Increased hepatic cholesterol synthesis in normal rats by cross-circulation with ileal bypassed partners.

Aortic cross-circulation between Holtzman rat littermates was employed to investigate the possible role of a blood-borne factor from the small intestine in the regulation of hepatic cholesterol synthesis. Experimental pairs, consisting of a normal rat and a distal 50% small bowel excluded partner, demonstrated significantly increased combined hepatic cholesterol synthesis when compared to control pairs, consisting of two normal rats, both at 3 and 5 days following parabiosis. This difference was accounted for by increased hepatic cholesterol synthesis in the normal rat in each experimental pair. Neither weight loss nor differences in dietary intake contributed to this effect. Whole blood cholesterol in the common circulation of both experimental and control pairs was lowered; while hepatic cholesterol content was transiently increased, at 3 but not 5 days following parabiosis. Thus, the intestinal bypassed rat stimulates, or releases inhibition of, hepatic cholesterol synthesis in a non-bypassed parabiotic partner. The mechanism for this phenomenon has yet to be defined.

Serial pulmonary function in systemic sclerosis.

The natural history of the pulmonary involvement in systemic sclerosis is not well studied. Reported here are the serial measurements of pulmonary function in a well defined population of patients with systemic sclerosis followed over a mean of 63 months. The mean rate of loss of vital capacity (0.10 liters per year) for the 38 patients serially studied was more than three times the expected rate of loss for a normal population. The mean rate of loss of diffusing capacity (0.33 ml/min/mm Hg per year) for the 27 patients serially studied was similar to that for a normal population. The percent forced vital capacity expired in the first second increased 0.53 percent per year consistent with a progressive restrictive ventilatory defect. Smokers tended to lose vital capacity at a slightly greater rate than nonsmokers (p = 0.069). Individual variability in the course of pulmonary function was observed. Although the overall trend in our population was towards a slowly progressive restrictive ventilatory defect, pulmonary function in the nonsmokers did not change at rates different from those in a nonsmoking reference population.

Long-term, continuous intravenous heparin administration by an implantable infusion pump in ambulatory patients with recurrent venous thrombosis.

We studied the effect of long-term intravenous heparin infusion, delivered by a self-recycling, totally implantable infusion pump developed in our laboratory, in 21 patients with recurrent thromboembolic disease. Continuous infusions were maintained in these patients from 1 to 36 months, during which pumps were refilled by percutaneous needle injection at 4- to 8-week intervals. We maintained plasma heparin levels between 0.1 and 0.3 U/ml plasma. This regimen prevented thromboembolic phenomena in all except one patient, who apparently is refractory to heparin as well as oral anticoagulant drug therapy. Marked reduction of pain and improvement of mobility were reported by several patients with vena cava ligature syndrome. No spontaneous hemorrhagic complications occurred; however, several episodes of pump site hemorrhage were associated with pump refills. Bone mineral densities measured in eight subjects after 1 year of heparin infusion [1.00 +/- 0.06 (SE) gm/cm] were not significantly (P = 0.5) different from baseline values (0.98 +/- 0.08 gm/cm); however, osteoporosis did occur in one subject. Serum calcium, phosphorus, alkaline phosphatase, cholesterol, and triglycerides also remained unchanged in these subjects. These data suggest that continuous long-term heparin infusion is a viable therapeutic alternative in subjects with refractory thromboembolic disease.

Comparisons between jejunoileal and gastric bypass operations for morbid obesity.

At the University of Minnesota, under the supervision of one staff surgeon, both the jejunoileal bypass (JIB) and gastric bypass (GIB) operations have been done for weight reduction in morbidly obese individuals. Over the past 11 years, end-to-end (40 to 4 cm) JIB performed for 727 patients. In addition, antecolic GIB was performed for 364 patients over the past 6 years. This report is based primarily on a comparison of 205 JIB and 106 GIB patients with surgery between July 1975 and July 1979. Adequate weight loss was seen in 75% of each group. The percentage of excess body weight loss was similar for the first year (65% for JIB and 62% for GIB); however, the JIB patients started at 214% of ideal weight and GIB patients at 197% of ideal weight. The operative mortality rate for either operation was well below 1%, and the immediate operative morbidity rate was low and only rarely delayed discharge from the hospital. The long-term complications for JIB were 37.7% arthralgia or arthritis, 7.1% oxalate urolithiasis, 5.6 incisional hernia, and 1.4% liver failure; complications of GIB were 10.2% nausea and/or vomiting, 1.9% reflux esophagitis, and 2.8% anastomotic problems. At 1 year, plasma cholesterol reductions for JIB patients averaged 42% (P less than 0.001), whereas for the GIB patients it ws only 14% (P less than 0.001). At 1 year after operation, 49% of 88 JIB patients showed progression of liver disease on sequential biopsies, with 31% unchanged and 20% improved. In 43 GIB patients, the biopsies showed improvement in 58%, an unchanged status in 30%, and worsening in 12%. The levels of serum glutamic oxaloacetic transaminase and alkaline phosphatase increased after JIB and eventually returned to normal, while GIB patients had only minor fluctuations of liver function tests. Comparable therapeutic weight results occurred with JIB and GIB; however, the GIB was associated with far fewer serious long-term complications and the JIB with a far greater cholesterol lowering. A percentage of the GIB patients showed progression of liver disease at 1 year after bypass.

Benign hepatocellular tumors.

PIP: Rare cases of benign hepatocellular (liver) tumors usually occur among women of childbearing age. Since 1973, 102 cases of this tumor had been observed among women on oral contraceptives (90% had positive steroid intake history). to investigate the possible association between oral contraceptives (OCs) and benign liver tumor, the University of Minnesota Hospitals analyzed 40 cases of benign hepatocellular from 1950 to 1976. Clinical and pathological records of patients with the tumor (with the exception of hemangiomas) were reviewed and reclassified according to Edmonson's nomenclature. Of the 40 cases, 18 were reclassified as focal nodular hyperplasia (FNH_, 10 as hepatocellular adenomas (HCS), 11 as bile duct adenomas (BDA), and one as mesenchmal hamartoma. These data, as well as information on steroid intake were detailed on Tables 2, 3 and 4. For FNH, the female:male ratio was 8:1, mean age was 43 years + or - (SD), and 8 patients had history of OCs or other steroid intake. For HCA, the female:male ratio was 4:1, with mean age of 33 years + or - 15 (SD); 3 patients had a positive history of OC intake. For BDA, the female:male ratio was 7:4, mean age was 57 years + or - 15 (SD). No definite, conclusive association was established between oral contraceptives and other steroids and incidence of these tumors. The tumors occurred in men, prepubertal children and women on contraceptives or not; they also occured even before the introduction of OCs in the United States in 1961. However, the conclusion does not rule out the possible contributing influence of OCs and other steroids on the development of these tumors.^ieng

Retarding Novikoff tumor growth by altering host rat cholesterol metabolism.

Tumor cells, in vitro, must derive the majority of their required cholesterol from their host milieu. To determine if limiting tumor-available cholesterol results in limited tumor growth in vivo, Holtzman rats were given 10 X 10(6) Novikoff ascites tumor cells subcutaneously. Prior to inoculation, animals received either distal small bowel exclusion or sham operation plus either standard chow or estrone-containing chow (0.0025% or 0.01%) diets. In three separate experiments it was shown that (1) tumor weight was positively correlated with whole plasma cholesterol levels (r = 0.495; P less than 0.05); (2) the lowest tumor weights were correlated with the lowest plasma cholesterol; (3) low density and very low density lipoprotein cholesterol levels were both individually and in combination positively correlated with tumor weight (R2 = 0.828; P less than 0.01); and (4) survival of subcutaneous tumor inoculated animals was significantly greater in those animals shown to have the lowest plasma cholesterol, 27 +/- 1 days versus 29 +/- 1 days; (P less than 0.05). These data support the concept that limiting tumor-available cholesterol by altering host cholesterol metabolism will limit tumor growth.

Apolipoprotein B synthesis in humans: liver synthesizes only apolipoprotein B-100.

Apolipoprotein (apo) B-100 and B-48 are prominent apolipoproteins in VLDL, IDL, and chylomicrons. Organ cultures of normal adult human liver were established to ascertain the form of apo B synthesized by hepatocytes in humans. Human liver was minced and incubated in 15 mL methionine-free RPMI-1640 medium with 10% dialyzed fetal calf serum plus 250 microCi 35S-methionine for eight hours at 37 degrees C. Lipoproteins secreted by the liver were isolated by ultracentrifugation and the content of newly synthesized apo B determined by quantitation of radioactivity in the apoB-100 and apoB-48 bands after separation by 3% NaDodSO4 gel electrophoresis. In the eight-hour period, 2.5% to 3.2% of added 35S-methionine was secreted in TCA-precipitable protein of which 0.34% was apo B. Ninety-nine percent of the apo B in VLDL, IDL, and LDL was in the apo B-100 electrophoretic band. No significant radioactivity was detected in the apo B-48 electrophoretic band. Eighty-nine percent of the total radioactivity of apo B-100 was in VLDL with 3% and 8% in IDL and LDL, respectively. These results establish that adult human liver in organ culture synthesizes apo B-100 but not apo B-48.

In vitro killing of melanoma by liposome-delivered intracellular irradiation.

To better understand and optimize the mechanism of alpha particle killing of tumors, an in vitro model utilizing liposomes as carrier vehicles was developed to study the killing of melanoma via intracellular alpha-irradiation. The radionuclide 212Pb (lead), with its 10.6-hour half-life and alpha-emitting daughter 212Bi (bismuth), was encapsulated in liposomes to achieve the intracellular irradiation of melanoma cells in culture. In dose-response experiments, B16F10 mouse melanoma cells were incubated with liposomes 212Pb/212Bi bound to dextran 70. Plating efficiency and growth of the melanoma cells cultured on gridded petri dishes after incubation were compared with controls at 24 and 48 hours. Greater than 85% cell killing occurred by 48 hours, with administered radioactivity levels of 1.6 dpm/mumol of lipid/cell, which corresponds to intracellular delivery of five to seven alpha particles per cell. These alpha doses can be exceeded in vivo with recirculation or in a perfusion circuit, and more efficient cytotoxic action may be possible.

Composite tissue transfer in limb-salvage surgery.

After extensive resection due to extremity sarcoma, the inability to cover the defect for satisfactory healing and limb function has been an indication for amputation rather than limb salvage. We report herein our experience with seven limb-salvage cases in which we closed difficult and complex defects with composite tissue transfers utilizing microvascular techniques. Free-flap transfers were used to cover soft-tissue defects after extensive resection of primary and locally recurrent tumor and to manage radiation-induced complications. The grafts healed well when infected irradiated tissue was covered, and the grafts tolerated postoperative irradiation. Composite tissue transfer also provided soft-tissue coverage around distal joints that would not have been adequately protected with a skin graft. Complications were minimal, and all patients maintained good extremity function. No patient who underwent composite tissue transfer has had a local recurrence. A free-flap composite tissue transfer can extend the indications for limb-salvage surgery and offers an alternative to amputation in selected patients.

Resident experience and opinions about physician-assisted death for cancer patients.

HYPOTHESIS: Surgical residents and staff oncologists (surgical, medical, and radiation therapy) have similar opinions on participation in physician-assisted death for patients with terminal cancer. DESIGN: Prospective survey. SETTING: Tertiary care referral center. PARTICIPANTS: Residents undergoing surgical training (n = 56) and faculty oncologists (n = 24) of all specialties (surgical, medical, and radiation therapy). MAIN OUTCOME MEASURES: Subjects were queried regarding previous experience and willingness to participate (either directly or indirectly) in assisted death for terminal cancer patients. RESULTS: Response rates were 39% (22 of 56) for the residents and 87% (21 of 24) for the oncologists. Of those who responded, 86% (19 of 22) of the residents would aid any of the hypothetical patients with assisted death, whereas only 19% (4 of 21) of the staff oncologists expressed willingness to perform the same service. Furthermore, 32% (7 of 22) of the residents reported previous involvement in a case of assisted death from any disease, whereas only 19% (4 of 21) of the staff oncologists reported previous direct experience with assisted death in the terminal cancer patient. CONCLUSIONS: Surgical residents tend to have more experience with assisted death and are much more willing than staff oncologists to aid terminal cancer patients with this procedure. These opinions and practices are probably not the result of medical education but are developed from personal values.

Cost-benefit analysis of biopsy methods for suspicious mammographic lesions; discussion 994-5.

HYPOTHESIS: Stereotactic core biopsy (SCB) is more cost-effective than needle-localized biopsy (NLB) for evaluation and treatment of mammographic lesions. DESIGN: A computer-generated mathematical model was developed based on clinical outcome modeling to estimate costs accrued during evaluation and treatment of suspicious mammographic lesions. Total costs were determined for evaluation and subsequent treatment of cancer when either SCB or NLB was used as the initial biopsy method. Cost was estimated by the cumulative work relative value units accrued. The risk of malignancy based on the Breast Imaging Reporting Data System (BIRADS) score and mammographic suspicion of ductal carcinoma in situ were varied to simulate common clinical scenarios. MAIN OUTCOME MEASURES: Total cost accumulated during evaluation and subsequent surgical therapy (if required). RESULTS: Evaluation of BIRADS 5 lesions (highly suggestive, risk of malignancy = 90%) resulted in equivalent relative value units for both techniques (SCB, 15.54; NLB, 15.47). Evaluation of lesions highly suspicious for ductal carcinoma in situ yielded similar total treatment relative value units (SCB, 11.49; NLB, 10.17). Only for evaluation of BIRADS 4 lesions (suspicious abnormality, risk of malignancy = 34%) was SCB more cost-effective than NLB (SCB, 7.65 vs. NLB, 15.66). CONCLUSIONS: No difference in cost-benefit was found when lesions highly suggestive of malignancy (BIRADS 5) or those suspicious for ductal carcinoma in situ were evaluated initially with SCB vs. NLB, thereby disproving the hypothesis. Only for intermediate-risk lesions (BIRADS 4) did initial evaluation with SCB yield a greater cost savings than with NLB.

Comparison of minimally invasive esophagectomy with transthoracic and transhiatal esophagectomy.

HYPOTHESIS: Minimally invasive esophagectomy can be performed as safely as conventional esophagectomy and has distinct perioperative outcome advantages. DESIGN: A retrospective comparison of 3 methods of esophagectomy: minimally invasive, transthoracic, and blunt transhiatal. SETTING: University medical center. PATIENTS: Eighteen consecutive patients underwent combined thoracoscopic and laparoscopic esophagectomy from October 9, 1998, through January 19, 2000. These patients were compared with 16 patients who underwent transthoracic esophagectomy and 20 patients who underwent blunt transhiatal esophagectomy from June 1, 1993, through August 5, 1998. MAIN OUTCOME MEASURES: Operative time, amount of blood loss, number of operative transfusions, length of intensive care and hospital stays, complications, and mortality. RESULTS: Patients who had minimally invasive esophagectomy had shorter operative times, less blood loss, fewer transfusions, and shortened intensive care unit and hospital courses than patients who underwent transthoracic or blunt transhiatal esophagectomy. There was no significant difference in the incidence of anastomotic leak or respiratory complications among the 3 groups. CONCLUSION: Minimally invasive esophagectomy is safe and provides clinical advantages compared with transthoracic and blunt transhiatal esophagectomy.

Intraoperative autotransfusion in hepatic resection for malignancy. Is it safe?

To evaluate whether intraoperative autologous transfusion increases the risk of hematogenous dissemination of tumor we reviewed the risk of lung metastasis as well as disease-free and long-term survival of patients who underwent resection of malignant hepatic neoplasms with this technique. A retrospective review of patients undergoing liver resection for malignant disease revealed 39 patients in whom intraoperative autologous transfusion was used. The 2-year actuarial survival in the patients in this series, as calculated with the Kaplan-Meier method, was predicted to be 75%. Two-year actuarial disease-free survival was predicted to be 28%, and the risk of developing lung metastasis at 3 years was estimated to be 40%. The predicted overall survival and risk of recurrence in this series compare favorably with published data for patients in whom intraoperative autologous transfusion was not used.

Clinical immunoscintigraphy of recurrent ovarian cancer with indium 111-labeled B72.3 monoclonal antibody.

OBJECTIVE: To prospectively evaluate the ability for immunoscintigraphy with monoclonal antibody CYT-103 labeled with indium 111 to detect tumor presence in 15 patients with ovarian cancer undergoing second-look surgery. DESIGN: Prospective, open-label, nonrandomized trial. SETTING: Hospital-based nuclear medicine facility and operating room. STUDY PARTICIPANTS: Patients with previous ovarian cancer scheduled for second-look surgery. MAIN OUTCOME MEASURE: Correctness of prediction of immunoscintigraphy for presence or absence of ovarian cancer compared with serum CA 125 titer and computed tomography. RESULTS: Immunoscintigraphy, computed tomography, and serum CA 125 titer had respective sensitivities of 92%, 42%, and 42%; specificities of 67%, 100%, and 100%; accuracies of 87%, 53%, and 53%; and diagnostic values of 59%, 42%, and 42%. The full regional extent of recurrent tumor was correctly detected in 45% of patients by immunoscintigraphy and in none of the patients by computed tomography. Immunoscintigraphy detected miliary tumor in two of four patients and computed tomography, as expected, was unable to detect miliary disease. CONCLUSIONS: Recurrent ovarian cancer often presents as multiple small lesions throughout the abdominal cavity. In this subset of patients, immunoscintigraphy may be particularly well suited for detection of the presence of recurrent tumor.

A simplified technique to resect abnormal bony radiolocalizations using a gamma counter.

A simplified technique for localizing and verifying the correct biopsy site of lesions identified on a bone scan has been utilized. A hand-held gamma counter was used for localization of incision placement, determination of extent of bone to be resected, and verification that appropriate tissue was resected. This technique was used to guide biopsy of bony lesions in five patients and to guide resection of a pubic ramus chondrosarcoma. We conclude that intraoperative use of a gamma counter to guide biopsy of bony lesions minimizes surgery time, increases the confidence of obtaining correct tissue, and makes a frequently frustrating procedure very simple. In addition, the probe may assist with determining adequate margins at definitive resection of tumours which accumulate technetium-99m MDP.

Availability of content information does not improve performance on computerized case simulations.

BACKGROUND: A previous study evaluated repeated, serial administrations of computer-based simulations. The data demonstrated an increase in scores across rotations during the academic year, but no difference between scores in successive years. METHODS: The initial study only indirectly assessed the effect of information sharing on measured performance. To directly assess the effect of information transfer, 8 computer-based case simulations were administered over 2 consecutive years to 220 third-year students at the conclusion of 12 surgical clerkship rotations (6 per year). During the second year of administration information regarding content area, in the form of the case stem or introductory lead-in material, was provided to each rotation of students prior to the examination based on a sequential algorithm. RESULTS: The data demonstrate no increase in overall mean score for the examination over the 2 years. Scores were significantly different for 2 of the 8 cases, increasing in the one and decreasing in the other. CONCLUSIONS: The data demonstrate no evidence that prior knowledge of content area influences the scores of successive classes on computerized models of performance assessment.

Repeated use of computerized case simulations in a test format does not present a security risk.

BACKGROUND: Computer-based examination formats permit evaluation of patient care strategies in a realistic context. Because such examinations are complex and difficult to develop, the same case simulations must often be used on multiple occasions. METHODS: To determine if repeated, serial administration of computerized case simulations influences performance, 8 simulations were administered over 2 consecutive years to 252 third-year medical students at the conclusion of 16 surgical clerkship rotations (8 per year). One-way analyses of variance were used to compare scores across rotations during the year and to compare scores between 2 consecutive academic years. Scheffe pairwise comparisons were used to identify trends within each academic year. RESULTS: The data demonstrate an increase in scores across rotations during the year. There is, however, no difference between scores in successive years. CONCLUSIONS: The data are consistent with an increase in knowledge during the course of the year, without evidence that test information transfer influences the performance of successive classes.

Liver resection and laser hyperthermia.

Table 2 provides a comparison of these interstitial and in situ techniques, assessing several criteria and utilizing and expanding on an excellent review by Masters et al. The rapid advance of technology and cross-fertilization between groups using different interstitial techniques will lead to a clear understanding of the benefits and limits of each. However, there is essentially no information at the present time to suggest that these techniques should be used in lieu of hepatic resection in an attempt to cure patients who are good operative risks. There are insufficient data of a controlled nature to determine that there has been a survival or palliative benefit in many of the patients so treated. Nevertheless, as it is clear that these treatments cause tissue destruction in an appropriate nonmorbid way and that they are well tolerated with low risk to the patients, it is entirely conceivable that interstitial techniques will replace hepatic resection in some instances in the future, particularly for lesions smaller than 3 cm.

The dynamics of folic acid metabolism in an adult given a small tracer dose of 14C-folic acid.

Folate is an essential nutrient that is involved in many metabolic pathways, including amino acid interconversions and nucleotide (DNA) synthesis. In genetically susceptible individuals and populations, dysfunction of folate metabolism is associated with severe illness. Despite the importance of folate, major gaps exist in our quantitative understanding of folate metabolism in humans. The gaps exist because folate metabolism is complex, a suitable animal model that mimics human folate metabolism has not been identified, and suitable experimental protocols for in vivo studies in humans are not developed. In general, previous studies of folate metabolism have used large doses of high specific activity tritium and 14C-labeled folates in clinical patients. While stable isotopes such as deuterium and 13C-labeled folate are viewed as ethical alternatives to radiolabeled folates for studying metabolism, the lack of sensitive mass spectrometry methods to quantify them has impeded advancement of the field using this approach. In this chapter, we describe a new approach that uses a major analytical breakthrough, Accelerator Mass Spectrometry (AMS). Because AMS can detect attomole concentrations of 14C, small radioactive dosages (nCi) can be safely administered to humans and traced over long periods of time. The needed dosages are sufficiently small that the total radiation exposure is only a fraction of the natural annual background radiation of Americans, and the generated laboratory waste may legally be classified non-radioactive in many cases. The availability of AMS has permitted the longest (202 d) and most detailed study to date of folate metabolism in a healthy adult human volunteer. Here we demonstrate the feasibility of our approach and illustrate its potential by determining empirical kinetic values of folate metabolism. Our data indicate that the mean sojourn time for folate is in the range of 93 to 120 d. It took > or = 350 d for the absorbed portion of small bolus dose of 14C-folic acid to be eliminated completely from the body.