Utility of routine postoperative laboratory studies in patients undergoing potentially curative resection for adenocarcinoma of the colon and rectum.

In an effort to lower healthcare costs, this study was undertaken to evaluate the utility of routine postoperative (PO) laboratory studies and determine whether abnormalities alter patient (PT) care. This was a retrospective review of 105 PTs undergoing elective curative resection for colorectal cancer. A serum electrolyte and liver panel and a hematologic panel were drawn in all PTs. OF 8749 total laboratory values obtained, 5894 (67%) were normal. Two of these (0.03%) elicited a therapeutic intervention. Of the 2004 values that were low (23%), 103 (5.1%) elicited a therapeutic response. Of the 851 that were high (10%), 21 (2.5%) elicited a therapeutic response. Of 2089 preoperative laboratory values, 252 (12%) were abnormal, but in only 15 incidences in 9 PTs was any action taken. Three PTs required potassium supplementation and 6 PTs were transfused packed red blood cells before surgery. In the PO period 2603 laboratory values of 6660 obtained (39%) were abnormal. Of these, 735 (28%) were high and 1868 (72%) were low. Twenty of 735 (27%) high values triggered a therapeutic response that most commonly required administration of insulin for elevated serum glucose in 17 of 197 occasions in five diabetic PTs. On three occasions potassium was removed from intravenous fluids. Five of 275 (1.8%) low calcium values were treated in five patients. Potassium was replaced in 17 of 32 occasions in 14 patients where it was low. In this group of PTs, PO serum potassium, hemoglobin levels, and serum glucose in diabetics were the only values important in making therapeutic decisions. If laboratory studies can be streamlined into only those necessary, substantial savings in health care will be seen without sacrificing quality medical care.

Novel cellular determinants for reversal of multidrug resistance in cells expressing P170-glycoprotein.

The newly synthesized calcium channel blocker, Ro44-5912, significantly potentiates doxorubicin (Dox)-induced cytotoxicity at non-cytotoxic concentrations in Dox-resistant human ovarian cell line, A2780/DX5, overexpressing P170-glycoprotein (Pgp). Induction of DNA single- and double-strand breaks (ssbs and dsbs) was measured using alkaline elution and constant-field gel electrophoresis (CFGE) assays. The results indicate that potentiation of the cytotoxicity of Dox by Ro44-5912 was accompanied by significant increases in both, Dox-induced DNA ssbs and dsbs in the resistant cells. Pulsed-field gel electrophoresis (PFGE) analysis showed that Dox induced DNA fragments in the 50-800 kilobase (kb) and 0.8-5.7 megabase (Mb) ranges. The majority of the newly synthesized DNA fragments were in the 50-800 kb range. Ro44-5912 treatment resulted in significant potentiation of DNA fragmentation in the 50-800 kb range with a minor increase in 0.8-5.7 Mb DNA fragments, suggesting that the modulator functions by potentiating nascent DNA fragmentation in the resistant cells. Exposure to Dox with Ro44-5912 was associated with a prolonged blockage of cells in the S-phase. In contrast, exposure to Dox alone resulted in temporary blockage of cells in G2/M phase (approximately 24 h) followed by restoration of cell proliferation and normal DNA histograms at 48 h after 2 h drug exposure. Incorporation of BrdUrd by flow cytometric analysis was inhibited by Dox in the presence of Ro44-5912, showing that there is a block of DNA replication. An increased damage in newly synthesized DNA could concur with a blocked DNA replication. Moreover, slowing progression through the S-phase in cells exposed to Dox in combination with Ro44-5912 is accompanied by increased sensitivity of Dox poisons, indicating a correlation of specific S-phase perturbation with the reversal of Dox resistance by Ro44-5912 in cells expressing Pgp. The results suggest that drug-induced augmentation of nascent DNA fragmentation and specific cell-cycle perturbation are potentially important molecular determinants for reversal of multidrug resistance in addition to restoration of intracellular drug retention.

Basic science research in postgraduate surgical training: difficulties encountered by clinical scientists.

BACKGROUND: Clinical training of physicians and surgeons involves teaching students and residents both the science and the art of medicine. The science of medicine involves clinical skills honed through reading textbooks and journals and experience in diagnosing and treating myriad diseases. The art of medicine involves the important communication skills necessary for a good doctor-patient relationship. A third aspect of training, basic science research, is frequently de-emphasized or omitted entirely. In general, training programs frequently do not allow protected time in a laboratory setting for the resident. The few weeks to months that some programs allow is insufficient to establish a thorough understanding of scientific method. METHODS, RESULTS: The article describes the introduction of one of the authors from a clinically oriented training background into the laboratory and outlines the pitfalls frequently encountered when a clinician embarks on basic science research training. CONCLUSION: The necessity for sufficient protected time in the laboratory away from clinical responsibilities is recognized.

d,l-buthionine-(S,R)-sulfoximine potentiates in vivo the therapeutic efficacy of doxorubicin against multidrug resistance protein-expressing tumors.

Intracellular glutathione (GSH) has been implicated as a regulatory determinant of multidrug resistance protein (MRP) function. The objective of the present study was to evaluate in vivo the ability of d,l-buthionine-(S,R)-sulfoximine (d,l-BSO), a potent inhibitor of GSH biosynthesis, to reverse MRP-mediated drug resistance to doxorubicin. Athymic nude mice (nu/nu) bearing advanced parental human fibrosarcoma HT1080 and MRP-expressing HT1080/DR4 tumors were treated with the maximum tolerated dose of doxorubicin (10 mg/kg, i. v. push). This therapy produced an overall response rate of 50% (20% complete response and 30% partial response) in mice bearing parental HT1080 xenografts, whereas no significant antitumor activity against HT1080/DR4 tumors was observed. Treatment of mice bearing HT1080 and HT1080/DR4 xenografts with a continuous i.v. infusion of nontoxic doses of d,l-BSO (300 and 600 mg/kg/day) produced a 60% reduction of GSH plasma levels and greater than 95% reduction in GSH tumor levels in both parental and multidrug-resistant tumors; however, this treatment possessed no in vivo antitumor activity by itself. Under these treatment conditions, a combination of d,l-BSO with the maximum tolerated dose of doxorubicin administered at 24 h during a 48-h i.v. infusion of d,l-BSO completely restored the response of MRP-expressing HT1080/DR4 tumors to doxorubicin (overall response rate, 63%; complete response rate, 38%) with no potentiation of host toxicity. The d,l-BSO-induced in vivo reversal of MRP-mediated drug resistance correlated in vitro with the restoration of intracellular doxorubicin retention in cultured HT1080/DR4 cells. Depletion of GSH by d,l-BSO in drug-sensitive HT1080 tumors that do not express MRP did not alter the in vivo response to doxorubicin. Using the same treatment schedule, dose, and administration of doxorubicin with and without d,l-BSO in nude mice bearing P-170 glycoprotein-expressing A2780/Dx5 tumors, no potentiation of the therapeutic index of doxorubicin was found, demonstrating the in vivo selectivity of d, l-BSO-induced GSH depletion on MRP-function. The data reported herein indicate that in vivo function of MRP as a mediator of doxorubicin resistance requires the presence of sufficient GSH pools. d,l-BSO may provide an example of an effective in vivo modulator of MRP-mediated drug resistance.

Total pelvic exenteration with or without sacral resection in patients with recurrent colorectal cancer.

Pelvic recurrence from colorectal cancer produces significant morbidity. Radiation can help palliate the pain produced by this recurrence. Frequently patients with recurrent colorectal cancer will progress to a constant unrelenting pain and obstructive uropathy with sacral and bladder involvement. These patients can be candidates for an aggressive surgical resection with the hope of significant palliation and prolonged survival. From October 1988 to December 1991, six patients had total pelvic exenteration at our institution. Of these six patients, two had en bloc sacral resection at levels S1-S2 and one at S2-S3. Two patients had residual disease at the time of primary surgery, and in the other four patients, recurrence occurred 7 to 48 months after primary resection. One patient died with disease at 7 months, and five patients are alive at 9, 25, 25, 37, and 37 months since the pelvic resection; four have no evidence of disease. The present Karnofsky performance status is 80% or greater in all patients. There were no operative deaths. Of the five living patients, the survival from diagnosis of the primary lesion is 25 to 97 months. Total pelvic exenteration and abdomino-sacral exenteration can produce significant palliation and prolong survival in a selected group of patients with pelvic recurrence from colorectal cancer.

Management of cancer of the opposite breast following breast preservation.

Breast preservation has been shown to be a good alternative to mastectomy in selected patients with breast cancer. The purpose of this study was to evaluate the characteristics of cancer developing in the opposite breast to determine if breast preservation should be attempted in that breast as well. From 1979 to 1988, 172 women underwent tylectomy, axillary dissection and irradiation for carcinoma of the breast. All had follow-up mammogram. Mean age was 55 years. Mean follow-up time was 50 months. Thirteen patients (7.6%) developed cancer in the opposite breast. Three cancers were carcinoma in situ, nine were stage I, and one was stage IIa. Nine of 13 patients had breast preservation therapy, and four had mastectomies. Ten patients are alive with no evidence of disease, two are alive with disease and one died with disease. Breast preservation for bilateral breast cancer is a safe alternative if patients can be followed closely.

Protecting the ischemic spinal cord during aortic clamping. The influence of anesthetics and hypothermia.

Infrarenal circumaortic occlusion devices were operatively placed in 74 New Zealand white rabbits. Two days after operation the animals were randomly assigned to one of seven treatment groups: I, control, n = 23; II, halothane, n = 8; III, thiopental, n = 12; IV, ketamine (30 mg/kg intravenously), n = 6; V, halothane+hypothermia, n = 8; VI, thiopental+hypothermia, n = 12; VII, ketamine+hypothermia, n = 5. In each group, the infrarenal aorta was occluded for 21 minutes. Final neurologic recovery after restitution of blood flow was graded as acute paraplegia, delayed paraplegia (neurologic deficit developing after initial recovery), or normal. Halothane alone was of no benefit. Hypothermia with any anesthetic was completely protective and reduced neurologic deficits to 0% compared with 91% in controls (p less than 0.05). Thiopental and ketamine treatment each reduced acute paraplegia to 17% (as compared with 61% in controls) and increased delayed paraplegia from 30% in controls to 75% and 50%, respectively (p less than 0.05 for thiopental, p = 0.10 for ketamine). The authors interpret the increase in delayed deficits and decrease in acute deficits as being the result of partial spinal cord protection. These findings document that this model of spinal cord ischemia is sufficiently sensitive to identify interventional treatments that protect the ischemic spinal cord.

Gastrointestinal myoelectric and clinical patterns of recovery after laparotomy.

The objective of this study was to define the patterns of myoelectric activity that occur throughout the gastrointestinal tract during normal recovery from laparotomy. Electrodes were placed on the stomach, jejunum, and transverse colon of 44 patients undergoing laparotomy. Basal electric rhythms in all areas showed no changes in frequency after operation (up to 1 month). Gastric spike wave activity showed a gradient of increasing activity from fundus to antrum. Antral spike activity was unchanged during the study. Jejunal spike activity was present in the earliest recordings and occurred in 45.9% +/- 3.5% to 59.9% +/- 5.5% of slow waves. Recovery of normal colon discrete and continuous electric response activity occurred on postoperative day 5.9 +/- 1.5. Bowel sounds returned on day 2.4 +/- 0.5 and passage of flatus and stool occurred on day 5.1 +/- 0.2. The myoelectric parameters measured are not absolutely predictive of uneventful recovery from postoperative ileus but they are, as a group, more informative than any currently available clinical criteria.