Stefan P. Mönig

Lymph Node Size and Metastatic Infiltration in Colon Cancer

Background: Detection of metastatic lymph nodes in colon cancer is essential for determining stage and adjuvant treatment modalities. Lymph node size has been used as one possible criterion for nodal metastasis. Although enlarged regional lymph nodes are generally interpreted as metastases, few data are available that correlate lymph node size with metastatic infiltration in colon cancer.Methods: In a prospective morphometric study, the regional lymph nodes from 30 colon specimens from consecutive patients with primary colon cancer were analyzed. The lymph nodes were counted and the largest diameter of each lymph node was measured and analyzed for metastatic involvement by histological examination.Results: A total of 698 lymph nodes were present in the 30 specimens examined for this study. A mean number of 23 (range, 19–39) lymph nodes was found in each specimen. Of these nodes, 566 (81%) were tumor-free and 132 (19%) contained metastases. The mean diameter of the lymph nodes free of metastases was 3.9 mm, whereas those infiltrated by metastases averaged 5.9 mm in diameter (P< 0.0001). Of the tumor-free lymph nodes, 528 (93%) measured < 5 mm in diameter, whereas 70 (53%) lymph nodes containing metastases measured < 5 mm in diameter.Conclusions: Lymph node size is not a reliable indicator for lymph node metastasis in colon cancer. A careful histological search for small lymph node metastasis in the specimen should be undertaken to avoid false-negative node staging.

MUC1 and Nuclear β-Catenin Are Coexpressed at the Invasion Front of Colorectal Carcinomas and Are Both Correlated with Tumor Prognosis

Purpose: Overexpression of MUC1 and cytosolic interaction of the mucin with β-catenin are claimed to be involved in colorectal carcinogenesis. In vitro data published recently suggest that MUC1 overexpression results in an increase of steady state levels of nuclear β-catenin. We tried to elucidate the coexpression of both molecules in colorectal cancer to demonstrate possible correlations with clinical, pathological, and prognostic data. Experimental Design: An immunohistochemical double staining study was performed to characterize the expression and subcellular distribution of MUC1 and β-catenin in a series of 205 patients with colorectal carcinoma. The results were correlated with clinicopathological variables as well as overall survival. Results: MUC1 was strongly expressed in the tumor center and at the invasion front in ∼50% of the cases. Similar results were obtained with regard to nuclear accumulation of β-catenin at the invasive tumor parts. MUC1 protein expression in the tumor center correlated significantly with a low grade of differentiation, and nuclear β-catenin in the tumor periphery was more frequent in carcinomas of the left colon and rectum. Overexpression of MUC1 and β-catenin, as well as their nuclear coexpression at the invasion front correlated with a worse overall survival in an univariate analysis. However, only pathological tumor-node-metastasis staging and MUC1 at the invasion front revealed as independent prognostic factors. Conclusions: These results suggest that MUC1 and β-catenin are coexpressed at the invasion front of colorectal carcinomas and that this feature is associated with an accelerated course of disease and worse prognosis.

Early gastric cancer: lymph node metastasis starts with deep mucosal infiltration.

Objective:The purpose of this study was to evaluate the frequency of lymph node metastasis according to the depth of tumor infiltration of the mucosa and submucosa. Background Data:Currently some endoscopists extend the indication for endoscopic mucosal resection in gastric cancer to the submucosa. However, the decision between endoscopic mucosectomy or gastrectomy with lymphadenectomy for early gastric cancer depends especially on the probability of lymph node metastasis. Methods:One hundred twenty-six patients either had subtotal resection (n = 29) or total gastrectomy (n = 97) for T1 gastric cancer. The median number of resected lymph nodes was 21 (1–63). In the histopathologic analysis of the specimens the tumors were differentiated according to their wall penetration in the upper (m1), middle (m2), lower (m3) third of the mucosa or submucosa (sm1, sm2, sm3). The greatest diameter of the lesions, the Grading and the Goseki-, Ming-, WHO-, and Laurén classification were determined. Results:Patients with m1 (n = 3) and m2 (n = 5) layer infiltration had no lymphatic metastasis compared with 13% for m3 (n = 39). The rate of lymphatic metastasis in submucosal carcinomas was 21% for sm1 (n = 29), 16% for sm2 (n = 23) and 40% for sm3 (n = 25). Carcinomas with papillary differentiation, Grading G1 or <1 cm in diameter had no lymph node metastasis. The size of tumor <2 cm or ≥2 cm showed independent influence on the rate of lymph node metastasis. Conclusions:Endoscopic mucosectomy in m3 carcinoma is questionable and in all submucosal carcinomas and lesions ≥2 cm it is not indicated.

Expression of MMP-2 is associated with progression and lymph node metastasis of gastric carcinoma.

Expression of MMP‐2 is associated with progression and lymph node metastasis of gastric carcinoma

Correlation of the immunohistochemical reactivity of mucin peptide cores MUC1 and MUC2 with the histopathological subtype and prognosis of gastric carcinomas.

The expression of MUC1 and MUC2 mucin peptide core antigens in gastric carcinomas was studied by immunohistochemistry to determine correlations with TNM stage and histo‐pathological classifications as well as a possible prognostic impact. Paraffin‐embedded specimens from 128 gastric carcinomas with a minimal follow‐up of 5 years were immunostained. In addition to a polyclonal antiserum generated against polymorphic epithelial mucin (MUC1) from human milk, 2 monoclonal antibodies (MAbs), HMFG2 (anti‐MUC1) and 4F1 (anti‐MUC2), were applied. Reactivity of carcinomas was correlated with the classifications of the UICC (TNM), WHO and Laurén. Correlations with overall survival were analyzed using the Kaplan and Meier product limit method. MUC1 immunoreactivity was associated with an advanced pTNM stage. The demonstration of both mucin species (MUC1, MUC2) displayed a statistically significant correlation with tubular/papillary vs. signet‐ring cell differentiation as well as with intestinal‐type vs. diffuse‐type of tumor growth according to Laurén. In particular, MUC2 was only rarely detectable in signet‐ring cell and diffuse‐type tumors. MUC1 correlated with poor prognosis in all cases and the subgroup of stage I tumors. According to the histopathological classifications, a similar result was observed in signet‐ring cell and diffuse‐type carcinomas. In contrast, MUC2 reactivity was associated with a favourable prognosis of intestinal‐type carcinomas. In the non‐neoplastic gastric mucosa, both peptide cores were recognized in the superficial epithelium, whereas parietal cells contained only MUC1, and intestinal metaplasia almost exclusively MUC2 antigens.

Improving informed consent of surgical patients using a multimedia-based program?: results of a prospective randomized multicenter study of patients before cholecystectomy.

Objective:The term “informed consent” explains the process by which a patient, before treatment, is provided comprehensive and impartial information regarding a planned operative procedure so that he/she understands the implications of the procedure before consenting. The goal of the current study was to investigate whether standard methods of consenting can be improved using a multimedia-based information program (MM-IP). Patients and Methods:In a prospective multicenter study, 80 patients undergoing laparoscopic cholecystectomy went through the standard informed consent process. One group of patients was also given access to a MM-IP. Questionnaires were completed before surgery. These evaluated how patients perceived their own understanding of important aspects of their illness (ie, disease, therapeutic alternatives, operation, risks) and satisfaction with the consenting process. Patients’ anxiety levels were also assessed. These questionnaires were used to evaluate the effectiveness of the MM-IP for improving the consent process. Results:Seventy-six patients (47 women, 29 men, median age 54 years) were included. There was no significant age or gender variation between the groups (standard n = 41 and MM-IP n = 35). Eighty-two percent of all respondents were satisfied with the standard informed consent process. However, perceived understanding of the material was significantly improved in the MM-IP group (P < 0.001). Patients with less formal education profited particularly from the MM-IP. Preoperative anxiety did not vary between the groups. Conclusion:Use of the multimedia-based program was positively evaluated by patients, and significantly improved patients’ perceived understanding of their disease and its treatment. It is, therefore, valuable in the informed consent process.

Comparative evaluation of the prognostic value of MUC1, MUC2, sialyl-Lewisa and sialyl-Lewisx antigens in colorectal adenocarcinoma

Comparative evaluation of the prognostic value of MUC1, MUC2, sialyl‐Lewisa and sialyl‐Lewisx antigens in colorectal adenocarcinoma

Splenectomy in proximal gastric cancer: Frequency of lymph node metastasis to the splenic hilus

The indication for splenectomy in proximal gastric cancer remains controversial. Splenectomy is performed because of possible lymph node metastasis of the splenic hilus or infiltration/metastasis of the spleen. The purpose of this study was to investigate the frequency of lymph node metastasis to the splenic hilus and metastasis to the spleen in proximal gastric carcinomas.

Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial

BACKGROUND Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma, but has not yet been evaluated in the context of resectable patients. Here we report findings from the phase 2 part of the phase 2/3 FLOT4 trial, which compared histopathological regression in patients treated with a docetaxel-based triplet chemotherapy versus an anthracycline-based triplet chemotherapy before surgical resection. METHODS In this randomised, open-label, phase 2/3 study, eligible participants were recruited from 28 German oncology centres. Patients with resectable gastric or gastro-oesophageal junction cancer who had clinical stage cT2 or higher, nodal positive (cN+) disease, or both were randomly assigned (1:1) to either three preoperative and three postoperative 3-week cycles of intravenous epirubicin 50 mg/m2 on day 1, intravenous cisplatin 60 mg/m2 on day 1, and either fluorouracil 200 mg/m2 as continuous intravenous infusion or capecitabine 1250 mg/m2 orally (two doses of 625 mg/m2 per day) on days 1 to 21 (ECF/ECX group) or four preoperative and four postoperative 2-week cycles of docetaxel 50 mg/m2, intravenous oxaliplatin 85 mg/m2, intravenous leucovorin 200 mg/m2, and fluorouracil 2600 mg/m2 as a 24 h infusion, all on day 1 (FLOT group). Randomisation was done centrally with an interactive web-response system based on a sequence generated with blocks (block size 2) stratified by Eastern Cooperative Oncology Group performance status, location of primary tumour, age, and nodal status. No masking was done. Central assessment of pathological regression was done according to the Becker criteria. The primary endpoint was pathological complete regression (tumour regression grade TRG1a) and was analysed in the modified intention-to-treat population, defined as all patients who were randomly assigned to treatment excluding patients who had surgery but did not provide resection specimens for central evaluation. The study (including the phase 3 part) has completed enrolment, but follow-up is ongoing and this is an interim analysis. The trial is registered with ClinicalTrials.gov, number NCT01216644. FINDINGS Between Aug 18, 2010, and Aug 10, 2012, 300 patients (152 patients in the ECF/ECX group; 148 patients in the FLOT group) were enrolled into the phase 2 part of the study, 265 of whom (137 in the ECF/ECX group; 128 in the FLOT group) were assessable on a modified intention-to-treat basis. 119 (93%) of 128 patients in the FLOT group and 126 (92%) of 137 patients in the ECF/ECX group were given all planned preoperative cycles of treatment. FLOT was associated with significantly higher proportions of patients achieving pathological complete regression than was ECF/ECX (20 [16%; 95% CI 10-23] of 128 patients vs eight [6%; 3-11] of 137 patients; p=0·02). 44 (40%) of 111 patients in the ECF/ECX group and 30 (25%) of 119 patients in the FLOT group had at least one serious adverse event involving a perioperative medical or surgical complication. The most common non-surgical grade 3-4 adverse events were neutropenia (52 [38%] of 137 patients in the ECF/ECX group vs 67 [52%] of 128 patients in the FLOT group), leucopenia (28 [20%] vs 36 [28%]), nausea (23 [17%] vs 12 [9%]), infection (16 [12%] vs 15 [12%]), fatigue (19 [14%] vs 11 [9%]), and vomiting (13 [10%] vs four [3%]). INTERPRETATION Perioperative FLOT was active and feasible to administer, and might represent an option for patients with locally advanced, resectable gastric or gastro-eosophageal junction adenocarcinoma. FUNDING None.

Altered levels of the onco-microRNA 21 and the tumor-supressor microRNAs 143 and 145 in advanced rectal cancer indicate successful neoadjuvant chemoradiotherapy

microRNAs (miRNAs) are small non-coding RNAs with important post-transcriptional regulatory functions. miRNA-21 (miR-21) is upregulated and miR-143 and miR-145 are downregulated in colorectal carcinoma. The aim of our study was to determine if these miRNAs change their expression levels in response to neoadjuvant chemoradiotherapy in advanced rectal cancer. Forty patients with advanced rectal cancer (clinical uT3/T4 Nx) were included. All patients underwent neoadjuvant chemoradiotherapy and surgical resection. Expression of miR-21, -143 and -145 was examined in macrodissected tumor tissue before and after chemoradiotherapy and normal rectal tissue from the resection specimen. RNA was extracted from formalin-fixed and paraffin-embedded tissue by TRIzol method, polyadenylated, reverse transcribed and analyzed by real-time PCR. Therapy response was assessed according to pathological tumor regression. miR-21 was more highly expressed in tumor tissue than in non-tumorous tissue. However, there was a moderately lower expression in post-therapeutic tumor tissue compared to pre-therapeutic tumor tissue. There was a significant upregulation of miR-143 and miR-145 in post-therapeutic tumor tissue compared to pre-therapeutic tumor tissue. According to the predictive and prognostic value of the analyzed miRNAs, a significant correlation between miR-145 expression and tumor regression was seen. Patients with a low intratumoral post-therapeutic expression had significantly more often a worse response to neoadjuvant therapy compared to patients with a high expression of miR145. The present results support the hypothesis that chemoradiotherapy can profoundly alter miRNA expression profiles. miRNAs might play important roles as molecular biomarkers in the prediction of response to treatment and prognosis.