliplatin. SRC expression was determined with immunohistochemical staining from pretreatment biopsies (n=152) and residual tumor tissue from the resection specimens (n=163). The results were correlated with clinicopathological parameters and long-term follow-up. The expression of SRC was determined in pretherapeutic biopsies (mean H-Score: 229) and resection specimens (mean H-Score: 254). High SRC expression in pretherapeutic tumor samples significantly correlated with a negative postoperative nodal status (p=0.005). Furthermore an increased protein expression in residual tumor tissue was associated with fewer distant metastases (p=0.04). The overexpression of SRC in pretreatment tumor biopsies showed also a trend for a longer cancer-specific survival (CSS; p=0.05) and fewer local relapses (p=0.06) during long-term follow-up. High SRC expression in rectal cancer seems to be associated with a better long-term outcome. This finding could help in the future to stratify patients for a recurrence risk adapted postoperative treatment.

ß-catenin-independent WNT signaling and Ki67 in contrast to the estrogen receptor status are prognostic and associated with poor prognosis in breast cancer liver metastases.

Liver metastasis development in breast cancer patients is common and confers a poor prognosis. So far, the prognostic significance of surgical resection and clinical relevance of biomarker analysis in metastatic tissue have barely been investigated. We previously demonstrated an impact of WNT signaling in breast cancer brain metastasis. This study aimed to investigate the value of established prognostic markers and WNT signaling components in liver metastases. Overall N = 34 breast cancer liver metastases (with matched primaries in 19/34 cases) were included in this retrospective study. Primaries and metastatic samples were analyzed for their expression of the estrogen (ER) and progesterone receptor, HER-2, Ki67, and various WNT signaling-components by immunohistochemistry. Furthermore, ß-catenin-dependent and -independent WNT scores were generated and analyzed for their prognostic value. Additionally, the influence of the alternative WNT receptor ROR on signaling and invasiveness was analyzed in vitro. ER positivity (HR 0.09, 95 % CI 0.01-0.56) and high Ki67 (HR 3.68, 95 % CI 1.12-12.06) in the primaries had prognostic impact. However, only Ki67 remained prognostic in the metastatic tissue (HR 2.46, 95 % CI 1.11-5.44). Additionally, the ß-catenin-independent WNT score correlated with reduced overall survival only in the metastasized situation (HR 2.19, 95 % CI 1.02-4.69, p = 0.0391). This is in line with the in vitro results of the alternative WNT receptors ROR1 and ROR2, which foster invasion. In breast cancer, the value of prognostic markers established in primary tumors cannot directly be translated to metastases. Our results revealed ß-catenin-independent WNT signaling to be associated with poor prognosis in patients with breast cancer liver metastasis.

Hepatocellular carcinoma: Surgeon's view on latest findings and future perspectives.

Hepatocellular carcinoma (HCC) is the most common liver-derived malignancy with a high fatality rate. Risk factors for the development of HCC have been identified and are clearly described. However, due to the lack of tumor-specific symptoms, HCC are diagnosed at progressed tumor stages in most patients, and thus curative therapeutic options are limited. The focus of this review is on surgical therapeutic options which can be offered to patients with HCC with special regard to recent findings, not exclusively focused on surgical therapy, but also to other treatment modalities. Further, potential promising future perspectives for the treatment of HCC are discussed.

HER-2 and HER-3 expression in liver metastases of patients with colorectal cancer.

OBJECTIVE: In this study, we evaluate the frequency of HER-2 and HER-3 expression in liver metastases from patients with colorectal cancer (CRLM). We analyzed the potential of HER-2 and HER-3 as therapeutic targets and evaluated their prognostic value. PATIENTS AND METHODS: Overall 208 patients with CRLM were enrolled. HER-2 and HER-3 expression were determined in metastatic tissue of diagnostic punch biopsies (n = 29) or resection specimens (n = 179). The results of immunohistochemistry (IHC) scoring and In-situ-hybridization (ISH)-amplification were correlated with clinical parameters and for the 179 resected patients with cancer-specific (CSS) and overall survival (OS). The mean follow-up time was 56.7 months. RESULTS: Positivity of HER-2 status (IHC score 2+/ISH+ and IHC 3+) was found in 8.2% of CRLM. High expression of HER-3 (IHC score 2+ and IHC 3+) was detected in 75.0% of liver metastases. CSS after liver surgery was determined and was independent from the HER-2 status (p = 0.963); however HER-3 was prognostic with a favorable course for patients showing an overexpression of HER-3 (p = 0.037). CONCLUSIONS: HER-2 overexpression occurs in only 8% of patients with CRLM but with 75% of cases HER-3 is frequently overexpressed in CRLM. Therefore, HER-2 and particularly HER-3 could serve as novel targets to be addressed within multimodal treatment approaches.

Etiologic influence on chromosomal aberrations in European hepatocellular carcinoma identified by CGH.

Previous studies suggest different pathways in the molecular development of hepatocellular carcinoma (HCC). We investigated the pattern of chromosomal imbalances in HCC depending on the type of underlying liver disease as detected by comparative genomic hybridization in 67 cases of primary HCC occurring in non-cirrhotic livers (n=30), in liver cirrhosis (LC) related to alcohol intake (n=9), cryptogenic or metabolic changes (n=11), and chronic viral hepatitis B or C (n=17). HCC were treated by liver resection in 48 patients and transplantation in 19 patients. The 10-year disease-free and overall survival rates were 51% and 68%, respectively. The copy number changes occurring in more than 10% of cases were gains at 8q (55%), 1q (49%), 7q (15%), 7p (13%), 6p (12%), and 20q (12%), as well as losses at 8p (55%), 4q (33%), 6q (33%), 13q (25%), 14q (24%), 17p (22%), 16q (19%), 1p (18%), 18q (16%), 9p (13%), 10q (13%), 4p (12%), and 9q (12%). HCC arising in alcoholic LC showed a different pattern with significantly fewer net changes (p=0.008), particularly fewer chromosomal gains (p=0.008) and fewer breakpoints (p=0.003) compared to the other investigated HCC subgroups. Future clinical studies should evaluate the prognostic relevance of these findings.

Lymph node metastases in rectal cancer after preoperative radiochemotherapy: impact of intramesorectal distribution and residual micrometastatic involvement.

INTRODUCTION: After neoadjuvant chemoradiation (CRT), the pathologic determined lymph node (LN) status is the most important prognostic factor in rectal cancer patients. Here we assessed the prognostic impact of residual LN micrometastases (<0.2 cm) and the intramesorectal distribution of LN metastases. PATIENTS AND METHODS: Surgical specimens from 81 patients with cUICC II/III rectal cancer undergoing neoadjuvant CRT and total mesorectal excision within the German Rectal Cancer Trial CAO/ARO/AIO-04 were prospectively evaluated. The entire mesorectal compartment was paraffin embedded and screened microscopically. The number and distribution of mesorectal LN macrometastases and micrometastases were correlated with disease-free (DFS) and cancer-specific overall survival (CSS). RESULTS: A total of 2412 LNs were detected (mean 29.8±13.7). Twenty-five patients had residual LN metastases (ypN+). The incidence of metastases in the peritumoral mesorectum was higher (7.7%) than that proximal to the tumor (1.5%), whereas no metastases were identified below the tumor level. Patients with both proximal and peritumoral involvement showed a significantly reduced CSS (hazard ratio=5.4; P<0.05). Fourteen patients with ypN+ status (56%) had micrometastases, 9 patients (36%) had only micrometastatic involvement. Patients with nodal macrometastases had a reduced DFS (P<0.01) and CSS (P<0.005) as compared with ypN0 patients, whereas residual micrometastases had no influence on survival. CONCLUSIONS: Despite the high incidence of residual LN micrometastases they did not seem to have a prognostic impact in this series. Micrometastases might indicate responsive tumors to CRT with a more favorable biology. The intramesorectal distribution of LN metastases had a prognostic impact and should be validated in further studies.