Immunocytochemical detection of disseminated tumor cells in the bone marrow of patients with esophageal carcinoma.

BACKGROUND: Approximately half of the patients diagnosed with localized esophageal cancer die of metastatic disease within the first 2 years following tumor resection. The development of monoclonal antibodies (MAbs) directed against epithelial cell-associated and tumor antigens has enabled the detection of single disseminated tumor cells in secondary organs. PURPOSE: We used MAbs directed against epithelial cell antigens (i.e., cytokeratins) to determine the proportion of patients with esophageal cancer who display isolated tumor cells in their bone marrow. In addition, we evaluated the prognostic significance of a finding of bone marrow tumor cells in patients with esophageal cancer whose tumors were completely resected. METHODS: Prior to the initiation of treatment, bone marrow was aspirated from both sides of the upper iliac crests of 90 patients with squamous cell carcinoma of the esophagus. Bone marrow was also obtained from a population of 30 individuals who had not been diagnosed with cancer. Tumor cells in cytologic bone marrow preparations were detected by use of an assay that employed the MAbs CK2 (directed against cytokeratin 18), KL1 (directed against a 56,000-kd pan-cytokeratin component), and A45-B/B3 (directed against an epitope common to cytokeratins 8, 18, and 19) plus the alkaline phosphatase anti-alkaline phosphatasestaining method. Bone marrow biopsies, for conventional histologic examination with Giemsa staining, were performed on 62 patients. The Kaplan-Meier method and the logrank test were used to assess disease-free and overall survival according to the presence or absence of tumor cells in the bone marrow of 42 patients with completely resected tumors. Reported P values are two-sided. RESULTS: Cytokeratin-positive tumor cells were detected in the bone marrow of 37 (41.1%) of the 90 total patients. The number of tumor cells detected per 10(5) mononuclear bone marrow cells ranged from one to 82. No significant differences in the numbers of disseminated tumor cells were noted for patients diagnosed with tumors at different stages. Only two (3.2%) of 62 bone marrow specimens examined after Giemsa staining showed morphologically identifiable tumor cells. Tumor cells were not detected in the bone marrow of patients who had not been diagnosed with cancer. After a median follow-up of 15.5 months (range, 6-33 months), 15 (79.0%) of 19 patients with completely resected tumors and tumor cells in their bone marrow had relapses compared with three (13.0%) of 23 patients with completely resected tumors and no tumor cells in their bone marrow (P = .019, logrank test). Patients with completely resected tumors and tumor cells in their bone marrow had significantly shorter overall survival than corresponding patients without tumor cells in their bone marrow (P = .036, logrank test). CONCLUSIONS AND IMPLICATIONS: Dissemination of esophageal cancer cells to the bone marrow is more frequent than expected from the rare occurrence of overt skeletal metastases. In general, the presence of tumor cells in the bone marrow may be an indicator of the disseminatory potential of individual tumors.

Prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in completely resected gastric cancer.

The prognostic impact of the proteolytic factors urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) was evaluated in 76 completely resected gastric cancer patients enrolled in a prospective study. All patients underwent macroscopically and microscopically residual tumor-free resection (category R0, Union International Contre Cancer, 1987). uPA and PAI-1 levels were quantified in detergent-extracted (Triton X-100) specimens of primary gastric tumors by enzyme-linked immunosorbent assays. Median values of 1.57 ng uPA/mg protein were determined in tumor tissue extracts compared to 0.14 ng uPA/mg protein in normal mucosa. For PAI-1, 0.93 ng PAI-1/mg protein versus 0.09 ng PAI-1/mg protein was calculated. uPA levels in tumor tissue extracts were significantly correlated with vascular invasion, Laurén classification, and WHO classification, whereas PAI-1 levels showed a significant correlation with advanced lymph node involvement, depth of invasion, tumor stage, site of tumor, and the Laurén, Borrmann, and WHO classifications. Elevated uPA and PAI-1 levels were found to be associated with poor prognosis. The optimal cutoff values indicating a group of patients with shorter survival were 1.5 ng uPA/mg protein and 1.25 ng PAI-1/mg protein, respectively (Classification and Regression Tree analysis). Patients with either high uPA or PAI-1 values were significantly associated with decreased survival (median time of survival was 23 months (high) versus 44 months (low). By univariate Cox regression analysis, it was shown that TNM categories, WHO classification, size of tumor, uPA and PAI-1 levels were all significantly associated with survival. However, in multivariate Cox regression analysis of these grouped variables, nodal status, PAI-1 levels, and WHO classification were the only independent prognostic factors. The relative risks of failure were 5-, 2.9-, and 2.4-fold, respectively. We conclude that PAI-1 and uPA positivity may serve as new prognostic factors in gastric cancer, predicting shorter survival even in clinically important subgroups of patients.

Epithelial tumour cells in bone marrow of patients with pancreatic carcinoma detected by immunocytochemical staining.

In the present study, epithelial cells in the bone marrow of 42 patients with pancreatic carcinoma were identified immunocytochemically with monoclonal antibodies (MAbs) CK2, KL1 and A45-B/B3 directed to epithelial cytokeratins (CK), using the alkaline phosphatase anti-alkaline phosphatase method. The specificity of the MAbs was demonstrated by negative staining of marrow from 25 non-carcinoma age-matched control patients. Analysis of bone marrow aspirates from cancer patients revealed CK-positive cells in 14 (58.3%) of 24 cancer patients treated with curative intent and 10 (55.6%) of 18 patients with extended disease. After a median follow-up of 15.6 months (range 3-31 months), 5 (35.7%) out of 14 patients who underwent complete surgical resection but had tumour cells in bone marrow presented with distant metastasis and 6 (42.9%) with local relapse as compared to none of 10 corresponding patients without such cells (P < 0.05). The described technique may help to identify patients with pancreatic cancer and potential high risk of early metastatic relapse. The results promise to be of important assistance in determining prognosis and consequences in therapy of early stage pancreatic cancer.

Low molecular weight heparin and prevention of postoperative thrombosis in abdominal surgery.

In a prospective, double-blind, randomized multicenter trial the efficacy and safety of low molecular weight heparin and unfractionated heparin were compared for the prevention of postoperative deep vein thrombosis in patients undergoing abdominal surgery. Six hundred and seventy-three patients were randomly allocated to the two prophylaxis groups; 20 of these, however, did not undergo surgery and did not receive any prophylaxis. Of the remaining 653 patients 323 received one subcutaneous injection of 3,000 anti-Xa units of low molecular weight heparin and 330 received subcutaneously 5,000 U heparin three times a day. Treatment was initiated 2 h preoperatively and continued for 7 to 10 days. The occurrence of DVT was determined by the 125I-labelled fibrinogen uptake test and phlebography. Venous thrombosis was diagnosed in 24 of 323 patients (7.4%) treated with low molecular weight heparin and in 26 of 330 patients (7.9%) treated with low-dose heparin. DVT of proximal veins was detected in four patients of the low molecular weight heparin group and in three patients of the low-dose heparin group. During the observation period three pulmonary emboli - one fatal and two non-fatal - occurred in patients receiving prophylaxis with low-dose heparin. No pulmonary embolism was found in patients treated with low molecular weight heparin. Both prophylactic schemes were well tolerated. Intra- and postoperative blood loss, incidence of wound hematoma, frequency and volume of intra- and postoperative blood transfusion were similar in both groups with a slight advantage for the low molecular weight heparin group.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunocytochemical detection of isolated epithelial tumor cells in bone marrow of patients with pancreatic carcinoma.

Epithelial cells in the bone marrow of 42 patients with pancreatic carcinoma were identified immunocytochemically with monoclonal antibodies directed to epithelial cytokeratins. The occurrence of tumor relapse in patients who underwent complete surgical resection was significantly associated with cytokeratin-positivity in bone marrow. The presence of these cells in indicative of an increased disseminative capability of the primary tumor and defines a new category of patients for neoadjuvant therapy.

Carcinoma of the periampullary region: who benefits from portal vein resection?

BACKGROUND: The prognosis of patients with carcinoma of the periampullary region infiltrating the portal vein is dismal. PATIENTS AND METHODS: We assessed the morbidity, mortality, and prognosis of pancreatoduodenectomy in 31 patients in whom a tangential excision (n = 9) or a segmental resection (n = 22) of the portal vein or superior mesenteric vein was performed in an attempt to achieve complete tumor removal. RESULTS: There was no postoperative mortality. Tumor infiltration of the resected vein could be documented histopathologically in 19 of the 31 (61.3%) patients. All patients with pancreatic or bile duct carcinoma (n = 29) died within 16 months of the resection (median survival 8 months). In contrast, 2 patients with cystadenocarcinoma and acinous cell carcinoma are alive with no evidence of recurrence at 23 and 54 months, respectively. CONCLUSION: Portal vein resection does not prolong survival in patients undergoing partial pancreatoduodenectomy for carcinoma of the pancreas or distal bile duct. Only the occasional patient with a rare tumor at this region may benefit from this approach.

The acute and subchronic toxicity of BRB-I-28, a novel class Ib antiarrhythmic agent, in CD-1 mice.

The acute and subchronic toxic effects of BRB-I-28 (7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane HCl), a novel class Ib antiarrhythmic agent, were investigated in male and female mice. The estimated oral LD(50) for BRB-I-28 was 128 mg/kg (male mice) and 131 mg/kg (female mice). In subchronic oral studies, four groups of mice (15/sex/group/dose) were fed daily with diets containing BRB-I-28 for 90 consecutive days. The equivalent daily doses were approximately 0, 16, 32, 76 (male) and 0, 18, 37, 89 mg/kg (female). All mice survived. Food consumption per day was decreased, but water consumption per day was increased (in a non-dose-dependent manner). However, both mean body weight and mean body weight gain were not significantly changed as were true for hematological and clinical chemistry profiles, except for serum Na(+) concentration (male) and serum K(+) concentration in male and female mice (high dose levels). Hepatocellular necrosis occurred in male and female mice (in a dose-dependent fashion). Renal cortical vacuoles and myocardial necrosis with low numbers of lymphocytic infiltrations were present in female mice (middle and high doses). Lesions in the liver, kidney and heart were mild with (very small) changes in serum biochemical values. These data suggest that BRB-I-28 has limited toxic potential, and coupled with low proarrhythmic and other desirable cardiovascular effects, makes BRB-I-28 worthy of further development.

New aspects of prognostic factors in adenocarcinomas of the small bowel.

BACKGROUND/AIMS: Primary small bowel tumors are rare and the prognosis is generally considered to be poor. Histologically chiefly adenocarcinomas are reported. The surgeon is challenged in their treatment, because of the infrequency, unspecific symptoms and delay in diagnosis. Retrospectively we investigated the surgical therapy, combined morbidity, survival rates and prognostic factors in a large series of primary adenocarcinomas of the small bowel at a single surgical center. METHODOLOGY: Between 1985 and 1998, 94 patients with a primary tumors of the small bowel (malignant n = 62 [65.9%], benign n = 32 [34.1%]) were operated on. The subgroup of the adenocarcinomas (n = 22) were considered for this study. RESULTS: The median follow-up is 8.4 years (range: 0.9-14.2 years). Sixteen patients had a follow-up more than 5 years. The main surgical procedure was a small bowel segment resection. Morbidity was 13.6% (only in patients with a duodenal tumors) and the 30-day mortality 5.6%. The estimated 2-year-survival rate was 66%, the 5-year-survival rate 45%. Univariate analysis identified the presence of the residual tumor (R-status) (P = 0.004), tumor stage according to the UICC (P = 0.01), lymph node metastasis (P = 0.007), distant metastasis (P = 0.001), lymphangiosis carcinomatosa (P = 0.001) and vascular invasion (P = 0.0008) as prognostic factors. CONCLUSIONS: A complete macroscopic and microscopic tumor resection including a systemic lymph node dissection has to be the aim of any curative surgical approach in patients with adenocarcinoma of the small bowel.

The role of surgery in the treatment of liver metastases for colorectal cancer patients.

BACKGROUND/AIMS: Liver metastases deriving from colorectal cancer can be treated with curative intention in a select number of patients. Controversy does, however, persist pertaining to the impact of adjuvant treatment strategies. The aim of this study is to elucidate upon the various treatment modalities for patients suffering from liver metastases of colorectal primary tumor as well as to provide a rationale for surgical and adjuvant treatment. METHODOLOGY: From November 1987 to September 1998, a total of 449 consecutive patients suffering from liver metastases deriving from a colorectal cancer were documented at our institution in a prolective study. Prognostic factors providing the most beneficial outcome (whether with surgical and/or adjuvant treatment modalities) were analyzed by univariate and multivariate analysis. RESULTS: Whenever possible, curative (R0) surgical resection of colorectal liver metastases provides the most benefit to the patient. Multivariate analysis revealed tumor infiltration of the lymph nodes of the hepatoduodenal ligament and metachronous occurrence of liver metastases as most independent factors related to survival. CONCLUSIONS: Adjuvant post-operative chemotherapy fails to significantly improve survival following resection of liver metastases when compared to the liver resection only group. In patients with unresectable metastases, regional arterial chemotherapy did not improve survival significantly when compared with systemic chemotherapy.

[Analysis of prognosis-associated factors in pancreatic head and peri-ampullary cancer]. / Analyse prognoseassoziierter Faktoren beim Pankreaskopf- und periampullären Carcinom.

Between 1982-1990 we treated 461 patients with adenocarcinoma of the pancreas or the periampullary region. 125 (68 ductal pancreatic and 57 periampullary carcinomas) of these patients (27.1%) underwent resection. Hospital lethality was 3.6% (n = 4). Distribution of pT stages (UICC 1987) and frequency of complete resection (R0 vs. R1/R2) were significantly different between the periampullary and pancreatic tumors. This appeared to be due to the high frequency of pT1/2 periampullary tumors (49.2%) as compared to the prognostically equivalent pT1 tumors of the pancreas (1.9%). The absence of lymph node metastases significantly improved survival of periampullary tumors. This was not observed in tumors of the head of the pancreas. This data indicate that the poor prognosis of ductal pancreatic compared to periampullary cancer is primarily caused by their advanced stage at the time of diagnosis. In addition current resection techniques only inadequately respect the complex lymphatic drainage of the head of the pancreas.

[Does the new UICC classification allow better prognostic assessment for ductal pancreatic carcinoma?]. / Erlaubt die neue UICC-Klassifikation eine bessere Prognoseabschätzung für das duktale Pankreascarcinom?

INTRODUCTION: To compare treatment results an international established classification is necessary. In 1997 the TNM classification of 1992 was modified. METHODS: Between 1983 and 1997, 159 patients with a ductal carcinoma of the pancreas underwent resection. All data of the resected specimens were documented in standardized manner prospectively in a protocol that offered ready transfer of the collected data to a new classification. The TNM categories and stage groupings were transferred to the new UICC classification of 1997 and analyzed in comparison to the classification of 1992. RESULTS: The inclusion of a pT4 category equivalent to the other GI tumors made a new stage grouping necessary. Also division into pN1 a and pN1 b was established. According to the clinical experience only few tumors in early stages (pT1/2 and stage I) were observed in the new classification. There was a significant improval in the patient's distribution to the new stage grouping because of the homogeneous groups. In comparison to the 1992 classification the new stage II shows a relevant prognostic value and a significant difference to stage III. CONCLUSION: We conclude that the new UICC classification relates to prognosis better than the old classification.

[Pancreatic carcinoma--preoperative diagnosis and indications for surgery]. / Pankreascarcinom--präoperative Diagnostik und Indikationsstellung.

Symptomatic pancreas tumors are diagnosed in general by ERCP, transabdominal ultrasonography, and computed tomography. Endoscopic ultrasonography, angiography (facultative) and video laparoscopy in combination with laparoscopic sonography and peritoneal lavage are providing preoperatively important additional information about the spreading of the tumor. Preoperative diagnostic procedures should allow the surgeon to exclude patients with an unresectable tumor from extended resection. In most of these patients satisfactory palliation can be achieved endoscopically. The indication for surgical treatment of resectable pancreatic tumors is based on the mortality of pancreaticoduodenectomy far beyond 5% in experienced centers. Improved surgical techniques and improved perioperative management together with the implementation of accurate preoperative analysis of risk factors allow resection of primary pancreatic tumors with a low morbidity and mortality.

[Risk of surgical therapy of stomach cancer in Germany. Results of the German 1992 Stomach Cancer Study. German Stomach Cancer Study Group ('92)]. / Risiko der chirurgischen Therapie des Magencarcinoms in Deutschland. Ergebnisse der Deutschen Magencarcinom-Studie 1992. Deutsche Magencarcinom-Studiengruppe (GGCS '92).

The German Gastric Cancer Study (GGCS '92) permits a representative pictures of the current situation in surgery for gastric carcinoma at university centers in Germany. The analysis of frequency of resection, complication rate and mortality provides a quality measure for anybody who performs surgical therapy for gastric carcinoma. The results of multivariate analyses will have therapeutic consequences.

[Primary extranodal non-Hodgkin lymphoma of the stomach. Value of surgery within the scope of a multimodality treatment concept]. / Das primär extranodale Non-Hodgkin-Lymphom des Magens. Stellenwert der Operation im Rahmen eines multimodalen Behandlungskonzeptes.

The clinical course of 22 patients was analyzed in a retrospective study; all of these were suffering from malignant lymphoma of the stomach and most underwent radical resection as the only therapeutic measure. A unrelated effect on the survival rate was found in a high-grade malignancy metastatic disease of celiac lymph nodes (stage II2E) and tumor size. On the basis of the presented data we assume that low-grade malignant lymphomas stages IE can be cured by radical resection. In stage II1E and II2E we recommend multi-disciplinary treatment strategy with radical resection followed by radiation therapy in low-grade malignancy or chemotherapy in high-grade malignancy.

Metabolism and metabolite pharmacokinetics of BRB-I-28, a class Ib antiarrhythmic agent.

The metabolism of BRB-I-28 (7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane), a novel class Ib antiarrhythmic agent, was characterized in vivo in dogs and rats and in vitro with rat liver microsomal preparations containing a NADPH-generating system. In dogs, rats and the in vitro hepatic microsomal oxidation system, BRB-I-28 was extensively metabolized to form 7-benzyl-3-thia-7-azabicyclo [3.3.1]nonane-3-oxide (I), a major metabolite. The metabolite I was produced via S-oxidation, presumably by the hepatic P-450 system. Formation of minor metabolite, 7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane (II) via the oxidation of the benzylic site was also identified in rats. Following intravenous and oral administration of BRB-I-28 to dogs, the plasma concentration of major metabolite I could be test described by a 1-compartmental model. The plasma AUC of metabolite I was 20% (i.v.) and 179.4% (oral) of that of the parent BRB-I-28, respectively, suggesting that BRB-I-28 was metabolized significantly by the first pass effect following oral administration. Extensive metabolism of BRB-I-28 to form metabolites I and II, which have demonstrated much lower antiarrhythmic activities, further supports previously observed pharmacodynamic and pharmacokinetic findings.

[Results of surgical treatment of pelvic fractures in polytraumatized patients]. / Ergebnisse der operativen Behandlung von Beckenfrakturen bei polytraumatisierten Patienten.

High-speed accidents involving automobiles and two-wheeled vehicles with resultant entrapment and crush injuries have led to an ever-increasing incidence of pelvic fracture within the realm of multiple trauma. Between the years 1982 and 1986 ninety-eight cases of pelvic fracture were operatively stabilised by the Department of Surgery and the Outpatient Department of the Technical University, Klinikum Rechts der Isar, Munich, West Germany. This paper is a report on fifty-five of these patients who were discovered to have suffered additional multitrauma. Independent from those patients found to have sustained multitraumatisation, twenty-four cases of isolated acetabulum fracture as well as four instances of pelvic ring fracture and one fracture of the pelvic brim were also documented. Combinations of the above mentioned fractures were uncovered in twenty-six patients. With fifty-four of the fracture injuries, osteosynthesis was carried out while in one case primary alloarthroplasty was deemed necessary. Following a mean post-treatment period of twenty-six months forty-five of the patients were objectively evaluated for results of treatment according to the methodology of Merle d'Aubigne. 70% of those patients assessed were rated with a "good" result. At the time of follow-up thirty-five (78%) of the forty-five reexamined individuals reported to be once again employed. Early operative treatment along with internal stabilisation and prompt initiation of physiotherapy have proved decisive in obtaining a favourable postoperative result.