Effect of sublethal liver injury on doxorubicin metabolism.

Centrilobular hepatocyte contribution to doxorubicin (DOX) metabolism and myelotoxicity was probed with bromobenzene (BRB), a known centrilobular hepatotoxin. New Zealand White rabbits were given DOX, 3 mg/kg i.v. After 4 weeks, the rabbits were pretreated i. p. with 2.6 ml/kg 40% solution of BRB in corn oil followed 72 h later with a 3-mg/kg dose of DOX. Pharmacokinetics of DOX after BRB pretreatment was mildly changed from control. Significantly increased plasma concentrations of doxorubicinol and its aglycone product, 7-deoxydoxorubicinol aglycone, were detected. Treatment with BRB alone was not lethal; however, in three of seven rabbits, the combination of DOX and BRB was. The mortality appeared to be related to myelosuppression. We conclude that toxin-induced hepato-cellular necrosis causes increased DOX-induced myelotoxicity. Following BRB pretreatment, the relatively small pharmacokinetic changes of parent compound concentrations as compared with greater changes in plasma pharmacokinetics of its alcohol metabolites suggest systemic changes in drug metabolism and distribution in the setting of hepatic disease may be the cause of increased toxicity.

Ingestion of green tea rapidly decreases prostaglandin E2 levels in rectal mucosa in humans.

The objective of this Phase I/II study was to assess the potential for green tea to be used as a colorectal cancer chemopreventive agent. This study measured the dose-related biological effects of administration of a single dose of green tea on the rectal mucosa of normal volunteers. Volunteers were admitted to the Robert Wood Johnson Medical School Clinical Research Center for 24 h. Baseline blood and rectal biopsy samples were obtained before the volunteers drank 0.6, 1.2, or 1.8 g of green tea solids dissolved in warm water. Blood samples were taken 2, 4, 8, and 24 h after the tea administration. Rectal biopsies were obtained at 4, 8, and 24 h. Prostaglandin E2 (PGE2) levels were analyzed by ELISA. Tea polyphenol levels in the blood, urine, and rectal tissue were measured by high-performance liquid chromatography using a Coulochem electrode array detection system. Statistical comparisons were made using ANOVA. Decreased levels of PGE2 in rectal mucosa were observed at 4 and 8 h after consumption of green tea. There was no correlation between inhibition of PGE2 and tissue or plasma levels of tea polyphenols. Ten of 14 subjects demonstrated a response to green tea, as evidenced by at least a 50% inhibition of PGE2 levels at 4 h. We conclude that green tea constituents have biological activity in inhibiting PGE2 synthesis. Given the 71% "response rate," we believe these data support the study of green tea as a colorectal chemopreventive agent in more long-term Phase II trials.

Effects of purified green and black tea polyphenols on cyclooxygenase- and lipoxygenase-dependent metabolism of arachidonic acid in human colon mucosa and colon tumor tissues.

The effects of green and black tea polyphenols on cyclooxygenase (COX)- and lipoxygenase (LOX)-dependent arachidonic acid metabolism in normal human colon mucosa and colon cancers were investigated. At a concentration of 30 microg/mL, (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), and (-)-epicatechin-3-gallate (ECG) from green tea and theaflavins from black tea inhibited LOX-dependent activity by 30-75%. The formation of 5-, 12-, and 15-LOX metabolites was inhibited to a similar extent. Tea polyphenols also inhibited COX-dependent arachidonic acid metabolism in microsomes from normal colon mucosa, with ECG showing the strongest inhibition. The formation of thromboxane (TBX) and 12-hydroxyheptadecatrienoic acid (HHT) was decreased to a greater extent than other metabolites. The inhibitory effects of tea polyphenols on COX activity, however, were less pronounced in tumor microsomes than in normal colon mucosal microsomes. Theaflavins strongly inhibited the formation of TBX and HHT, but increased the production of prostaglandin E(2) (PGE(2)) in tumor microsomes. The enhancing effect of theaflavins on PGE(2) production was related to the COX-2 level in the microsomes. Although theaflavin inhibited ovine COX-2, its activity in the formation of PGE(2) was stimulated by theaflavin when ovine COX-2 was mixed with microsomes, suggesting that theaflavin affects the interaction of COX-2 with other microsomal factors (e.g. PGE synthase). The present results indicate that tea polyphenols can affect arachidonic acid metabolism in human colon mucosa and colon tumors, and this action may alter the risk for colon cancer in humans.

Tenckhoff catheter administration of intraperitoneal fluid and electrolytes for long-term management of intractable ileostomy diarrhea: a case report.

Often, maintenance of fluid and electrolyte homeostasis is the most challenging dilemma posed by short bowel syndrome. This report describes the management of a patient with intractable, dehydrating, salt-wasting diarrhea after small and large bowel resection for Crohn's disease complicated by rectal cancer. Intraperitoneal fluid and electrolyte therapy delivered through a Tenckhoff catheter was used to achieve long-term outpatient stability without chronic intravenous therapy. The concept of intraperitoneal fluid and electrolyte therapy is discussed and its potential role in the treatment of short bowel syndrome is described.

Breast reconstruction in older women.

BACKGROUND: More than 50% of breast cancer care in the United States occurs in women over age 65 years. This study investigates age-related differences in breast reconstruction practices after mastectomy for breast cancer. METHODS: Retrospective review of University of Michigan Breast Care Center patients revealed 242 female patients with breast cancer who underwent postmastectomy breast reconstruction from 1980 through 1991. Data were complied concerning patient age, reconstruction interval (immediate or delayed), type of breast reconstruction performed, reconstruction-associated complications, and the number of postreconstruction procedures required to obtain the final result. Statistical comparisons were made with the chi-squared test. RESULTS: There were 224 patients aged less than 60 years (range 27 to 59 years; median, 44 years) and 18 patients aged 60 years or more (oldest, 68 years). Of the 18 older patients, three underwent delayed transverse rectus abdominus muscle (TRAM) reconstruction; one received a delayed latissimus dorsi flap placed over a silicone gel prosthesis, and 14 underwent 18 reconstructions (4 bilateral) with silicone gel implants (6 immediate, 12 delayed). The younger patients underwent 269 breast reconstructions (45 bilateral), including 92 autogenous tissue reconstructions (34 immediate TRAM, 58 delayed TRAM), 60 immediate and 88 delayed insertions of an expander or prosthesis, and 29 latissimus dorsi flaps with implant reconstructions (3 immediate, 26 delayed). Seven complications (32%) occurred in the 22 breast reconstructions performed in older women, including capsular contracture surrounding an implant (six patients) and a ventral hernia in one patient with a TRAM flap. Complications occurred in 134 breast reconstructions (50%) performed in younger women. All were related to the reconstruction. In the older women a mean of 1.7 +/- 0.7 operations was required to achieve a final reconstruction result versus 2.1 +/- 1.1 in the younger women (not significant). More operations were required in younger women undergoing prosthetic reconstruction than in older women, but this difference was not statistically significant (2.4 +/- 1.2 versus 1.9 +/- 0.7; p = 0.07). Autogenous tissue reconstruction was performed less frequently in older women (14% versus 34%; p < 0.05). No age-related difference was noted in the rate of immediate (versus delayed) reconstruction (27% versus 36%, respectively). Complications occurred more frequently in women who underwent prosthetic breast reconstruction, particularly in younger women (32% in older women and 64% in younger women; p < 0.01). The complication rate for immediate breast reconstruction in older women (all prosthetic) was less than in younger women (17% versus 59%; p < 0.05). For delayed prosthetic reconstructions, complications also occurred less frequently in older than younger women (38% versus 67%; p < 0.05). Between 1988 and 1992, 91 older women and 180 younger women underwent mastectomy for breast cancer; only 7% of older women versus 38% of younger women underwent breast reconstruction (p < 0.001). CONCLUSIONS: Breast reconstruction is a safe option for older women requiring mastectomy. The full array of reconstruction options (autogenous tissue or implants, immediate or delayed) should be considered for use in women of all ages.

Treatment of proximal biliary tract carcinoma: an overview of techniques and results.

Proximal biliary tract cancer carries a dismal prognosis. Few patients have a curative option. However, worthwhile palliation can be achieved in many patients by relieving obstructive jaundice. An overview is presented to place in perspective the treatment methods described and the results obtained.

Parathyroid carcinoma: the relationship of nuclear DNA content to clinical outcome.

This article reports the use of flow cytometry to determine tumor nuclear DNA content and its correlations with clinical outcome in a series of patients with parathyroid carcinoma. Information concerning nine patients with parathyroid cancer (aged 25 to 88 years) was reviewed. Paraffin-embedded, formalin-fixed archival tissue was used to determine tumor DNA content flow cytometrically. Twenty-five operative procedures were performed in nine patients, including 11 parathyroidectomies, two wide local excisions, six central neck dissections, and four median sternotomies for resection of metastases. With flow cytometry used to determine a tumor DNA index, five patients had evidence of tumor aneuploidy; in two patients two aneuploid peaks were evident. The DNA index ranged from 0.7 (hypodiploid) to 1.92 (mean, 1.31). Follow-up ranged from 1 to 18 years. Four patients died. Five were alive 1 to 13 years after diagnosis of parathyroid disease. Four of the five patients with evidence of tumor aneuploidy had metastatic disease and died, and the fifth has had three local recurrences. The four patients with diploid tumors were alive and free of disease 1, 3, 4, and 8 years after the initial operation. It is concluded that in patients with clinically or pathologically demonstrated parathyroid cancer, flow cytometry may help differentiate those whose cancers are likely to behave indolently (diploid tumors) from those with tumors (aneuploid) more likely to behave aggressively by recurring locally or metastasizing.

Technique to facilitate open placement of permanent pacing leads through the cephalic vein.

A technique is described that can facilitate open placement of permanent pacing leads through a difficult or suboptimal cephalic vein using the popular guidewire and peel-apart introducer kits.

Augmentation of hepatic doxorubicin extraction with extracorporeal filtration avoids the dose-dependent, nonlinear increase in AUC observed with systemic administration.

PURPOSE: Regional therapy of primary or metastatic liver cancer with low hepatic extraction ratio drugs such as doxorubicin is constrained by development of systemic toxicity. To examine the effect of augmentation of hepatic drug extraction, a swine model of hepatic artery infusion (HAI) with minimally invasive hepatic venous isolation and hepatic venous drug extraction (HVDE) was developed to study the comparative pharmacokinetic profiles of regional and systemically administered doxorubicin. METHODS: Doxorubicin 0.5-9 mg/kg was administered to 31 pigs over 90 min either by HAI with simultaneous HVDE or by standard systemic vein infusion. Systemic artery and hepatic vein plasma samples were collected periodically (0 to 240 min) for determination of doxorubicin concentrations by high-performance liquid chromatography. Pharmacokinetic profiles were modeled with PCNONLIN 4.2. RESULTS: Concentration-time data were best described in all pigs by a two-compartment open model of elimination. Independent of the route of administration, AUC and Cmax values increased with dose. Mean systemic AUC and Cmax values were consistently lower with regional administration, with statistically significant decreases at the 0.5 and 3 mg/kg doses, whereas there was no relationship between hepatic vein parameters and route of administration. There was a linear relationship between mean systemic AUC values and dose in pigs receiving doxorubicin via HAI with HVDE, whereas mean systemic AUC values increased exponentially at doses of 5 mg/kg or above with systemic vein administration. CONCLUSIONS: Administration of doxorubicin by HAI with simultaneous HVDE significantly decreases systemic exposure in comparison with standard systemic vein drug infusion, and may protect against nonlinear increases in exposure at higher doses.

Immediate transverse rectus abdominis musculocutaneous flap reconstruction after mastectomy.

BACKGROUND: This study examines the early and long-term outcomes of immediate transverse rectus abdominis musculocutaneous (TRAM) reconstruction of the breast after mastectomy. STUDY DESIGN: The records of all patients undergoing mastectomy and immediate TRAM breast reconstruction between December 1989 and October 1993 were reviewed retrospectively using hospital and breast care center databases. RESULTS: Fifty-three patients underwent a total of 73 immediate TRAM breast reconstructions. Reconstruction was successfully completed in all patients, using 46 pedicle flaps and 27 free tissue transfers. There were no flap losses or cardiopulmonary complications. Overall, the complication rate was 26 percent (29 percent for pedicle TRAM and 22 percent for free TRAM flaps). The median follow-up period among the 53 patients was 22.6 months (range of three to 48 months). All patients employed preoperatively resumed their occupations postoperatively. CONCLUSIONS: Our experience indicates that immediate TRAM breast reconstruction is a safe and viable option for patients seeking reconstruction at the time of mastectomy.

Pharmacokinetic evaluation of percutaneous hepatic venous isolation for administration of regional chemotherapy.

Hepatic artery infusion (HAI) chemotherapy has been used to treat patients with unresectable liver tumours. We report a preclinical study of the pharmacokinetics of HAI combined with hepatic venous drug extraction (HVDE) for regional administration of doxorubicin. HVDE was aided by a double balloon catheter inserted via femoral vein cutdown into the inferior vena cava to collect all hepatic vein blood. Pigs received doxorubicin 0.5-9.0 mg kg-1 over 90 min via HAI or systemic infusion (SYSI). HVDE was performed for 240 min. SYSI pigs underwent hepatic venous isolation without drug filtration. Doxorubicin levels were assayed using high-pressure liquid chromatography (HPLC). HAI/HVDE reduced systemic exposure to doxorubicin with equivalent hepatic exposure at all doses. Pharmacokinetic enhancement ranged from 7.0 to 22.3 for peak concentration, 8.8-23.2 for the area under the curve and 2.9-4.2 for tissue concentration. HAI/HVDE also prevented the mortality which was observed with SYSI administration of high-dose (5.0 and 9.0 mg kg-1) doxorubicin. We conclude that HAI/HVDE reduces systemic exposure to doxorubicin as compared with SYSI of equivalent doses. Pharmacokinetic enhancement indices suggest that HAI/HVDE may allow equivalent hepatic drug exposure with reduced systemic exposure. This method may be applicable to other drugs and to other anatomic settings in which enhanced regional drug delivery is desirable.

Hepatoma registry of the Western world. Repeat Hepatic Resection Registry.

The western HCC registry comprised data from 322 patients who underwent hepatic resection for HCC over a 50-year period. The majority of patients had lesions > 4 cm and were symptomatic at presentation. Lesions were mostly unicentric. Cirrhosis was not a prevalent problem, unlike the East. In the most recent decade, 1980-1989, we noted a significant decrease in operative mortality from 19% to 10% overall, and 15% to 4% in the noncirrhotic group. We identified four variables that resulted in poorer postresectional outcome: cirrhosis, regional nodal disease, multicentric disease, and tumor-free resectional margin < 1 cm. Although these factors are associated with a poorer outcome after resection, whether they should serve as contraindications to surgery should be determined by individual surgeons, taking into account the patient's overall status, concomitant risk factors, and treatment objectives.

Creation of a specialized nutrition support outcomes research consortium: if not now, when?

BACKGROUND: There is a compelling need to determine the benefits of sophisticated, costly, and potentially hazardous nutrition support interventions. The clinical efficacy and cost effectiveness of specialized nutrition support must be quantitatively defined. Creation of a national outcomes research consortium to study the use of specialized nutrition support can meet these objectives. METHODS: Nutrition support and outcomes research literature were reviewed to develop a model for the application of outcomes research methods to clinical, professional, administrative, and financial problems currently challenging the discipline of nutrition support. RESULTS: A multi-institutional nutrition support outcomes research consortium involving creation of a large, practice-based data base is proposed. Relevant clinical, administrative, methodologic, and implementation issues are discussed. CONCLUSIONS: A multi-institutional nutrition support outcomes research consortium offers the means to collect rigorous data that can be used to improve patient outcomes, improve the cost-effectiveness of nutrition support, establish a firm scientific basis for the discipline of nutrition support, and assist nutrition support clinicians in the cost-cutting climate that currently characterizes health care in the United States. Given the timeliness of these objectives and the human, professional, and financial costs of not achieving them in a timely fashion, it is fair to ask of a nutrition support outcomes research consortium, "If not now, when?"

Home parenteral nutrition for patients with inoperable malignant bowel obstruction.

The use of home parenteral nutrition (HPN) in patients with inoperable malignant bowel obstruction (IMBO) is controversial. The efficacy, safety, and indications for HPN in these patients is uncertain, and its benefit is difficult to demonstrate. The records of 17 patients (9, ovarian cancer; 4, colon cancer; 4, other) with IMBO receiving HPN managed by the Nutrition Support Team (NST) at Yale-New Haven Hospital from 1980 to 1989 were reviewed. Median survival was 53 days and was longest in the two patients with appendiceal carcinomatosis (208 and 159 days), intermediate in patients with colon cancer (median 90 days), and shortest in patients with ovarian cancer (median 39 days). Survival was unrelated to age or sex. All patients died of their underlying disease; 82% of deaths occurred at home. Only one treatment-related complication requiring readmission occurred. Fourteen patients and their families (82%) perceived their therapy as highly beneficial or beneficial. The NST agreed with this assessment in 11 patients but did not share this perception in three patients. These three patients had a short duration of HPN (less than 25 days) or minimal rehabilitation. It is concluded that HPN for patients with IMBO is associated with a low complication rate, may be most beneficial for those patients with gastrointestinal tract primary tumors, and is usually perceived by patients and care providers as beneficial. HPN has palliative benefit and facilitates compassionate home care for carefully selected patients with IMBO.

Theoretic and experimental aspects of regional liver infusion.

Pharmacokinetic theory of hepatic arterial infusion chemotherapy predicts that parameters, such as hepatic blood flow, hepatic drug extraction, and extrahepatic drug clearance, may potentially be manipulated to enhance the selectivity of hepatic artery drug administration. In practice, diminution of hepatic blood flow through the use of degradable starch microspheres or gelatin sponge embolization has been accomplished and has improved drug selectivity. Likewise, augmentation of hepatic drug extraction improves the pharmacokinetic advantages of regional chemotherapy for liver tumors. Development of optimal hepatic infusion chemotherapy approaches can be undertaken rationally and in an expeditious fashion by applying pharmacokinetic principles to create innovative treatment regimens and by testing them in preclinical and phase I investigations.

Immediate, bilateral transverse rectus abdominis musculocutaneous (TRAM) flap reconstruction after mastectomy.

Although breast reconstruction has been shown to provide psychological benefits in mastectomy patients, there is reluctance to perform immediate, bilateral TRAM flap reconstruction because of concerns regarding magnitude of the procedure, length of hospitalization, potential complications, and long-term recovery. Between June, 1990 and March 1992, 15 patients underwent immediate, bilateral TRAM flap reconstruction following bilateral mastectomy at the University of Michigan Hospitals. Diagnoses included lobular carcinoma in situ (nine patients), strong family history of breast cancer (five), or bilateral breast cancer (one). Invasive breast cancer was present in three patients. Three modified radical mastectomies and 27 simple mastectomies were performed. Bilateral pedicle TRAM flap reconstruction was carried out at the same time in all patients (30 flaps total). Marginal loss occurred in one flap (3%). Additional complications included marginal necrosis of the abdominal donor site wound (one), wound infection (two), and abdominal donor site hernia (one). Median hospital stay was 7 days. Median follow-up was 13 months (range 4-25 months). All patients have resumed their accustomed pre-operative activity patterns. These findings demonstrate that immediate, bilateral TRAM flap reconstruction is a safe and effective option for breast reconstruction after mastectomy.

Patient evaluation of care within a multidisciplinary breast care center.

To understand patient perceptions of multidisciplinary medical care, a survey instrument was developed to poll 1,023 consecutive visitors to the University of Michigan Breast Care Center (BCC). Factors influencing patient satisfaction included staff concern for patients, one-stop shopping, medical thoroughness, and length of waiting in the reception area (negative correlation). These factors are well addressed by a multidisciplinary approach to medical care. Similar models of multidisciplinary care can probably be implemented at other institutions and in other clinical settings.