Eastern Cooperative Oncology Group phase II studies in advanced measurable colorectal cancer. I. Razoxane, Yoshi-864, piperazinedione, and lomustine

During a 6-month interval, Eastern Cooperative Oncology Group randomized 127 patients who had received prior chemotherapy, and who had advanced measurable, surgically incurable colorectal cancer, to receive piperazinedione (PZD), Yoshi-864, or razoxane (ICRF-159). The observed response (and median survival) rates were: PZD, one of 35 patients (17 weeks); Yoshi-864, one of 34 (19 weeks), and ICRF-159, none of 38 (23 weeks). Among 107 evaluable patients, there were five episodes of life-threatening toxicity with PZD (one death) and four with ICRF-159 (two deaths). In the same protocol, 42 evaluable patients who had not received prior chemotherapy were randomized to be treated with lomustine (CCNU) or one of the three drugs in the "previously treated" trial. One CR (41 weeks) was seen with ICRF-159 and two PRs were seen with CCNU. Life-threatening toxicity occurred in three patients, two who received CCNU (one death) and one who received PZD. No survival advantage was seen. We do not encourage further phase II trials in colorectal cancer with the agents studied.     

Mesenchymal stem cell transplantation to promote bone healing

An overall decline in the availability of osteogenic precursor cells and growth factors in the bone marrow microenvironment have been associated with impaired bone formation and osteopenia in humans. The objective of the current study was to determine if transplantation of mesenchymal stromal cells (MSC) from a healthy, young donor mouse into an osteopenic recipient mouse could enhance osseointegration of a femoral implant. MSC harvested from normal young adult mice differentiated into bone forming osteoblasts when cultured on implant grade titanium surfaces ex vivo and promoted bone formation around titanium-coated rods implanted in the femoral canal of osteopenic recipient mice. Micro computed tomographic imaging and histological analyses showed more, better quality, bone in the femur that received the MSC transplant compared with the contra-lateral control femur that received carrier alone. These results provide pre-clinical evidence that MSC transplantation promotes peri-implant bone regeneration and suggest the approach could be used in a clinical setting to enhance bone regeneration and healing in patients with poor quality bone.     

Encircling guidewire facilitates complete excision of image-localized breast lesions

BACKGROUND: An innovative encircling guidewire defines three sides of a target lesion with a single puncture to achieve negative margins. METHODS: Twenty-five patients requiring image-guided surgery were localized with an encircling guidewire. Although the deployed wire is circular, it is straight when placed, using a straight outer needle. After image-guided placement of the wire around the lesion, all patients underwent standard surgical excision. Each patient was categorized by proper localization of the target lesion, presence of negative margins, closest margin, and need for reexcision. RESULTS: The circlewire wire identified the target lesion in all cases. There were no complications relative to either version of the leading tip on the guidewire. Negative margins were achieved in all pure invasive ductal carcinomas. Positive margins were found in all 3 patients with extensive noncalcified in-situ disease and 1 patient with multifocal invasive lobular carcinoma. CONCLUSIONS: An innovative encircling localizing guidewire device gives the surgeon a new option to completely remove a nonpalpable breast lesion.     

Prospective, Randomized, Multi-Center Trial of Antibody Induction Therapy in Simultaneous Pancreas-Kidney Transplantation

A randomized, multicenter, prospective study was conducted at 18 pancreas transplant centers in the United States to determine the role of induction therapy in simultaneous pancreas-kidney (SPK) transplantation. One hundred and 74 recipients were enrolled: 87 recipients each in the induction and noninduction treatment arms. Maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil, and corticosteroids. There were no statistically significant differences between treatment groups for patient, kidney, and pancreas graft survival at 1-year. The 1-year cumulative incidence of any treated biopsy-confirmed or presumptive rejection episodes (kidney or pancreas) in the induction and noninduction treatment arms was 24.6% and 31.2% (p = 0.28), respectively. The 1-year cumulative incidence of biopsy-confirmed, treated, acute kidney allograft rejection in the induction and noninduction treatment arms was 13.1% and 23.0% (p = 0.08), respectively. Biopsy-confirmed kidney allograft rejection occurred later post-transplant and appeared to be less severe among recipients that received induction therapy. The highest rate of Cytomegalovirus (CMV) viremia/syndrome was observed in the subgroup of recipients who received T-cell depleting antibody induction and received organs from CMV serologically positive donors. Decisions regarding the routine use of induction therapy in SPK transplantation must take into consideration its differential effects on risk of rejection and infection.     

Venous thromboembolism after retrieval of inferior vena cava filters

PURPOSE: To determine the incidence of venous thromboembolism (VTE) after removal of retrievable inferior vena cava (IVC) filters. MATERIALS AND METHODS: Retrospective study was conducted of 67 patients who underwent 72 consecutive filter retrievals at a single institution. Data collected included VTE status at the time of filter placement, anticoagulant medications at the time of filter retrieval and afterward, new or recurrent VTE after filter removal, and insertion of subsequent filters. Patient questionnaires were completed in 50 cases, chart review in all patients. RESULTS: At the time of filter placement, 30 patients had documented VTE, 19 had a history of treated VTE, and 23 were at risk for but had neither previous nor present VTE. Mean duration of follow-up after filter removal was 20.6 months +/- 10.9. A total of 52 patients (57 filters) received anticoagulation and/or antiplatelet medications after filter removal. There were two documented episodes of recurrent deep vein thrombosis (2.8% of filters removed), both in patients who had VTE at the time of filter placement and underwent therapeutic anticoagulation at the time of filter removal. One of these patients (1.4% of filters removed) also experienced pulmonary embolism. Of the 23 patients without VTE when the filter was placed, none developed VTE after filter removal. Four patients (5.5% of filters removed) required subsequent permanent filters, three for complications of anticoagulation, one for failure of anticoagulation. CONCLUSIONS: VTE was rare after removal of IVC filters, but was most likely to occur in patients who had VTE at the time of filter placement.     

The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis.

Teriparatide [rhPTH(1-34)] increases bone mineral density and reduces the risk of vertebral fracture in women. We randomized 437 men with spine or hip bone mineral density more than 2 SD below the young adult male mean to daily injections of placebo, teriparatide 20 microg, or teriparatide 40 microg. All subjects also received supplemental calcium and vitamin D. The study was stopped after a median duration of 11 months because of a finding of osteosarcomas in rats in routine toxicology studies. Biochemical markers of bone formation increased early in the course of therapy and were followed by increases in indices of osteoclastic activity. Spine bone mineral density was greater than in placebo subjects after 3 months of teriparatide therapy, and by the end of therapy it was increased by 5.9% (20 microg) and 9.0% (40 microg) above baseline (p < 0.001 vs. placebo for both comparisons). Femoral neck bone mineral density increased 1.5% (20 microg; p = 0.029) and 2.9% (40 microg; p < 0.001), and whole body bone mineral content increased 0.6% (20 microg; p = 0.021) and 0.9% (40 microg;p = 0.005) above baseline in the teriparatide subjects. There was no change in radial bone mineral density in the teriparatide groups. Bone mineral density responses to teriparatide were similar regardless of gonadal status, age, baseline bone mineral density, body mass index, smoking, or alcohol intake. Subjects experienced expected changes in mineral metabolism. Adverse events were similar in the placebo and 20-microg groups, but more frequent in the 40-microg group. This study shows that teriparatide treatment results in an increase in bone mineral density and is a potentially useful therapy for osteoporosis in men.     

Technical and immunologic progress in simultaneous pancreas-kidney transplantation

BACKGROUND: During the past few years the use of new immunosuppressants and refinements in surgical technique of simultaneous pancreas-kidney (SPK) transplantation have resulted in markedly improved outcomes. This is a retrospective study of 208 SPK transplants performed at Northwestern University, demonstrating the advances made at a single center that are reflective of the field at large. METHODS: An 8.5-year time span was split into 4 distinct eras marking sequential changes in immunosuppression and surgical technique that ensued. SPK transplant outcomes of patient and graft survival and rejection rates were compared. Also examined were end points related to the changing risk profile of the recipients, as well as quality of allograft function and rates of rehospitalizations. RESULTS: Recipients receiving tacrolimus/mycophenolate mofetil-based immunosuppression had patient, kidney, and pancreas survival rates significantly higher than those of earlier cohorts. The elimination of corticosteroids did not reduce survival rates or increase rejection risk. The use of pancreatic exocrine enteric drainage technique over bladder drainage reduced rehospitalizations. CONCLUSIONS: Advances in immunosuppression management combined with technical refinements have made SPK transplantation a safer and more effective treatment option for the diabetic, uremic patient.     

Pretransplant evaluation of renal transplant candidates

Kidney transplantation should be strongly considered for all medically suitable patients with chronic and end-stage renal disease (ESRD). Improvements in outcomes after renal transplantation have resulted in a more liberal selection of patients. High-risk category patients including human immunodeficiency virus (HIV)-positive, highly sensitized patients, T-cell positive cross-match, and ABO blood group-incompatible patients are now considered potential renal transplant candidates. Unfortunately, the demand for kidney transplants far exceeds the supply of available organs, causing a persistent increase in the number of patients on the waiting list with a parallel increase in the waiting time for a cadaveric kidney transplant. This has 2 major consequences. First, patients on the waiting list are getting sicker and older. Second, living donors have assumed increasing importance in renal transplantation. Pre-existing morbidities including malignancies, cardiovascular disease, infections, and coagulopathies should be extensively evaluated before proceeding to transplantation. Special attention should be given to cardiovascular risk factors because the leading cause of death after renal transplant is cardiovascular disease. A full immunologic evaluation with ABO blood group determination, human leukocyte antigen (HLA) typing, screening for antibody to HLA phenotypes, and cross-matching need to be gathered before transplantation to avoid antibody-mediated hyperacute rejection or to proceed with specific protocols in highly sensitized or in positive T-cell cross-match patients. With the increased rate of donation from living donors, regular follow-up evaluation of kidney donors is recommended to detect hypertension or proteinuria in those who may develop it.     

Comparison of two methods of screw fixation in periacetabular osteotomy

The optimal method of fixation during periacetabular osteotomy is unknown. Periacetabular osteotomies were created on both sides of six whole pelves from fresh cadavers and were fixed randomly either with three long 4.5-mm cortical screws from the iliac crest to the osteotomized fragment (iliac fixation) or with two such screws supplemented by a transverse screw from the acetabular segment to the ilium (transverse fixation). Pelvis loading in simulated push-off phase of the gait cycle was accomplished using a custom-made fixture. Linear potentiometers measured displacements at the pubic and ischial osteotomies. Fracture site stiffness was calculated from actuator force and pubic osteotomy displacement data. Displacement of the pubic osteotomy averaged 12.8 mm in the iliac fixation group and average 12.45 mm in the transverse group fixation. The ultimate loads beyond which catastrophic failure occurred were measured from 531.27 N to 1103.3 N (mean, 741.5 N) and 660.9 N to 1273.9 N (mean, 930.8 N), respectively. Effective stiffness ranged from 38.9 N/mm to 117 N/mm in the iliac fixation group (mean, 77.8 N/mm), and from 99 N/mm to 315 N/mm in the transverse construct (mean, 182 N/mm). Although the transverse screw provided statistically significantly greater local stiffness to the periacetabular construct fixation, neither type of fixation provided enough stability to allow immediate weightbearing after periacetabular osteotomy.