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. RESULTS: Sixty-two patients were included in the study. The MTD of cetuximab administered on an every-second-week schedule was not reached. The safety profiles were similar across all groups. Response rates in the cetuximab monotherapy and combination therapy phases were 15% and 42%, respectively. Trough levels for the 500, 600 mg/m(2) and standard weekly regimens were comparable. CONCLUSION: Cetuximab can be safely administered once every second week at doses between 400 and 700 mg/m(2), with 500 mg/m(2) being the most convenient and feasible dose for future studies.

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. The identity of these fragments was confirmed by comparison of the experimentally determined protein sequence to that of a clone of canine angiostatin. Importantly, these fragments were absent in urine collected from the same dogs after complete surgical removal of the primary tumor. We also demonstrate that canine prostate cancer cells are capable of processing plasminogen to angiostatin in vitro. These findings provide rationale for using spontaneous canine tumor models to isolate endogenous angiogenesis inhibitors and to investigate their therapeutic use against cancer.

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. We determined that pancreatic cancer cells process angiostatin isoforms from plasminogen. Additionally, we isolated and characterized an uncleaved "latent" antiangiogenic antithrombin (aaAT) molecule processed from systemically available AT by pancreatic cancer cells as well as a cleaved form of aaAT processed from systemically available AT by pancreatic cancer cells. Human AT, cleaved with human neutrophil elastase, inhibits angiogenesis in the chorioallantoic membrane assay. This human aaAT molecule is able to inhibit the growth of pancreatic tumors in immune-compromised mice. Our work represents the first demonstration of multiple angiogenesis inhibitors from a single tumor and suggests that antiangiogenic therapies may provide an avenue for future treatment of pancreatic 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. This protocol was based on experimental studies in which animals were treated by s.c. bolus once a day. However, it was not clear in the previous studies whether this schedule could be maximized further. Therefore, we developed experimental models involving continuous administration of endostatin to determine the potency and efficacy of this approach. Endostatin was administered to tumor-bearing mice either s.c. or i.p. in single bolus doses. The efficacy of these regimens was compared with endostatin administered continuously via an i.p. implanted mini-osmotic pump. Our results show that endostatin remains stable and active in mini-osmotic pumps for at least 7 days. We show that endostatin injected i.p. is rapidly cleared within 2 h, whereas endostatin administered continuously via mini-osmotic pump maintains systemic concentrations of 200-300 ng/ml for the duration of administration. Furthermore, continuous i.p. administration of endostatin results in more effective tumor suppression at significantly reduced doses (5-fold), compared with bolus administration. Additional experiments using a human pancreatic cancer model in severe combined immunodeficient mice showed that there was a significant decrease in the microvessel density between the treatment groups and the control group. These data show that continuous administration of human endostatin results in sustained systemic concentrations of the protein leading to: (a) increased efficacy manifested as increased tumor regression; and (b) an 8-10-fold decrease in the dose required to achieve the same antitumor effect as the single daily bolus administration of endostatin. On the basis of this approach, an additional clinical trial has been designed and initiated and is under way in two countries.

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. METHODS: Severe combined immunodeficient (SCID) mice were xenotransplanted subcutaneously with tumor tissue (n = 55) or cell suspension of a human liposarcoma cell line (SW-872) or subclones (n = 28), with varying cell proliferation rates. Xenograft tumor growth was recorded for up to 6 months. Tumor tissues were then removed and analyzed for tumor cell apoptosis, microvessel density, and cell proliferation. All statistical tests were two-sided. RESULTS: Pieces of tumor derived from the parental cell line or its clones gave rise to three kinds of tumors: 1) highly angiogenic and fast-growing (aggressive) tumors, 2) weakly angiogenic and slow-growing tumors, and 3) nonangiogenic and stable tumors. Most tumors retained the original phenotype of their parental tumor. Tumor volume correlated positively with microvessel density (Spearman correlation coefficient [r] =.89; P< or =.0001) and inversely with tumor cell apoptosis (Spearman r = -.68; P =.002). Tumor volume was less strongly but still positively correlated with tumor cell proliferation in vivo (Spearman r =.55; P =.02). CONCLUSIONS: Human liposarcoma cells appear to be heterogeneous in their angiogenic activity. When tumor cells with little or no angiogenic activity are transplanted into SCID mice, a microscopic, dormant tumor results that may not grow further. Because such tiny tumors are neither grossly visible nor palpable, they have previously been called "no take." The finding that an angiogenic tumor can contain subpopulations of tumor cells with little or no angiogenic activity may provide a novel mechanism for dormant micrometastases, late recurrence, and changes in rate of tumor progression.

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. New blood vessel formation or angiogenesis is critical for tumour expansion and metastasis. Here we show that the plasmin reductase isolated from conditioned medium of fibrosarcoma cells is the glycolytic enzyme phosphoglycerate kinase. Recombinant phosphoglycerate kinase had the same specific activity as the fibrosarcoma-derived protein. Plasma of mice bearing fibrosarcoma tumours contained several-fold more phosphoglycerate kinase, as compared with mice without tumours. Administration of phosphoglycerate kinase to tumour-bearing mice caused an increase in plasma levels of angiostatin, and a decrease in tumour vascularity and rate of tumour growth. Our findings indicate that phosphoglycerate kinase not only functions in glycolysis but is secreted by tumour cells and participates in the angiogenic process as a disulphide reductase.

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. The inhibition of angiogenesis represents a new concept in cancer therapy. METHODS: We evaluated the in vitro effect of TNP-470 on the proliferation of bovine capillary endothelial cells (BCE), the superficial transitional cell carcinoma (TCC) cell line (KK-47), and the invasive TCC cell line (MGH-U1). To evaluate the in vivo effect of TNP-470 on the growth of advanced TCCs, both cell lines were injected subcutaneously into SCID mice. When tumors grew to a size of 100 to 200 mm(3), therapy either with TNP-470 or phosphate-buffered saline was initiated. RESULTS: TNP-470 strongly inhibited endothelial cell proliferation in vitro. The in vitro proliferation of both bladder carcinoma cell lines was also inhibited by TNP-470. However, the doses inhibitory to bladder carcinoma cells were 100-fold higher than the doses that were effective in the inhibition of endothelial cell proliferation. In vivo, TNP-470 significantly inhibited the growth of advanced KK-47 (67%) and MGH-U1 (68%) tumors in SCID mice. CONCLUSIONS: Our results indicate that antiangiogenic therapy with TNP-470 is equally effective in advanced superficial and invasive bladder carcinoma models in mice. When our results are taken together with the reports of other laboratories, TNP-470 appears to be a promising candidate as a tumor suppressor in superficial and invasive bladder cancer.

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. METHODS: Nineteen patients with cystic tumors of the pancreas were evaluated, including K-ras mutation analysis based on polymerase chain reaction and restriction digestion assays and direct DNA sequencing, to screen for parameters that accurately predict malignancy. RESULTS: All malignant cystic pancreatic tumors (five cystadenocarcinomas and three mucin-producing adenocarcinomas) harbored K-ras mutations at codon 12 or 13. K-ras mutations were also detected in the percutaneous fine-needle aspirates of two of these patients. In contrast, none of nine benign cystadenomas or the solid-papillary neoplasm had K-ras mutations. None of the patients with a benign tumor carrying K-ras wild-type sequences developed recurrent disease after a mean follow-up of 50 months. Seven of the 8 malignant cystic pancreatic tumors, but none of the 11 benign tumors, showed dilatation of the main pancreatic duct on computed tomography or endoscopic retrograde cholangiopancreatography. CONCLUSIONS: K-ras mutation analysis seems to be a powerful tool to determine the malignant potential of cystic pancreatic tumors before and after surgery. Dilatation of the main pancreatic duct on computed tomography or endoscopic retrograde cholangiopancreatography is highly suggestive for malignancy in these rare 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. Altogether 10 patients had duodenal wall gastrinoma, 14 patients pancreatic gastrinoma, and the tumor was not found in 1 patient. Only 15 tumors (60%) (2 duodenal wall and 13 pancreatic gastrinomas) could be visualized preoperatively. Intraoperatively, 24 of 25 primary gastrinomas were localized. The mean size of duodenal wall gastrinomas (9.6 mm) was significantly smaller than that of pancreatic gastrinomas (28.7 mm) (p < 0.05). At the time of surgical exploration, five duodenal and seven pancreatic gastrinomas had metastasized. The incidence of lymph node metastases was similar for both tumor sites, whereas patients with pancreatic gastrinomas more frequently had liver metastases. The presence of liver metastases was the most important determinant for survival. Four patients (40%) with duodenal and seven with pancreatic (50%) gastrinomas (mean follow-up 5.2 years) were biochemically cured by operation. Of the remaining patients, eight are still alive with recurrent disease. Our results suggest that preoperative localization of gastrinomas often fails despite all modern imaging methods. Therefore a standardized surgical exploration of the pancreas including IOUS and a duodenal exploration should be performed to achieve optimal results. Preoperative diagnostic imaging tests should include computed tomography, ultrasonography, and somatostatin receptor scintigraphy to exclude diffuse metastases. In contrast to liver metastases, lymph node metastases do not have a significant influence on survival.

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 aim of this study, therefore, was to accurately determine the normal anatomy of the anal canal and correlate it with the findings obtained by anal endosonography. METHODS: Eight postmortem specimens of the anal canal were examined by endosonography. The findings were correlated with macroscopical dissection and gross sectional histology of the same specimens. RESULTS: The external echogenic ring is composed of two anatomical structures: the LM and the external anal sphincter (EAS). However, during anal endosonography the LM cannot always be differentiated from the EAS. Histologically, the relation of the diameters of the LM and the EAS ranged from 0.45:1 to 1.25:1. The narrow hyperechogenic ring between the inner hypoechoic layer and the external hyperechoic ring is an artificial finding that cannot be related to a distinct anatomical structure and most likely represents a sonographic interface. CONCLUSIONS: This study exactly outlines the relation of diameters of the conjoined longitudinal muscle and external anal sphincter for the first time. Until now, the LM has been underestimated in its dimensions. The role of such a thick muscular structure should be included in the conception of anal continence in the future. Especially in view of the fact that anal endosonography is increasingly used in the diagnostic workup of incontinence and fistula in ano, it is essential to understand the anatomical basis of endosonography. This study accurately delineates the sonomorphology of the anal muscles. When viewed in light findings reported here, endosonographic findings in diseases of the anal canal are nor based on a correct idea of the correlation between endosonomorphology and anal anatomy.

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. Results of the three imaging modalities were compared with findings at surgical exploration. RESULTS: None of the insulinomas were localized by somatostatin-receptor scintigraphy, but 4 of 6 insulinomas were detected by computed tomography and ultrasonography. Of 17 gastrinomas, 9 were detected by somatostatin-receptor scintigraphy; computed tomography and ultrasonography localized only 7. Metastases from the gastrinoma were localized by somatostatin-receptor scintigraphy in all cases; computed tomography and ultrasonography detected metastases in only 6 of 9 patients. Nonfunctioning tumors could be localized by somatostatin-receptor scintigraphy, computed tomography, and ultrasonography in 4, 7, and 8 of 10 cases, respectively. Detection rate for corresponding metastases was the same for all three imaging techniques. Primary carcinoids were identified by somatostatin-receptor scintigraphy, ultrasonography, and computed tomography in 7, 8, and 11 of 22 cases, respectively. Extra-abdominal metastases were detected by somatostatin-receptor scintigraphy in only 7 of 19 patients. CONCLUSIONS: In patients with insulinomas, somatostatin-receptor scintigraphy is not indicated because none of the six tumors was imaged. This holds true for nonfunctional pancreatic endocrine tumors and their metastases because no advantage for somatostatin-receptor scintigraphy was found over computed tomography and ultrasonography. In contrast, somatostatin-receptor scintigraphy is superior to computed tomography and ultrasonography for determining the extent of the disease in patients with gastrinomas or carcinoids. The problem of detecting primary tumors in these patients is not solved by somatostatin-receptor scintigraphy.

"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 22.4%) and clinical as well as follow-up data were compared in the remainder. RESULTS: The overall accuracy, sensitivity, and specificity of the clinical diagnosis of AA were 84.9%, 51.3%, and 94.6% and those of US were 93. 6%, 83.1%, and 96.6%. Joint evaluation of the results from clinical evaluation and US further improved diagnostic performance (accuracy 93.4%, sensitivity 84.1%, specificity 96.2) and significantly reduced the rate of diagnostic errors to 3.4% (p < 0.001) and unnecessary laparotomies to 9.6% (p < 0.01) in patients with suspected AA. CONCLUSIONS: Ultrasonographic evaluation of the patient with suspected AA is considered to be of value in surgical practice.

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. Patients who had surgery for generalized peritonitis were excluded, leaving 143 for evaluation. Ultrasonographic findings and clinical assessment on admission were correlated with the patient's clinicopathological data and discharge diagnosis respectively. RESULTS: Of 74 patients with proven ACD (prevalence 52 per cent) the diagnosis was made by ultrasonography in 62, with an accuracy of 88 per cent, sensitivity 84 per cent and specificity 93 per cent. Ultrasonography gave a false-negative result in 12 patients (negative predictive value (NPV) 84 per cent) and there were five false-positive findings (positive predictive value (PPV) 93 per cent). The final diagnosis in the latter five patients was colitis (two patients), caecal carcinoma (one), colonic ileus due to perforated sigmoid carcinoma (one) and suppurative pyosalpingitis with involvement of the sigmoid colon (one). The accuracy of clinical evaluation on admission was 71 per cent (sensitivity 82 per cent, specificity 55 per cent, PPV 72 per cent, NPV 68 per cent); however, in only 53 per cent of patients was the diagnosis considered clinically unequivocal. CONCLUSION: Ultrasonography is a useful and valid modality for imaging ACD and its differential diagnoses in the hands of sonographically trained surgeons. It is especially helpful when the clinical findings are equivocal.

[Reactive thymus dysplasia following therapy for ACTH-producing tumors]. / Reaktive Thymushyperplasie infolge der Therapie ACTH-produzierender Tumoren.

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 corresponding radiographic feature is the "rebound" enlargement of the thymus occurring about six months after remission of hypercortisolism. Histological examination reveals benign thymus hyperplasia. Especially in cases of still unknown primary tumor the appearance of this anterior mediastinal mass can lead to misdiagnosis. We present the cases of two patients with diffuse thymic hyperplasia following surgical and medical correction of hypercortisolism. One patient suffered from classic Cushing's disease responding to transsphenoidal resection of an ACTH-secreting pituitary microadenoma. Six months later CT of the chest incidentally demonstrated an anterior mediastinal mass known as thymic hyperplasia. The second patient presented with an ectopic, still unkown source of ACTH-production. Six months after medical correction of hypercortisolism CT of the thorax showed an enlargement of the anterior mediastinum. Thymectomy was performed in order to exclude thymus carcinoid. Histological examination revealed benign thymus hyperplasia with negative immunostaining. CONCLUSION: Radiologists and clinicians should be familiar with the pathophysiological changes resulting from precipitously dropping cortisol levels in order to prevent diagnostic errors and unnecessary operations.

[Diagnostic localization of insulinoma. Experiences with 25 patients with solitary tumors]. / Lokalisationsdiagnostik bei Insulinomen. Erfahrungen bei 25 Patienten mit sporadischen Tumoren.

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. PATIENTS AND METHODS: In total 25 patients have been included in our study since 1987. All showed sporadic insulinomas and underwent surgery. The following preoperative localization methods had been used: ultrasonography (US): 25 patients, computed tomography (CT): 23 patients, somatostatin receptor scintigraphy (SRS): four patients since 1990, angiography: six patients, endosonography (ES): five patients since 1995, selective portal venous sampling (PVS): two patients, magnetic resonance imaging (MRI): four patients since 1993. All 25 patients underwent a bidigital palpation in combination with intraoperative ultrasonography (IOUS). Four of the 25 patients were reoperated and had a prior unsuccessful operation elsewhere. RESULTS: Preoperatively 19 of 25 insulinomas were localized (76%). The following sensitivity rates had been found: ultrasonography: 56%, computed tomography: 43%, endosonography: 100%, angiography: 66%, magnetic resonance imaging: 25%, selective portal venous sampling: 100%, somatostatin receptor scintigraphy: 0%. All 25 insulinomas were detected during operation, 100% by palpation in combination with intraoperative ultrasonography and 92% by palpation on its own. CONCLUSION: After an insulinoma is biochemically proven and after exclusion of a malignant metastasizing tumor by ultrasonography, all patients should be operated on. Intraoperative ultrasonography should be performed in any case. As other preoperative localization methods did not prove a convincing cost-utility-relation, one should not consider the usage of these methods before the initial operations. Before re-operations one should consider the use of costly pre-operative methods to localize insulinomas. Here endosonography and selective portal venous sampling are recommended as the first procedures of choice.

Expression and potential role of E-cadherin in pancreatic carcinoma.

CONCLUSION: Our results indicate that loss of E-cadherin might be associated with a more invasive phenotype in pancreatic cancer. BACKGROUND: A reduced expression of the calcium-dependent E-cadherin cell-cell adhesion molecule on tumor cells has been described as an important factor for tumor invasion and metastasis. METHODS: Pancreatic tissues (carcinoma, chronic pancreatitis, and normal) as well as 12 pancreatic tumor cell lines were investigated for E-cadherin expression by immunohistochemistry. To correlate the motility of pancreatic tumor cells in vitro with E-cadherin expression, we used a Boyden chamber assay. RESULTS: In pancreatic carcinoma tissues, diffuse growing tumor cells showed a decrease or loss of E-cadherin expression, whereas in areas of compact tumor growth, only a slight decrease of E-cadherin was observed compared to normal pancreas or chronic pancreatitis. No correlation between the E-cadherin expression and the grading of the tumor cells, the tumor stage, or the disease progression was detectable. Of four tumor cell lines that migrated in the Boyden chamber, three were predominantly E-cadherin negative. In contrast, seven of eight cell lines that did not migrate in vitro revealed E-cadherin expression.

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. Therefore in most cases an assessment of the primary tumor and its metastases must be performed. To determine the value of somatostatin receptor scintigraphy (SRS) for localizing carcinoid tumors, we compared the results of SRS with those obtained with computed tomography (CT) and ultrasonography (US) in 22 patients who had not undergone surgery for removal of the primary tumor. We could not find an advantage of SRS over CT and US for detecting the primary lesions. Tumors > 2 cm in diameter were regularly detected using all methods. SRS was not superior to CT or US for the detection of liver metastases. SRS showed the liver metastases in 16 of 18 patients, whereas CT and US detected liver metastases in all patients. For localization of extrahepatic abdominal and extraabdominal metastases (lymph nodes, bone), whole-body SRS showed an advantage over CT and US. We conclude that SRS is not superior to CT or US for localization of primary carcinoid tumors or liver metastases, although it did prove successful for visualizing extrahepatic and extraabdominal tumor spread. Additionally, SRS is useful for identifying receptor-positive metastases that may be treated by somatostatin analogs. Thus SRS should be performed in patients with a known carcinoid tumor, except those with an appendiceal carcinoid measuring < 1 cm in diameter.

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. Lymph node metastases are most commonly found with small bowel carcinoids (20-45%), providing the rationale for an extended resection including the adjacent lymph node drainage area. Carcinoid tumors of the appendix < 1 cm in diameter rarely metastasize, simply requiring appendectomy for treatment. Lesions > 2 cm should be treated by right hemicolectomy because of their approximately 30% risk of lymph node metastases. Resection should always be done for carcinoid tumors of the colon resection as for adenocarcinomas. Rectal carcinoids < 2 cm rarely metastasize, directing the conclusion that for these smaller lesions local excision is sufficient; for lesions >2 cm a standard cancer resection should be performed provided distant metastases are absent. In general, the younger the patient or the larger the primary tumor, the more aggressive the treatment should be.

Frequent mutations of CDKN2 in primary pancreatic adenocarcinomas.

The gene encoding the cell-cycle regulatory protein p16, CDKN2, is localized on chromosome band 9p21. CDKN2 is frequently deleted or mutated in a variety of tumor cell lines, including pancreatic cancer cell lines and xenografts, as well as in some primary tumors. We examined 32 primary pancreatic adenocarcinomas for CDKN2 mutations and for loss of heterozygosity of 9p21 sequences to assess the role of CDKN2 in pancreatic carcinogenesis. Single-strand conformation variant analysis (SSCV) and direct sequencing of the variants revealed somatic CDKN2 mutations in 11 of 32 tumors (five frame-shift mutations, five nonsense mutations, and one missense mutation). One tumor appeared to be characterized by homozygous deletion of CDKN2. These results suggest that CDKN2 plays an important role during tumorigenesis or tumor progression in a significant proportion of pancreatic adenocarcinomas.

Tumor cell-induced platelet aggregation in vitro by human pancreatic cancer cell lines.

BACKGROUND: Tumor cell-induced platelet aggregation (TCIPA) is considered to be a critical step in hematogenous metastasis. METHODS: TCIPA was studied in vitro in six human pancreatic carcinoma cell lines (PC 3, PC 44, AsPC1, BxPC3, Capan2, Panc1). RESULTS: Whereas all cell lines induced aggregation of washed platelets in the presence of minimal amounts of platelet-poor plasma, five cell lines also induced aggregation of platelets in platelet-rich plasma. The thrombin-antagonist hirudin inhibited TCIPA in all cell lines indicating that TCIPA is thrombin-dependent. Since pretreatment of tumor cells with phospholipase A2 or C inhibited TCIPA, the thrombin-generating activity might be confined to the tumor cell surface. Further support for a prothrombinase activity was provided by the observation that all cell lines were able to induce the aggregation of washed platelets after addition of purified coagulation factors II and V. CONCLUSIONS: Pancreatic carcinoma cells are able to induce platelet aggregation via activation of thrombin. This might support metastasis in pancreatic cancer and possibly explain the incidence of thrombosis in this tumor.