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.

Preoperative evaluation of pancreatic masses with positron emission tomography using 18F-fluorodeoxyglucose: diagnostic limitations.

Identification of pancreatic cancer in patients presenting with an enlarged pancreatic mass is a major diagnostic problem. Positron emission tomography (PET) using the radiolabeled glucose analogue 18F-fluorodeoxyglucose (FDG) has been suggested to provide excellent accuracy for noninvasive determination of suspicious pancreatic masses. We conducted a prospective study to verify these results. Forty-two patients admitted for pancreatic surgery underwent PET scanning. Image analysis was based on visual film evaluation and quantification of regional tracer uptake. PET imaging was visually analyzed by three observers blinded for the results of other diagnostic tests; they qualitatively graded the scans using a five-point scale (I = low to V = high) for the presence and intensity of focal FDG uptake. Diagnosis was proven by histology (n = 38) or follow-up (n = 4). Furthermore, the results of PET were compared with helical computed tomography (CT) and conventional ultrasonography (US), done during the routine diagnostic workup before pancreatic cancer surgery. Regarding only the results with scores of IV and V as positive for representing definite malignancy yielded a sensitivity of 71% and a specificity of 64% for film reading. Quantification of regional tracer uptake contributed no significant diagnostic advantage for differentiation between benign and malignant tumors. Helical CT revealed a sensitivity of 74% and a specificity of 45.5% and abdominal US 56% and 50%, respectively. We concluded that PET imaging provides only fair diagnostic accuracy (69%) for characterizing enlarged pancreatic masses. PET does not allow exclusion of malignant tumors. In doubtful cases, the method must be combined with other imaging modalities, such as helical CT. The results indicate that the number of invasive procedures is not significantly reduced by PET imaging.

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.

[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.

Prognostic factors in gastric stump carcinoma.

OBJECTIVE: To compare prognostic results in patients with gastric stump cancer (GSC) versus those with primary gastric cancer (PGC). SUMMARY BACKGROUND DATA: Gastric stump carcinomas have often been described as having low resectability rates and a poor prognosis. METHODS: Results of surgical treatment of 50 patients with GSC were compared with that of 516 patients with PGC. RESULTS: The resectability rate was 94% for GSC patients and 96.5% for PGC patients, without significant differences in terms of postoperative complications, death rate, and median survival time (31.6 vs. 32.9 months). The multivariate analysis showed an independent prognostic effect for R0 resection, pT1 and pT2 category, and age older than 65 years. CONCLUSION: The prognosis after resection and adequate lymphadenectomy does not differ between patients with GSC and PGC.

Preliminary acute and subchronic toxicity studies of GLG-V-13, a novel class III antiarrhythmic agent, in mice.

The acute and subchronic toxic effects of GLG-V-13 (3-[4-(1H-imidazol-1-yl)benzoyl]-7-isopropyl-3,7-diazabicyclo[3.3.1]nona ne dihydroperchlorate, CAS 155029-33-7), a novel class III with some class Ib antiarrhythmic activity, were investigated in mice. The estimated LD50 for GLG-V-13 given orally were 419 mg/kg for male mice and 383 mg/kg for female mice, respectively. The acute toxic signs appeared to be of the central nervous system in origin. Four groups of mice (15 per sex, group and dose) were fed daily with diets containing GLG-V-13 for 90 consecutive days. The equivalent daily doses were 0, 22, 50 and 121 mg/kg/day and 0, 27, 60 and 136 mg/kg/day for male and female mice, respectively. All of the mice survived. Food consumption was decreased. However, mean body weight and body weight gain were not significantly changed. Gross pathological changes, especially in the lungs and liver, were found in the middle and high dose groups. Consistent increased mean corpuscular hemoglobin concentration and decreased mean corpuscular hemoglobin were observed in all dose groups. Hepatocellular necrosis was found in both male and female mice treated with the drug and was dose-dependent. Marked vacuolation of the X zone in the adrenal gland with mild to moderate deposition of ceroid pigments (brown degeneration) was observed in female mice. Lesions in the kidneys and adrenal glands may be a possible reason for changes in serum sodium and potassium ions concentrations leading to an increase in water intake. A significant reduction in cholesterol in the high dose group may be a favorable pharmacological effect of GLG-V-13. The data from the 90-day subchronic toxicity studies indicate that GLG-V-13 appears to have limited systemic toxicity potential.

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.

Micrometastases in bone marrow: prognostic indicators for pancreatic cancer.

Minimal residual disease in patients with operable pancreatic carcinoma is frequently missed by current noninvasive tumour staging. We applied an immunocytochemical cytokeratin assay that allows identification of individual pancreatic carcinoma cells disseminated to bone marrow. Prior to therapy, bone marrow was aspirated from the upper iliac crest of 48 patients with ductal adenocarcinoma of the pancreas at various disease stages and an age-matched control group of 33 noncarcinoma patients. Tumor cells in cytologic bone marrow preparations were detected with monoclonal antibodies (mAbs) CK2, KL1, and A45-B/B3 to epithelial cytokeratins (CK) using the alkaline phosphatase antialkaline phosphatase method. CK-positive cells were found in 14 (48.4%) of 31 cancer patients treated with curative intent and in 10 (58.8%) of 18 patients with extended disease. The overall frequency of these cells was 1 to 83 per 5x10(5) mononuclear cells with no significant differences between patients at different tumor stages and lymph node involvement. After a median follow-up of 22.8 months (range 3-48 months), 6 (40.0%) of 15 patients who underwent complete surgical resection but had tumor cells in bone marrow presented with distant metastasis and 7 (46.7%) had local relapse compared to none of 12 corresponding patients without such cells (p<0.05). Univariate survival analyses revealed that the presence of CK-positive cells was predictive of reduced overall survival. In conclusion, anticytokeratin mAbs are reliable probes for the immunocytochemical detection of single pancreatic cancer cells disseminated to bone marrow. Thus the described technique may help identify patients with pancreatic cancer and at potentially high risk of early metastatic relapse. The results promise to be of important assistance for determining prognosis and the consequences in therapy of early stage pancreatic cancer.

Detection of micrometastasis in bone marrow of pancreatic cancer patients.

DESIGN: Here we applied an immunocytochemical cytokeratin assay that allows the identification of individual pancreatic carcinoma cells disseminated to bone marrow. PATIENTS AND METHODS: Prior to therapy, bone marrow was aspirated from the upper iliac crest of 48 patients with ductal adenocarcinoma of the pancreas at various disease stages as well as an age-matched control group of 33 non-carcinoma patients. Tumor cells in cytologic bone marrow preparations were detected with monoclonal antibodies (mAbs) CK2, KL1 and A45-B/B3 to epithelial cytokeratins (CK), using the alkaline phosphatase anti-alkaline phosphatase method. RESULTS: CK+ cells were found in 25 (52.1%) of 48 cancer patients. The overall frequency of these cells was 1 to 85 per 5 x 10(6) mononuclear cells. 4 (8.3%) cancer patients had specimens that stained with the mAb CK2, compared with 16 (33.3%) patients who displayed KL1+ cells and 9 (18.6%) patients who showed A45-B/B3+ cells. After a median follow up of 22.8 (range 3-48) months, the occurrence of tumor relapse was significantly associated with the outcome of the immunocytochemical screening before the time of primary surgery. 6 (40.0%) out of 15 patients who underwent complete surgical resection but had tumor cells in bone marrow presented with distant metastasis and 7 (46.7%) with local relapse as compared to none of 12 corresponding patients without such cells (p < 0.02). Univariate survival analysis revealed that the presence of CK+ cells in bone marrow was predictive of reduced overall survival (p < 0.03). CONCLUSIONS: Anti-CK mAbs are reliable probes for the immunocytochemical detection of single pancreatic cancer cells disseminated to bone marrow. Thus 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.

Stented versus nonstented pancreaticojejunostomy after pancreatoduodenectomy: a prospective study.

OBJECTIVE: To compare morbidity and mortality rates of stented versus nonstented pancreaticojejunostomy after partial pancreatoduodenectomy. BACKGROUND DATA: Despite a marked reduction in the mortality rate after partial pancreatoduodenectomy in recent years, leakage of the pancreaticojejunostomy still occurs in 5% to 25% of patients and remains the major source of complications. METHODS: The authors compared the morbidity and mortality rates of 85 consecutive patients who had a partial pancreatoduodenectomy with (n = 44) or without (n = 41) temporary stented external drainage of the pancreatic duct between 1994 and 1997. RESULTS: A pancreatic fistula was diagnosed in 3 of the 44 patients (6.8%) with stents versus 12 of the 41 patients (29.3%) without stents. Surgical reintervention was necessary in 1 of the 3 patients with a pancreatic fistula in the stented group and 3 of the 12 patients with a pancreatic fistula in the nonstented group. There were two deaths after surgery, both in the nonstented group. The median hospital stay after surgery was 13 days in patients with stents and 29 days in patients without stents. CONCLUSION: In this nonrandomized prospective observational study, temporary external drainage of the pancreatic duct with a PVC tube significantly reduced the leakage rate of the pancreaticojejunostomy as well as the duration of hospital stay after partial pancreatoduodenectomy. Although promising, these observations require confirmation by further studies.

Prognostic factors in resected primary small bowel tumors.

We report a retrospective analysis of 71 patients, operated for primary small bowel tumors (SBT): 47 malignant (66.2%) and 24 benign (33.8%) tumors. Of the malignant tumors, adenocarcinomas predominated (38.3%), followed by neuroendocrine tumors (31.9%), Non-Hodgkin lymphomas (NHL) (12.8%), leiomyosarcomas (10.6%) and other rare entities (6.4%). Morbidity of surgical treatment was 16. 9%, 30-day mortality 7%. The estimated 5-year survival rate in malignant lesions was 31.8%. Univariate analysis identified the presence of distant metastasis and the resection status (R status) as prognostic factors (p = 0.034 and p = 0.001). There was no influence of T, N status or grading on survival. A complete macroscopic and microscopic tumor resection has to be the aim of any curative surgical approach in patients with SBT.

Relevant prognostic factors in gastric cancer: ten-year results of the German Gastric Cancer Study.

OBJECTIVE: In 1986 a prospective multicenter observation trial in patients with resected gastric cancer was initiated in Germany. An analysis of prognostic factors based on the 10-year survival data is now presented. PATIENTS AND METHODS: A total of 1654 patients treated for gastric cancer between 1986 and 1989 at 19 centers in Germany and Austria were included. The resected specimen were evaluated histopathologically according to a standardized protocol. The extent of lymphadenectomy was classified after surgery based on the number of removed lymph nodes on histopathologic assessment (25 or fewer removed nodes, D1 or standard lymphadenectomy; >25 removed nodes, D2 or extended lymphadenectomy). Endpoint of the study was death. Follow-up is complete for 97% of the included patients (median follow-up of the surviving patients is 8.4 years). Prognostic factors were assessed by multivariate analysis. RESULTS: A complete macroscopic and microscopic tumor resection (R0 resection according to the UICC 1997) could be achieved in 1182 of the 1654 patients (71.5%). The calculated 10-year survival rate in the entire patient population was 26.3% +/- 4.7%; it was 36.1% +/- 1.6% after an R0 resection. In the total patient population there was an independent prognostic effect of the ratio between invaded and removed lymph nodes, the residual tumor (R) category, the pT category, the presence of postsurgical complications, and the presence of distant metastases. Multivariate analysis in the subgroup of patients who had a UICC R0 resection confirmed the nodal status, the pT category, and the presence of postsurgical complications as the major independent prognostic factors. The extent of lymph node dissection had a significant and independent effect on the 10-year survival rate in patients with stage II tumors. This effect was present in the subgroups with (pT2N1) and without (pT3N0) lymph node metastases on standard histopathologic assessment. The beneficial effect of extended lymph node dissection for stage II tumors persisted when patients with insufficient lymph node dissection (<15 nodes) were excluded from the analysis. There was no difference in the postsurgical morbidity and mortality rates between patients with standard and extended lymph node dissection. CONCLUSIONS: Lymph node ratio and lymph node status are the most important prognostic factors in patients with resected gastric cancer. In experienced centers, extended lymph node dissection does not increase the mortality or morbidity rate of resection for gastric cancer but markedly improves long-term survival in patients with stage II tumors. This effect appears to be independent of the phenomenon of stage migration.

Classification of regional lymph node metastasis from gastric carcinoma. German Gastric Cancer Study Group.

BACKGROUND: Classification of lymph node metastasis from gastric carcinoma was based on the localization (International Union Against Cancer/American Joint Committee on Cancer [UICC/AJCC] 1992). The authors analyzed the data of the German Gastric Cancer Study (GGCS) to determine whether the number of involved lymph nodes related to the prognosis independent of their anatomic localization (UICC/AJCC 1997). METHODS: For 477 patients of the GGCS resected for cure (UICC/AJCC R0 resection) who had involved regional lymph nodes and no evidence of distant metastases, the 1992 UICC/AJCC classification was compared with the new UICC/AJCC classification (1997) based on the number of involved lymph nodes (ILN). RESULTS: Two hundred fifty-eight patients (54.1%) had 1-6 ILN, 137 patients (28.7%) had 7-15, and 82 patients (17.2%) had more than 15. When the 1992 and 1997 UICC/AJCC classifications were compared, the prognosis of patients classified as pN1 (n = 187) in the 1992 pN classification was homogeneous, whereas there was a marked lack of homogeneity among the patients classified as pN2 (n = 290). For 103 of 290 patients with 1-6 ILN, the prognosis appeared to be more favorable (5-year survival rate, 45.5%), whereas 137 of 290 patients with 7-15 ILN had an intermediate prognosis (5-year survival rate, 29.7%). Eighty-two of 290 patients had a dismal prognosis, with a 5-year survival rate of 10.4%. There was a highly significant difference in survival (P < 0.0001). Within the groups with 1-6, 7-15, and more than 15 ILN, the localization of ILN did not significantly alter the prognosis. CONCLUSIONS: The UICC/AJCC classification based on the number of involved regional lymph nodes allows for an estimation of prognosis superior to the 1992 classification. In addition, the new classification can now be applied without methodologic problems and seems more reproducible.

[Can the extent of pancreatic tumors be evaluated reliably enough by positron emission tomography (PET)]. / Kann die Dignität von Pankreastumoren durch die Positronen-Emissions-Tomographie (PET) sicher genug beurteilt werden?

We made PET scans using 18 FDG for 46 patients admitted for pancreatic surgery. The method yielded a sensitivity of 86% and a specificity of 67%. PET does not allow precise exclusion of malignant tumors and therefore invasive diagnostic procedures may not be reduced.

Efficacy and safety of a low-molecular-weight heparin and standard unfractionated heparin for prophylaxis of postoperative venous thromboembolism: European multicenter trial.

A randomized, double-blind multicenter trial was performed to compare the safety and efficacy of a new low-molecular-weight heparin (LMWH) (LU 47311, Clivarine) and standard unfractionated heparin for the prophylaxis of postoperative venous thromboembolism. Altogether 1351 patients scheduled to undergo abdominal surgery were included. Main outcome measures included the incidence of thromboembolic events (deep vein thrombosis, pulmonary embolism, or both) and bleeding complications, including wound hematoma. A total of 655 patients received 1750 anti-Xa IU of LMWH plus a placebo injection daily; 677 patients received 5000 IU of unfractionated heparin (UFH) twice a day. Both drugs were found to be equally effective, as 4.7% of patients in the LMWH group and 4.3% in the UFH group developed postoperative thromboembolic complications. However, the incidence of bleeding complications was significantly reduced in the LMWH group: 55 (8.3%) patients in the LMWH group and 80 (11.8%) in the UFH group developed bleeding complications, a relative risk (RR) of 0.70 (95% CI 0.51-0.97;p = 0.03); wound hematoma occurred in 29 (4.4%) of the LMWH group compared with 55 (7.7%) in those in the UFH group for an RR of 0.57 (95% CI 0.37-0.88;p = 0.01). This study confirmed that a very low dose of 1750 anti-Xa IU daily of this new LMWH is as effective as 10,000 IU of UFH for preventing postoperative deep vein thrombosis. At this dose its administration is associated with a significant reduction in the risk of bleeding including wound hematoma.