A role for IL-12 receptor expression and signal transduction in host defense in leprosy.

The generation of cell-mediated immunity against intracellular infection involves the production of IL-12, a critical cytokine required for the development of Th1 responses. The biologic activities of IL-12 are mediated through a specific, high affinity IL-12R composed of an IL-12Rbeta1/IL-12Rbeta2 heterodimer, with the IL-12Rbeta2 chain involved in signaling via Stat4. We investigated IL-12R expression and function in human infectious disease, using the clinical/immunologic spectrum of leprosy as a model. T cells from tuberculoid patients, the resistant form of leprosy, are responsive to IL-12; however, T cells from lepromatous patients, the susceptible form of leprosy, do not respond to IL-12. We found that the IL-12Rbeta2 was more highly expressed in tuberculoid lesions compared with lepromatous lesions. In contrast, IL-12Rbeta1 expression was similar in both tuberculoid and lepromatous lesions. The expression of IL-12Rbeta2 on T cells was up-regulated by Mycobacterium leprae in tuberculoid but not in lepromatous patients. Furthermore, IL-12 induced Stat4 phosphorylation and DNA binding in M. leprae-activated T cells from tuberculoid but not from lepromatous patients. Interestingly, IL-12Rbeta2 in lepromatous patients could be up-regulated by stimulation with M. tuberculosis. These data suggest that Th response to M. leprae determines IL-12Rbeta2 expression and function in host defense in leprosy.

Effects of mastectomy versus lumpectomy on emotional adjustment to breast cancer: a prospective study of the first year postsurgery.

PURPOSE: Procedure (mastectomy v lumpectomy) and choice of procedure were examined as predictors of adjustment to breast cancer in a prospective study of the experiences of the first year after surgery. PATIENTS AND METHODS: Breast cancer patients were interviewed the day before surgery, 10 days after surgery, and at the 3-month, 6-month, and 12-month follow-ups. Patients included 24 women who received mastectomy on strong recommendation, 24 who chose mastectomy for other reasons, and 15 who chose lumpectomy. Subjective well-being was assessed in terms of mood disturbance, perceived quality of life, life satisfaction, marital satisfaction, perceptions of social support, and self-rated adjustment. RESULTS: Surgical groups differed in well-being in only one respect: lumpectomy patients reported a higher-quality sex life at 6 and 12 months postsurgery than mastectomy patients. Choice of surgical procedure predicted higher levels of life satisfaction at 3 months. CONCLUSION: The lack of difference between surgical groups in areas other than sexual adjustment replicates previous findings, but extends them by (1) using a fully prospective design, (2) providing data on the period surrounding the surgery (as well as later periods), and (3) examining a broader range of indices of well-being than usual.

A phase II study of weekly 24-hour infusion with high-dose fluorouracil with leucovorin in colorectal carcinoma.

Twenty-two patients with advanced colorectal carcinoma were enrolled in this study. Ten patients had received prior chemotherapy that included the combination of fluorouracil (5-FU) and leucovorin (LV). All patients required subcutaneous port insertion and portable external infusion pumps to allow outpatient treatment. 5-FU (2,600 mg/m2) was administered concurrently with LV (500 mg/m2) over 24 hours of continuous infusion. The mean steady-state plasma concentration of 5-FU was 10 mumol/L (range, 7 to 14 mumol/L). The 5-FU dose was based on our previous phase I study, in which maximum-tolerated dose (MTD) of 5-FU was determined to be 2,600 mg/m2 in combination with a fixed dose of LV at 500 mg/m2. The treatment was repeated weekly. Twenty-two patients received a total of 560 courses of treatment. Eleven instances of grade 2-3 toxicity were observed: diarrhea (five), stomatitis (three), hand/foot syndrome (three). The overall objective response was 45% (10 of 22) and among previously untreated patients was 58%. Three of the responders achieved complete response (CR), with lung and liver as the metastatic sites. The median duration of survival for the previously untreated patients was not reached at 22 months, and was 10 months for the previously treated patients. These results suggest that short-term infusional therapy of 5-FU and LV in patients with advanced metastatic colorectal cancer generates acceptable toxicity, with equivalent or superior survivability in previously treated and untreated patients versus alternative methods of administration of the two agents.

Nonoperative techniques for tissue diagnosis in the management of thyroid nodules and goiters.

As only 10% of thyroid nodules are malignant, the surgical oncologist is faced with the challenge of selecting for thyroidectomy only those patients likely to benefit therapeutically from surgery. Demonstration of nonfunction on scintigraphic thyroid scan increases the yield of cancer only by 15% to 20%. Aspiration cytology and needle biopsy are potent aids in selecting patients for thyroidectomy. In 1,504 patients for whom a benign or malignant cytological diagnosis was made prior to thyroidectomy, the sensitivity of this technique was 92.0%, specificity was 97.3%, and overall diagnostic accuracy 95.7%. Morbidity is minimal. The reliability of these techniques is dependent on proficient specimen procurement and the cytopathologist's expertise and experience. Differentiation of benign from malignant follicular and lymphocytic lesions is not possible with conventional cytology preparations; 28% of such "indeterminant" lesions prove to be cancer at thyroidectomy. Aspiration cytology is a simple, reliable technique for selection of patients with thyroid nodules for surgery.

Segmental mastectomy without radiotherapy for T1 and small T2 breast carcinomas.

We describe 111 patients with invasive breast cancer treated by segmental mastectomy at the University of Miami (Fla) since 1975. Postoperative adjuvant radiotherapy was recommended as optional rather than mandatory to 64 of these patients based on small (2.5 cm or less) primary tumor size, adequate resection margins, no lymphatic or vascular invasion within the segmental mastectomy specimen, and minimal associated in situ cancer. Fifty-one of these patients elected to forego postoperative adjuvant radiotherapy. At 72 months median follow-up, relapse occurred in the ipsilateral breast in three patients who elected to forego postoperative adjuvant radiotherapy (6% by Kaplan-Meier analysis). Retrospective pathologic review revealed that tumor grade may also be important in determining whether postoperative adjuvant radiotherapy is necessary following segmental mastectomy. These data suggest that postoperative adjuvant radiotherapy may not be required in every patient treated by segmental mastectomy. Further studies to define which patients can be spared the inconvenience, expense, and potential morbidity of postoperative adjuvant radiotherapy are warranted.

Stapled transabdominal lower esophageal anastomosis without purse-string suture.

Because of anatomic limitations at the EG junction in total and subtotal gastric resections, gastrointestinal reconstruction is technically challenging. In stapled anastomosis, suboptimal application of a purse-string suture to the distal esophagus may lead to anastomotic breakdown. We describe herein a technique in which this step is eliminated to achieve a sound, full thickness anastomosis with the use of the Roticulator TA 30 and the EEA Premium stapling instruments.

Signet ring cell sinus histiocytosis. A previously unrecognized histologic condition mimicking metastatic adenocarcinoma in lymph nodes.

The axillary lymph nodes in a radical mastectomy specimen from a 70-year-old insulin-dependent diabetic patient contained significantly vacuolated sinus histiocytes. The histologic picture closely resembled metastatic signet ring cell adenocarcinoma. The signet ring histiocytes did not stain with the mucicarmine or periodic acid-schiff stains or any of the immunohistochemical epithelial markers. The differential diagnosis and the possible origin of these vacuolated histiocytes are discussed.

Exercise-mediated peripheral tissue and whole-body amino acid metabolism during intravenous feeding in normal man.

1. The effect of a daily submaximal exercise regimen on whole-body and peripheral tissue amino acid metabolism during weight-stable intravenous feeding (IVF) was evaluated in 11 normal volunteers. Five of the subjects performed 1 h of daily bicycle exercise at 75 W during IVF, while the remaining six subjects received IVF without daily exercise. Body nitrogen balance, leg and forearm plasma amino acid flux and whole-body kinetics were measured before and on day 10 of IVF using a [1-13C]leucine and [15N]glycine tracer. 2. At the end of the IVF period, exercised subjects demonstrated leg uptake of total amino acids (237 +/- 103 nmol min-1 100 ml-1 of tissue, mean +/- SEM) which was significantly (P less than 0.05) different than in non-exercised subjects (-1101 +/- 253 nmol min-1 100 ml-1 of tissue). 3. In the non-exercised forearm, a significant (P less than 0.05) decrease in total amino acid flux was observed in exercised subjects (-162 +/- 88 nmol min-1 100 ml-1 of tissue) compared with non-exercised subjects (-460 +/- 105 nmol min-1 100 ml-1 of tissue) on day 10 of IVF. 4. Efflux of 3-methylhistidine significantly (P less than 0.05) decreased from the leg in those subjects who performed daily exercise (-0.29 +/- 0.12 nmol min-1 100 ml-1 of tissue) compared with those subjects receiving IVF without daily exercise (-1.46 +/- 0.35 nmol min-1 100 ml-1 of tissue).(ABSTRACT TRUNCATED AT 250 WORDS)

Adjunctive therapy for nutritional support in hospitalized patients.

It would be unrealistic to expect that a single adjuvant modality may be applicable to all patients receiving nutritional support, either IV or enterally. Further characterization of the optimal application of each adjuvant modality may establish the precise role of adjuvant anabolic stimulation throughout the clinical course. Better definition of IV formulas with addition of stable glutamine dipeptides may be of benefit in patients at high risk for sepsis and significant skeletal muscle wasting, while use of met-hGH may improve nitrogen retention and whole-body net protein accrual under these circumstances. Chronic, low- to moderate-intensity exercise may be applicable in a select group of patients, particularly patients at risk for developing complications after surgical intervention in whom aggressive nutritional support has been shown to improve operative outcome.

Management of islet cell carcinoma.

Presentation, treatment, and outcome data were analyzed for 33 patients with islet cell carcinoma who were admitted over a 4 1/2-year period to the surgical service at our institution. The patients were stratified into three groups according to primary mode of therapy as follows: (1) aggressive surgical resection (n = 12); (2) bypass with chemotherapy (n = 13); and (3) diagnostic exploratory laparotomy or bypass without any further therapy (n = 8). Of the patients, 67% were initially seen with advanced disease. Overall, 33% of the tumors were functioning, with a predominance of nonfunctioning tumors in the two groups that were not resectable. Chemotherapy was administered on an individual basis, with symptom palliation as the most common indication. The mean follow-up period was 12.7 +/- 13.1 months (range, 0 to 47.2 months), with an overall estimated 3-year survival rate of 76% calculated by life-table analysis, with 56% alive with disease. The estimated 3-year survival rate was 100% for those who underwent resection, with 83% free of disease. Those patients who had a biopsy or bypass and received chemotherapy had a calculated 3-year survival rate of 34% (p = 0.01 vs. resection), and those who underwent bypass and biopsy only had a 3-year survival rate of 58%. Islet cell carcinoma remains a difficult problem, with primary resection the primary therapeutic modality.

Breast cancer: management of the opposite breast.

Women who have or had cancer in one breast are at especially high risk for developing cancer in the contralateral breast. Other risk factors for second primary breast tumors include age, the use of radiation in treating the index cancer, and pathological characteristics of the original cancer. Management approaches range from close clinical and mammographic surveillance only to immediate prophylactic contralateral mastectomy. Routine and selective biopsy of the opposite breast at the time of treatment of the initial cancer have their proponents. The authors discuss these methods and the effect of a second cancer on overall prognosis.

Effect of total parenteral nutrition on whole body protein kinetics in cachectic patients with benign or malignant disease.

The metabolic effects of total parenteral nutrition on malnourished cancer and noncancer patients were investigated by determining whole-body protein metabolism before and during intravenous nutritional support. The results were compared to similar studies reported in normal subjects. Primed-continuous infusion of 15N glycine was used and the isotopic enrichments in urinary urea and ammonia were measured. The end product average values were used in the calculation of whole body protein turnover. After 10 days of nutritional support in cancer and noncancer patients whole body protein breakdown decreased by 50% (p = 0.01), and 59% (p = 0.001), whereas protein synthesis decreased by 21% (p = 0.005) and 33% (p = 0.025), respectively. Protein turnover did not change in noncancer patients but increased by 15% (p = 0.005) in cancer patients. The efficiency of utilization of the endogenous supply of amino acids from the breakdown of body proteins for synthetic purposes was 77% in this group of subjects. The utilization efficiency of the intravenously infused amino acids for synthesis of body protein was 39% in cancer and noncancer patients but 51% (p less than 0.05) in normals. The data suggest that depleted patients synthesize proteins from intravenous amino acids less well than normals.

The effect of starvation and total parenteral nutrition on skeletal muscle amino acid content and membrane potential difference in normal man.

Skeletal muscle intracellular amino acids and transmembrane potential difference (Em) were measured in hospitalized volunteers during starvation and refeeding with total parenteral nutrition (TPN). Healthy volunteers underwent extremity amino acid flux measurement, percutaneous skeletal muscle biopsy and determination of skeletal muscle Em after ten days of starvation (ST), and after a subsequent ten day period of TPN. ST produced a significant (p less than 0.05) decrease in plasma essential amino acids when compared with normal ambulatory volunteers. Subsequent administration of TPN produced a significant extremity uptake of all essential amino acids except for threonine and uptake of the nonessential amino acids taurine, glutamate, tyrosine and arginine. ST produced a significant reduction in skeletal muscle free intracellular glutamine and a significant increase in isoleucine and leucine. These changes in free intracellular amino acids were not reversed by administration of TPN. At the conclusion of ten days of ST and ten days of TPN, there was a significant reduction (p less than 0.05) in skeletal muscle Em. The results demonstrate that abnormalities of intracellular amino acid concentrations and reduction of muscle Em are not specific to stress conditions, but rather they can be present during both unstressed ST and intravenous nutritional repletion.

Effect of starvation and total parenteral nutrition on electrolyte homeostasis in normal man.

Elemental balances, and skeletal muscle membrane potential (Em) and biopsy were utilized to evaluate electrolyte homeostasis and body composition in 11 healthy adult volunteers after 10 days of starvation. This controlled, acute malnutrition was followed by refeeding for 10 days with two different, commonly used, total parenteral nutrition (TPN) solutions. Six subjects were refed with crystalline amino acids and dextrose (dextrose group), while five subjects received amino acids, dextrose, and lipid (lipid group). During starvation, negative balances for potassium, phosphorous, magnesium, and nitrogen were observed in both groups. When compared to starvation, total parenteral nutrition produced statistically significant (p less than 0.05) equilibrium or positive electrolyte and nitrogen balances for both, the dextrose and lipid groups. During TPN, there was a significantly (p less than 0.001) positive chloride balance in the lipid group when compared to the dextrose group. At the conclusion of the 10-day period of TPN, there was a decrease (p less than 0.05) in skeletal muscle Em. This change, in concert with the electrolyte balance data obtained during parenteral repletion, lead us to postulate that restoration of lean tissue protein and cellular function does not occur at a rate which might be inferred from the positive nitrogen balance observed in this model. A persistent defect in cellular function which was evident after starvation, suggests that a brief period of TPN is insufficient to restore skeletal muscle integrity.

Submaximal exercise during intravenous hyperalimentation of depleted subjects.

The peripheral nitrogen wasting and loss of functional capacity caused by the malnutrition of disease and the immobilization of hospitalization may not be readily reversed by refeeding alone. In order to examine submaximal exercise as an adjunctive anabolic stimulus to intravenous refeeding (IVF) in depleted subjects, 14 volunteers were studied in the postabsorptive (PA) state, after 10 days of total starvation, and again after 10 days of nutritional repletion with I.V. feedings. The subjects were randomized to one group that received IVF alone and one group that performed 1 hour of submaximal (51% of VO2max) stationary bicycle exercise daily during IVF. The exercised group was not significantly different from the nonexercised group in urinary nitrogen balance, resting energy expenditure, extremity amino acid flux, or maximal oxygen consumption. Acute exercise did not induce significant derangements in electrolytes or counter-regulatory hormone concentrations. Ten days of submaximal exercise does not appear to be detrimental in this population recovering from moderate hospitalized malnutrition, but additional anabolic stimulae may be needed for improvements in protein accrual or functional capacity.

Protein and substrate metabolism during starvation and parenteral refeeding.

1. Healthy male volunteers underwent 10 days of hospitalized protein-calorie starvation and a subsequent 10 day repletion phase with complete intravenous nutritional support (IVF). Non-protein calories were provided as either all D-glucose or as 50% D-glucose/50% lipid. 2. In comparison with starvation, whole-body protein breakdown, as assessed by [15N]glycine, [13C]leucine and urinary excretion of 3-methylhistidine (3-MH), was diminished during IVF. The administration of parenteral nutrition did not specifically suppress peripheral tissue protein breakdown, as measured by extremity 3-MH efflux. 3. Despite the differential insulin response to D-glucose/amino acid (50 +/- 6 m-units/ml) as compared with the D-glucose/lipid/amino acid regimen (25 +/- 4 m-units/ml), there was no difference in nitrogen retention between the regimens. Indirect calorimetric determinations revealed that oxidation of substrate during IVF was related to the proportion of D-glucose and lipid infusion.

Whole body lipid and energy metabolism in the cancer patient.

The relationship between whole-body energy and lipid kinetics in eight cancer patients was investigated after an overnight fast. Respiratory gas exchange and indirect calorimetry were used to obtain resting energy expenditure (REE) and net substrate oxidation rates. Free fatty acid (FFA) turnover, oxidation, and clearance rates were obtained after a primed-constant infusion of albumin bound 1-14C-Na palmitate. This was followed by a primed-constant, two-stage infusion of unlabeled glycerol to measure plasma glycerol turnover and clearance. The REE was 1.3 times the predicted (by the Harris-Benedict equation) basal energy expenditure. FFA and glycerol, plasma concentrations, and turnover rates were higher in these depleted but hypermetabolic cancer patients, compared to reported values for healthy normals. The ratio of FFA turnover to glycerol turnover was 3.14 +/- 0.38, which is close to the theoretical value of 3, suggesting complete hydrolysis of triglycerides and the absence of any extensive reesterification of FFA in adipose tissue. The net fat oxidation accounts for 53 +/- 5% of fat mobilized and 29 +/- 3% of the FFA turnover was converted to CO2 in the process of supplying energy in cancer patients. The results suggest that fat is efficiently mobilized and utilized as a fuel source in hypermetabolic cancer patients in the postabsorptive state.

Effect of hormonal and substrate backgrounds on cell membrane function in normal males.

Hormonal and substrate influences on in vivo cellular membrane function were evaluated in 15 healthy male volunteers. Each subject underwent serial evaluations of membrane function in the anterior tibialis muscle, as assessed by transcutaneous measurement of resting membrane potential (Em). Group A subjects (n = 9) underwent measurement of resting Em in the basal state and again during the 10th day of intravenous feeding (IVF). Group B subjects (n = 6) underwent measurement of resting Em in the basal state during epinephrine infusion and again during epinephrine infusion on the 7th day of IVF. Percutaneous needle biopsy of the vastus lateralis muscle permitted calculation of transmembrane electrolyte distribution from the Nernst equation, using the measured Em and the chloride space method. Hospitalization with intake of a defined-formula enteral diet for 3 days resulted in depolarization (P less than 0.05) of resting Em (-75.3 +/- 1.6 mV) compared with normal (-79.8 +/- 0.9 mV). Despite 10 days of subsequent IVF, further depolarization (P less than 0.05) of resting Em (-71.2 +/- 1.2 mV) was observed. In the dual presence of IVF and exogenous epinephrine infusion, there was an increase (P less than 0.05) in intracellular potassium concentration and repolarization of resting Em (-80.6 +/- 0.8 mV) to normal levels. These data indicate that hormonal background and substrate availability contribute to the in vivo modulation of cellular membrane function in human skeletal muscle, possibly through facilitation of sodium-dependent amino acid transport across the cell membrane.

Thermogenic and nitrogen response to submaximal exercise in parenterally repleted normal man.

To determine whole-body energy and nitrogen responses to submaximal exercise during repletion levels of intravenous feeding (IVF), five normal male volunteers were hospitalized and underwent serial changes in nutritional intake consisting of weight-maintaining oral feeding (4 d), starvation (10 d), and weight-increasing parenteral feeding (10 d). Twelve-hour aliquots for urinary nitrogen, creatinine, and 3-methylhistidine were collected during the final 36 h of oral feeding and IVF. During these experimental periods, indirect calorimetry was utilized to determine resting oxygen consumption and that occurring during a 1-h period of submaximal (40% of maximal) upright, bicycle exercise. Despite differences in the route of nutrient delivery, oxygen uptake during a fixed rate of exercise (75 W) was similar during oral (16.7 +/- 0.4 mL X kg-1 X min-1) and IVF (14.7 +/- 1.0 mL X kg-1 X min-1). When compared with basal urinary losses, submaximal exercise resulted in diminished nitrogen (p less than 0.01, oral) and 3-methylhistidine (p less than 0.05, oral; p less than 0.01, IVF) excretion during a 12-h post-exercise recovery period.