Regulation of insulin binding to human mammary carcinoma.

In vitro binding of labeled insulin was measured in crude membrane fractions of tumor and fat obtained at the time of breast cancer surgery in 23 women. There was significant insulin binding in 22 of 23 tumor specimens and in all 23 fat samples. High-affinity binding sites were present in tumors [Ka = 1.38 +/- 0.88 (S.E.) x 10(9) M-1 and adjacent fat membranes (Ka = 1.12 +/- 0.15 x 10(9) M-1]. The level of insulin binding was not related to either estrogen receptor status or tumor histological grade. There was a significant negative correlation between insulin binding to fat membranes and fasting insulin levels. In contrast, there was no significant relationship between insulin binding to tumor tissue and serum insulin levels, suggesting the loss of the capacity to "down-regulate" insulin-binding sites by breast tumor cells. The absence of this ability to regulate insulin-binding capacity could result in an increased sensitivity of breast tumor cells to the stimulatory effects of insulin.

Implementation of a pharmacogenomics consult service to support the INGENIOUS trial.

Hospital systems increasingly utilize pharmacogenomic testing to inform clinical prescribing. Successful implementation efforts have been modeled at many academic centers. In contrast, this report provides insights into the formation of a pharmacogenomics consultation service at a safety-net hospital, which predominantly serves low-income, uninsured, and vulnerable populations. The report describes the INdiana GENomics Implementation: an Opportunity for the UnderServed (INGENIOUS) trial and addresses concerns of adjudication, credentialing, and funding.

Differential immunogenetic determinants of polyclonal insulin autoimmune syndrome (Hirata's disease) and monoclonal insulin autoimmune syndrome.

The insulin autoimmune syndrome (IAS), or Hirata's disease, is characterized by the combination of fasting hypoglycemia, high concentration of total serum immunoreactive insulin, and presence of autoantibodies to native human insulin in serum. Autoantibody production is classified as monoclonal or polyclonal, with the majority of IAS cases classified as polyclonal. Previously, we observed a striking association between the human leukocyte antigen (HLA) class II alleles DRB1*0406/DQA1* 0301/DQB1*0302 and Japanese IAS patients with polyclonal insulin autoantibodies (IAAs) and T-cell recognition of human insulin in the context of DRB1*0406 molecules. Because of such a strong HLA association in IAS, we performed intra- and interethnic studies on IAS-associated DRB1 alleles and searched for the critical amino acid residue(s) for IAS pathogenesis. Glutamate at position 74 in the HLA-DR4 beta 1-chain was presumed to be essential to the production of polyclonal IAA in IAS, whereas alanine at the same position of the HLA-DR beta 1-chain might be important in the production of monoclonal IAA.

Nonprogression of subclinical beta-cell dysfunction among first-degree relatives of IDDM patients. 5-yr follow-up of the Seattle Family Study.

It is unknown among first-degree relatives of individuals with insulin-dependent diabetes mellitus (IDDM) whether the disease process occurs in relatively few but always progresses to clinical IDDM or whether subclinical disease is more common but remains nonprogressive in many cases. Islet cell antibodies (ICAs) were found in 21 of 724 (2.9%) first-degree relatives during screening in the greater Seattle area between 1983 and 1988. Measures of beta-cell function (glucose disappearance rate [Kg], fasting insulin, acute insulin response to intravenous arginine [AIRarg], acute insulin response to intravenous glucose [AIRgluc], slope of glucose potentiation of AIRarg) and insulin sensitivity were obtained. Twenty individuals, 9 ICA+ relatives and 11 ICA- relatives, were evaluated prospectively. When expressed in relation to the expected AIRgluc based on each subject's sensitivity index, AIRgluc in 18 of 20 relatives fell below 100%, indicating inappropriately low insulin secretion (subclinical beta-cell dysfunction). After a median follow-up of 42 mo, 10 of 11 ICA- relatives remained ICA-. None showed deteriorating beta-cell dysfunction, and none developed diabetes. Five ICA+ relatives showed persistent immunologic positivity. beta-Cell function remained remarkably stable in all except 2 relatives. One was a 15-yr-old boy who developed IDDM shortly after screening and before evaluation of beta-cell function could be carried out. The other was an 18-yr-old monozygotic twin who developed IDDM after 27 mo. Both of these individuals had ICAs of 80 Juvenile Diabetes Foundation U and had been discordant for less than 5 yr.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin autoimmunity as a cause of hypoglycemia.

"Autoimmune" hypoglycemia is a syndrome consisting of fasting hypoglycemia, hyperinsulinemia, and insulin-binding antibodies in a patient who has never been exposed to exogenous insulin. The stimulus for insulin-antibody formation and the mechanism of the hypoglycemia in this condition remain unknown. Three patients with this rare syndrome had severe hypoglycemia of limited duration. Two had received a drug containing a sulfhydryl group (methimazole and penicillamine) as treatment for an autoimmune disorder (Graves' disease and rheumatoid arthritis, respectively). A third patient who underwent surgery for a suspected insulinoma was found to have pancreatic beta cell hyperplasia. Drugs containing a sulfhydryl group may have a role in the etiology of the syndrome. Additionally, our findings suggest a relationship between circulating insulin antibodies and beta cell hyperplasia.

Flocculation and loss of potency of human NPH insulin.

In late 1986, several vials of Humulin N (NPH human insulin, recombinant DNA origin) came to our attention because of a clumped, white coating on the inside of the vials. To determine the frequency of this phenomenon, we surveyed 100 consecutive patients who used Humulin N. Ten patients had encountered 21 vials of flocculated insulin in the previous 12 mo, reflecting an incidence of 1 per 72 vials. Insulin drawn from affected vials was markedly reduced in potency: 20.9 +/- 3.4 U/ml vs. the labeled potency of 100 U/ml. Several patients reporting flocculated insulin, including one hospitalized with ketoacidosis, experienced unusual and unexplained elevation in blood glucose concentration for several days before flocculation was observed. Patients who use NPH human insulin should be aware of this phenomenon and carefully inspect their vials for evidence of insulin precipitation before each injection.

Age-Related Changes in MicroRNA Expression and Pharmacogenes in Human Liver.

Developmental changes in the liver can significantly impact drug disposition. Due to the emergence of microRNAs (miRNAs) as important regulators of drug disposition gene expression, we studied age-dependent changes in miRNA expression. Expression of 533 miRNAs was measured in 90 human liver tissues (fetal, pediatric [1-17 years], and adult [28-80 years]; n = 30 each). In all, 114 miRNAs were upregulated and 72 were downregulated from fetal to pediatric, and 2 and 3, respectively, from pediatric to adult. Among the developmentally changing miRNAs, 99 miRNA-mRNA interactions were predicted or experimentally validated (e.g., hsa-miR-125b-5p-CYP1A1; hsa-miR-34a-5p-HNF4A). In human liver samples (n = 10 each), analyzed by RNA-sequencing, significant negative correlations were observed between the expression of >1,000 miRNAs and mRNAs of drug disposition and regulatory genes. Our data suggest a mechanism for the marked changes in hepatic gene expression between the fetal and pediatric developmental periods, and support a role for these age-dependent miRNAs in regulating drug disposition.

Defects in beta-cell function and insulin sensitivity in normoglycemic streptozocin-treated baboons: a model of preclinical insulin-dependent diabetes.

During the preclinical period of human insulin-dependent diabetes, both impaired pancreatic beta-cell function and increased insulin resistance are found, although normoglycemia is preserved. To better understand the changes in beta-cell function and insulin sensitivity that occur in preclinical insulin-dependent diabetes, we performed a panel of in vivo beta-cell function tests and measured insulin sensitivity in adolescent male baboons both in normal health and after a small dose of streptozocin which did not induce hyperglycemia. Nine animals were studied before (stage 1) and 1 week after receiving a low dose of streptozocin (stage 2). There was no change in fasting plasma glucose or insulin. The mean glucose disposal rate (Kg) remained within the normal range, but dropped from 2.0 +/- 0.2% +/- SE) to 1.2 +/- 0.1%/min (P less than 0.01), the acute insulin response to arginine (AIR(arg)) fell from 67.7 +/- 19.4 microU/mL (485.8 +/- 139.2 pmol/L) to 32.8 +/- 7.2 microU/mL (235.3 +/- 51.7 pmol/L; P less than 0.05), and the acute insulin response to glucose (AIR(gluc)) fell from 881 +/- 243 microU/mL.10 min (6321 +/- 1744 pmol/L.10 min) to 334 +/- 82 microU/mL.10 min (2396 +/- 588 pmol/L.10 min; P less than 0.01). The most dramatic change, however, was in the ability of hyperglycemia to potentiate AIR(arg) (expressed as the slope of potentiation). This was reduced by 94% from 1.8 +/- 0.5 to 0.1 +/- 0.1 (P less than 0.01), with almost no overlap in values between stages 1 and 2. Insulin sensitivity was also lower 1 week after streptozocin treatment. When the animals were restudied 8 weeks after streptozocin treatment (stage 3) most measures of beta-cell function were not significantly different from those in stage 1. The fasting plasma glucose level was 85.4 +/- 4.3 mg/dL (4.7 +/- 0.2 mmol/L), Kg was 1.8 +/- 0.3%/min, fasting plasma insulin was 35.9 +/- 8.5 microU/mL (257.6 +/- 61.0 pmol/L), AIR(arg) was 67.0 +/- 15.4 microU/mL (480.7 +/- 110.5 pmol/L), and AIR(gluc) was 615.3 +/- 265.3 microU/mL.10 min (4413 +/- 1901 pmol/L.10 min), and tissue insulin sensitivity was 2.7 +/- 0.4 x 10(4) min/microU.mL. These values show extensive overlap with those of stage 1, from which they are not significantly different. The slope of glucose potentiation, however, remained low in all animals at stage 3.(ABSTRACT TRUNCATED AT 400 WORDS)

Insulin antibodies in patients receiving penicillamine.

In a patient receiving penicillamine for treatment of rheumatoid arthritis, antibodies to insulin developed, which resulted in symptomatic hypoglycemia. When 30 additional patients receiving penicillamine were screened, another patient was discovered to have antibodies to insulin. The level of antibody fell sharply in both patients after penicillamine was discontinued. This particular immunologic reaction to penicillamine has not been reported previously.

Early discharge with drain in situ following axillary lymphadenectomy for breast cancer.

One-hundred and two women had axillary lymphadenectomy for breast cancer and were randomised to early discharge with axillary drain in situ on the third postoperative day or standard duration 7 day hospital stay. The two groups did not differ with respect to seroma formation, wound infection or psychological profile as measured by the Hospital Anxiety and Depression Scale and Spielberger State Trait and Anxiety Inventory. Patient satisfaction levels were high in the early discharge group. The results confirm that early discharge after axillary lymphadenectomy is safe, practicable and satisfactory for patients. Such a policy offers considerable resource savings.

The effect of surgical technique on local recurrence rates following mastectomy.

The effects of two different axillary techniques, i.e. sampling and dissection, in combination with mastectomy for operable carcinoma are compared. The dissection technique when combined with radiotherapy gives better local disease control than sampling. This also confirms the proposition that an axillary sampling technique is an inefficient method of staging breast cancer and its use will result in inferior local disease control.

The prognostic value of the tumour markers CA 195 and CEA in patients with adenocarcinoma of the pancreas.

The serum levels of CA 195 were determined in 52 patients with histologically proven pancreatic carcinoma and compared with carcino-embryonic antigen (CEA), serum bilirubin and albumin. CA 195 levels were raised above the upper limit of 20 U/ml in 42 cases, giving a sensitivity of 80% for the detection of pancreatic carcinoma, whereas CEA was raised in only 55%. The levels of CA 195 and CEA were significantly higher in patients with metastatic disease, but potentially curable cases were not discriminated. Bilirubin and albumin levels were not significantly related to either the presence of metastases or the levels of the tumour markers. At the time of initial presentation, levels of both tumour markers correlated with the eventual duration of survival, but bilirubin and albumin did not. Significant increases in CEA and CA 195 were found in sequential blood samples, as the disease progressed. Neither CA 195 nor CEA was of sufficient sensitivity to be of value for screening, but both give an indication of the presence of metastases and of the subsequent duration of survival. CA 195 appeared to be more sensitive and might help to assess progress of the disease.

The tumour marker CA 195 in colorectal and pancreatic cancer.

The aim of this study was to measure the serum level of the tumour markers CA 195 and CEA in patients with either colorectal or pancreatic cancer both before and at serial intervals after operation. CA 195 and CEA were measured in 199 patients with colorectal cancer and 52 patients with pancreatic cancer. The median concentrations of CA 195 were 3.0 u/ml (interquartile range 3.0-4.5 u/ml) in patients with a Dukes' stage A lesion, 5.8 u/ml (3.0-18.2 u/ml) in patients with a Dukes' stage B lesion, 6.1 u/ml (3.0-24.7 u/ml) in patients with a Dukes' stage C and 23.8 u/ml (11.1-409.0 u/ml) in patients with metastatic disease (normal range 0-7 u/ml). The median levels of CEA were 2.6 ng/ml (1.7-3.3 ng/ml) for Dukes' stage A, 3.3 ng/ml (1.7-7.2 ng/ml) for Dukes' stage B, 3.7 ng/ml (2.2-7.9 ng/ml) for Dukes' stage C and 34.5 ng/ml (13.3-289.4 ng/ml) for metastatic disease. A rising level of CA 195 or CEA after operation suggested recurrence of the tumour. In none of these patients was the recurrence operable. In patients with pancreatic adenocarcinoma, the level of CA 195 was significantly higher in patients with metastatic disease but it did not discriminate between resectable and unresectable disease. The duration of survival correlated with the initial level of CA 195 (Rs = -0.66, p less than 0.001).

Seven-year follow-up on 334 patients treated by breast conserving surgery and short course radical postoperative radiotherapy: a report of the Yorkshire Breast Cancer Group.

A total of 334 patients have been entered into a prospective protocol of breast conserving treatment, which consisted of clinically complete excision, axillary dissection, and radical postoperative radiotherapy given in 20 fractions over 4 weeks. After 7 years' follow-up, 22 patients (6.6%) have had an isolated local recurrence and 24 (7.2%) a local recurrence associated with metastic disease. Cosmetic assessment shows that patients are more satisfied with the result than their treating consultants, and that 81% have scored themselves as having an excellent or very good result more than 5 years after treatment.

Transabdominal bilateral adrenalectomy for metastatic breast carcinoma.

A case is made for the more general adoption of the transabdominal approach to the adrenal glands as this has obvious advantages over bilateral loin incisions.

Marlex mesh wrapping of abdominal aortic aneurysm.

While resection with grafting is now the operation of choice for the treatment of abdominal aortic aneurysms there is still a need for a less traumatic procedure suitable for the elderly, poor-risk patient. Such a technique is described, the aneurysm being mobilized and wrapped in a double sheet of Marlex mesh. Two illustrative cases are reported with survival for 3 years and 2 1/4 years respectively.

Non-tumour morbidity and mortality after modified radical mastectomy.

From 1985 to 1987 148 patients underwent mastectomy for breast cancer, of whom 91 underwent modified radical mastectomy. Of these patients (median age 60 years (range 31-86 years)), 89 have been assessed for early (< 30 days) and late (> 30 days) non-tumour morbidity and mortality. A total of 41 patients had nodal metastases. Adjunctive therapy used was tamoxifen in 70 patients and radiotherapy in 20. Overall, 47 patients (53%) developed a total of 75 complications, and there was one 30-day mortality. Of the patients, 26 developed one complication, 14 had two complications and 7 three complications. Early complications were lymphocoele/seroma (n = 22), wound infection (n = 9) and cardiopulmonary problems (five deep vein thrombosis, two pulmonary embolus (1 death), one myocardial infarct). Late complications were lymphoedema (n = 10), pectoralis major wasting (n = 6), frozen shoulder (n = 7), intercostobrachial neuralgia (n = 4), and a small number of self-limiting wound problems (n = 9). There were two late deaths (myocardial infarcts). Early complications were not related to nodal status, and late complications were related to neither nodal status nor radiotherapy. Significant morbidity is attached to radical surgery for breast cancer. Most complications are minor and self-limiting, but there are a small number of late complications which may affect quality of life.

Provision and acceptability of day case breast biopsy: an audit of current practice.

The introduction of a national breast cancer screening programme and wider public awareness of breast disease have contributed to an increasing workload for breast surgeons. One method of dealing with this problem efficiently is to encourage day case surgery for breast biopsy patients. We studied our own day case breast biopsy workload, asked other surgeons what proportion of breast biopsies they performed in this way and assessed its acceptability to patients. Of surgeons working in units with facilities available, 40.3% perform 25% or less of breast biopsies as a day case. Of 235 patients undergoing breast biopsy in our unit during an 11-month period, 195 (83%) were performed as day cases. Of these, 192 were under general anesthesia. In all, 97.2% of patients were satisfied with their treatment as a day case, and only 4.5% would have preferred admission postoperatively. Carcinoma was present in 22 (11%) lesions biopsied, 11 (50%) of which occurred in patients under 50 years of age. Surgical complications were encountered in 32 (16.4%) cases; significant bruising 26 (13.3%), wound infections 4 (2.05%), dehiscence 1 (0.51%), and retained suture 1 (0.51%). Breast biopsy is an appropriate and acceptable procedure to undertake as a day case.

Operations upon the biliary tract in patients with acute pancreatitis: aims, indications and timing.

The management of gallstones in patients with acute pancreatitis (AP) is controversial. This paper reports an analysis of 171 attacks of AP associated with gallstones. Whilst awaiting elective cholecystectomy 56% of patients had further symptoms and 1 died. Non-urgent operations during the same admission as the pancreatitis (n = 34) resulted in 2 deaths and 7 septic complications, but prediction of complications may be possible. Urgent surgery (n = 5) was followed by 3 deaths. This study suggests that in most patients, cholecystectomy should be performed as soon as the patient is adequately fit. Urgent removal of an impacted ampullary stone (preferably by endoscopic papillotomy) may be required in a small minority if severe pancreatitis fails to respond to medical treatment, or if cholangitis supervenes .

'Surgical' peritonitis in the CAPD patient.

Peritonitis is the most frequent cause for emergency hospital admission in continuous ambulatory peritoneal dialysis (CAPD) patients. Patients may present with 'surgical' peritonitis from other intra-abdominal pathology, but are treated initially as CAPD-related peritonitis. We present nine such cases, each failing to respond to standard conservative treatment, and ultimately coming to laparotomy. Of the nine patients, six survived, five transferring to long-term haemodialysis and one patient returning to CAPD. Failure to respond to standard measures should alert the physician to the possibility of an intra-abdominal emergency. The presence of enteric organisms, particularly E. coli, is an additional suspicious feature. The diagnosis may be difficult and we recommend early surgical referral and appropriate surgical measures (laparotomy rather than simple catheter removal) in order to decrease morbidity and mortality.