Citations

Abstract The majority of candidates for breast cancer prevention have not accepted tamoxifen because of the perception of an unfavorable risk/benefit ratio and the acceptance of raloxifene remains to be determined. One means of improving this ratio is to identify women at very high risk of breast cancer. Family history, age, atypia in a benign biopsy, and reproductive factors are the main parameters currently used to determine risk. The most powerful risk factor, mammographic density, is not presently employed routinely. Other potentially important factors are plasma estrogen and androgen levels, bone density, weight gain, age of menopause, and fracture history, which are also not currently used in a comprehensive risk prediction model because of lack of prospective validation. The Breast Cancer Prevention Collaborative Group (BCPCG) met to critically examine and prioritize risk factors that might be selected for further testing by multivariate analysis using existing clinical material. The BCPCG reached a consensus that quantitative breast density, state of the art plasma estrogen and androgen measurements, history of fracture and height loss, BMI, and waist–hip ratio had sufficient priority for further testing. As a practical approach, these parameters could be added to the existing Tyrer–Cuzick model which encompasses factors included in both the Claus and Gail models. The BCPCG analyzed potentially available clinical material from previous prospective studies and determined that a large case/control study to evaluate these new factors might be feasible at this time.

The coexistence of urologic malignancy (UM) and abdominal aortic aneurysm (AAA) is rare. Simultaneous treatment may increase morbidity, whereas staged operations delay necessary treatment. We reviewed our experience to develop guidelines for evaluation and management. Clinical data of all patients diagnosed between 1980 and 1998 with both AAA and UM, who also had staged or simultaneous surgical treatment were reviewed. Four thousand forty-seven patients underwent AAA repair during the study period at our institution. Of these, 18 (0.44%) patients, 16 men and two women (mean age: 74 years, range: 61 to 92) had UM. UM was discovered incidentally in nine patients with AAA with computed tomography (CT) scan (7) and ultrasonography (2). In one patient with AAA, hematuria raised the suspicion of UM. Eight patients were diagnosed with AAA during evaluation of UM by CT scan or ultrasound (7) or during laparotomy (1). Initial signs and symptoms included abdominal pain (33%), gross hematuria (33%), and urinary tract infections (17%), although 33% were asymptomatic. The AAA was symptomatic at first examination in three (17%) patients, 14 (78%) patients had hypertension, and two (11%) had renal insufficiency (overall mean serum creatinine: 1.6, range: 0.8 to 3.7). Mean AAA diameter was 5.8 cm (range: 3.8 to 8 cm). Aortography documented significant contralateral renal artery disease in two patients. Twelve patients underwent simultaneous AAA repair and resection of UM; the operations were staged in six (AAA repair first in 2, nephrectomy first in 4). One patient required emergent repair of a ruptured AAA three days after nephrectomy. UM was treated with nephrectomy in 17 patients, and with bilateral ureterectomy and cystectomy in one. A straight aortic graft was implanted in seven patients, a bifurcated graft in ten, and one had extra-anatomic reconstruction. Two patients required reconstruction of the contralateral renal artery. The 30-day mortality rate was 0% after staged and 6% after simultaneous repair (p= >0.1). Major perioperative complications occurred more frequently after simultaneous (42%) than after staged repair (33%), although the difference was not significant (p= >0.1). Two patients developed postoperative renal failure. Seventeen patients were followed for an average of 3.9 years (14 days to 10.8 years). Three (17%) patients died of recurrent cancer at 1, 10.7, and 10.8 years after surgery. Patients with resectable UM have satisfactory long-term survival, which justifies aggressive treatment of concomitant AAA. Aortography in these patients is suggested to exclude contralateral renal artery disease. Complications were frequent, but simultaneous repair did not increase morbidity or mortality significantly. The risk of AAA rupture after nephrectomy, need to correct contralateral renal artery disease at the time of nephrectomy, and disadvantage of delaying treatment of UM are compelling reasons to favor simultaneous treatment of AAA and UM.

The objective of this study was to assess the usefulness of a comparison of clinical failure and restenosis rates of endovascular procedures at 1 year in patients with peripheral arterial disease. The resulting comparison is presented as “clinical failure/restenosis coordinate.” The authors screened 171 papers describing the outcome of lower extremity angioplasty or stent placement. In 20 of them, authors reported detailed outcomes of interest, including baseline demographic measurements, location of arterial occlusive lesions, a measure of restenosis (measured by ankle-brachial indices, ultrasonography, or angiography), and clinical outcomes (mortality, repeat percutaneous transluminal angioplasty, or amputation). An overview of these 20 angioplasty papers was performed. Besides the usual meta-analyses of each end point separately, data were also plotted as coordinates of clinical failure versus restenosis. The clinical failure-to-restenosis coordinate was calculated and reported for percutaneous transluminal angioplasty of the aortoiliac and femoropopliteal distributions. Clinically reported outcomes in the literature were used to calculate the clinical failure/restenosis coordinate. This value was significantly different for various locations of the angioplasty and various baseline angiographic characteristics. A numeric coordinate pair of clinical failure and restenosis is identifiable in patients undergoing endovascular treatment of peripheral arterial disease. The varying coordinates may be important in elucidating the incidence and mechanisms of clinical failure after endovascular treatment. The coordinate reported in this article is hypothesis-generating about mechanisms of endovascular treatment failure. This coordinate is important in determining the role of restenosis in the clinical failure of endovascular therapy of peripheral arterial disease.

Proteolytic processing of the amyloid precursor protein (APP) by β-secretase, β-site APP cleaving enzyme (BACE1), is the initial step in the production of the amyloid β (Aβ) peptide, which is involved in the pathogenesis of Alzheimer's disease. The normal cellular function of the prion protein (PrP C ), the causative agent of the transmissible spongiform encephalopathies such as Creutzfeldt–Jakob disease in humans, remains enigmatic. Because both APP and PrP C are subject to proteolytic processing by the same zinc metalloproteases, we tested the involvement of PrP C in the proteolytic processing of APP. Cellular overexpression of PrP C inhibited the β-secretase cleavage of APP and reduced Aβ formation. Conversely, depletion of PrP C in mouse N2a cells by siRNA led to an increase in Aβ peptides secreted into the medium. In the brains of PrP knockout mice and in the brains from two strains of scrapie-infected mice, Aβ levels were significantly increased. Two mutants of PrP, PG14 and A116V, that are associated with familial human prion diseases failed to inhibit the β-secretase cleavage of APP. Using constructs of PrP, we show that this regulatory effect of PrP C on the β-secretase cleavage of APP required the localization of PrP C to cholesterol-rich lipid rafts and was mediated by the N-terminal polybasic region of PrP C via interaction with glycosaminoglycans. In conclusion, this is a mechanism by which the cellular production of the neurotoxic Aβ is regulated by PrP C and may have implications for both Alzheimer's and prion diseases.

Multiple myeloma is a radiosensitive malignancy that is currently incurable. Here, we generated a novel recombinant vesicular stomatitis virus [VSV(Δ51)-NIS] that has a deletion of methionine 51 in the matrix protein and expresses the human sodium iodide symporter (NIS) gene. VSV(Δ51)-NIS showed specific oncolytic activity against myeloma cell lines and primary myeloma cells and was able to replicate to high titers in myeloma cells in vitro. Iodide uptake assays showed accumulation of radioactive iodide in VSV(Δ51)-NIS–infected myeloma cells that was specific to the function of the NIS transgene. In bg/nd/xid mice with established subcutaneous myeloma tumors, administration of VSV(Δ51)-NIS resulted in high intratumoral virus replication and tumor regression. VSV-associated neurotoxicity was not observed. Intratumoral spread of the infection was monitored noninvasively by serial gamma camera imaging of 123I-iodide biodistribution. Dosimetry calculations based on these images pointed to the feasibility of combination radiovirotherapy with VSV(Δ51)-NIS plus 131I. Immunocompetent mice with syngeneic 5TGM1 myeloma tumors (either subcutaneous or orthotopic) showed significant enhancements of tumor regression and survival when VSV(Δ51)-NIS was combined with 131I. These results show that VSV(Δ51)-NIS is a safe oncolytic agent with significant therapeutic potential in multiple myeloma.

The reverse radial forearm fascial (RRFF) flap is widely used in soft-tissue reconstruction of the hand. The traditional RRFF flap incorporates the radial artery from the forearm and is perfused by retrograde flow through the palmar arch. In patients with an abnormal Allen test because of an incomplete palmar arch, the traditional RRFF flap is contraindicated unless a vein graft is used to reconstruct the radial artery. A simpler alternative approach for hand reconstruction in such patients is a distally based RRFF flap based on radial artery perforators, which preserves the radial artery. We used RRFF flaps based on radial artery perforators in five patients who had palmar or dorsal soft-tissue loss. All five recovered full hand function, and only one had any complications (full-thickness skin graft loss at recipient site). The RRFF flap based on distal radial artery perforators is suitable for thin coverage of soft-tissue defects in hands with either a complete or an incomplete palmar arch.

Purpose Southwest Oncology Group (SWOG)/Intergroup study 9623 was undertaken to compare treatment with an anthracycline-based adjuvant chemotherapy regimen followed by high-dose chemotherapy (HDC) with autologous hematopoietic progenitor cell support (AHPCS) with a modern dose-dense dose-escalated (nonstandard) regimen including both an anthracycline and a taxane. Patients and Methods Participants in this phase III randomized study had operable breast cancer involving four or more axillary lymph nodes and had completed mastectomy or breast-conserving surgery. Patients were randomly assigned to receive four cycles of doxorubicin and cyclophosphamide followed by HDC with AHPCS or to receive sequential dose-dense and dose-escalated chemotherapy with doxorubicin, paclitaxel, and cyclophosphamide. The primary end point of this study was disease-free survival (DFS). Results Among 536 eligible patients, there was no significant difference between the two arms for DFS or overall survival (OS). Estimated five-year DFS was 80% (95% CI, 76% to 85%) for dose-dense therapy and 75% (95% CI, 69% to 80%) for transplantation. Estimated 5-year OS was 88% (95% CI, 84% to 92%) for dose-dense therapy and 84% (95% CI, 79% to 88%) for transplantation. Conclusion There is no evidence that transplantation was superior to dose-dense dose-escalated therapy. Transplantation was associated with an increase in toxicity and a possibly inferior outcome, although the hazard ratios were not significantly different from 1.

A retrospective chart review for the period between 1998 and 2006 was conducted to evaluate microneurolysis combined with a hypothenar fat pad flap (HTFPF) for patients at Mayo Clinic, Scottsdale, Arizona, who were being treated for recurrent carpal tunnel syndrome. After exclusion of patients with incomplete release of the transverse carpal ligament at the time of the original operation, 28 consecutive patients were identified. Their average age was 68.5 years (range 43–89 years). The average interval between the original carpal tunnel release and reexploration was 82 months (range 5–298 months). The average follow-up was 10.5 months (range 3–48.4 months). The preoperative two-point discrimination tests averaged 7 mm (range 5–12 mm). At surgery, all patients were found to have fibrosis surrounding the median nerve with adherence of the nerve to the radial leaf of the transverse carpal ligament. After surgery, the Tinel sign disappeared in 26 of 28 patients and two-point discrimination improved to an average of 6 mm (range 4–8 mm). Postoperative grip strength averaged 20 kg, compared with 11 kg preoperatively. Pain completely disappeared in 83% of patients (average improvement 93%, range 5–100%). Numbness completely disappeared in 42% of patients (average improvement 82.9%, range 5–100%). Tingling disappeared in 50% of patients (average improvement 84.7%, range 5–100%). No patient reported being worse after reoperation. These results suggest that the combination of microneurolysis and HTFPF can restore median nerve gliding and provide soft-tissue coverage, improving symptoms in patients with recurrent carpal tunnel syndrome.

We report a brief treatment format for young sexually abused boys that has both diagnostic and therapeutic implications. A general format is outlined, and then a group is described in more detail. Examples from each session are given that illustrate both therapeutic issues and issues related to the effects of sexual abuse on this sample. Implications for longer, more intensive treatment are given.