Anti-SARS-CoV-2 antibody-containing plasma improves outcome in patients with hematologic or solid cancer and severe COVID-19: a randomized clinical trial.

Patients with cancer are at high risk of severe coronavirus disease 2019 (COVID-19), with high morbidity and mortality. Furthermore, impaired humoral response renders severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines less effective and treatment options are scarce. Randomized trials using convalescent plasma are missing for high-risk patients. Here, we performed a randomized, open-label, multicenter trial ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001632-10/DE ) in hospitalized patients with severe COVID-19 (n = 134) within four risk groups ((1) cancer (n = 56); (2) immunosuppression (n = 16); (3) laboratory-based risk factors (n = 36); and (4) advanced age (n = 26)) randomized to standard of care (control arm) or standard of care plus convalescent/vaccinated anti-SARS-CoV-2 plasma (plasma arm). No serious adverse events were observed related to the plasma treatment. Clinical improvement as the primary outcome was assessed using a seven-point ordinal scale. Secondary outcomes were time to discharge and overall survival. For the four groups combined, those receiving plasma did not improve clinically compared with those in the control arm (hazard ratio (HR) = 1.29; P = 0.205). However, patients with cancer experienced a shortened median time to improvement (HR = 2.50; P = 0.003) and superior survival with plasma treatment versus the control arm (HR = 0.28; P = 0.042). Neutralizing antibody activity increased in the plasma cohort but not in the control cohort of patients with cancer (P = 0.001). Taken together, convalescent/vaccinated plasma may improve COVID-19 outcomes in patients with cancer who are unable to intrinsically generate an adequate immune response.

Predictive Value of Preoperative Endoscopic Ultrasound (EUS) After Neoadjuvant Chemotherapy in Locally Advanced Esophagogastric Cancer - Data From a Randomized German Phase II Trial.

PURPOSE: The role of EUS before or after neoadjuvant chemotherapy (nCTX) in advanced esophagogastric cancer (EGC) is still unclear. The phase II NEOPECX trial evaluated perioperative chemotherapy with or without panitumumab in this setting. The aim of this sub-study was to investigate the prognostic value of EUS-guided preoperative staging before and after nCTX. MATERIALS AND METHODS: Preoperative yuT/yuN stages by EUS were compared with histopathological ypT/ypN stages after curative resection. Reduction in T-stage from baseline to preoperative EUS was defined as downstaging (DS+) and compared to progression-free (PFS) and overall survival (OS) of patients without downstaging (DS-). In addition, preoperative EUS N-stages (positive N+ or negative N-) were correlated with clinical data. RESULTS: The preoperative yuT-stage correlated with the ypT-stage in 48% of cases (sensitivity 48%, specificity 52%), while the preoperative yuN-stage correlated with the ypN-stage in 64% (sensitivity 76%, specificity 52%). Within DS+ patients who were downstaged by ≥ 2 T-categories, a trend towards improved OS was detected (median OS DS+: not reached (NR), median OS DS-: 38.5 months (M), p=0.21). Patients with yuN+ at preoperative EUS had a worse outcome than yuN- patients (median OS yuN-: NR, median OS yuN+: 38.5 M, p = 0.013). CONCLUSION: The diagnostic accuracy of EUS to predict the response after nCTX in patients with advanced EGC is limited. In the current study the endosonographic detection of lymph node metastasis after nCTX indicates a poor prognosis. In the future, preoperative EUS with sectional imaging procedures may be used to tailor treatment for patients with advanced EGC.

Sniffer dogs can identify lung cancer patients from breath and urine samples.

BACKGROUND: Lung cancer is the most common oncological cause of death in the Western world. Early diagnosis is critical for successful treatment. However, no effective screening methods exist. A promising approach could be the use of volatile organic compounds as diagnostic biomarkers. To date there are several studies, in which dogs were trained to discriminate cancer samples from controls. In this study we evaluated the abilities of specifically trained dogs to distinguish samples derived from lung cancer patients of various tumor stages from matched healthy controls. METHODS: This single center, double-blind clinical trial was approved by the local ethics committee, project no FF20/2016. The dog was conditioned with urine and breath samples of 36 cancer patients and 150 controls; afterwards, further 246 patients were included: 41 lung cancer patients comprising all stages and 205 healthy controls. From each patient two breath and urine samples were collected and shock frozen. Only samples from new subjects were presented to the dog during study phase randomized, double-blinded. This resulted in a specific conditioned reaction pointing to the cancer sample. RESULTS: Using a combination of urine and breath samples, the dog correctly predicted 40 out of 41 cancer samples, corresponding to an overall detection rate of cancer samples of 97.6% (95% CI [87.1, 99.9%]). Using urine samples only the dog achieved a detection rate of 87.8% (95% CI [73.8, 95.9%]). With breath samples, the dog correctly identified cancer in 32 of 41 samples, resulting in a detection rate of 78% (95% CI [62.4, 89.4%]). CONCLUSIONS: It is known from current literature that breath and urine samples carry VOCs pointing to cancer growth. We conclude that olfactory detection of lung cancer by specifically trained dogs is highly suggestive to be a simple and non-invasive tool to detect lung cancer. To translate this approach into practice further target compounds need to be identified.

Loss of LLGL1 Expression Correlates with Diffuse Gastric Cancer and Distant Peritoneal Metastases.

Background: Loss of LLGL1 has been associated with loss of cellular adhesion and dissemination of cells from colorectal cancer and malignant melanoma. Regulation and relevance of LLGL1 were analyzed in gastric cancer patients with lymphatic and distant dissemination. Furthermore, LLGL1 expression was analyzed in relation to the cellular adhesion protein E-cadherin. Methods: LLGL1 and E-cadherin transcription levels were evaluated in 56 gastric cancer patients and five gastric cancer cell lines. IHC staining for LLGL1 was performed on 39 gastric cancer specimens. LLGL1 was stably transfected into LLGL1 negative gastric cancer cell line SNU16 (del(17) (p11.2)) for functional in vitro assays and a xenograft bioassay. Results: Gastric cancer specimens and cell lines displayed LLGL1 and E-cadherin expression levels with variable intensity. In gastric mucosa, LLGL1 exhibited weak cytoplasmic and strong cortical staining. Loss of LLGL1 expression occurred in 65% of gastric cancers and significantly correlated with loss of E-cadherin expression (P=0.00009). Loss of LLGL1 expression was associated with the diffuse type of gastric cancer (P=0.029) with peritoneal carcinomatosis (M1; P=0.006) and with female gender (P=0.017). Stable reexpression of LLGL1 in SNU16 cells significantly increased both plastic surface adhesion and extracellular matrix proteins laminin and fibronectin, but had no impact on in vitro proliferation, apoptosis, or invasion or on in vivo proliferation or differentiation in our xenograft bioassay. Conclusion: LLGL1 is coexpressed with E-cadherin. Loss of expression of either protein is associated with diffuse gastric cancer and peritoneal metastases. LLGL1 does not impact on proliferation or epithelial-mesenchymal transition (EMT) rather increasing cellular adhesion.

Last line therapy with sorafenib in colorectal cancer: A retrospective analysis.

AIM: To analyze the efficacy of last line sorafenib treatment in colorectal cancer patients. METHODS: All patients receiving chemotherapy for colorectal cancer in the outpatient clinic of the University of Mainz since 2006 were retrospectively analyzed for last line sorafenib exposure. Charts of identified patients were analyzed for clinic-pathological parameters, like data on gender, age, date of initial diagnosis, UICC stage, number and kind of the pre-therapies, therapy start and end of sorafenib, sorafenib mediated treatment cessation, side effects, response rates, time to progression and overall survival. RESULTS: Ten patients with a median of 3.0 prior chemotherapy lines had received a last line sorafenib therapy either alone (10%) or in combination with 5-fluorouracil derivates (90%). All patients suffered from colorectal cancer stage UICC 4 and were routinely seen in 2-wk intervals in the oncology outpatient clinic. Median duration of treatment was 142.0 d. At 8 wk 80% of patients showed stable disease but we did not observe any remissions. Median time to progression was 140.5 d (4.7 mo), while median overall survival reached 176.5 d. One patient ceased treatment due to side effects. Reason for treatment stop was bleeding complication in one case and non-specified sorafenib intolerance in another case. Due to the retrospective approach we did not further quantify side effects. CONCLUSION: This retrospective analysis encourages further investigation of sorafenib in colorectal cancer last line therapy.

Immunotherapy in gastrointestinal cancer: Recent results, current studies and future perspectives.

The new therapeutic approach of using immune checkpoint inhibitors as anticancer agents is a landmark innovation. Early studies suggest that immune checkpoint inhibition might also be effective in patients with gastrointestinal cancer. To improve the efficacy of immunotherapy, different strategies are currently under evaluation. This review summarises the discussion during the European Organisation for Research and Treatment of Cancer Gastrointestinal Tract Cancer Translational Research Meeting in Mainz in November 2014 and provides an update on the most recent results of immune therapy in gastrointestinal cancers. Knowledge of potential relationships between tumour cells and their microenvironment including the immune system will be essential in gastrointestinal malignancies. In this context, the density of T cell infiltration within colorectal cancer metastases has been associated with response to chemotherapy, and a high expression of programmed cell death ligand 1 (PD-L1) in advanced gastric cancer has been related with poor prognosis. Effective targets might include neo-antigens encoded from genes carrying tumour-specific somatic mutations. Tailored immunotherapy based on such mutations could enable the effective targeting of an individual patient's tumour with vaccines produced on demand. Other strategies considering checkpoint inhibitors have shown efficacy by targeting cytotoxic T-lymphocyte-associated protein 4 and PD-1 or PD-L1. DNA mismatch repair-deficient tumours appear to be potentially the best candidates for these therapies. Finally, the combination of oncolytic viruses with immunotherapy might boost antitumour activity as well. Further evaluation of these promising immunological therapeutic approaches will require large prospective clinical studies.

Analysis of the expression of SDF-1 splicing variants in human colorectal cancer and normal mucosa tissues.

C-X-C motif chemokine ligand 12 (CXCL12), also termed stromal cell-derived factor-1 (SDF-1) is a small protein 8-14 kDa in length that is expressed as six isoforms, consisting of SDF-1α, SDF-1ß, SDF-1γ, SDF-1δ, SDF-1ε and SDF-1θ. All six isoforms are encoded by the single CXCL12 gene on chromosome 10. This gene regulates leukocyte trafficking and is variably expressed in a number of normal and cancer tissues. The potential role of the novel CXCL12 splice variants as components of the CXCR4 axis in cancer development is not fully understood. The present study aimed to analyze the expression profile of the various SDF-1 isoforms and SDF-1 polymorphisms, and the association with the clinicopathological features and overall survival of patients with colorectal cancer (CRC). SDF-1 polymorphism analysis was performed using restriction fragment length polymorphism (RFLP) analysis in 73 histologically confirmed human CRC tissue samples at various stages of disease. The expression pattern of the SDF-1 isoforms was analyzed by reverse transcription-polymerase chain reaction in 40 histologically confirmed human CRC tissue samples obtained at various stages of disease, as well as in matched adjacent normal mucosa samples. The presence of the CXCL12 gene polymorphism rs1801157 demonstrated an association with local progression of the primary tumor, as indicated by the T stage. The frequency of the GG genotype was slightly increased in patients with stage 3 and 4 tumors (78.0%) compared with the incidence of the GA/AA genotype (69.5%; P=0.067). The expression of SDF-1ß was associated with the presence of metastases (P=0.0656) and the expression of SDF-1γ was significantly associated with tumor size (P=0.0423). The present study is the first to analyze the association between the expression profile of the chemokine CXCL12 splice variants in human CRC tissues and their clinical relevance. The present results reveal that the CXCL12 G801A polymorphism is a low-penetrance risk factor for the development of CRC, and was associated with the T stage. All six isoforms of SDF-1 were expressed in CRC tissues. The expression of SDF-1ß was found to be associated with metastases and SDF-1γ appears to be a possible tumor marker for local tumor progression.

Murine genetic deficiency of neuronal nitric oxide synthase (nNOS(-/-) ) and interstitial cells of Cajal (W/W(v) ): Implications for achalasia?

BACKGROUND AND AIM: Nitric oxide (NO) is an important inhibitory mediator of esophageal function, and its lack leads to typical features of achalasia. In contrast, the role of intramuscular interstitial cells of Cajal (ICC-IM) and vasoactive intestinal peptide (VIP) in lower esophageal sphincter (LES) function is still controversial. Therefore, we examined the function and morphology of the LES in vivo in NO-deficient (nNOS(-/-) ), ICC-IM-deficient (W/W(v) )-, and wild-type (WT) mice. METHODS: Esophageal manometry was performed with a micro-sized transducer catheter to quantify LES pressure, swallow evoked LES relaxation, and esophageal body motility. The LES morphology was examined by semiquantitative analysis of the immunoreactivity (reduction grade I-IV) of neuronal NOS (nNOS), ICC-IM, and VIP and their correlation with esophageal function. RESULTS: nNOS(-/-) in comparison to WT mice showed a significantly higher LES mean resting pressure with an impaired swallow induced relaxation, whereas W/W(v) mice had a hypotensive LES with decreased relaxation. W/W(v) and nNOS(-/-) mice demonstrated differing degrees of tubular esophageal dysfunction. The reduced immunoreactivity of nNOS correlated with an increased LES pressure and decreased LES relaxation, respectively. Cajal-cell reduction correlated with impaired LES relaxation, whereas VIP reduction revealed no correlation with esophageal function. CONCLUSIONS: The reduction of ICC-IM and nNOS can cause dysfunction of the LES and esophageal peristalsis, whereas VIP reduction seems to have no effect. ICC-IM and nNOS deficiency might be independent relevant causes of esophageal dysfunction similar to that seen in human achalasia.

Cetuximab-induced skin exanthema: prophylactic and reactive skin therapy are equally effective.

PURPOSE: Treatment with cetuximab is accompanied by the development of an acneiform follicular skin exanthema in more than 80 % of patients. Severe exanthema (grade III/IV) develops in about 9-19 % of patients with the necessity of cetuximab dose reduction or cessation. METHODS: The study presented was a retrospective analysis of 50 gastrointestinal cancer patients treated with cetuximab in combination with either FOLFIRI or FOLFOX. One cohort of 15 patients received an in-house reactive skin protocol upon development of an exanthema. A second cohort of 15 patients received a skin prophylaxis starting with the first dose of cetuximab before clinical signs of toxicity. A third historic group of 20 patients had received no skin prophylaxis or reactive treatment. RESULTS: 19/20 patients of the historic group developed a skin exanthema. Grade III/IV exanthema was observed six times. Forty percent discontinued cetuximab therapy. The average time to exanthema onset was 14.7 days. Applying the reactive skin protocol after the first occurrence of an exanthema, the exanthema was downgraded as follows: No patients developed grade IV° exanthema, and two patients developed a grade II/III exanthema. In the majority of cases, the reactive skin protocol controlled the exanthema (grade 0-I°). No dose reductions in cetuximab were necessary. Applying the prophylactic skin protocol starting at the beginning of cetuximab application was not superior to the reactive skin protocol. CONCLUSIONS: Cetuximab-induced skin exanthema can be coped with a reactive protocol equally effective as compared to a prophylactic skin treatment. A prospective study with higher patient numbers is planned.

Prospective, open, multi-centre phase I/II trial to assess safety and efficacy of neoadjuvant radiochemotherapy with docetaxel and oxaliplatin in patients with adenocarcinoma of the oesophagogastric junction.

BACKGROUND: This phase I/II-trial assessed the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of neoadjuvant radiochemotherapy (RCT) with docetaxel and oxaliplatin in patients with locally advanced adenocarcinoma of the oesophagogastric junction. METHODS: Patients received neoadjuvant radiotherapy (50.4 Gy) together with weekly docetaxel (20 mg/m(2) at dose level (DL) 1 and 2, 25 mg/m(2) at DL 3) and oxaliplatin (40 mg/m(2) at DL 1, 50 mg/m(2) at DL 2 and 3) over 5 weeks. The primary endpoint was the DLT and the MTD of the RCT regimen. Secondary endpoints included overall response rate (ORR) and progression-free survival (PFS). RESULTS: A total of 24 patients were included. Four patients were treated at DL 1, 13 patients at DL 2 and 7 patients at DL 3. The MTD of the RCT was considered DL 2 with docetaxel 20 mg/m(2) and oxaliplatin 50 mg/m(2). Objective response (CR/PR) was observed in 32% (7/22) of patients. Eighteen patients (75%) underwent surgery after RCT. The median PFS for all patients (n = 24) was 6.5 months. The median overall survival for all patients (n = 24) was 16.3 months. Patients treated at DL 2 had a median overall survival of 29.5 months. CONCLUSION: Neoadjuvant RCT with docetaxel 20 mg/m2 and oxaliplatin 50 mg/m(2) was effective and showed a good toxicity profile. Future studies should consider the addition of targeted therapies to current neoadjuvant therapy regimens to further improve the outcome of patients with advanced cancer of the oesophagogastric junction. TRIAL REGISTRATION: NCT00374985.

Single-agent therapy with sorafenib or 5-FU is equally effective in human colorectal cancer xenograft--no benefit of combination therapy.

BACKGROUND: We initiated this preclinical study in order to analyze the impact of sorafenib single treatment versus combination treatment in human colorectal cancer. METHODS: The effect of increasing sorafenib doses on proliferation, apoptosis, migration, and activation of signal cascades was analyzed in vitro. The effect of sorafenib single treatment versus 5-fluorouracil (5-FU) single treatment and combination therapy on in vivo proliferation and target cytokine receptor/ligand expression was analyzed in a human colon cancer xenograft mouse model using HT29 tumor cells. RESULTS: In vitro, SW480 and HT29 cell lines were sensitive to sorafenib, as compared to Caco2 and SW620 cell lines, independent of the mutation status of K-ras, Raf, PTEN, or PI3K. The effect on migration was marginal, but distinct differences in caspases activation were seen. Combination strategies were beneficial in some settings (sorafenib + 5-FU; irinotecan) and disadvantageous in others (sorafenib + oxaliplatin), depending on the chemotherapeutic drug and cell line chosen. Sensitive cell lines revealed a downregulation of AKT and had a weak expression level of GADD45ß. In resistant cell lines, pp53 and GADD45ß levels decreased upon sorafenib exposure. In vivo, the combination treatment of sorafenib and 5-FU was equally effective as the respective monotherapy concerning tumor proliferation. Interestingly, treatment with either sorafenib or 5-FU resulted in a significant decrease of VEGFR1 and PDGFRß expression intensity. CONCLUSIONS: In colorectal cancer, a sensitivity towards sorafenib exists, which seems similarly effective as a 5-FU monotherapy. A combination therapy, in contrast, does not show any additional effect.

Combination therapies with oxaliplatin and oral capecitabine or intravenous 5-FU show similar toxicity profiles in gastrointestinal carcinoma patients if hand-food syndrome prophylaxis is performed continuously.

The use of anticancer drugs in palliative settings is often limited by their severe toxic effects. In gastrointestinal carcinomas the 5-fluorouracil-based palliative regimen FOLFOX-4 is often preferred to the equally effective, but more convenient oral capecitabine-based regimen XELOX. This preference is mainly based on the fact that the highly effective oral agent capecitabine induces hand-foot syndrome (HFS). In this study, we investigated whether the continuous administration of skin prophylaxis (10% urea, panthenol, bisabolol, vitamin A, C and E) is capable of protecting against capecitabine-induced HFS and allowing a more convenient oral therapeutic option. In this retrospective analysis, the toxicity profiles, according to NCI CTCAE 3.0 criteria, of 54 patients with gastrointestinal cancer who received either XELOX (34 patients) or FOLFOX-4 (20 patients) were compared using Fisher tests. The treatment protocols that were compared, herein, did not differ significantly in the majority of the analyzed items, with the exception of increased nausea (XELOX-70), fatigue (XELOX-130) and tumor pain (XELOX-70 and XELOX-130). No significant differences were observed among the various groups with regard to emesis, diarrhea, mucositis, exanthema, alopecia, loss of weight and the incidence of infections. In particular, no significant differences in toxicity levels occurred in terms of dose, and HFS was limited if skin prophylaxis was performed continuously. XELOX-based palliative regimens provide an equally effective and comparably toxic therapeutic alternative to FOLFOX-4 if HFS prophylaxis is performed continuously. Since the oral administration of capecitabine is a more convenient method of application, it provides patients with a quality of life-preserving therapeutic alternative.

SNP rs1801157 significantly correlates with distant metastasis in CXCL12 expressing esophagogastric cancer.

We performed this study in order to evaluate the impact of the chemokine CXCL12 and its single-nucleotide polymorphism (SNP) rs1801157 on clinicopathological parameters and survival in patients undergoing surgery for esophagogastric cancer. The expression pattern of CXCL12 and its polymorphisms were analyzed by RT-PCR and PCR-RFLP in 69 consecutive fresh-frozen samples of human esophagogastric junction and gastric adenocarcinomas and statistically analyzed. Expression of the CXCL12 (SNP rs1801157) polymorphisms GA/AA significantly correlated with distant metastasis (P=0.026), but not with prognosis. However, CXCL12 expression was not significantly associated with the tumor infiltration depth, lymphatic metastasis and grading. As CXCL12 polymorphisms mediate tumor cell dissemination in esophagogastric cancer, they could represent a marker indicating advanced disease. Antagonists targeting the CXCL12/ CXCR4 axis may be a novel therapeutic option in this entity.

Expression of chemokine receptor CCR5 correlates with the presence of hepatic molecular metastases in K-ras positive human colorectal cancer.

BACKGROUND: Molecular metastases are precursors of postoperative recurrence, detected by molecular-biological tools. Chemokines and their receptors contribute to dissemination and local immune recognition. A strong expression of the chemokine receptor CCR5 is associated with non-metastatic colorectal cancer and increased CD8+ T-cell infiltration. The aim of this study was to analyze whether CCR5 expression correlates with the presence of hepatic molecular metastases (MM). METHODS: Ninety-three patients undergoing elective surgery for colorectal cancer were assessed. The K-ras mutation status was defined by PCR-RFLP, and the CCR5 expression status was analyzed by CCR5-specific reverse transcription (RT-PCR) analysis. Liver biopsy samples had been intra-operatively taken to screen for MM. MM were detected by K-ras-specific PCR-RFLP and nested CK20/GCC RT-PCR. Prevalence of MM was correlated with CCR5 expression status. RESULTS: Human colorectal cancer harboured K-ras mutations in 53% (codon 12: 47%; codon 13: 6%) of cases. Among K-ras mutants, MM were detected in 27-53% of patients, dependent on the technique applied (K-ras-specific PCR-RFLP assay vs. nested CK20/GCC RT-PCR approach (P = 0.004)). CCR5 expression of K-ras mutants ranged from absent (23/49: 47%), weak (17/49: 35%), intermediate (4/49: 8%) to strong (5/49: 10%). MM were found in 30% of CCR5 negative and in 23% of CCR5 positive cancer patients by the K-ras-specific PCR-RFLP assay. The nested CK20/GCC RT-PCR assay detected MM in 87% of CCR5 negative and in 27% of CCR5 positive colorectal cancer patients (P = 0.00002). CONCLUSION: Thus, CCR5 expression of the primary cancer might be a valuable biomarker indicating the absence of hepatic molecular metastases.

VEGF-D correlates with metastatic disease in gastric cancer patients undergoing surgery.

BACKGROUND: The present study was designed to evaluate the impact of the tyrosine kinase ligands VEGF-A/C/D, PDGF-A/B on tumor dissemination and survival in gastric cancer. This is the first study analyzing all these parameters in a homogeneous patient population undergoing surgery. METHODS: The expression pattern of VEGF-A/C/D and PDGF-A/B was analyzed by reverse transcriptase polymerase chain reaction (RT-PCR) in 69 samples of human gastric adenocarcinoma and correlated with tumor stage and survival. RESULTS: Expression of the ligand VEGF-D significantly correlated with distant metastatic disease (P=0.00001) but not with patient survival. However, VEGF-A inversely correlated with M1 and grading, PDGF-A inversely correlated with pT and pN category. In contrast, VEGF-C and PDGF-B did not have an impact on clinicopathological parameters. CONCLUSIONS: The ligand VEGF-D, rather than the other ligands or tyrosine kinase receptors analyzed, is associated with progressive disease in gastric cancer patients undergoing surgery. The VEGF-D ligand might be a helpful marker indicating disseminated disease, and targeting VEGF-D may be a potential therapeutic strategy, although limitations imposed by the selected sample population have to be considered critically.

Efficacy and safety of irinotecan-based chemotherapy for advanced colorectal cancer outside clinical trials: an observational study.

BACKGROUND: This prospective observational study in typical community-based outpatient clinics evaluated the efficacy and toxicity of weekly and biweekly irinotecan-based chemotherapies and their compatibility depending on age. METHODS: 601 patients with advanced or metastatic colorectal cancer receiving first-, second-, or third-line irinotecan-based therapy were regularly analyzed for response and toxicity until the end of therapy. RESULTS: The median age was 65 (28-87) years, approximately one-third of the patients were ≥70 years old. Of all patients, 405 were treated weekly and 68 biweekly. Median overall survival (OS) for first-line therapy was 26.5 months for the <70-year-old patients and 19.4 months for the ≥70-year-old patients. Toxicities were moderate in all groups. Tumor growth control rates (TCR) and median time to progression (TTP) were marginally better for patients <70 years old. Median TTP was 9.9 months in first-line therapy, 9.8 months after adjuvant therapy, 7.7 months in second-line, and 6.4 months in third-line therapy. CONCLUSIONS: Toxicity and response data from this observational study clearly confirm the positive results from previous clinical studies and show a slight ad-vantage in efficacy for the <70-year-old patients.

Does expression of receptor tyrosine kinases in gastric adenocarcinoma correlate with clinicopathological parameters?

BACKGROUND/AIMS: This study was initiated in order to define the (co-)expression patterns of target receptor tyrosine kinases (RTKs) in human gastric adenocarcinoma and to correlate them with clinicopathological parameters. METHODOLOGY: The (co-)expression pattern of VEGFR1, VEGFR2, VEGFR3, PDGFRalpha, PDGFRbeta and EGFR1 was analyzed in 56 samples of human gastric adenocarcinoma and correlated with staging and survival. RESULTS: VEGFR1, VEGFR2, VEGFR3, PDGFRalpha, PDGFRbeta and EGFR1 were expressed at relevant levels in 79%, 50%, 50%, 63%, 55% and 30%, respectively. VEGFR2, VEGFR3, and PDGFRbeta were significantly co-expressed. Thirty-four percent of gastric adenocarcinoma samples revealed a co-expression of 6 receptors, 27% expressed 5 receptors and only 23% showed expression of 3 receptors or less. Expression of VEGFR1, VEGFR2, VEGFR3, PDGFRalpha, PDGFRbeta and EGFR1 in gastric adenocarcinoma did not significantly correlate with a higher pT-category, the presence of lymph node metastasis (pN+) or overall survival. However, a trend towards a higher pT-category was seen for expression of VEGFR1 without reaching statistical significance. CONCLUSIONS: The data obtained reveal that specific RTKs are significantly co-expressed. However, co-expression of RTKs did not impact on staging or survival. It has to be further analyzed, if the expression of the respective ligands is of higher relevance than the expression of the receptor itself.

Low expression of chemokine receptor CCR5 in human colorectal cancer correlates with lymphatic dissemination and reduced CD8+ T-cell infiltration.

BACKGROUND: Chemokines and their receptors have been proposed to distinctly contribute to tumor growth, dissemination, and local immune escape. The aim of this study was to evaluate the relevance of the chemokine receptor CCR5 expression for the progression of human colorectal cancer. METHODS: CCR5 expression was assessed by RT-PCR analysis in 103 colorectal cancer patients. Intensity of CCR5 expression was correlated with both tumor and patient characteristics. Infiltration of tumor margins with CD8(+) T cells in the context of CCR5 expression was analyzed by immunohistochemistry in additional 18 colorectal cancer specimens. RESULTS: Human colorectal cancer revealed variable intensities of CCR5 expression ranging from absent (48/103: 47%), weak (30/103: 29%), intermediate (13/103: 13%), to strong (12/103: 12%). Absent or weak CCR5 expression was significantly associated with advanced UICC stages (P=0.02) and lymphatic metastasis (P=0.05). In addition, CCR5 expression positively correlated with CD8(+) T-cell infiltration in tumor margins (P=0.001). CONCLUSION: In summary, intermediate and strong CCR5 expression was significantly associated with nonmetastatic colorectal cancer and increased CD8(+) T-cell infiltration.

K-ras mutation status correlates with the expression of VEGFR1, VEGFR2, and PDGFRalpha in colorectal cancer.

AIM: We initiated this study in order to analyze whether the expression level of targeted receptor tyrosine kinases (RTK) is associated with the K-ras mutation status. METHODS: The expression pattern of VEGFR1, VEGFR2, VEGFR3, PDGFRalpha, PDGFRbeta, and EGFR1 was analyzed in 93 samples of human colorectal carcinoma samples and correlated with the K-ras mutation status as identified by PCR-RFLP. RESULTS: VEGFR1, VEGFR2, VEGFR3, PDGFRalpha, PDGFRbeta, and EGFR1 were expressed at relevant levels in 95%, 46%, 46%, 85%, 62%, and 82%, respectively. K-ras mutations were present in 53% (codon 12, 47%; codon 13, 6%). Expression of VEGFR1 (P = 0.0263), VEGFR2 (P = 0.0466), and PDGFRalpha (P = 0.0063) was significantly linked to K-ras codon 12 or 13 mutation. In addition, co-expression of VEGFR2 and PDGFRalpha was significantly associated with K-ras mutation (P = 0.0145). CONCLUSION: Our data reveal that specific RTKs are over-expressed in K-ras mutated cancers. It needs to be addressed in prospective studies whether these patients will benefit from tyrosine kinase inhibitors more than K-ras wild-type.