Adjuvant chemotherapy for colorectal hepatic metastases: role of route of administration and timing.

Improved results in the adjuvant and therapeutic treatment of colon cancer has led to renewed interest in the role of adjuvant chemotherapy following liver resection for colorectal hepatic metastases. However, little is known about the most effective method or timing of delivery of adjuvant chemotherapy. Sixty-nine BD-IX rats underwent a right hepatic lobectomy following tumour inoculation via a splenic injection of 10(7) K12/TRb colon cancer cells. The rats were then randomized to receive systemic FUdR (1 mg kg-1 d-1 for 7 d) or regional (hepatic artery or portal vein) FUdR (2 mg kg-1 d-1 for 7 d) immediately or 72 h following tumour injection. On Day 28, a laprotomy was performed, and tumour nodules in the liver were counted. The animals were followed to death, and at autopsy the cause of death from hepatic or extrahepatic metastases was determined. All methods of FUdR infusion were superior to no treatment. Immediate portal vein (PV) FUdR infusion delayed the appearance of hepatic tumour (P = 0.003), changed the cause of death from hepatic to extrahepatic disease (P = 0.019), and prolonged survival (P < 0.05). Infusion of FUdR via the PV 72 h later did not delay the appearance of hepatic tumours nor prolong survival. In contrast, delayed HA FUdR infusion controlled hepatic metastases (P = 0.04) and improved survival (P < 0.05).     

Serosal cytologic study to determine free mesothelial penetration of intraperitoneal colon cancer.

BACKGROUND. The presence of complete transmural penetration with tumor cells at the free mesothelial surface in patients with intraperitoneal colon cancer is an important prognostic feature and may alter the decision regarding adjuvant chemotherapy. METHODS. In this prospective study of 65 patients, specimens obtained by scraping the serosa overlying the primary tumor mass were analyzed by routine Papanicolaou cytologic study. RESULTS. Malignant cells were present in 23.1% of patients. In 46 patients with histologic pT3 tumors (through the muscularis propria but not through serosa), serosal cytologic study results were positive in 26.1% of patients. Serosal cytologic results were positive from an area of normal colon at least 10 cm proximal or distal to the primary tumor in one patient. CONCLUSIONS. Serosal cytologic study appeared to be a simple and reliable method to detect serosal penetration and the presence of tumor cells at the mesothelial surface.     

Outcome and Natural History of Patients with Stage IV Colorectal Cancer Receiving Chemotherapy Without Primary Tumor Resection

Background  

There is a trend toward nonsurgical management of patients with nonobstructing metastatic (stage IV) colorectal cancer (CRC), although some will eventually undergo surgery. We examined patients with metastatic CRC who were managed with an intact primary tumor.     

Effects of recombinant human granulocyte-macrophage colony-stimulating factor on intracellular pH in mature granulocytes

We studied the effects of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSFrh) on the internal pH of granulocytes using the fluorescent probe BCECF. GM-CSFrh did not directly alter the resting pH of granulocytes isolated from the peripheral blood; however, when the cells were preincubated for 90 minutes with the growth factor and then activated with the chemotactic peptide N-formyl met leu phe (fMLP), they exhibited both an acceleration in the initial rate of acidification and a marked delay in realkalinization. The kinetic changes both in initial acidification and in subsequent realkalinization induced by GM-CSFrh priming were not prevented by protein synthesis inhibitors and were observed in granulocytes harvested from patients with both sex-linked and autosomal recessive chronic granulomatous disease (CGD). By directly quantitating H+ ion secretion, by monitoring the effects of sodium repletion on intracellular pH, and through use of the sodium channel inhibitors amiloride and dimethyl amiloride and the Na+/K+-ATPase inhibitor ouabain, we showed that the altered kinetics of intracellular acidification and alkalinization following fMLP stimulation of GM-CSFrh- primed granulocytes could not be accounted for by changes in transmembrane proton exportation regulated by the Na+/H+ antiport channel. Although the initial acidification following fMLP was abrogated by 2-deoxy-D-glucose in both GM-CSFrh-pretreated and GM-CSFrh- untreated granulocytes, retardation of the subsequent phase of alkalinization was observed in GM-CSFrh-primed cells even after inhibition of both glycolytic and mitochondrial metabolism. Our data indicate that the increased cytosolic acidification following fMLP stimulation in granulocytes "primed" with GM-CSFrh does not result from disordered proton excretion but instead from increased release of intracellular free acid which is only partially coupled to glucose catabolism or to the generation of superoxide anion (O2-).     

Demonstration of reversible priming of human neutrophils using platelet- activating factor

Exposure of neutrophils to agents such as lipopolysaccharide, tumor necrosis factor-alpha (TNF-alpha), and the granulocyte-macrophage colony-stimulating factor causes a major upregulation of subsequent agonist-induced NADPH oxidase activation. This priming effect is a prerequisite for neutrophil-mediated tissue damage and has been widely considered to be an irreversible process. We have investigated the potential for neutrophils to recover from a priming stimulus by studying the effects of platelet-activating factor (PAF). PAF did not stimulate respiratory burst activity directly, but caused a rapid (maximal at 10 minutes) and concentration-dependent (EC50 50.2 nmol/L) increase in N-formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated superoxide anion release. At time-points > 10 minutes, this priming effect spontaneously declined, with return to basal levels of fMLP- stimulated superoxide anion generation by 120 minutes. An identical priming time-course was observed with N-methyl carbamyl PAF, a nonmetabolizable analogue of PAF, indicating that the transient nature of PAF-induced priming was not secondary to PAF metabolism. Two structurally diverse PAF receptor antagonists (UK-74,505 and WEB 2086), added 10 minutes after PAF addition, increased the rate of decay of the priming effect. In contrast, TNF-alpha-induced priming, which was of a similar magnitude to that observed for PAF, was slower to evolve (maximal at 30 minutes) and remained constant for at least 120 minutes. The reversible nature of PAF-induced priming was confirmed by demonstrating that PAF-, but not TNF-alpha-, induced cell polarization (shape change) and CD11b-dependent neutrophil binding of albumin-coated latex beads was also transient, with return to basal, unstimulated levels by 120 minutes. Furthermore, cells that had spontaneously deprimed following PAF exposure retained their capacity to be fully reprimed by a subsequent addition of either PAF or TNF-alpha. These data imply that neutrophil priming is not an irreversible event: the demonstration of a cycle of complete priming, depriming, and repriming offers the potential for functional recycling of neutrophils at sites of inflammation.     

Molecular and cellular effects of antisickling concentrations of alkylureas

Alkylureas are capable of inhibiting sickling in vitro and the gelation of solutions of hemoglobin S at concentrations between 0.05 and 0.1 M with increasing effectiveness that is directly proportional to the length of the alkyl chain (butyl greater than propyl greater than ethyl greater than methyl). 6The inhibitory effect is independent of pH between 6.5 and 7.5 and is a process driven by entropy. The alkylureas at concentrations of 0.1 M have minimal effects on several erythrocyte functions. Oxygen equilibria, osmotic fragility, reduced glutathione content, and glutathione reductase activity are totally unaffected, while pyruvic kinase activity is decreased only by butylurea by about 20%, and glucose-6-phosphate dehydrogenase activity is decreased progressively to a maximum of 30% in direct proportion to the length of the alkyl chain. Alkylureas not only inhibit sickling but are also capable of desickling erythrocytes that have been maintained in the deoxygenated state. They have little effect on several erythrocyte functions at antisickling concentrations, but their toxicity must be evaluated before they can be examined as potential therapeutic agents for the treatment or prevention of acute episodes in sickle cell anemia.     

Studies of circulating hemopoietic progenitor cells in human fetal blood

High levels of committed erythroid and granulocytic/monocytic progenitor cells have been demonstrated in fresh blood obtained at fetoscopy. The fetal progenitor cells were more sensitive to appropriate stimuli (erythropoietin and colony-stimulating factor) than adult progenitor cells grown under the same conditions, and this was shown to be due to intrinsic differences in the progenitor cells at the different developmental stages.     

Bone marrow involvement in small cell lung cancer: Prognostic significance and correlation with hematological and biochemical parameters

The more metastatic sites and bone marrow metastasis in small cell lung cancer (SCLC), the worse the prognosis. Diagnosing the bone marrow invasion at the beginning of the therapy is important for determining of the prognosis and planning the treatment. Abnormalities of some blood parameters may help to estimate the extent of bone marrow invasion by cancer cells. In this retrospective review, the changes in routine laboratory tests that may indicate bone marrow invasion, the predictive values of these tests, and the prognostic importance of bone marrow invasion were evaluated in SCLC patients who were being followed up according to a protocol. One hundred and forty‐four patients with SCLC were enrolled in this study. Retrospectively, it was evaluated that 25 (17.4%) of the patients had bone marrow metastasis. According to univariate analysis, there was a significant difference between hemoglobin, white blood cell count, platelet count, lactate dehydrogenase, alkaline phosphatase and uric acid of the patients with and without bone marrow involvement. Among the biochemical parameters, the elevated LDH and AP had the highest sensitivity and specificity as indicators of bone marrow invasion (0.80–0.82 and 0.84–0.78, respectively). The median overall survival of extensive‐stage disease with and without bone marrow metastasis were 4.0 ± 1.0 months (95% CI 2.2–5.7) and 7.0 ± 1.2 months (95% CI 4.7–9.3), respectively (P = 0.03). Bone marrow metastasis was found to be an indicator of a bad prognosis. Bone marrow biopsy, that is an invasive procedure, can be performed on selected patients who have changes of routine laboratory tests suggesting bone marrow invasion.