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A combination of olanzapine and samidorphan (OLZ/SAM) received US Food and Drug Administration approval in May 2021 for the treatment of adults with schizophrenia or bipolar I disorder. OLZ/SAM provides the efficacy of olanzapine, while mitigating olanzapine-associated weight gain. This exploratory study characterized the metabolic profile of OLZ/SAM in healthy volunteers to gain mechanistic insights. Volunteers received once-daily oral 10 mg/10 mg OLZ/SAM, 10 mg olanzapine, or placebo for 21 days. Assessments included insulin sensitivity during an oral glucose tolerance test (OGTT), hyperinsulinemic-euglycemic clamp, other measures of glucose/lipid metabolism, and adverse event (AE) monitoring. Treatment effects were estimated with analysis of covariance. In total, 60 subjects were randomized (double-blind; placebo, n = 12; olanzapine, n = 24; OLZ/SAM, n = 24). Olanzapine resulted in hyperinsulinemia and reduced insulin sensitivity during an OGTT at day 19, changes not observed with OLZ/SAM or placebo. Insulin sensitivity, measured by hyperinsulinemic-euglycemic clamp, was decreased in all treatment groups relative to baseline, but this effect was greatest with olanzapine and OLZ/SAM. Although postprandial (OGTT) glucose and fasting cholesterol concentrations were similarly increased with olanzapine or OLZ/SAM, other early metabolic effects were distinct, including post-OGTT C-peptide concentrations and aspects of energy metabolism. Forty-nine subjects (81.7%) experienced at least 1 AE, most mild or moderate in severity. OLZ/SAM appeared to mitigate some of olanzapine's unfavorable postprandial metabolic effects (e.g., hyperinsulinemia, elevated C-peptide) in this exploratory study. These findings supplement the body of evidence from completed or ongoing OLZ/SAM clinical trials supporting its role in the treatment of schizophrenia and bipolar I disorder., (© 2021. The Author(s).)

Purpose: Evaluating the effects of cibinetide in diabetic macular edema (DME)., Methods: Phase 2 trial. Naïve patients with >400 µm central retinal thickness (CRT) DME in one/both eyes were recruited (May 2016-April 2017) at the Belfast Health and Social Care Trust. The study eye was that with best vision and lowest CRT. Patients self-administered cibinetide 4 mg/day subcutaneously for 12 weeks. Primary and secondary outcomes: mean change from baseline to week 12 in best corrected visual acuity (BCVA), CRT, central retinal sensitivity, tear production, patient-reported outcomes, adverse events and antibodies to cibinetide. Descriptive statistics were used; exploratory analyses focused on non-study eyes, diabetic control, serum cytokines and albuminuria., Results: Nine patients were recruited; eight completed the study. There was no improvement in mean change baseline-week 12 in BCVA (-2.9 + 5.0), CRT (10 + 94.6 microns), central retinal sensitivity (-0.53 + 1.9 dB) or tear production (-0.13 + 7.7 mm), but there was an improvement in National Eye Institute Visual Function Questionnaire (NEI VFQ-25) composite scores (2.7 + 3.1). Some participants experienced improvements in CRT, tear production, diabetic control and albuminuria. No serious adverse events/reactions or anti-cibinetide antibodies were seen., Conclusions: The cibinetide 12-week course was safe. Improvements in NEI VFQ-25 scores, CRT, tear production, diabetic control and albuminuria, observed in some participants, warrant further investigation., Trial Registration: EudraCT number: 2015-001940-12. ISRCTN16962255-registration date 25.06.15.

Purpose: Sarcoidosis frequently is complicated by small nerve fiber loss (SNFL), which can be quantified using corneal confocal microscopy (CCM). Prior studies suggest that the innate repair receptor agonist cibinetide reverses corneal nerve loss. This phase 2b, 28-day, randomized trial of 64 subjects with sarcoid-associated SNFL and neuropathic pain assessed the effect of cibinetide on corneal nerve fiber area (CNFA) and regenerating intraepidermal fibers (GAP-43+) as surrogate endpoints for disease modification, pain severity, and functional capacity (6-minute walk test [6MWT])., Methods: Cibinetide (1, 4, or 8 mg/day) was compared to placebo. The primary study endpoint was a change in CNFA at 28 days., Results: The placebo-corrected mean change from baseline CNFA (μm2) at day 28 was 109 (95% confidence interval [CI], -429, 647), 697 (159, 1236; P = 0.012), and 431 (-130, 992) in the 1, 4, and 8 mg groups, respectively. Intraepidermal GAP-43+ fibers increased in the 4 mg group (P = 0.035). Further, changes in CNFA correlated with changes in GAP-43+ (ρ = 0.575; P = 0.025) and 6MWT (ρ = 0.645; P = 0.009). Pain improved significantly in all groups, with subjects having moderate-severe pain reporting a clinically meaningful placebo-corrected decrease in pain intensity in the 4 mg group (P = 0.157)., Conclusions: Cibinetide significantly increased small nerve fiber abundance in the cornea and skin, consistent with a disease modifying effect. The relationships between CNFA and other clinical measures of disease support its use as a surrogate endpoint to assess potential disease modifying therapies for neuropathy.

Objective: To determine whether body fat distribution is associated with the onset of breast cancer., Design: Case-control study., Setting: Memorial Sloan-Kettering Cancer Center, New York, New York., Patients: Three hundred thirteen healthy, white women, born in the United States., Measurements: Waist and hip circumferences were measured on the day before diagnostic breast surgery, and an extensive risk assessment of clinical and family history data was done. After the results of diagnostic breast surgery were obtained, study participants were divided into three groups: women with breast cancer (n = 156); controls (n = 126) with benign tissue at biopsy and an average risk for breast cancer; and high-risk women (n = 31), defined as being at a risk for breast cancer development of 1% per year, based on rigorous histologic or clinical criteria., Results: The waist-to-hip ratios (WHR) were identical (mean +/- SD) in case patients (0.80 +/- 0.06), controls (0.80 +/- 0.06), and high-risk women (0.80 +/- 0.08). Further, no trend could be detected between increasing WHR and breast cancer risk; the estimated relative risk for cancer incidence in women with WHR greater than or equal to 0.81 was 0.78 (95% Cl, 0.36 to 1.71), compared with women with WHR of less than 0.73. No difference in WHR was noted between the case patients and controls when analyzed separately according to menopausal status, age, absolute weight, or relative weight., Conclusion: In the women studied, body fat topography as defined by WHR was not associated with breast cancer development.

To achieve a high percentage of durable complete remissions (CR) and prolonged survivals and reduce toxicity in patients with early-stage and intermediate-stage Hodgkin's disease, a randomized trial of four cycles of mechlorethamine, 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 greater than 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.

Hypomagnesemia is a common but frequently overlooked electrolyte disorder that occurs as part of a complex metabolic profile. It often is associated with a spectrum of nonspecific symptoms secondary to other electrolyte deficiencies. These symptoms then are associated with the primary illness, thereby masking the presence of this disorder. In most clinical situations, magnesium deficiency is transitory and responds well to short-term supplementation. Certain populations of patients with cancer may have an increased risk of developing severe hypomagnesemia requiring continued supplementation; patient populations receiving aminoglycoside antibiotics or cisplatin therapy are considered to be high-risk groups. This paper describes the causes, signs, and symptoms of chronic hypomagnesemia; patient populations at risk of developing this disorder; and a unique treatment approach using a subcutaneous pump infusion system. A case study illustrates the complexity of clinical and nursing management of this disorder.

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 glucoregulatory 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.

With the euglycemic clamp technique, we evaluated the effects of graded doses of insulin on glucose turnover rates and forearm lactate balance in five weight-losing patients with cancer before surgery and five age- and weight-matched healthy volunteers (control subjects). Insulin was infused sequentially at increasing rates of 0.5 (low physiologic), 1.0 (high physiologic), and 4.0 (supraphysiologic) mU/kg.min for 120 minutes each. Concurrently, rates of glucose appearance and disappearance were derived from [3-3H] glucose infusion. The mean postabsorptive rate of glucose appearance in patients (2.9 +/- 0.1 mg/kg.min) was significantly higher (p less than 0.02) than that of control subjects (1.98 +/- 0.16 mg/kg.min). Complete suppression of endogenous glucose production occurred at high physiologic insulin concentrations. With progressive insulin infusion, the rate of glucose disappearance increased to 3.6 +/- 1.2, 8.7 +/- 0.8, and 13.7 +/- 1.1 mg/kg/min in control subjects and 2.9 +/- 0.4, 5.3 +/- 0.3, and 10.9 +/- 0.9 mg/kg.min in patients, significantly different from that of control subjects (p less than 0.05) during the intermediate (high physiologic) insulin infusion. A comparable slight increase in arterial plasma lactate concentration was observed in both groups with progressive hyperinsulinemia. Baseline peripheral lactate flux was identical in patients (-272 +/- 56 nmol/100 gm.min) and in controls (-271 +/- 57 nmol/100 gm.min). Progressive physiologic hyperinsulinemia resulted in significantly (p less than 0.05) augmented peripheral lactate efflux in patients (-824 +/- 181 nmol/100 gm.min) compared with control subjects (-287 +/- 64 nmol/100 gm.min). Supraphysiologic insulin abolished this increased lactate efflux in patients. Postabsorptive rates of endogenous glucose appearance in weight-losing patients with cancer were elevated, but complete suppression was achieved with insulin concentrations in the physiologic range. Total body glucose use was diminished in these patients, consistent with a state of insulin resistance. This impaired insulin action on peripheral glucose use was associated with an increase in peripheral lactate release in patients.

Hypercalcemia is a potentially lethal endocrine disorder occurring in 10% to 20% of cancer patients at some time during the course of their disease. Clinical manifestations vary in severity, depending on the degree and duration of hypercalcemia, rapidity of onset, patient's age, performance status, sites of metastases, previous antineoplastic therapy, and the presence of hepatic or renal dysfunction. The clinical features of hypercalcemia are protean and affect multiple organ systems, resulting most prominently in neurologic, gastrointestinal, renal, cardiovascular, and musculoskeletal morbidity. Recognition of the disorder requires a high index of suspicion because many of its symptoms, such as nausea, anorexia, weakness, fatigue, lethargy, and confusion, are non-specific and, in the patient with a malignancy, can result from other complications of the primary disorder. If identified appropriately as being related to hypercalcemia, such symptomatology is potentially reversible with treatment. Whereas in the ambulatory general medical population the most common cause of hypercalcemia is primary hyperparathyroidism, in cancer patients and hospitalized patients in general, the most common cause is malignancy. Hypercalcemia in cancer patients is, in most cases, due to advanced metastasized disease. Diagnostic tests are useful in the differential diagnosis of hypercalcemia, and such tests, together with an accurate history and careful clinical observation, permit the best therapeutic approach to an individual patient.

Purpose: Women with Hodgkin's 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 Hodgkin's disease and ovarian failure (Group I); six patients with Hodgkin's disease and ovarian failure who received estrogen replacement (Group II); 15 patients with Hodgkin's disease and normal ovarian function (Group III); 16 premenopausal control subjects (Group IV); and 11 postmenopausal control subjects (Group V). All patients with Hodgkin's 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.

There is a growing body of literature detailing the endocrine consequences of cancer therapy. Certain conclusions can be drawn from the data presented. Patients who have received incidental hypothalamic--pituitary gland irradiation need to be followed carefully with serial dynamic hormonal evaluations, as they are at high risk of developing growth hormone and prolactin abnormalities and can develop other pituitary tropic hormone deficiencies as well. Children especially should be monitored closely as GH deficiency can be corrected if detected early. Patients who have received radiation to the head and neck region will need long-term (up to 30 years) surveillance for the development of thyroid cancer, hyperparathyroidism or hypothyroidism. Persistent elevations of TSH after incidental thyroidal irradiation are frequently seen and should be reversed with thyroid hormone administration in an attempt to minimize TSH stimulation of the irradiated gland. Radiation to the gonads will cause graded damage dependent on the dose delivered and the mode of fractionation. Age in a woman seems to be a significant factor of radiation sensitivity. Certain chemotherapeutic agents are radiomimetic in their gonadal effects; to date the alkylating agents have been most commonly implicated. FSH elevations herald gonadal damage (aspermia or loss of follicles) and should be looked for in patients receiving abdominal radiation or systemic chemotherapy. Leydig cell dysfunction occurs less frequently. Of all the iatrogenic endocrine complications discussed, some are eminently treatable, and some are quite preventable. Greater awareness of the unexpectedly high incidence of hormonal dysfunction can help lessen therapy-induced morbidity in long-term cancer survivors.

A 50-yr-old man with a large goiter had elevated serum levels of T4 (22 micrograms/dl), T3 (228 ng/dl), and free T4 (6.6 ng/dl), a high 24-h 131I-thyroidal uptake (69%), and an elevated TSH level (3.6 microU/ml), as well as hyperresponsiveness of TSH to TRH (peak TSH, 47 microU/ml). Normal serum alpha-subunit concentrations and sella turcica films mitigated against the presence of a pituitary tumor. A normal basal metabolic rate and minimally elevated concentration of testosterone-estradiol binding globulin were consistent with generalized resistance to thyroid hormone. Mild lactotroph resistance was also present. The patient was given bromocriptine for 16 months (2.5-10 mg daily). Basal serum TSH levels decreased (less than 0.3-2 microU/ml), as did the TSH response to TRH; serum T4 levels (14-17 micrograms/dl); and 24-h 131I-thyroidal uptake (28%) were reduced. Serum T3 levels, however, changed little. The thyroid gland decreased to normal size, and the basal metabolic rate and testosterone-estradiol binding globulin remained normal. Bromocriptine was stopped for 4 months. Serum TSH increased to 4.5 microU/ml; T4 and T3 increased to 27 micrograms/dl and 328 ng/dl; the patient became clinically mildly hyperthyroid. Thus, bromocriptine in this patient was useful in decreasing TSH secretion and decreasing goiter size, while maintaining clinical euthyroidism. Only a small amount of TSH was necessary to maintain iodine uptake and thyroid hormone synthesis and secretion in a responsive thyroid gland. We speculate that this patient may be secreting a highly bioactive form of TSH and/or have increased thyroid sensitivity to TSH.

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.

To evaluate the impact of glucagon deficiency on the response to glucagon replacement, we infused physiological doses of glucagon (1.25 ng/kg X min) into 9 totally pancreatectomized (PX) diabetic patients (C-peptide, undetectable) 1) for 24 h during their usual diet and insulin regimen and/or 2) for 6 h in a fasted insulin-withdrawn state. During both glucagon infusions, plasma glucagon rose from 46 +/- 2 (+/- SE) pg/ml (0-10% 3500 mol wt glucagon) to 112 +/- 9 pg/ml. In the 24-h study (n = 4), glucagon significantly increased mean 24-h glucose levels (272 +/- 27 mg/dl; P less than 0.05) and glycosuria (29 +/- 5 g/day; P less than 0.01) compared to preinfusion (158 +/- 14 mg/dl and 4 +/- 4 g/day, respectively) and postinfusion (200 +/- 35 mg/dl and 3 +/- 2 g/day) control periods. Blood ketones did not change. The 24-h glucagon infusion significantly lowered the fasting levels of the glucogenic amino acids aspartate (43%; P less than 0.01), threonine (46%; P less than 0.05), serine (46%; P less than 0.02), glycine (47%; P less than 0.01), and methionine (34%; P less than 0.02). Fasting alanine levels decreased from 835 +/- 236 to 393 +/- 66 microM (P less than 0.05). The 6-h glucagon infusion caused a 101 +/- 14 mg/dl maximal plasma glucose increment in PX (n = 8) vs. 33 +/- 11 in 5 insulin-withdrawn type I diabetic patients serving as controls (P = 0.022). Furthermore, when glucagon was infused at a higher rate (3 ng/kg X min) in 12 additional type I diabetic patients, the mean maximal plasma glucose increment (54 +/- 15 mg/dl) was still less than half that in PX, despite a 3-fold higher infusion plasma glucagon level (326 +/- 37 pg/ml). The 6-h glucagon infusion caused a significant decrease in the concentrations of glucogenic amino acids in the glucagon-deficient patients, but not in the type I diabetic patients. We conclude that 1) glucagon replacement in the PX patient markedly alters blood glucose and glucogenic amino acids, but not ketone levels; and 2) the metabolic response to glucagon is considerably more pronounced in PX patients than in type I diabetic patients. These data suggest that glucagon responsiveness is enhanced in the chronic hormone-deficient state.

A 73-year-old woman developed temporal balding and "hoarseness" over a 3-year interval. Investigation including extensive endocrinologic screening, abdominal computed tomography scanning, pelvic ultrasonography, iodocholesterol (NP-59) adrenal scanning, and selective retrograde venous sampling revealed only an elevated serum testosterone level without localization of the source. At laparotomy a 2.0 cm left ovary was found to contain a hilus (Leydig) cell tumor. The testosterone level in a blood sample from the left ovarian vein obtained intraoperatively was 9000 ng/dl, whereas a blood sample from the right ovarian vein contained 213 ng/dl. One week later her peripheral blood testosterone level was normal (8 ng/dl). The records of six other patients with ovarian hilus cell tumors were reviewed from the Memorial Hospital Registry (from 1959 to 1982). All tumors were small (ovaries were 2 to 4 cm in diameter) and benign. The average patient's age was 63 years (range: 57 to 73 years). Only three of the seven patients in our series were first seen with virilization; the tumors in the remaining four patients were found incidentally. Ovarian hilus cell tumors are rare and are difficult to diagnose, but surgeons and endocrinologists should think of this tumor when they investigate older female patients with virilization. Careful intraoperative examination of even normal-appearing ovaries is imperative, particularly if no adrenal disease is found.