Cetuximab administered once every second week to patients with metastatic colorectal cancer: a two-part pharmacokinetic/pharmacodynamic phase I dose-escalation study.

Background: This phase I dose-escalation study was designed to determine the maximum tolerated dose (MTD) and recommended dose of cetuximab administered on an every-second-week schedule to patients with metastatic colorectal cancer, on the basis of safety, pharmacokinetic and pharmacodynamic evaluation.

Patients And Methods: The study comprised two parts: a 6-week cetuximab monotherapy dose-escalation phase and a subsequent combination therapy phase, during which patients received cetuximab, at the same dose/schedule as in the monotherapy phase, followed by irinotecan plus infusional 5-fluorouracil/folinic acid (FOLFIRI). Patients in the control group received cetuximab as a 400 mg/m(2) initial dose, then 250 mg/m(2)/week and in the dose-escalation group, at 400-700 mg/m(2), every second week.

EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer.

Purpose: To determine whether adding cetuximab to irinotecan prolongs survival in patients with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine and oxaliplatin.

Patients And Methods: This multicenter, open-label, phase III study randomly assigned 1,298 patients with epidermal growth factor receptor-expressing mCRC who had experienced first-line fluoropyrimidine and oxaliplatin treatment failure to cetuximab (400 mg/m(2) day 1 followed by 250 mg/m(2) weekly) plus irinotecan (350 mg/m(2) every 3 weeks) or irinotecan alone. Primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), response rate (RR), and quality of life (QOL).

Phase II trial of cetuximab in combination with fluorouracil, leucovorin, and oxaliplatin in the first-line treatment of metastatic colorectal cancer.

Purpose: This phase II study investigated the efficacy and safety of cetuximab combined with standard oxaliplatin-based chemotherapy (infusional fluorouracil, leucovorin, and oxaliplatin [FOLFOX-4]) in the first-line treatment of epidermal growth factor receptor-expressing metastatic colorectal cancer (mCRC).

Patients And Methods: The activity of cetuximab plus oxaliplatin was investigated in colon cancer cell lines and xenograft models. In the clinical study, patients with mCRC received on day 1 of a 14 day cycle, cetuximab (initial dose 400 mg/m(2) during week 1, then 250 mg/m(2) weekly) followed by FOLFOX-4 (oxaliplatin 85 mg/m(2) on day 1; leucovorin 200 mg/m(2) on days 1 and 2, followed by fluorouracil 400 mg/m(2) bolus then 600 mg/m(2) intravenous infusion during 22 hours on days 1 and 2).

Therapeutic efficacy of endostatin exhibits a biphasic dose-response curve.

We show here that recombinant endostatin protein has a biphasic effect on the inhibition of endothelial cell migration in vitro. In tumor-bearing animals, there is a similar biphasic effect on the inhibition of tumor growth and on circulating endothelial cells after once-daily s.c.

Pancreatic tumor growth is regulated by the balance between positive and negative modulators of angiogenesis.

There is increasing evidence for the implication of tumor-derived angiogenic and anti-angiogenic factors in controlling tumor growth in vivo. In this study, we documented the production of inhibitors of angiogenesis by pancreatic cancer cells and examined how changes in the balance between pro- and anti-angiogenic factors regulate tumor growth in vivo. The human pancreatic cancer cell line Hs-776T (HS-W) produces slow-growing tumors in SCID mice.

Vitamin D binding protein-macrophage activating factor (DBP-maf) inhibits angiogenesis and tumor growth in mice.

We have isolated a selectively deglycosylated form of vitamin D binding protein (DBP-maf) generated from systemically available DBP by a human pancreatic cancer cell line. DBP-maf is antiproliferative for endothelial cells and antiangiogenic in the chorioallantoic membrane assay. DBP-maf administered daily was able to potently inhibit the growth of human pancreatic cancer in immune compromised mice (T/C=0.

Treatment of human pancreatic cancer in mice with angiogenic inhibitors.

Tumor growth is dependent on the balance of positive and negative regulators of angiogenesis. Antiangiogenic compounds inhibit endothelial cell biology in vitro and angiogenesis in vivo. Therefore antiangiogenic therapy presumes to be an effective treatment for pancreatic cancer.

Adenovirus-mediated delivery of a soluble form of the VEGF receptor Flk1 delays the growth of murine and human pancreatic adenocarcinoma in mice.

Background: Because pancreatic adenocarcinoma is poorly responsive to chemotherapy and radiation therapy, novel treatments such as antiangiogenic gene therapy may have use in the adjuvant treatment of this malignancy. We evaluated the antitumor effects of the in vivo administration of an adenovirus vector encoding a soluble form of Flk1 (Flk1-Fc), a receptor for vascular endothelial growth factor, in 3 murine models of pancreatic adenocarcinoma.

Methods: In a first model, immunocompetent C57Bl/6 mice were injected subcutaneously with Panc02 murine pancreatic adenocarcinoma cells before treatment.

The role of angiostatin in the spontaneous bone and prostate cancers of pet dogs.

Angiostatin is a potent inhibitor of angiogenesis generated in cancer-bearing hosts by tumor-derived proteases. Because the naturally occurring bone and prostate cancers of pet dogs provide unique model systems to study factors that regulate cancer progression and tumor dormancy, we investigated the capacity of these tumors to generate angiostatin. We determined that angiostatin fragments are present in urine of dogs with bone cancer.

Continuous administration of endostatin by intraperitoneally implanted osmotic pump improves the efficacy and potency of therapy in a mouse xenograft tumor model.

In the first Phase I clinical trials of endostatin as an antiangiogenic therapy for cancer, the protein was administered as an i.v. bolus for approximately 20-30 min each day.

Generation of multiple angiogenesis inhibitors by human pancreatic cancer.

A primary inoculum of human pancreatic cancer cells (BxPC-3) has the ability to inhibit the growth of a secondary tumor in an in vivo animal model. Such ability suggests that the primary tumor is producing inhibitors that act at the site of the secondary tumor. Accordingly we attempted to discover which inhibitors are produced by pancreatic cancer cells.

Heterogeneity of angiogenic activity in a human liposarcoma: a proposed mechanism for "no take" of human tumors in mice.

Background: Tumor cells are known to be heterogeneous with respect to their metastatic activity, proliferation rate, and activity of several enzymes. However, little is known about the heterogeneity of tumor angiogenic activity. We investigated whether heterogeneity of angiogenic activity could be responsible for the well-known observation of "no take" of human tumors transplanted into immunodeficient mice.

Phosphoglycerate kinase acts in tumour angiogenesis as a disulphide reductase.

Disulphide bonds in secreted proteins are considered to be inert because of the oxidizing nature of the extracellular milieu. An exception to this rule is a reductase secreted by tumour cells that reduces disulphide bonds in the serine proteinase plasmin. Reduction of plasmin initiates proteolytic cleavage in the kringle 5 domain and release of the tumour blood vessel inhibitor angiostatin.

Efficacy of antiangiogenic therapy with TNP-470 in superficial and invasive bladder cancer models in mice.

Objectives: To evaluate the efficacy of antiangiogenic therapy with O-(chloracetyl-carbamoyl) fumagillol (TNP-470) in a superficial and an invasive bladder cancer model in mice. The control of recurrent superficial and metastatic bladder cancer constitutes a major problem in urologic practice. Although the established therapies for these cases (immunotherapy, chemotherapy, and radiation therapy) have improved during the previous decades, further improvement and the reduction of existing side effects are needed.

K-ras oncogene mutations indicate malignancy in cystic tumors of the pancreas.

Objective: To evaluate clinical parameters, presurgical diagnostic tests, histologic findings, and the presence of K-ras oncogene mutations in cystic tumors of the pancreas to determine which best predict malignancy.

Summary Background Data: Because presurgical, intraoperative, and final pathologic differentiation is difficult in cystic tumors of the pancreas, it would be a major benefit to identify markers that accurately predict malignancy in these rare tumors. The role of K-ras oncogene mutations as an indicator of malignancy has not been determined in these tumors.

Localization, malignant potential, and surgical management of gastrinomas.

Between 1987 and 1996 a total of 25 patients with proved Zollinger-Ellison syndrome (ZES) have been treated in our department. If preoperative imaging studies did not show diffuse metastatic disease, patients were scheduled for operation with a standardized surgical approach including thorough exploration and intraoperative ultrasonography (IOUS) of the pancreas and a longitudinal duodenotomy, with separate palpation of the anterior and posterior walls. Postoperatively, patients were followed up by physical examination, fasting gastrin levels, and the secretin stimulation test.

[Reactive thymus dysplasia following therapy for ACTH-producing tumors].

Unlabelled: Surgical or conservative treatment of ACTH-producing tumors results in acute drop of the previously excessively high cortisol levels. The following associated pathophysiological changes also occur in the organism's recovery from stress, such as trauma, operation or chemotherapy of tumors. Both cases result in a regeneration of the immune system, which might even be exalted.

The anatomical basis of anal endosonography. A study in postmortem specimens.

Purpose: Anal endosonography is an imaging modality new to the diagnostic workup of incontinence. Interpretations even of normal endosonomorphologic findings now vary considerably. The conjoined longitudinal muscle (LM), a widely ignored structure, has until recently not been fully recognized by anal endosonography.

The value of somatostatin-receptor scintigraphy in newly diagnosed endocrine gastroenteropancreatic tumors.

Background: Conventional imaging techniques do not routinely detect endocrine gastroenteropancreatic tumors preoperatively. The purpose of this study was to determine whether the new technique of somatostatin-receptor scintigraphy would improve the detection rate of these tumors before initial treatment.

Study Design: In a prospective study, 55 patients with a recent diagnosis of endocrine gastroenteropancreatic tumors (22 intestinal carcinoids, 17 gastrinomas, 10 nonfunctioning pancreatic tumors, and 6 insulinomas), were examined with somatostatin-receptor scintigraphy, computed tomography, and ultrasonography.

"Surgical" ultrasound in suspected acute appendicitis.

Background: Ultrasonography (US) by acknowledged experts enhances the diagnostic performance and reduces the rate of negative laparotomies in patients with suspected acute appendicitis (AA).

Methods: The diagnostic accuracy and clinical impact of routine US performed by surgical residents was prospectively studied in 504 unselected patients admitted for AA. Clinical and US findings were correlated with laparotomy findings and pathological outcome in 135 patients (113 cases with proven AA, prevalence 22.

Prospective evaluation of ultrasonography in acute colonic diverticulitis.

Background: The clinical diagnosis of acute colonic diverticulitis (ACD) can be difficult and ultrasonography by experts is valuable in establishing the diagnosis. This prospective observational trial aimed to assess the diagnostic accuracy and clinical value of ultrasonography performed routinely by surgical residents in training.

Methods: The clinical course of 187 unselected consecutive patients admitted with suspected ACD was studied prospectively.

[Diagnostic localization of insulinoma. Experiences with 25 patients with solitary tumors].

Objective: The most effective way to localize the mostly small ( < 2 cm), benign and solitary insulinomas is still under discussion. Especially the evaluation of the different preoperative localization methods is not clarified. The aim of our study was to support the ongoing discussion in that matter.

Surgical management for carcinoid tumors of small bowel, appendix, colon, and rectum.

Carcinoid tumors occur most frequently in the gastrointestinal tract. Despite their ability to produce hormones, most of the midgut and hindgut carcinoids covered in this study are clinically silent, and the diagnosis is often not made before emergency surgery or evaluation for liver metastases. Because the rate of lymph node involvement and the prognosis of carcinoid tumors depend on their site and size, surgery refers to these two factors too.

Value of somatostatin receptor scintigraphy for preoperative localization of carcinoids.

Most carcinoid primary tumors are small and do not cause symptoms until complications (e.g. intestinal obstruction) or symptoms and signs of the carcinoid syndrome occur.