Treatment Algorithm for Patients With Gastric Adenocarcinoma: An Austrian Consensus on Systemic Therapy.

Despite recent advances in the treatment of gastric cancer, mortality related to this disease is still substantial. Surgery and chemotherapy represent the cornerstones of patient management. Targeted treatments that include anti-angiogenic agents and the advent of immunotherapies can contribute to improved patient prognosis. Herein, we present an Austrian consensus on the systemic treatment of patients with gastric adenocarcinoma and lower gastroesophageal junction, including those with human epidermal growth factor receptor 2 (HER2)-positive disease. The consensus considers the curative setting, as well as first-line to late-line systemic treatment options in the palliative setting. For HER2-positive disease, first-line and second-line therapies are discussed, as well as HER2 testing. Potential future therapies are also listed, with a focus on anti-angiogenic treatments and checkpoint inhibition, that might provide a further step forward in the management of patients with gastric cancer.

Randomized multicenter phase II trial of oxaliplatin plus irinotecan versus raltitrexed as first-line treatment in advanced colorectal cancer.

PURPOSE: Irinotecan and oxaliplatin are two new agents with promising activity in advanced colorectal cancer. Based on preclinical and clinical evidence that both drugs act synergistically, a randomized phase II study was initiated to investigate the therapeutic potential and tolerance of this combination in the front-line setting. PATIENTS AND METHODS: Ninety-two patients with previously untreated, measurable disease were randomized to receive biweekly oxaliplatin 85 mg/m(2) plus irinotecan 175 mg/m(2) or raltitrexed 3 mg/m(2) given on day 1 every 3 weeks. Upon development of progressive disease, second-line treatment with the opposite arm was effected. RESULTS: Patients allocated to oxaliplatin/irinotecan had a significantly better radiologically confirmed response rate (43.5% v 19.6%; P =.0025) and longer progression-free survival (median, 7.1 v 5.0 months; P =.0033). Improvement in overall survival, however, did not reach the level of significance (median, 16.0 v 16.5 months; P =.3943). The response rate after cross-over was 33.3% (eight of 24) for assessable patients treated with oxaliplatin/irinotecan compared with 14.2% (three of 21) for those treated with second-line raltitrexed. Oxaliplatin/irinotecan caused more hematologic and gastrointestinal toxicities, necessitating dose reductions in 10 of the first 20 patients. After adjustment of the irinotecan starting dose from 175 to 150 mg/m(2), tolerance of treatment was acceptable; the most commonly encountered events (all grades) were neutropenia (81%), alopecia (65%), nausea/emesis (62%), peripheral sensory neuropathy (62%), and diarrhea (46%). CONCLUSION: Oxaliplatin/irinotecan seems beneficial as first-line therapy in advanced colorectal cancer, with an acceptable toxicity profile at the reduced irinotecan dose level. Its promising therapeutic potential is supported by the high response activity noted in the raltitrexed control arm after cross-over, which may also explain the lack of a difference in overall survival.

Changes in Mcl-1 expression in rectal cancer in relation to neo-adjuvant radiotherapy.

BACKGROUND: Expression of the antiapoptotic protein myeloid cell leukemia-1 (Mcl-1) may be disordered in malignancies of the rectum. High levels of Mcl-1 may correlate with unfavourable clinical outcome. AIM OF THE STUDY: The aim of the study was to determine the biologic significance and the prognostic value of the protein Mcl-1 in a group of patients with rectal cancer using immunohistochemical staining in archival specimens. PATIENTS AND METHODS: Expression of the Bcl-2 family member Mcl-1 was determined in 23 rectal malignancies. Half of the patients with rectal cancer were treated with preoperative short-term radiation therapy of 25 Gy followed by radical surgery; the other patients were treated just with radical surgery. Differences in Mcl-1 expression between irradiated and non-irradiated rectal cancer cells were analysed immunohistochemically, and Mcl-1 expression was correlated with overall survival. Induction of Mcl-1 expression by irradiation versus control in colorectal cancer cells was detected using Western blot. RESULTS: Mcl-1 was expressed at high levels in 35% of all specimens. Significantly stronger expression was detected in specimens of irradiated rectal cancer compared with non-irradiated tissues (p-value: 0.005). No association was seen between marker expression patterns and clinicopathological data of the respective patients. CONCLUSION: Our findings indicate that irradiated rectal cancer produces significantly higher levels of the antiapoptotic protein Mcl-1 than non-irradiated rectal carcinoma. The data also suggest that the high level of Mcl-1 was induced by the radiotherapy. As Mcl-1 is an antiapoptotic regulator, its over-expression in irradiated rectal cancer could constitute a detrimental development antagonizing the potential benefit of adjuvant radiotherapy. Further evaluation of the correlation between Mcl-1 expression and overall survival seems warranted.

Uptake of indium-111-labeled human polyclonal immunoglobulin G in pancreatic cancer: in vivo and in vitro studies.

Radiolabeled human non-specific polyclonal immunoglobulin G (HIG), is used for the diagnosis of inflammation/infection. Focal uptake of HIG in malignant lesions has also been reported. We investigated the diagnostic value of In-111-HIG in patients with known pancreatic cancer. Fourteen consecutive patients with histologically verified pancreatic cancer were included in this prospective study. Four of them had undergone potentially curative surgery for their primary cancer. Eight patients had liver metastases. Planar and SPECT images of the abdomen were performed after administration of In-111-HIG (74-92 MBq). Scintigraphic results were compared to conventional imaging by means of CT scanning. In addition, In-111-HIG uptake was investigated in a panel of four representative human pancreatic cancer cell lines. Primary pancreatic tumors were visualized by In-111-HIG in 6 out of 10 patients (sensitivity 60%), while 1 was false positive. In comparison, CT scanning was true positive in 9 out of 10 patients (sensitivity 90%), and no false positive. Visualization of liver lesions by means of In-111-HIG was possible in 6 out of 8 patients (sensitivity 75%), while 1 was false positive. In vitro studies revealed only minimal uptake of In-111-HIG into cells (about 3% of activity). Our data demonstrate that In-111-HIG is able to visualize pancreatic primary cancers as well as liver metastases. However, the minimal uptake into tumor cells, as shown in vitro, suggests non-specific tumor related inflammatory reactions, increased vascular permeability, release of indium from In-111-DTPA-labeled antibody and local retention to be responsible for visualization of the tumor site.

[Drug therapy of colorectal carcinoma]. / Die medikamentöse Therapie des kolorektalen Karzinoms.

Colorectal cancer represents one of the most common malignant diseases worldwide. Because of the expanding understanding of the biology of this disease entity, and the development/availability of a number novel antitumor agents, therapeutic options have considerably improved within the past few years. As for new drug development, therapeutic advances comprise the oral fluoropyrimidine prodrugs, specific thymidilate synthase inhibitors, irinotecan, oxaliplatin, and signal transduction inhibitors such as the anti-EGF-receptor monoclonal antibody Cetuximab. Compared to the area of conventional 5-fluorouracil therapy, much higher objective response rates and major improvements in overall survival can be achieved today, even in the case of disseminated disease. The aim of this review article is to provide the reader with an overview of presently available treatment options in the palliative, neoadjuvant and postoperative adjuvant setting in colon and rectal cancer, respectively. Furthermore, actual clinical-practice oriented and future perspectives in the management of this disease will be addressed.

Phase II trial of pegylated liposomal doxorubicin (Caelyx) plus Gemcitabine in chemotherapeutically pretreated patients with advanced breast cancer.

A phase II trial was performed to investigate the efficacy and tolerance of combined gemcitabine and liposomal doxorubicin +/- recombinant human granulocyte colony-stimulating factor (G-CSF) in patients with chemotherapeutically pretreated metastatic breast cancer. Thirty-four patients were entered in this trial. Chemotherapy consisted of gemcitabine and liposomal doxorubicin +/- G-CSF. Twenty seven patients received this regimen as 2nd line therapy, five patients as 3rd line and two patients as 4th line therapy after having failed taxane- and/or anthracycline-based chemotherapy or other drug combinations. After a median of six courses, an overall response rate of 26% (9 PR in 34 enrolled patients) was observed; 14 patients had disease stabilization (41%), and eight (24%) progressed. Three patients were not evaluable for response due to anaphylaxis after the first course and protracted thrombocytopenia. The median TTP was 7.5 months, and median overall survival was 15 months. Myelosuppression was the most frequently observed toxicity. Non-haematological side effects were generally mild to moderate. Our data suggest that gemcitabine and liposomal doxorubicin +/- G-CSF is an effective and fairly well tolerated regimen for chemotherapeutically pretreated patients with advanced breast cancer.

Neoplastic stem cells: a novel therapeutic target in clinical oncology.

Cancer is among the leading causes of morbidity and mortality in the Western world. Despite recent advances, most therapeutic approaches fail to eradicate the entire neoplastic clone. The remaining cells often develop metastasis and/or recurrences and therefore may represent attractive targets of therapy. A new exciting concept in this regard suggests that each neoplasm represents a heterogeneous population of cells that pertain to long-term tumor growth both in vivo in the natural host and in experimental animals. This concept postulates the existence of small fractions of 'tumor stem cells' that exhibit a capacity for self-renewal and unlimited growth and therefore are distinct from their progeny. Based on these hypotheses, the targeting of neoplastic stem cells is considered indispensable for eradication of the entire clone and for the development of curative treatment approaches. However, tumor stem cells often may be quiescent cells and may express a different profile of targets compared with 'more mature' tumor cells. Therefore, current efforts have attempted to characterize target expression profiles in cancer stem cells in various malignancies. In the this review, the authors have provided a brief summary of the current knowledge of neoplastic stem cells and the application of respective concepts in translational oncology with the ultimate objective of improving anticancer therapy.

Comparison of mucosal pressures induced by cuffs of different airway devices.

BACKGROUND: High pressures exerted by balloons and cuffs of conventional endotracheal tubes, the Combitube (Tyco Healthcare Nellcor Mallinckrodt, Pleasanton, CA), the EasyTube (Teleflex Ruesch, Kernen, Germany), the Laryngeal Mask Airway (LMA North America, San Diego, CA), the Intubating Laryngeal Mask Airway (Fastrach; LMA North America), the ProSeal (LMA North America), and the Laryngeal Tube (LT; VBM Medizintechnik, Sulz, Germany) may traumatize the pharyngeal mucosa. The aim of this study was to compare pressures exerted on the pharyngeal, tracheal, and esophageal mucosa by different devices designed for securing the patient's airways. METHODS: Nineteen fresh cadavers were included. To measure mucosal pressures, microchip sensors were fixed on the anterior, lateral, and posterior surfaces of the proximal balloon and the distal cuff of the investigated devices. Depending on the respective airway device, the cuff volume was increased in 10-ml increments at the proximal balloon starting from 0 to a maximum of 100 ml, and in 2-ml increments at the distal cuff starting from 0 up to 12 ml. RESULTS: Tracheal mucosal pressures were significantly higher using the Combitube compared with the endotracheal tube and the EasyTube. Maximal esophageal pressures were significantly higher using the EasyTube compared with the Combitube. Using cuff volumes according to the manufacturers' guidelines, we found the highest pharyngeal pressures with the Intubating Laryngeal Mask Airway versus all other devices. At maximal volumes, the Laryngeal Mask Airway, the Intubating Laryngeal Mask Airway, and the ProSeal induced significantly higher pharyngeal pressures compared with all other devices. Using a pharyngeal cuff volume of 40 ml, the Intubating Laryngeal Mask Airway followed by the Laryngeal Mask Airway exerted significantly higher pressures compared with the other devices. CONCLUSIONS: Although some devices exhibit a somewhat higher mucosal pressure when compared with others, the authors believe that the observed differences of the cuff pressures do not suggest a clinically relevant danger, because the investigated devices, except the endotracheal tubes, are not intended for prolonged use.

Mutations of the HFE gene in patients with hepatocellular carcinoma.

OBJECTIVE: Hepatocellular carcinoma (HCC) is a late consequence of severe liver disease. Patients with genetic hemochromatosis may be at risk for HCC, but limited information is available on the relationship of HCC and heterozygosity for the HFE gene mutations. METHODS: HFE mutations (C282Y and H63D) were assessed in 162 consecutive patients (131 men/31 women) with HCC. A total of 159 patients had cirrhosis. The most common etiologies of cirrhosis were chronic viral hepatitis (hepatitis C 39%, hepatitis B 9%) and alcoholic liver disease (36%). RESULTS: Five patients were C282Y homozygotes, four C282Y/H63D compound heterozygotes, and three H63D homozygotes. The C282Y and H63D allele frequencies in HCC were 8.3 (95% confidence limit = 5.3-11.3) and 11.1 (7.8-14.6), respectively, and not different from previously published data in healthy subjects or patients with chronic hepatitis C in Austria. Furthermore, there was no difference in the age at diagnosis in patients with or without HFE gene mutations. C282Y homozygotes had a 19-fold increased risk to develop HCC. In contrast, all other HFE allele constellations were not associated with such a risk. CONCLUSIONS: Except for C282Y homozygotes, HFE gene mutations do not increase the risk to develop HCC in patients with cirrhosis.