Daiva R. Bajorunas

Metabolic consequences of (regional) total pancreatectomy.

Little information has been reported on the metabolic characteristics of the totally pancreatectomized patient or the efficacy of medical management after radical pancreatic surgery. The prospective evaluation of 49 such patients, with 31% followed for 48 or more months, forms the basis of this report. The major immediate postoperative challenge is control of diarrhea and weight stabilization. Chronically patients have an increased daily caloric requirement (mean ± SE, 56 ± 1 kcal/kg), not wholly explained by moderate steatorrhea (fecal fat excretion, 16% ± 2% of unrestricted fat intake). Despite persistent malabsorption, deficiencies in fat-soluble vitamin, magnesium, and trace element serum levels can be prevented in most patients. Pancreatogenic diabetes is characterized by (1) absence of the major glucoregu-latory hormones insulin and glucagon, (2) instability, and (3) frequent hypoglycemia, with the latter parameters improving with rigorous home glucose monitoring. No patient has developed clinically overt diabetic micro- or macrovascular disease. Performance status in long-term survivors has been reasonable. However adverse chronic sequelae of the operation occur and include an unusual frequency of liver disease, characterized by accelerated fatty infiltration, and osteopenia, with an 18% reduction in radial bone mineral content noted in pancreatectomized patients studied more than 5 years after surgery.

Insulin secretion and action in patients with pancreatic cancer

The authors investigated insulin secretory capacity and insulin action in 11 preoperative patients with pancreatic carcinoma and 15 age‐matched and weight‐matched healthy subjects (C). Five patients were classified as diabetic (D), two as impaired glucose tolerant (IGT), and four as nondiabetic (ND). Postabsorptive serum insulin levels (mean ± SE, in uU/ml) in D (12 ± 2), IGT (17 ± 7), and ND (10 ± 2) were comparable. After administration of 100 g of oral glucose, peak insulin achieved in D (60 ± 11) was lower than in IGT (101 ± 26) and ND (83 ± 20), whereas peak insulin levels in IGT and ND were significantly (P < 0.05) higher than in C (45 ± 6). Comparable insulin response to nonglucose stimuli was documented in all subjects using the slow arginine infusion test with mean serum insulin of 27 ± 4 in D, 28 ± 6 in IGT, 34 ± 10 in ND, and 32 ± 5 in C. In six patients (P) and six controls, insulin action was assessed by the euglycemic hyperinsulinemic clamp technique, with glucose turnover rates estimated by [3‐3H]glucose infusion. Steady‐state plasma glucose concentrations were maintained at 92 ± 3 (P) and 91 ± 1 mg/dl (C). After insulin infusion at the rate of 1.0 mU/kg/min, comparable high physiologic insulin levels were observed in P (73 to 104 uU/ml) and in C (81 to 103 uU/ml). Postabsorptive rates of endogenous glucose appearance (Ra) were higher in P (2.86 to 3.02 mg/kg/min) than in C (1.50 to 2.80 mg/kg/min). At high physiologic insulin concentrations, negative Ra values were documented in all subjects, and complete suppression of Ra was assumed. Total body glucose use (M) was consistently lower in P (3.90 to 6.40 mg/kg/min) than in C (6.98 to 10.40 mg/kg/min), consistent with a state of insulin resistance. Patients with pancreatic cancer manifest insulin resistance by virtue of a decrease in total body glucose use (M) and decreased insulin response to glucose due to either inherent beta cell dysfunction or decreased islet cell mass. The latter is not identifiable by histologic morphology.

Endocrine and Exocrine Profiles of Men with Testicular Tumors Before Orchiectomy

In 15 patients with germ cell testicular tumors serum hormone profiles and semen analysis before orchiectomy were evaluated to determine the incidence of defective spermatogenesis associated with testicular tumors. Defective spermatogenesis was noted in 10 patients (66 per cent) on the basis of low sperm concentration, motility or semen volume. Of the 10 patients 7 had sperm concentrations less than 10 million per cc. Endocrine abnormalities occurred in 10 patients, the most common of which were elevations in serum human chorionic gonadotropin and estradiol, and a relative decrease in follicle-stimulating hormone. Three patients who presented with subfertile semen analyses were treated with orchiectomy alone. Repeat semen analyses 4 to 12 months after orchiectomy showed improvement in spermatogenesis and 2 patients achieved a normal semen analysis. Endocrine abnormalities and defective spermatogenesis are common in patients with testicular tumors. These abnormalities precede orchiectomy and imply that a primary germ cell defect exists in these patients.

Bone mineralization in women following successful treatment of Hodgkin's disease

PURPOSE Women with Hodgkins disease in whom a cure has been achieved may be at risk for osteoporosis because of therapy-induced premature menopause. Our objective was to gather information regarding the integrity of bone mass in such long-term cancer survivors. SUBJECTS AND METHODS Bone mineral density was measured using photon absorptiometry in five groups of women: 11 patients with Hodgkins disease and ovarian failure (Group I); six patients with Hodgkins disease and ovarian failure who received estrogen replacement (Group II); 15 patients with Hodgkins disease and normal ovarian function (Group III); 16 premenopausal control subjects (Group IV); and 11 postmenopausal control subjects (Group V). All patients with Hodgkins disease were in remission and had completed treatment more than five years earlier. RESULTS Subjects in Group I were found to have significantly decreased radial (p = 0.0009), lumbar spine (p = 0.002), and femoral neck (p = 0.0001) bone mineral density measurements compared with those in subjects in Group IV; the bone mineral density measurements at all sites of subjects in Group I were no different than those of subjects in Group V. Subjects in Group III had bone density measurements that were similar to those in Group IV, although the radial bone mineral density value was significantly lower (p = 0.0004). Determination of serum gonadotropins and estradiol was consistent with the menstrual status defining the five groups. No secondary causes for decreased bone mineral density values could be detected, since the mean serum levels of parathyroid hormone, calcium, phosphorus, and vitamin D metabolites were similar among the groups, and all prolactin levels were normal. CONCLUSION We have identified a new population of patients with a high risk of osteoporosis, and these results emphasize the importance of treatment-related ovarian failure in the pathogenesis of osteoporosis.

Four cycles of chemotherapy and regional radiation therapy for clinical early-stage and intermediate-stage Hodgkin's disease

To achieve a high percentage of durable complete remissions (CR) and prolonged survivals and reduce toxicity in patients with early‐stage and intermediate‐stage Hodgkins disease, a randomized trial of four cycles of mech‐Iorethamine, vincristine, procarbazine, and prednisone (MOPP) versus four cycles of thiotepa, bleomycin, and vinblastine (TBV) combined with regional radiation therapy (RT) was conducted. For MOPP and RT, the CR percentage was 98% (60 of 61), and at 5 years, the percentage of patients in CR was 90%, with freedom from progression of 89% and overall survival of 91%. For TBV and RT, the CR percentage was 93% (55 of 59), with a 5‐year duration of CR of 83%, freedom from progression of 81%, and overall survival of 91% (P > 0.15). The median follow‐up was 65 months (range, 7 to 96 months). For 27 patients with clinical Stage IIIA, the CR percentage for MOPP and RT was 75% (12 of 16), with 1 relapse and 4 deaths. For TBV and RT, the CR percentage for clinical Stage IIIA was 73% (8 of 11) with 2 relapses and 2 deaths. Short‐term toxicity except for transient leukopenia was less for TBV and RT than for MOPP and RT. Good results are achievable with combined treatment without excessive toxicity. Cancer 1992; 69:1052–1060.

Combined pneumocystis carinii and nocardia asteroides pneumonitis in a patient with an ACTH‐producing carcinoid

Combined Pneumocystis carinii and Nocardia asteroides pneumonia occurred in a patient with an adrenocorticotropin (ACTH)‐producing carcinoid after effective chemotherapy decreased elevated ectopic ACTH and endogenous corticosteroid levels. Implications regarding the pathogenesis of such infections in patients with paraneoplastic tumors are discussed.

Testicular failure in patients with extragonadal germ cell tumors

Eight patients with mediastinal or retroperitoneal germ cell tumors who had undergone testicular biopsy or orchiectomy were retrospectively analyzed for primary testicular abnormalities, subfertility, and abnormal sex hormone levels. Testicular tissue was abnormal in all patients, revealing peritubular fibrosis (six), decreased spermatogenesis (eight), interstitial edema (five), Sertoli cells only (one), and Leydig cell hyperplasia (two). Detailed hormone analysis in five patients revealed elevations of luteinizing hormone in four, decreased serum testosterone in two, elevations of estradiol in two, and elevation of human chorionic gonadotropin in one patient. A history of infertility was documented 2 months to 13 years before presentation in four patients and suspected in another. Extragonadal germ cell tumors, like their testicular counterparts are associated with primary germ cell defects, some of which seem to be independent of gonadotropin production by the tumor. In addition, the rather high incidence of antecedent infertility suggests that either a congenital or acquired primary germ cell defect contributes to defective spermatogenesis and the development of cancer in incompletely migrated germ cells.

Basal Glucagon Replacement in Chronic Glucagon Deficiency Increases Insulin Resistance

To evaluate the role of glucagon in insulin-mediated glucose metabolism, we studied four men and four women, ranging in age from 30–73 yr (mean ± SEM, 54 ± 5) who had undergone complete pancreatic resection for cancer or chronic pancreatitis 16–58 mo previously. The patients had undetectable C-peptide levels and established lack of biologically active 3500 mol wt glucagon. Euglycemic insulin clamp studies were performed with a 40 mU · m−2 · min−1 insulin infusion in the basal, post-absorptive, insulin-withdrawn state, before and during the last 3 h of a 72-h glucagon replacement-dose infusion (1.25 ng · kg−1 · min−1). In four patients, hepatic glucose production was determined by a primed-constant infusion of 3-[3H]glucose. Monocyte insulin-binding studies, pre- and postglucagon, were performed in all patients. The 72-h glucagon infusion, resulting in mean plasma glucagon levels of 124 ± 7 pg/ml, caused a significant rise in the mean plasma glucose level (249 ± 8 versus 170 ± 13 mg/dl preglucagon) and a sixfold increase in mean 24-h glucose excretion. Both with and without glucagon, euglycemic hyperinsulinemia achieved identical and complete suppression of hepatic glucose production. The mean glucose utilization rate (4.70 ± 0.36 mg · kg−1 · min−1 preglucagon) was significantly decreased by glucagon replacement (3.83 ± 0.31 mg · kg−1 · min−1 P < 0.02). Mean glucose clearance was also diminished with glucagon (4.49 ± 0.32 versus 5.73 ± 0.45 ml · kg−1 · min−1 preglucagon, P < 0.02). After glucagon administration, no significant change in the percent specific binding of insulin to monocytes could be demonstrated. These data support a role of physiologic concentrations of glucagon in the modulation of peripheral tissue glucose utilization.

Glucagon Immunoreactivity and Chromatographic Profiles in Pancreatectomized Humans: Paradoxical Response to Oral Glucose

The nature and origin of plasma immunoreactive glucagon (IRG) after pancreatectomy in humans remains controversial. Low plasma IRG levels and heterogeneity hamper accurate assessment. We studied plasma IRG levels and profiles in 12 patients 2–57 mo after a total pancreatectomy (with antrectomy and duodenectomy) for cancer (N = 9) or chronic pancreatitis (N = 3). After oral glucose, plasma IRG (with the COOH-terminal-specific 30K glucagon antibody) rose from 59 ± 7 to a peak of 113 ± 17 pg/ml at 60–120 min. Chromatographie profiles revealed four distinct IRG fractions. In every patient a plasma IRG fraction of 9000–15,000 Mr, detectable basally, increased markedly after oral glucose and accounted for the rise in total IRG observed in plasma. Nine of the 12 pancreatectomized subjects had no detectable 3500-Mr glucagon and the remaining 3 had very low levels. For the group as a whole, 3500-Mr IRG comprised 1–2% of the total recovered IRG. Two patients were also studied before pancreatectomy: sup-pressibility of glucagon (Mr 3500) was evident. After surgery this paradoxical response to oral glucose was demonstrated. Reproducibility of these responses was confirmed in two patients studied twice over 2 yr. Diabetic controls without pancreatectomy did not show this response. The absence or marked reduction of pancreatic glucagon was confirmed in five of the pancreatectomized patients after intravenous arginine or oral protein. Normal basal plasma IRG and profiles, oral glucose sup-pressibility, and arginine stimulation were present in five control patients with unresectable pancreatic malignancies. These findings suggest that in the chronic 3500-Mr IRG deficient state, a glucagon-related peptide arising from the gut is demonstrable by a paradoxical response to oral glucose. It is speculated that this IRG fraction might be a glucagon precursor.