Jürgen Weitz

Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial.

BACKGROUND Neoadjuvant chemotherapy for unresectable colorectal liver metastases can downsize tumours for curative resection. We assessed the effectiveness of cetuximab combined with chemotherapy in this setting. METHODS Between Dec 2, 2004, and March 27, 2008, 114 patients were enrolled from 17 centres in Germany and Austria; three patients receiving FOLFOX6 alone were excluded from the analysis. Patients with non-resectable liver metastases (technically non-resectable or > or =5 metastases) were randomly assigned to receive cetuximab with either FOLFOX6 (oxaliplatin, fluorouracil, and folinic acid; group A) or FOLFIRI (irinotecan, fluorouracil, and folinic acid; group B). Randomisation was not blinded, and was stratified by technical resectability and number of metastases, use of PET staging, and EGFR expression status. They were assessed for response every 8 weeks by CT or MRI. A local multidisciplinary team reassessed resectability after 16 weeks, and then every 2 months up to 2 years. Patients with resectable disease were offered liver surgery within 4-6 weeks of the last treatment cycle. The primary endpoint was tumour response assessed by Response Evaluation Criteria In Solid Tumours (RECIST), analysed by modified intention to treat. A retrospective, blinded surgical review of patients with radiological images at both baseline and during treatment was done to assess objectively any changes in resectability. The study is registered with ClinicalTrials.gov, number NCT00153998. FINDINGS 56 patients were randomly assigned to group A and 55 to group B. One patient in each group were excluded from the analysis of the primary endpoint because they discontinued treatment before first full dose, one patient in group B was excluded because of early pulmonary embolism. A confirmed partial or complete response was noted in 36 (68%) of 53 patients in group A, and 30 (57%) of 53 patients in group B (difference 11%, 95% CI -8 to 30; odds ratio [OR] 1.62, 0.74-3.59; p=0.23). The most frequent grade 3 and 4 toxicities were skin toxicity (15 of 54 patients in group A, and 22 of 55 patients in group B), and neutropenia (13 of 54 patients in group A and 12 of 55 patients in group B). R0 resection was done in 20 (38%) of 53 patients in group A and 16 (30%) of 53 of patients in group B. In a retrospective analysis of response by KRAS status, a partial or complete response was noted in 47 (70%) of 67 patients with KRAS wild-type tumours versus 11 (41%) of 27 patients with KRAS-mutated tumours (OR 3.42, 1.35-8.66; p=0.0080). According to the retrospective review, resectability rates increased from 32% (22 of 68 patients) at baseline to 60% (41 of 68) after chemotherapy (p<0.0001). INTERPRETATION Chemotherapy with cetuximab yields high response rates compared with historical controls, and leads to significantly increased resectability. FUNDING Merck-Serono, Sanofi-Aventis, and Pfizer.

Low-Dose Irradiation Programs Macrophage Differentiation to an iNOS+/M1 Phenotype that Orchestrates Effective T Cell Immunotherapy

Inefficient T cell migration is a major limitation of cancer immunotherapy. Targeted activation of the tumor microenvironment may overcome this barrier. We demonstrate that neoadjuvant local low-dose gamma irradiation (LDI) causes normalization of aberrant vasculature and efficient recruitment of tumor-specific T cells in human pancreatic carcinomas and T-cell-mediated tumor rejection and prolonged survival in otherwise immune refractory spontaneous and xenotransplant mouse tumor models. LDI (local or pre-adoptive-transfer) programs the differentiation of iNOS⁺ M1 macrophages that orchestrate CTL recruitment into and killing within solid tumors through iNOS by inducing endothelial activation and the expression of TH1 chemokines and by suppressing the production of angiogenic, immunosuppressive, and tumor growth factors.

Primary malignant hepatic epithelioid hemangioendothelioma : A comprehensive review of the literature with emphasis on the surgical therapy

Malignant hepatic epithelioid hemangioendothelioma (HEH) is a rare malignant tumor of vascular origin with unknown etiology and a variable natural course. The authors present a comprehensive review of the literature on HEH with a focus on clinical outcome after different therapeutic strategies. All published series on patients with HEH (n = 434 patients) were analyzed from the first description in 1984 to the current literature. The reviewed parameters included demographic data, clinical manifestations, therapeutic modalities, and clinical outcome. The mean age of patients with HEH was 41.7 years, and the male‐to‐female ratio was 2:3. The most common clinical manifestations were right upper quadrant pain, hepatomegaly, and weight loss. Most patients presented with multifocal tumor that involved both lobes of the liver. Lung, peritoneum, lymph nodes, and bone were the most common sites of extrahepatic involvement at the time of diagnosis. The most common management has been liver transplantation (LTx) (44.8% of patients), followed by no treatment (24.8% of patients), chemotherapy or radiotherapy (21% of patients), and liver resection (LRx) (9.4% of patients). The 1‐year and 5‐year patient survival rates were 96% and 54.5%, respectively, after LTx; 39.3% and 4.5%, respectively, after no treatment, 73.3% and 30%, respectively, after chemotherapy or radiotherapy; and 100% and 75%, respectively, after LRx. LRx has been the treatment of choice in patients with resectable HEH. However, LTx has been proposed as the treatment of choice because of the hepatic multicentricity of HEH. In addition, LTx is an acceptable option for patients who have HEH with extrahepatic manifestation. Highly selected patients may be able to undergo living‐donor LTx, preserving the donor pool. The role of different adjuvant therapies for patients with HEH remains to be determined. Cancer 2006.

Meta‐analysis of standard, restrictive and supplemental fluid administration in colorectal surgery

Optimal fluid therapy for colorectal surgery remains uncertain.

Arterial Resection During Pancreatectomy for Pancreatic Cancer: A Systematic Review and Meta-Analysis

Background:The majority of pancreatic cancers are diagnosed at an advanced stage. As surgical resection remains the only hope for cure, more aggressive surgical approaches have been advocated to increase resection rates. Institutions have begun to release data on their experience with pancreatectomy and simultaneous arterial resection (AR), which has traditionally been considered a general contraindication to resection. The aim of the present meta-analysis was to evaluate the perioperative and long-term outcomes of patients with AR during pancreatectomy for pancreatic cancer. Methods:The Medline, Embase, and Cochrane Library and J-East databases were systematically searched to identify studies reporting outcome of patients who underwent pancreatectomy with AR for pancreatic cancer. Studies that reported perioperative and/or long-term results after pancreatectomy with AR were eligible for inclusion. Meta-analyses included comparative studies providing data on patients with and without AR and were performed using a random effects model. Results:The literature search identified 26 studies including 366 and 2243 patients who underwent pancreatectomy with and without AR. All studies were retrospective cohort studies and the methodological quality was moderate to low. Meta-analyses revealed AR to be associated with a significantly increased risk for perioperative mortality [Odds ratio (OR) = 5.04; 95% confidence interval (CI), 2.69–9.45; P < 0.0001; I2 = 24%], poor survival at 1 year (OR = 0.49; 95% CI, 0.31–0.78; P = 0.002; I2 = 35%) and 3 years (OR = 0.39; 95% CI, 0.17–0.86; P = 0.02; I2 = 49%) compared with patients without AR. The increased perioperative mortality (OR = 8.87; 95% CI, 3.40–23.13; P < 0.0001; I2 = 5%) and lower survival rate at 1 year (OR = 0.50; 95% CI, 0.31–0.82; P = 0.006; I2 = 40%) was confirmed in the comparison to patients undergoing venous resection. Despite substantial perioperative mortality, pancreatectomy with AR was associated with more favorable survival compared with patients who did not undergo resection for locally advanced disease. Conclusions:AR in patients undergoing pancreatectomy for pancreatic cancer is associated with a poor short and long-term outcome. Pancreatectomy with AR may, however, be justified in highly selected patients owing to the potential survival benefit compared with patients without resection. These patients should be treated within the bounds of clinical trials to assess outcomes after AR in the era of modern pancreatic surgery and multimodal therapy.

Meta-analysis Shows That Detection of Circulating Tumor Cells Indicates Poor Prognosis in Patients With Colorectal Cancer

BACKGROUND & AIMS The prognostic significance of circulating (CTCs) and disseminated tumor cells in patients with colorectal cancer (CRC) is controversial. We performed a meta-analysis of available studies to assess whether the detection of tumor cells in the blood and bone marrow (BM) of patients diagnosed with primary CRC can be used as a prognostic factor. METHODS We searched the Medline, Biosis, Science Citation Index, and Embase databases and reference lists of relevant articles (including review articles) for studies that assessed the prognostic relevance of tumor cell detection in the peripheral blood (PB), mesenteric/portal blood (MPB), or BM of patients with CRC. Meta-analyses were performed using a random effects model, with hazard ratio (HR) and 95% confidence intervals (95% CIs) as effect measures. RESULTS A total of 36 studies, including 3094 patients, were eligible for final analyses. Pooled analyses that combined all sampling sites (PB, MPB, and BM) associated the detection of tumor cells with poor recurrence-free survival (RFS) (HR = 3.24 [95% CI: 2.06-5.10], n = 26, I(2) = 77%) and overall survival (OS) (2.28 [1.55-3.38], n = 21, I(2) = 66%). Stratification by sampling site showed that detection of tumor cells in the PB compartment was a statistically significant prognostic factor (RFS: 3.06 [1.74-5.38], n = 19, I(2) = 78%; OS: 2.70 [1.74-4.20], n = 16, I(2) = 59%) but not in the MPB (RFS: 4.12 [1.01-16.83], n = 8, I(2) = 75%; OS: 4.80 [0.81-28.32], n = 5, I(2) = 82%) or in the BM (RFS: 2.17 [0.94-5.03], n = 4, I(2) = 78%; OS: 1.50 [0.52-4.32], n = 3, I(2) = 84%). CONCLUSION Detection of CTCs in the PB indicates poor prognosis in patients with primary CRC.

A Complex of EpCAM, Claudin-7, CD44 Variant Isoforms, and Tetraspanins Promotes Colorectal Cancer Progression

High expression of EpCAM and the tetraspanin CO-029 has been associated with colorectal cancer progression. However, opposing results have been reported on CD44 variant isoform v6 (CD44v6) expression. We recently noted in rat gastrointestinal tumors that EpCAM, claudin-7, CO-029, and CD44v6 were frequently coexpressed and could form a complex. This finding suggested the possibly that the complex, rather than the individual molecules, could support tumor progression. The expression of EpCAM, claudin-7, CO-029, and CD44v6 expression was evaluated in colorectal cancer (n = 104), liver metastasis (n = 66), and tumor-free colon and liver tissue. Coexpression and complex formation of the molecules was correlated with clinical variables and apoptosis resistance. EpCAM, claudin-7, CO-029, and CD44v6 expression was up-regulated in colon cancer and liver metastasis. Expression of the four molecules did not correlate with tumor staging and grading. However, coexpression inversely correlated with disease-free survival. Coexpression was accompanied by complex formation and recruitment into tetraspanin-enriched membrane microdomains (TEM). Claudin-7 contributes to complex formation inasmuch as in the absence of claudin-7, EpCAM hardly associates with CO-029 and CD44v6 and is not recruited into TEMs. Notably, colorectal cancer lines that expressed the EpCAM/claudin-7/CO-029/CD44v6 complex displayed a higher degree of apoptosis resistance than lines devoid of any one of the four molecules. Expression of EpCAM, claudin-7, CO-029, and CD44v6 by themselves cannot be considered as prognostic markers in colorectal cancer. However, claudin-7–associated EpCAM is recruited into TEM and forms a complex with CO-029 and CD44v6 that facilitates metastasis formation. (Mol Cancer Res 2007;5(6):553–67)

Distinct Types of Tumor-Initiating Cells Form Human Colon Cancer Tumors and Metastases

Human colon cancer harbors a small subfraction of tumor-initiating cells (TICs) that is assumed to be a functionally homogeneous stem-cell-like population driving tumor maintenance and metastasis formation. We found unexpected cellular heterogeneity within the TIC compartment, which contains three types of TICs. Extensively self-renewing long-term TICs (LT-TICs) maintained tumor formation in serial xenotransplants. Tumor transient amplifying cells (T-TACs) with limited or no self-renewal capacity contributed to tumor formation only in primary mice. Rare delayed contributing TICs (DC-TICs) were exclusively active in secondary or tertiary mice. Bone marrow was identified as an important reservoir of LT-TICs. Metastasis formation was almost exclusively driven by self-renewing LT-TICs. Our results demonstrate that tumor initiation, self-renewal, and metastasis formation are limited to particular subpopulations of TICs in primary human colon cancer. We identify LT-TICs as a quantifiable target for therapies aimed toward eradication of self-renewing tumorigenic and metastatic colon cancer cells.

Partial Hepatectomy for Metastases From Noncolorectal, Nonneuroendocrine Carcinoma

Objective:To define perioperative and long-term outcome and prognostic factors in patients undergoing hepatectomy for liver metastases arising from noncolorectal and nonneuroendocrine (NCNN) carcinoma. Summary Background Data:Hepatic resection is a well-established therapy for patients with liver metastases from colorectal or neuroendocrine carcinoma. However, for patients with liver metastases from other carcinomas, the value of resection is incompletely defined and still debated. Methods:Between April 1981 and April 2002, 141 patients underwent hepatic resection for liver metastases from NCNN carcinoma. Patient demographics, tumor characteristics, treatment, and postoperative outcome were analyzed. Results:Thirty-day postoperative mortality was 0% and 46 of 141 (33%) patients developed postoperative complications. The median follow up was 26 months (interquartile range [IQR]) 10–49 months); the median follow up for survivors was 35 months (IQR 11–68 months). There have been 24 actual 5-year survivors so far. The actuarial 3-year relapse-free survival rate was 30% (95% confidence interval [CI], 21–39%) with a median of 17 months. The actuarial 3-year cancer-specific survival rate was 57% (95% CI, 48–67%) with a median of 42 months. Primary tumor type and length of disease-free interval from the primary tumor were significant independent prognostic factors for relapse-free and cancer-specific survival. Margin status was significant for cancer-specific survival and showed a strong trend for relapse-free survival. Conclusions:Hepatic resection for metastases from NCNN carcinoma is safe and can offer long-term survival in selected patients. Hepatic resection should be considered if all gross disease can be removed, especially in patients with metastases from reproductive tract tumors or a disease-free interval greater than 2 years.

Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma

Spontaneous antitumor T cell responses in cancer patients are strongly controlled by Tregs, and increased numbers of tumor-infiltrating Tregs correlate with reduced survival. However, the tumor antigens recognized by Tregs in cancer patients and the impact of these cells on tumor-specific T cell responses have not been systematically characterized. Here we used a broad panel of long synthetic peptides of defined tumor antigens and normal tissue antigens to exploit a newly developed method to identify and compare ex vivo the antigen specificities of Tregs with those of effector/memory T cells in peripheral blood of colorectal cancer patients and healthy subjects. Tregs in tumor patients were highly specific for a distinct set of only a few tumor antigens, suggesting that Tregs exert T cell suppression in an antigen-selective manner. Tumor-specific effector T cells were detectable in the majority of colorectal cancer patients but not in healthy individuals. We detected differences in the repertoires of antigens recognized by Tregs and effector/memory T cells in the majority of colorectal cancer patients. In addition, only effector/memory T cell responses against antigens recognized by Tregs strongly increased after Treg depletion. The selection of antigens according to preexisting T cell responses may improve the efficacy of future immunotherapies for cancer and autoimmune disease.