Background An autograft has traditionally been the gold standard for anterior cruciate ligament reconstruction (ACLR), but the use of allograft tissue has increased in recent years. While numerous studies have demonstrated that irradiated allografts are associated with increased failure rates, some report excellent results after ACLR with nonirradiated allografts. The purpose of this systematic review was to determine whether the use of nonirradiated allograft tissue is associated with poorer outcomes when compared with autografts. Hypothesis Patients undergoing ACLR with autografts versus nonirradiated allografts will demonstrate no significant differences in graft failure risk, laxity on postoperative physical examination, or differences in patient-oriented outcome scores. Study Design Systematic review. Methods A systematic review was performed to identify prospective or retrospective comparative studies (evidence level 1, 2, or 3) of autografts versus nonirradiated allografts for ACLR. Outcome data included graft failure based on clinical findings and instrumented laxity, postoperative laxity on physical examination, and patient-reported outcome scores. Studies were excluded if they did not specify whether the allograft had been irradiated. Quality assessment and data extraction were performed by 2 examiners. Results Nine studies comparing autografts and nonirradiated allografts were included. Six of the 9 studies compared bone– patellar tendon–bone (BPTB) autografts with BPTB allografts. Two studies compared hamstring tendon autografts to hamstring tendon allografts, and 1 study compared hamstring tendon autografts to tibialis anterior allografts. The mean patient age in 7 of 9 studies ranged from 24.5 to 32 years, with 1 study including only patients older than 40 years and another not reporting patient age. The mean follow-up duration was 24 to 94 months. Six of 9 studies reported clinical graft failure rates, 8 of 9 reported postoperative instrumented laxity measurements, 7 of 9 reported postoperative physical examination findings, and all studies reported patient-reported outcome scores. This review demonstrated no statistically significant difference between autografts and nonir-radiated allografts in any outcome measure. Conclusion No significant differences were found in graft failure rate, postoperative laxity, or patient-reported outcome scores when comparing ACLR with autografts to nonirradiated allografts in this systematic review. These findings apply to patients in their late 20s and early 30s. Caution is advised when considering extrapolation of these findings to younger, more active cohorts.
Estrogen receptor (ER) ؉ progesterone receptor (PR) ؊ tumors are a distinct subset of breast cancers characterized by aggressive behavior and tamoxifen resistance in spite of being ER ؉ . They are categorized as luminal B tumors and have greater genomic instability and a higher proliferation rate. High growth factor (GF) signaling and membranous ER activity contribute to the aggressive behavior of these tumors. The absence of PR is attributable to low serum estrogen, low levels of nuclear ER, and features of molecular crosstalk between GFs and membranous ER. PR expression is also downregulated by expression of mutated epidermal growth factor receptor (EGFRvIII). This subset of patients has greater expression of human epidermal growth factor receptor (HER)-1 and HER-2 and active GF signaling mediated by the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin pathway. Currently, aromatase inhibitors, fulvestrant, and chemotherapy may be the favored treatment approaches for this subset of patients. Overcoming tamoxifen resistance with targeted therapies such as gefitinib is being evaluated and strategies involving short courses of tamoxifen have been postulated for prevention of recurrence of this subtype. Understanding the interplay between molecular endocrinology and tumor biology has provided experimental therapeutic insights, and continued work in this area holds the promise of future advances in prognosis. The Oncologist 2011;16:276 -285
We present a case of a life-threatening toxicity associated with protein-bound paclitaxel (Abraxane r ). This new formulation of paclitaxel received FDA approval in January 2005. Older formulation paclitaxel has clear dosing guidelines for liver dysfunction, however, Abraxane r does not [1,2]. Abraxane r received FDA approval based on having greater efficacy and drug delivery than the older formulation paclitaxel [3]. With more active drug, greater concerns regarding drug metabolism should be considered.A 49-year-old African-American woman with breast cancer metastatic to the liver received her first cycle of Abraxane r . We chose to take the precaution of reducing the recommended 260 mg/m 2 to 180 mg/m 2 since our patient had an elevated bilirubin of 2.6 mg/dl (hematologic and renal laboratory values were unremarkable). We extrapolated the dose reduction from existing guidelines for the older formulation paclitaxel and from dose reduced studies of Abraxane r [3]. Despite this, six days following treatment our patient required hospitalization for febrile neutropenia (grade IV with absolute neutrophil count of <100/µl), mucositis (grade III), and nausea/vomiting (grade III).Upon recovery from her febrile neutropenia, she had improvement and normalization of her liver function tests. Also consistent with response was a re-evaluation computed tomography scan demonstrating the metastatic lesions in the liver had central necrosis, see Figure 1. With these findings, she continued three more cycles of Abraxane r and demonstrated further responses to treatment. No further dosing adjustments were made and no adverse complications occurred.Paclitaxel and protein-bound paclitaxel are both hepatically metabolized via the cytochrome P450 system, largely by CYP2C8 [4]. Decreased metabolic clearance of paclitaxel due to hepatic dysfunction can be the cause of severe drug toxicities. The presence of variant alleles of CYP2C8 that have lower levels of enzymatic activity could also be the cause of severe toxicities, however, none were detected in our patient, specifically the type II polymorphism found in 18% of African Americans (CYP2C8 polymorphism testing performed by Rusli Ismail, Pharm.D. and colleagues at the Institute for Research in Molecular Medicine of Universiti Sains Malaysia) [4].Abraxane r differs from prior formulation of paclitaxel because it is bound to albumin particles that confer water solubility; whereas older formulation must be delivered in the solvent Cremophor r , which has increased allergic reactions and limits dosing [5]. Larger doses of paclitaxel can now be administered, with better responses, but also increased risk for toxicity, especially with altered metabolism [3]. We believe there should be clear FDA warnings when hepatic insufficiency is present to minimize toxicity.Springer
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