Citations

Abstract High-risk susceptibility genes explain <40% of the excess risk of familial ovarian cancer. Therefore, other ovarian cancer susceptibility genes are likely to exist. We have used a single nucleotide polymorphism (SNP)–tagging approach to evaluate common variants in 13 genes involved in cell cycle control—CCND1, CCND2, CCND3, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, and CDKN2D—and risk of invasive epithelial ovarian cancer. We used a two-stage, multicenter, case-control study. In stage 1, 88 SNPs that tag common variation in these genes were genotyped in three studies from the United Kingdom, United States, and Denmark (∼1,500 cases and 2,500 controls). Genotype frequencies in cases and controls were compared using logistic regression. In stage 2, eight other studies from Australia, Poland, and the United States (∼2,000 cases and ∼3,200 controls) were genotyped for the five most significant SNPs from stage 1. No SNP was significant in the stage 2 data alone. Using the combined stages 1 and 2 data set, CDKN2A rs3731257 and CDKN1B rs2066827 were associated with disease risk (unadjusted P trend = 0.008 and 0.036, respectively), but these were not significant after adjusting for multiple testing. Carrying the minor allele of these SNPs was found to be associated with reduced risk [OR, 0.91 (0.85–0.98) for rs3731257; and OR, 0.93 (0.87–0.995) for rs2066827]. In conclusion, we have found evidence that a single tagged SNP in both the CDKN2A and CDKN1B genes may be associated with reduced ovarian cancer risk. This study highlights the need for multicenter collaborations for genetic association studies. [Cancer Res 2007;67(7):3027–35]

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.

OBJECTIVE—Multiple daily insulin injection programs are commonly accompanied by considerable glycemic variation and hypoglycemia. We conducted a randomized crossover design clinical trial to compare glargine with ultralente insulin as a basal insulin in type 1 diabetes. RESEARCH DESIGN AND METHODS—To determine whether the use of glargine insulin as a basal insulin would result in a comparable HbA1c and less glycemic variation and hypoglycemia than ultralente insulin, 22 individuals (aged 44 ± 14 years [±SD], 55% men) with type 1 diabetes who were experienced with multiple daily insulin injections and had an HbA1c of <7.8% were randomized in a crossover design to receive either glargine or ultralente as the basal insulin for 4 months. Aspart insulin was used as the prandial insulin. Physicians providing insulin dose adjustment advice were masked to the type of basal insulin. RESULTS—Treatment with glargine resulted in lower mean HbA1c (6.82 ± 0.13 vs. 7.02 ± 0.13, difference: 0.2 ± 0.08, P = 0.026), less nocturnal variability (plasma glucose 49.06 ± 4.74 vs. 62.36 ± 5.21 mg/dl, P = 0.04), and less hypoglycemia (24.5 ± 2.99 vs. 31.3 ± 4.04 events, P = 0.05), primarily due to less daytime hypoglycemia (P = 0.002). On the other hand, serious hypoglycemia and average glucose concentration measured with continuous subcutaneous glucose monitoring did not differ. CONCLUSIONS—We conclude that while use of either ultralente or glargine as a basal insulin can result in excellent glycemic control, treatment with glargine is associated with slightly but significantly lower HbA1c and less nocturnal glycemic variability and hypoglycemia.

First carpometacarpal joint arthritis is a common condition encountered by hand surgeons. Traditionally, surgical approaches have included arthrodesis, trapeziectomy or reconstructive arthroplasty techniques. Previously, we described a technique for arthroscopic debridement and interposition arthroplasty of the first carpometacarpal joint. Patients with Eaton stages II and III symptomatic first carpometacarpal joint arthritis recalcitrant to >6 months of non-operative therapy underwent arthroscopic debridement of the first carpometacarpal joint with interposition of an acellular dermal matrix allograft (GRAFTJACKET™). In this paper, we describe outcomes following this procedure. Postoperatively, all patients reported symptomatic relief and 94% stated that they were partially, or completely, satisfied. More than 70% of patients reported no to mild difficulty in performing activities of daily living (average grip strength = 18.5 kg, pinch strength = 3.9 kg). Complications were minimal. Outcomes from this study compare favourably to those of other series, demonstrating that this technique is a viable option for treatment of Eaton stages II and III first carpometacarpal arthritis.

Abstract Regulator of G-protein signaling–GAIP-interacting protein COOH terminus (GIPC) is involved in protein trafficking, endocytosis, and receptor clustering and is associated with insulin-like growth factor I receptor (IGF-IR), a receptor important for proliferation and anchorage-independent growth. Here, we described GIPC expression in different human pancreatic adenocarcinoma (PCA) cell lines and we examined the role of GIPC in the regulation of IGF-IR protein levels in PCA. Interestingly, inhibition of GIPC expression by RNA interference led to reduced IGF-IR protein levels and a subsequent decrease in proliferation of PCA cells. We also determined that the PDZ domain of GIPC is essential for the post-translational regulation and the binding of IGF-IR. The importance of GIPC in pancreatic cancer development and progression is supported by tissue microarray data of 300 pancreatic cancer specimens where GIPC is highly expressed in PCA. Taken together, our data suggest that GIPC is a central molecule for the stability of IGF-IR and could be a target for future therapy. (Cancer Res 2006; 66(21): 10264-8)

Purpose Large rotator cuff tears present a challenge to orthopaedic surgeons. Because tissue may be insufficient or of inadequate quality to undergo repair, a variety of materials have been used as adjuncts. Human dermal tissue may be processed to render it acellular, and thus less immunogenic, but with the extracellular matrix left intact, creating a collagen scaffold with favorable characteristics. Because of these traits, use in rotator cuff repair was proposed. Methods A canine model for a full‐thickness infraspinatus tendon tear was used. Tendon was excised from the bony interface to the myotendinous junction, and a human acellular dermal matrix graft (experimental) or the autologous excised tendon (control) was used to bridge the defect. Animals were sacrificed, and shoulders were evaluated histologically and biomechanically. Results At time 0, strength of control and experimental repairs was similar. At 6 weeks, the strength of the experimental repair was half that of the control side. Strength of control specimens remained the same at 6 and 12 weeks, but by 12 weeks, the strength of the experimental repair was equal to that of the control. Histologically, cells infiltrated the control and experimental specimens by 6 weeks; chronic inflammation was consistent with surgery and repair. At 6 months, control and experimental specimens mimicked normal tendon structure grossly and histologically. Conclusions Use of human acellular dermal matrix as a patch is a viable option in this model of large rotator cuff defects. Within 6 weeks, histologic evidence of native cell infiltration and neotendon development was observed. Within 12 weeks, the strength of the dermal matrix graft repair was equivalent to that of autologous tendon. At 6 months, control and graft specimens mimicked normal tendon structure grossly and histologically. Clinical Relevance This study provides in vivo animal data to support the use of this acellular dermal matrix graft for repair of full‐thickness rotator cuff defects. Additional studies are indicated to determine the role of this material in the treatment of humans with rotator cuff tears.

Abstract We previously identified HSulf-1 as a down-regulated gene in several tumor types including ovarian, breast, and hepatocellular carcinomas. Loss of HSulf-1, which selectively removes 6-O-sulfate from heparan sulfate, up-regulates heparin-binding growth factor signaling and confers resistance to chemotherapy-induced apoptosis. Here we report that HSulf-1 expression in MDA-MB-468 breast carcinoma clonal lines leads to reduced proliferation in vitro and reduced tumor burden in athymic nude mice in vivo. Additionally, xenografts derived from HSulf-1–expressing stable clones of carcinoma cells showed reduced vessel density, marked necrosis, and apoptosis, indicative of inhibition of angiogenesis. Consistent with this observation, HSulf-1–expressing clonal lines showed reduced staining with the endothelial marker CD31 in Matrigel plug assay, indicating that HSulf-1 expression inhibits angiogenesis. More importantly, HSulf-1 expression in the xenografts was associated with a reduced ability of vascular endothelial cell heparan sulfate to participate in a complex with fibroblast growth factor 2 (FGF-2) and its receptor tyrosine kinase FGF receptor 1c. In vitro, short hairpin RNA–mediated down-regulation of HSulf-1 in human umbilical vein endothelial cells (HUVEC) resulted in an increased proliferation mediated by heparan sulfate–dependent FGF-2, hepatocyte growth factor, and vascular endothelial growth factor 165 (VEGF165) but not by heparan sulfate–independent VEGF121. HSulf-1 down-regulation also enhanced downstream signaling through the extracellular signal–regulated kinase pathway compared with untreated cells. Consistent with the role of heparan sulfate glycosaminoglycan sulfation in VEGF-mediated signaling, treatment of HUVEC cells with chlorate, which inhibits heparan sulfate glycosaminoglycan sulfation and therefore mimics HSulf-1 overexpression, led to an attenuated VEGF-mediated signaling. Collectively, these observations provide the first evidence of a novel mechanism by which HSulf-1 modulates the function of heparan sulfate binding VEGF165 in proliferation and angiogenesis. (Cancer Res 2006; 66(12): 6025-32)