Plasma from patients undergoing major open surgery stimulates in vitro tumor growth: Lower insulin-like growth factor binding protein 3 levels may,in part,account for this change

BACKGROUND: Plasma from laparotomized mice has been shown to stimulate in vitro tumor growth when compared to results with preoperative plasma. This study assessed the effect of plasma from patients who underwent major open (OS) or laparoscopic surgery (LS) on in vitro tumor cell growth. METHODS: Eighty-four patients undergoing major abdominal surgery were studied (45 OS, 39 LS). Peripheral blood was collected preoperatively (PreOP) and on days 1 (POD1) and 3 (POD3) after operation. HT29 human colon cancer cells were plated with samples of the plasma. Proliferation was assessed by cell counts and the bromodeoxyuridine incorporation assay. Insulin-like growth factor binding protein 3 was detected in plasma by Western blot analysis. RESULTS: Increased mitogenic activity was noted in POD1 OS plasma when compared to PreOP OS plasma results (P <.005). This increase correlated with the length of incision (r = 0.58, P <.01). No differences were noted when the PreOP LS and POD1 LS results were compared or for any of the POD3 versus PreOP comparisons. CONCLUSIONS: Major OS is associated with alterations in plasma composition that promote HT29 tumor cell proliferation in vitro. As shown, this effect was due, at least in part, to surgery-related depletion of insulin-like growth factor binding protein 3 in peripheral blood.     

A serum-soluble factor(s) stimulates tumor growth following laparotomy in a murine modelrid=""id=""Presented at the annual meeting of the Society of American Gastrointestinal Endoscopic Surgeons (SAGES), San Antonio, TX, 26 March 1999

Background: Our laboratory and others have previously demonstrated that tumors grow larger and are more easily established following laparotomy than after CO₂ pneumoperitoneum. The etiology of increased tumor growth after surgery is unknown. We hypothesized that, following laparotomy, a serum soluble factor(s) is generated that causes tumors to proliferate more rapidly. The purpose of the current study was to determine if in vitro tumor cells proliferate faster when incubated with serum from laparotomized mice than cells incubated with sera from mice who have undergone CO₂ pneumoperitoneum or anesthesia alone. Methods: In the first experiment, female Balb/C mice (n= 84) were randomly divided into the following three groups: (a) control (AC), (b) CO₂ insufflation (INS), and (c) laparotomy (OPEN). The AC mice underwent no procedure. The INS group underwent CO₂ pneumoperitoneum at 4–6 mmHg for 20 min. The OPEN group had a midline incision from xiphoid to pubis. The serum of seven mice from each group were collected on postoperative days (POD) 1, 2, 4, and 7 via a cardiac puncture. The sera at each time point for each group were pooled. Twenty thousand C-26 colon cancer cells were incubated separately in growth media containing 10% mouse serum from each group (seven determinations/group) at each time point. In the second experiment, female Balb/C (n= 30) mice were divided into AC and OPEN groups. On POD4, sera were collected and pooled. Three separate studies were performed for the second experiment. In the first study, tumor cells were incubated with 10% AC sera or varying concentrations of OPEN mice sera (4–10%). In the second study, aliquots of sera from the OPEN group mice were then heated at 100°C for 1 or 5 min. Tumors were then incubated separately in media with 10% AC, OPEN, or heated OPEN group sera. In the third study, aliquots of sera from the OPEN group mice were dialyzed against PBS through a 3.5-kD or an 8-kD dialysis membrane tubing for 24 h. Tumors were then incubated separately in media with 10% AC, OPEN, or dialyzed OPEN group sera. For both experiments, tumor proliferation was determined and compared between groups after 72 h of incubation. Results: Tumor cells incubated with POD2 and POD4 sera from OPEN group mice proliferated twice as fast as those incubated with sera from either AC or INS group mice. The difference in proliferation was maximal on POD4 and started to decline by POD7. Proliferative activity from the OPEN group sera decreased significantly when heated for 1 min and was completely ablated after 5 min of heating. Proliferative activity from the OPEN group sera was completely ablated after dialysis. Conclusions: We conclude that there is a serum-soluble factor(s) present postoperatively that stimulates tumors to grow significantly faster after laparotomy. The mitogenic effect of laparotomized mice sera is dilutable. It is uncertain whether the factor is heat labile, since heating most likely destroys other necessary proteins in the sera. The size of the factor is undeterminable using the dialysis method. Further efforts to identify these factors are currently underway. Received: 8 February 1999/Accepted: 23 June 1999/Online publication: 24 March 2000     

American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptor-positive breast cancer: status report 2002.

OBJECTIVE: To conduct an evidence-based technology assessment to determine whether the routine use of anastrozole or any of the aromatase inhibitors in the adjuvant breast cancer setting is appropriate for broad-based conventional use in clinical practice. POTENTIAL INTERVENTIONS: Anastrozole, letrozole, and exemestane. OUTCOMES: Outcomes of interest include breast cancer incidence, breast cancer-specific survival, overall survival, and net health benefit. EVIDENCE: A comprehensive, formal literature review was conducted for relevant topics and is detailed in the text. Testimony was collected from invited experts and interested parties. The American Society of Clinical Oncology (ASCO)-prescribed technology assessment procedure was followed. BENEFITS/HARMS: The ASCO panel recognizes that a woman and her physician's decision regarding adjuvant hormonal therapy is complex and will depend on the importance and weight attributed to information regarding both cancer and non-cancer-related risks and benefits. CONCLUSION: The panel was influenced by the compelling, extensive, and long-term data available on tamoxifen. Overall, the panel considers the results of the Arimidex (anastrozole) or Tamoxifen Alone or in Combination (ATAC) trial and the extensive supporting data to be very promising but insufficient to change the standard practice at this time (May 2002). A 5-year course of adjuvant tamoxifen remains the standard therapy for women with hormone receptor-positive breast cancer. The panel recommends that physicians discuss the available information with patients, and, in making a decision, acknowledge that treatment approaches can change over time. Individual health care providers and their patients will need to come to their own conclusions, with careful consideration of all of the available data. (Specific questions addressed by the panel are summarized in Appendix 3.) VALIDATION: The conclusions of the panel were endorsed by the ASCO Health Services Research Committee and the ASCO Board of Directors.     

Working memory impairments in alcohol-dependent participants without clinical amnesia

BACKGROUND: The delayed alternation (DA) task is highly sensitive to the deficits of nonhuman animals with alcohol-related brain damage. DA is thought to measure working memory which serves as a temporary store for processing of information. However, performance on this type of task has only been investigated in alcohol-dependent humans with severe cognitive deficits. The aim of the current study was to explore the validity of DA as a test sensitive to alcohol-related brain damage by manipulating storage and processing components in three versions of the task. It was hypothesized that alcohol-dependent people would perform worse than control participants and that their deficits would be more pronounced in DA versions with maximal working memory demands. METHODS: A sample of 12 alcohol-dependent participants without Wernicke-Korsakoff syndrome was compared with a sample of 12 nonalcohol-dependent controls on three versions of DA. These versions, in order of increasing working memory demand, were single alternation (LR), double alternation (LLRR), and asymmetric alternation (LRRR). DA was administered on a personal computer and performance measured by the number of trials taken to reach criterion. RESULTS: Alcohol-dependent participants, compared with the control participants, took more trials to reach learning criterion on DA on all versions when analyzed together (p = 0.002). Performance on DA was also found to deteriorate with increased working memory demands in both groups of participants (p < 0.001). However, the deficits of alcohol-dependent participants were most pronounced on the DA task with moderate (LLRR) as opposed to extreme (LRRR) working memory demands. CONCLUSIONS: The results indicate that both storage and processing demands are necessary for task performance and demonstrate sensitivity of DA to alcohol-related brain injury.     

Evaluation of S9788 as a potential modulator of drug resistance against human tumour sublines expressing differing resistance mechanisms In Vitro

Significant activity has been identified using S9788, a triazineaminopiperidine derivative, as a new modulator of multidrug resistance against a series of drug-resistant human tumour-cell lines in vitro. Maximal non-cytotoxic concentrations (i.e., those resulting in ≤ 10% cytotoxicity) of S9788 or verapamil were tested in combination with vinblastine, Adriamycin or vincristine and cytotoxicity was evaluated using a clonogenic assay, or the metabolic dye reduction MTT assay, or by monitoring growth inhibition. Under these conditions, the extent of resistance modulation by verapamil and by S9788 was comparable in the various tumour cell lines tested, although a definite concentration-dependent modulation was noted with both compounds. The highest dose-modification factors were noted in the highly vinblastine-resistant classic multi-drug-resistant subline CEM/VLB 100, although resistance reversal was only partial. Resistance modulation by both verapamil and S9788 was noted in 4 drug-selected resistant sublines and 4 “intrinsically” resistant human tumour cell lines, which all exhibited significant P-glycoprotein expression. In contrast, in 2 drug-resistant human tumour sublines (GLC4/ADR and CEM/ VM-I) characterized by altered topoisomerase-II activity and proving to be P-glycoprotein-negative, no resistance modulation relative to parental cells was observed. These data are consistent with the proposal that resistance modulation is mediated by interaction between S9788 and P-glycoprotein and support its clinical evaluation in patients with P-glycoprotein-positive tumours.     

The effects of radiation therapy on quality of life of women with breast carcinoma: results of a randomized trial. Ontario Clinical Oncology Group

BACKGROUND: The purpose of this study was to evaluate the effect of breast irradiation on quality of life, including cosmetic outcome, for patients enrolled in a clinical trial. METHODS: Between 1984 and 1989, a randomized trial was conducted in Ontario, Canada, in which women with lymph node negative breast carcinoma who had undergone lumpectomy and axillary lymph node dissection were randomized to either breast irradiation or no further treatment. A modified version of the Breast Cancer Chemotherapy Questionnaire (BCQ) was administered to women at baseline, 1 month (4 weeks), and 2 months (8 weeks) after randomization. Irritation of the skin of the breast, breast pain, and appearance of the breast to the patient were also assessed every 3 months for the first 2 years of the study. RESULTS: Of 837 patients, 416 were randomly allocated to radiation therapy and 421 to no further treatment. The mean change in quality of life from baseline to 2 months was -0.05 for the radiation group and +0.30 for the control group. The difference between groups was statistically significant (P = 0.0001). Longer term radiation therapy increased the proportion of patients who were troubled by irritation of the skin of the breast and breast pain. Radiation therapy did not increase the proportion of patients at 2 years who were troubled by the appearance of the treated breast; 4.8% in irradiated and nonirradiated patients (P = 0.62). CONCLUSIONS: Breast irradiation therapy had an effect on quality of life during treatment. After treatment, irradiated patients reported increased breast symptoms compared with controls. However, no difference was detected between groups at 2 years in the rates of skin irritation, breast pain, and being upset by the appearance of the breast.     

Concentration and time-dependent inter-relationships for antitumour drug cytotoxicities against tumour cells in vitro

Cryopreserved tumour cells obtained from the ascitic fluid of a patient with an ovarian carcinoma were employed to determine the effect on in vitro drug cytotoxicities of varying both drug concentration and exposure time. Four antitumour drugs, in common clinical usage, were selected for study. Tumour-cell survival following drug treatment was measured by colony-forming ability in the soft-agar developed by Courtenay et al. (1978). Treatment with cis-platinum, adriamycin or vinblastine generated exponential survival curves with increasing cell kill resulting from either increasing drug concentrations or prolonging exposure times. In contrast, no detectable cell kill was elicited by treatment with hydroxyurea for short exposure times of 1 or 6 h, even at concentrations as high as 1 mg/ml, although continuous drug exposure resulted in a steep exponential survival curve. These results, obtained directly from biopsy material, are in close agreement with data from parallel studies employing a continuous human tumour-cell line (COLO 205 derived from a colon carcinoma). Duration of exposure is therefore an important determinant of drug-induced cytotoxicity under these assay conditions. The results with hydroxyurea, however, imply that prolonged incubation times are necessary to evaluate the cytotoxicity of certain agents and so the routinely employed 1 h exposure in most current human tumour drug sensitivity tests is inadequate for such drugs. These data therefore provide evidence that employing a single set of standard conditions of drug exposure to evaluate all antitumour drugs may be inappropriate.     

Bactericidal activity of metronidazole against Bacteroides fragilis

Metronidazole was found to be active against Bacteroides fragilis strains isolated from human lesions. The minimal inhibitory concentrations (MIC) were from 0.16 to 2.5 mug/ml and the minimal bactericidal concentrations (MBC) were from 0.16 to 2.5 mug/ml; usually the MIC and MBC figures were equivalent. These levels are easily attainable in the serum following normal therapeutic doses. The drug is not toxic and side effects are rare and it would therefore seem highly suitable for treating Bacteroides infections and also may be considered prophylactically in certain situations that are described.