Stefan B. Hosch

Portal application of autologous CD133+ bone marrow cells to the liver : a novel concept to support hepatic regeneration

The liver has a large capacity for regeneration after resection. However, below a critical level of future liver remnant volume (FLRV), partial hepatectomy is accompanied by a significant increase of postoperative liver failure. There is accumulating evidence for the contribution of bone marrow stem cells (BMSCs) to participate in liver regeneration. Here we report on three patients subjected to intraportal administration of autologous CD133+ BMSCs subsequent to portal venous embolization of right liver segments, used to expand left lateral hepatic segments as FLRV. Computerized tomography scan volumetry revealed 2.5‐fold increased mean proliferation rates of left lateral segments compared with a group of three consecutive patients treated without application of BMSCs. This early experience with portovenous application of CD133+ BMSCs could suggest that this novel therapeutic approach bears the potential of enhancing and accelerating hepatic regeneration in a clinical setting.

Effectiveness of radical systematic mediastinal lymphadenectomy in patients with resectable non-small cell lung cancer results of a prospective randomized trial

OBJECTIVE To evaluate the effectiveness of lymphadenectomy in the treatment of non-small cell lung cancer (NSCLC). SUMMARY BACKGROUND DATA The extent of lymphadenectomy in the treatment of NSCLC is still a matter of controversy. Although some centers perform mediastinal lymph node sampling (LS) with resection of only suspicious lymph nodes, others recommend a radical, systematic mediastinal lymphadenectomy (LA) to improve survival and to achieve a better staging. METHODS In a controlled, prospective, randomized clinical trial, the effects of LA on recurrence rates and survival were analyzed, comparing LS and LA in 169 patients with operable NSCLC. RESULTS After a median follow-up of 47 months, LA did not improve survival in the overall group of patients (hazard ratio: 0.78; 95% confidence interval: 0.47-1.24). Although recurrences rates tended to be reduced among patients who underwent LA, these decreases were not statistically significant (hazard ratio: 0.82; 95% confidence interval: 0.54-1.27). However, analysis of subgroups of patients according to histopathologic lymph node staging revealed that LA appears to prolong relapse-free survival (p = 0.037) with a borderline effect on overall survival (p = 0.058) in patients with limited lymph node involvement (pN1 disease or pN2 disease with involvement of only one lymph node level); in patients with pN0 disease, no survival benefit was observed. CONCLUSIONS Radical systematic mediastinal lymphadenectomy does not influence disease-free or overall survival in patients with NSCLC and without overt lymph node involvement. However, a small subgroup of patients with limited mediastinal lymph node metastases might benefit from a systematic lymphadenectomy.

Direct Genetic Analysis of Single Disseminated Cancer Cells for Prediction of Outcome and Therapy Selection in Esophageal Cancer

The increasing use of primary tumors as surrogate markers for prognosis and therapeutic decisions neglects evolutionary aspects of cancer progression. To address this problem, we studied the precursor cells of metastases directly for the identification of prognostic and therapeutic markers and prospectively analyzed single disseminated cancer cells from lymph nodes and bone marrow of 107 consecutive esophageal cancer patients. Whole-genome screening revealed that primary tumors and lymphatically and hematogenously disseminated cancer cells diverged for most genetic aberrations. However, we identified chromosome 17q12-21, the region comprising HER2, as the most frequent gain in disseminated tumor cells that were isolated from both ectopic sites. Survival analysis demonstrated that HER2 gain in a single disseminated tumor cell but not in primary tumors conferred high risk for early death.

Esophageal Cancer: The Mode of Lymphatic Tumor Cell Spread and Its Prognostic Significance

PURPOSE: Data on skip metastases and their significance are lacking for esophageal cancer. This issue is important to determine the extent of lymphadenectomy for esophageal resection. In this study we examined the lymphatic spread in esophageal cancer by routine histopathology and by immunohistochemistry. PATIENTS AND METHODS: A total of 1,584 resected lymph nodes were obtained from 86 patients with resected esophageal carcinoma and evaluated by routine histopathology. Additionally, frozen tissue sections of 540 lymph nodes classified as tumor-free by routine histopathology were screened for micrometastases by immunohistochemistry with the monoclonal antibody Ber-EP4. The lymph nodes were mapped according to the mapping scheme of the American Thoracic Society modified by Casson et al. RESULTS: Forty-four patients (51%) had pN1 disease, and 61 patients (71%) harbored lymphatic micrometastases detected by immunohistochemistry. Skip metastases detected by routine histopathology were present in 34% of pN1 pat...

Mode of spread in the early phase of lymphatic metastasis in non-small-cell lung cancer: Significance of nodal micrometastasis☆☆☆★★★♢

The impact of lymphatic micrometastases on prognosis of non-small-cell lung cancer has not been clearly established. We therefore prospectively assessed the frequency, mode of mediastinal spread, and prognostic significance of lymphatic micrometastases in lymph nodes of 93 patients with completely resected non-small-cell lung cancer staged as pT1 to pT4 pN0 and pN1 by conventional histopathologic techniques. Frozen tissue sections from 471 lymph nodes that were staged as free of metastases by routine histopathologic examination were screened for micrometastases by the alkaline phosphatase-antialkaline phosphatase immunostaining technique with the monoclonal antibody Ber-Ep-4. Twenty of 73 patients (27.4%) with disease staged as pN0 and nine of 20 patients (45.0%) with disease staged as pN1 had nodal micrometastases. Eight of 17 patients with upper lobe primary tumors and five of 12 patients with lower lobe primary tumors exhibited skip micrometastases. Mean relapse-free survival was significantly increased in patients with pN0 disease without micrometastases (41.1 vs 29 months, p = 0.0081). In patients with pN1 disease, mean relapse-free and cancer-related survivals were also significantly increased if no micrometastases were found (34.8 and 38.2 months vs 18 and 23.5 months, p = 0.0157 and p = 0.0094). Patients with disease staged as pN0 and pN1 with micrometastases revealed no difference in cancer-related survival compared with a control population of patients with disease staged as pN2. The mode of spread was erratic. The prognosis of patients after upstaging of pN0 and pN1 disease according to results of immunohistochemical staining correlated strongly with the prognosis of patients whose disease was staged at the higher stages by conventional histopathologic examination. These findings could represent a new indication for adjuvant therapy, supporting extensive lymph node sampling for staging purposes.

Ep-CAM expression in squamous cell carcinoma of the esophagus: a potential therapeutic target and prognostic marker

BackgroundTo evaluate the expression and test the clinical significance of the epithelial cellular adhesion molecule (Ep-CAM) in esophageal squamous cell carcinoma (SCC) to check the suitability of esophageal SCC patients for Ep-CAM directed targeted therapies.MethodsThe Ep-CAM expression was immunohistochemically investigated in 70 primary esophageal SCCs using the monoclonal antibody Ber-EP4. For the interpretation of the staining results, we used a standardized scoring system ranging from 0 to 3+. The survival analysis was calculated from 53 patients without distant metastasis, with R0 resection and at least 2 months of clinical follow-up.ResultsEp-CAM neo-expression was observed in 79% of the tumors with three expression levels, 1+ (26%), 2+ (11%) and 3+ (41%). Heterogeneous expression was observed at all expression levels. Interestingly, tumors with 3+ Ep-CAM expression conferred a significantly decreased median relapse-free survival period (log rank, p = 0.0001) and median overall survival (log rank, p = 0.0003). Multivariate survival analysis disclosed Ep-CAM 3+ expression as independent prognostic factor.ConclusionOur results suggest Ep-CAM as an attractive molecule for targeted therapy in esophageal SCC. Considering the discontenting results of the current adjuvant concepts for esophageal SCC patients, Ep-CAM might provide a promising target for an adjuvant immunotherapeutic intervention.

Extended resections are beneficial for patients with locally advanced colorectal cancer

PURPOSE: Locally advanced colorectal cancer often requires extended resection to radically remove all tumor. This is the only chance for cure in these patients, but a higher complication rate would be expected. To evaluate the overall benefit for the patient, this study assesses morbidity and mortality as well as long-term survival of patients who underwent extended resection for a T3–T4 carcinoma. METHODS: Two hundred twenty patients with locally advanced adenocarcinoma of the colorectum were included. One hundred fifty presented with a T3 and 70 with a T4 tumor. Eighty-three patients underwent extended resection. In 38 patients extendeden blocresection was performed because of inflammatory adherence mimicking infiltration. Thirty-three patients who underwent extended resections were over 70 years of age. There were no significant differences between the groups that underwent extended or nonextended resections in age, sex, stage, or grading. RESULTS: pT4 lesions were significantly more frequent in the extended resection group than in the nonextended resection group. Mean survival was 44 months after extended resections and 45 months after nonextended resections. In the extended resection group there was no significant difference in mean survival between pT3 and pT4 stage patients within 46 and 38 months, respectively. In patients who underwent nonextended resections, however, there was a significant difference in mean survival within 48 months for pT3 and 28 for pT4 patients (P< 0.05). Postoperative morbidity and mortality were comparable between the extended resection group and the non-extended resection group. The presence of residual tumor influenced prognosis of patients significantly; RO resections fared significantly better than patients who underwent R1 or R2 resections (55 and 51 to 14/12 and 23/8 months) (P< 0.01). Nodal stage and International Union Against Cancer stage were also significant determinants of prognosis. After extended resections mean survival morbidity and 30-day mortality in patients more than 70 years was similar to those less than 70 years. CONCLUSION: Because extended resections can achieve comparable results in locally more advanced colorectal cancer as nonextended resections in less advanced cancer, an aggressive surgical approach is warranted.

Early Lymphatic Tumor Cell Dissemination in Pancreatic Cancer : Frequency and Prognostic Significance

Tumor relapse occurs frequently in patients with ductal pancreatic head cancer despite the absence of residual tumor detectable at primary surgery. Therefore it has to be assumed that current tumor staging procedures fail to detect minimal amounts of disseminated tumor cells present in secondary organs, which might be the seed for subsequent meta-static relapse. We evaluated lymph nodes from 18 patients without overt metastases who had undergone radical tumor resection (R0 resection). Lymph nodes judged as “tumor-free” by routine histopathology were further examined for the presence of single tumor cells using immunohistochemistry with the antiepithelial monoclonal antibody Ber-EP4. Sixteen of 37 “tumor-free” lymph nodes (43.2%), obtained from 13 of 18 patients (72.2%), displayed Ber-EP4+ tumor cells. Twelve of these 18 patients presented at pT2 stage. Nine of 12 patients (75%) staged as pN0 had these cells. Two of six pN1 patients had no Ber-EP4+ in histopathologically tumor-free lymph nodes. Using multivariate Coxs regression analysis, the presence of Ber-EP4+ cells in “tumor-free” lymph nodes was an independent factor for a significantly reduced relapse-free survival (p = 0.006) and overall survival (p = 0.01). Remarkably, all patients who were restaged as lymph node negative by both histopathology and immunohistochemistry survived the observation period without recurrence. The frequent occurrence of disseminated tumor cells in patients with pancreatic cancer and their prognostic impact support the need for a refined staging system of excised lymph nodes, which should include immunohistochemical examination. Thus patients with a minimal residual tumor load who might benefit from an adjuvant therapy could be selected.

Copy Number of Chromosome 17 but Not HER2 Amplification Predicts Clinical Outcome of Patients With Pancreatic Ductal Adenocarcinoma

PURPOSE To determine the frequency and the potential clinical use of HER2 (17q21) gene amplification and chromosome 17 aneuploidy in pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS Serial tissue sections of 50 resected PDACs were analyzed with chromogenic in situ hybridization using locus-specific HER2 probes and centromeric probes for chromosome 17. Centromeric probes for chromosome 7 and 8 were hybridized to confirm ploidy levels. Expression of HER2 protein was assessed by immunohistochemistry. Correlations of experimental findings with clinical and follow-up data were tested. RESULTS The HER2 gene locus was frequently (24%) amplified in PDAC and the rate of overexpression (2+ and 3+) was 10%, but no prognostic significance was found. Copy number analysis of chromosomes 7, 8, and 17 revealed disomic (40%), trisomic (36%), and hypertetrasomic (24%) tumors. Compared with patients with disomic tumors, patients with hypertetrasomic tumors exhibited a significantly decreased relapse-free and overall survival (5.0 v 13.0 months, P = .0144 and 7.0 v 20.0 months, P = .0099, respectively). Multivariate analysis confirmed the independent prognostic significance of hypertetrasomy. CONCLUSION Tumor ploidy levels correlate with prognosis of PDAC patients, indicating characteristic biologic properties of PDAC with high chromosomal instability. In contrast, no prognostic influence on patient outcome was found for the amplification of the HER2 oncogene or p185(HER2) overexpression. Therefore, evaluation of ploidy levels offers new opportunities for patient stratification in clinical trials and enables novel approaches to study the well-known aggressiveness of PDAC.

O‐Linked glycosylation and functional incompatibility of porcine von Willebrand factor for human platelet GPIb receptors

Abstract:  Background:  Xenograft rejection is associated with vascular inflammation, thrombocytopenia and the accelerated consumption of coagulation factors. Primary biological incompatibilities of the xenograft in the regulation of clotting appear to amplify pathological processes associated with rejection. The functional incompatibility of porcine von Willebrand factor (vWF) expressed within the xenograft vasculature may heighten interactions with the primate platelet receptor GPIb, hence augmenting formation of platelet microthrombi and vascular injury. Here, we address the functional impact of O‐linked glycosylation of the vWF A1 domain on primate platelet activation.