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.

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.

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.

'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.

Ductal carcinoma in situ of the breast: the clinical significance of histological classification.

One hundred and twenty-one cases of ductal carcinoma in situ, including 26 cases with T1a invasive carcinoma, were reviewed. Seventy-nine patients (65%) were treated by mastectomy and 42 (35%) had conservative surgery. Ductal carcinoma in situ was classified as well differentiated (11%), intermediately differentiated (22%) or poorly differentiated (67%) according to nuclear morphology and the presence or absence of cell polarization. Poorly differentiated lesions were significantly larger than intermediately and well differentiated lesions (P = 0.03 and P = 0.01, respectively) and were significantly associated with the presence of extensive necrosis, marked periductal inflammation and periductal fibrosis (P < 0.0001). Invasive carcinoma was more common in the poorly differentiated group (25% compared with 18% in the intermediate group and 8% in the well differentiated group) but this was not statistically significant. The spectrum of differentiation was similar in symptomatic and mammographically detected ductal carcinoma in situ. Clinical follow-up was available in 90 patients (median period 45 months in patients who had undergone mastectomy and 23 months in those who had conservative surgery). Two incidences of recurrent local disease were recorded in the mastectomy group: one patient had well differentiated and the other poorly differentiated ductal carcinoma in situ. No local recurrences were observed in the conservative surgery group, possibly reflecting the shorter follow up period. All histological grades of ductal carcinoma in situ have the potential to progress to invasive carcinoma and mastectomy does not guarantee a cure.

Gallstone ileus--beware the silent second stone.

Gallstone ileus remains a rare but important cause of small bowel obstruction. We report a case of recurrent gallstone ileus, presumably caused by an unidentified second stone resident within the gallbladder at the time of the initial laparotomy. This raises important questions about the traditional surgical management of this interesting condition.

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.

Influence of laparoscopic and conventional cholecystectomy upon cell-mediated immunity.

Surgery, trauma and anaesthesia induce a state of transient immunosuppression. Laparoscopic cholecystectomy has several well documented clinical advantages over traditional cholecystectomy and provokes a lower acute phase response, thought to be a result of the smaller wound size. The influence of laparoscopic cholecystectomy (21 patients) and conventional open cholecystectomy (13 patients) upon components of the cell-mediated immune system was investigated. Cell-mediated immunity was studied by in vitro assays of T lymphocyte proliferation to different mitogens, and by natural killer cell cytotoxicity using a standard 51Cr release assay. Blood samples were taken before and 24 h after the start of the operation. In the sample taken after operation there was significant depression of T lymphocyte proliferation to phytohaemagglutinin (stimulation index 149.4 versus 33.3, P < 0.002), staphylococcal enterotoxin B (85.2 versus 52.6, P = 0.01) and toxic shock syndrome toxin (48.4 versus 14.8, P = 0.08) in the group of patients who underwent open surgery, but not in the group treated by laparoscopic surgery. There was a small but statistically insignificant decrease of natural killer cell cytotoxicity in both groups of patients. These findings suggest that laparoscopic cholecystectomy causes less depression of cell-mediated immunity than open cholecystectomy.

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.

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.