CXCR2 expression during melanoma tumorigenesis controls transcriptional programs that facilitate tumor growth.

Background: Though the CXCR2 chemokine receptor is known to play a key role in cancer growth and response to therapy, a direct link between expression of CXCR2 in tumor progenitor cells during induction of tumorigenesis has not been established. Methods: To characterize the role of CXCR2 during melanoma tumorigenesis, we generated tamoxifen-inducible tyrosinase-promoter driven Braf V600E /Pten -/- /Cxcr2 -/- and NRas Q61R /INK4a -/- /Cxcr2 -/- melanoma models. In addition, the effects of a CXCR1/CXCR2 antagonist, SX-682, on melanoma tumorigenesis were evaluated in Braf V600E /Pten -/- and NRas Q61R /INK4a -/- mice and in melanoma cell lines. Potential mechanisms by which Cxcr2 affects melanoma tumorigenesis in these murine models were explored using RNAseq, mMCP-counter, ChIPseq, and qRT-PCR; flow cytometry, and reverse phosphoprotein analysis (RPPA). Results: Genetic loss of Cxcr2 or pharmacological inhibition of CXCR1/CXCR2 during melanoma tumor induction resulted in key changes in gene expression that reduced tumor incidence/growth and increased anti-tumor immunity. Interestingly, after Cxcr2 ablation, Tfcp2l1 , a key tumor suppressive transcription factor, was the only gene significantly induced with a log 2 fold-change greater than 2 in these three different melanoma models. Conclusions: Here, we provide novel mechanistic insight revealing how loss of Cxcr2 expression/activity in melanoma tumor progenitor cells results in reduced tumor burden and creation of an anti-tumor immune microenvironment. This mechanism entails an increase in expression of the tumor suppressive transcription factor, Tfcp2l1, along with alteration in the expression of genes involved in growth regulation, tumor suppression, stemness, differentiation, and immune modulation. These gene expression changes are coincident with reduction in the activation of key growth regulatory pathways, including AKT and mTOR.

Unequal distribution of N6-methyladenosine in influenza virus mRNAs.

Influenza virus mRNA is posttranscriptionally methylated at internal adenosine residues to form N6-methyladenosine (m6A). It has been previously shown that there is an average of three m6A residues per influenza virus mRNA (R. M. Krug, M. A. Morgan, and A. J. Shatkin, J. Virol. 20:45-53, 1976). To determine the distribution of m6A in the different influenza virus mRNAs, we purified six of the mRNAs by hybrid selection, digested them with nuclease, and determined their methylation patterns by high-pressure liquid chromatography. The amount of m6A in the different mRNAs varied from one in matrix to eight in hemagglutinin.

Relation of tumor-cell ploidy to survival in children with medulloblastoma.

PURPOSE: To assess the value of tumor-cell ploidy as a predictor of survival in medulloblastoma. PATIENTS AND METHODS: Ploidy determinations were based on the flow-cytometric analysis of cellular DNA content in fresh tumor specimens taken from 34 consecutively treated children with newly diagnosed medulloblastoma. Patients were assigned a high or low risk of failure depending on tumor size and invasiveness, and the presence or absence of metastatic disease. Treatment consisted of radiotherapy, with or without chemotherapy, according to institutional or cooperative group protocols. RESULTS: Univariate analysis of candidate prognostic factors showed that only tumor-cell ploidy and clinical risk group had a statistically significant influence on survival. Patients with hyperdiploid stem lines (n = 9) had significantly longer survival times (P = .04) than did those with diploid lines (n = 20). The estimated 5-year survival probabilities (+/- SE) for these two subgroups were 89% +/- 11% and 48% +/- 13%, respectively. Although clinical risk status (high v low) showed essentially the same predictive strength as ploidy, the two features identified largely nonoverlapping subgroups. Thus, within the clinical high-risk group, it was possible to distinguish hyperdiploid patients whose 5-year survival rate (83% +/- 15%) was comparable to that of patients with localized, low-risk tumors. CONCLUSION: This prospective study indicates that both ploidy and clinical risk group are important prognostic factors in medulloblastoma. Their combined use at diagnosis would distinguish patients who require more aggressive therapeutic intervention (diploid, clinical high-risk group) from those who could be expected to benefit most from standard treatment.

Patient characteristics associated with high-risk methotrexate concentrations and toxicity.

PURPOSE: Following high-dose methotrexate (HD-MTX) treatment, delayed MTX elimination is an important problem because it necessitates increased leucovorin rescue and additional hospitalization for hydration and urinary alkalinization. Our purpose was to identify factors associated with high-risk MTX plasma concentrations (defined by plasma concentration > or = 1.0 mumol/L at 42 hours from the start of MTX) and with toxicity. PATIENTS AND METHODS: Variables associated with MTX concentrations and toxicity were assessed in 134 children treated with one to five courses of HD-MTX (900 to 3,700 mg/m2 intravenously [i.v.] over 24 hours for a total of 481 courses) for acute lymphoblastic leukemia (ALL). RESULTS: High-risk MTX concentrations, toxicity (usually mild mucositis), and delay in resuming continuation chemotherapy occurred in 106 (22%), 123 (26%), and 66 (14%) of 481 courses, respectively. Using a mixed effects model for repeated measures, high-risk MTX concentrations were significantly associated with a higher MTX area-under-the-concentration-time curve (AUC), low urine pH, emesis, low MTX clearance, low urine output relative to intake, use of antiemetics during the MTX infusion, and concurrent intrathecal therapy (all p values < .01). Clinical toxicities and delay in resumption of continuation chemotherapy due to myelosuppression were more common in those with high 42-hour MTX concentrations, despite increased leucovorin rescue for all patients with high-risk MTX concentrations. However, with individualized rescue, no patient developed life-threatening toxicity. A more aggressive hydration and alkalinization regimen for subsequent courses reduced the frequency of high-risk MTX concentrations to 7% of courses (13 of 183) (P = .0001), and the frequency of toxicity decreased to 11% of courses (P = .0074). CONCLUSION: This study identified several clinical variables that influence MTX disposition that, when modified, can reduce the frequency of high-risk MTX concentrations and toxicity.

Phase I study of liposomal vincristine.

PURPOSE: A phase I study of vincristine encapsulated inside 120-nm-diameter distearoylphosphatidylcholine-cholesterol liposomes was performed. The primary objectives were to determine the maximum-tolerated dose (MTD), recommended phase II dose, toxicity, and pharmacokinetics of liposomal vincristine (ONCO-TCS). PATIENTS AND METHODS: Twenty-five patients with histologically confirmed malignancies were enrolled and assessable. Vincristine doses were increased from 0.5 mg/m2 to 1.0, 1.5, 2.0, 2.4, and 2.8 mg/m2 with cohorts of three or more patients per dose level. A total of 64 courses of ONCO-TCS were administered intravenously once every 3 weeks. The pharmacokinetics of total vincristine content in plasma were determined using a high-performance liquid chromatography method. RESULTS: Patients were treated with vincristine doses up to 2.8 mg/m2; however, 2.4 mg/m2 was defined as the MTD and 2.0 mg/m2 as the phase II recommended dose. Pain and obstipation were the dose-limiting toxicites. Other toxicities were fever, rigors, fatigue, myalgias, and peripheral neuropathy. Hematologic toxicity was mild. All patients who were treated with doses above 1.5 mg/m2 received in excess of 2.0 mg of vincristine, with doses as high as 6.2 mg. One partial response was seen in a patient with pancreatic cancer. Tumor response not meeting partial response criteria was seen in two other patients. Pharmacokinetic studies revealed significantly elevated concentrations of total vincristine, but parameters varied and were not directly correlated with toxicity or response. CONCLUSION: The ability to administer elevated doses of vincristine, as well as indications of efficacy, suggests that ONCO-TCS warrants further clinical investigation in a phase II setting.

Phase I/II trial of biweekly paclitaxel and cisplatin in the treatment of metastatic breast cancer.

PURPOSE: To determine the maximum-tolerated dose of escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ) administered biweekly with a fixed dose of cisplatin, to assess the toxicity, and to evaluate the activity of this combination in a phase I/II trial in metastatic breast cancer. PATIENTS AND METHODS: Twenty-nine women with metastatic breast cancer were enrolled; 27 were assessable for response and 29 for toxicity. All but two of the women had received prior adjuvant chemotherapy, with 23 receiving anthracyclines and six previous cisplatin. RESULTS: The initial starting dose of paclitxel 90 mg/m2 and cisplatin 60 mg/m2 became the phase II dose due to dose-limiting neutropenia. Responses were seen in 85% of assessable patients, with three patients (11%) achieving a complete response (CR) and 20 patients (14%) a partial response (PR), for an overall response rate of 85% (95% confidence interval [CI], 66% to 96%). The time to disease progression for patients who achieved a CR was 110 to 200 days, and for those with a PR, it was 96 to 377+ days, with a median time to progression of 7.1 months and a median response duration of 7.9 months. Sites of CR were skin, soft tissue, and lung, and all occurred in women with previous exposure to anthracyclines. Septic events were rare, with two grade 3 infections (7%), only one of which required hospital admission. There were no grade 4 nonhematologic toxicity and minimal grade 3 toxicity. A total of 251 chemotherapy cycles were given -- 16 with paclitaxel alone in five patients. Forty-five percent of patients required dose reductions, while 52% had delays due to neutropenia. CONCLUSION: Biweekly paclitaxel and cisplatin is an active combination in the treatment of metastatic breast cancer, including for patients with previous exposure to anthracyclines.

Promoter recognition by Escherichia coli RNA polymerase. Role of the spacer DNA in functional complex formation.

The available evidence suggests that during the process of formation of a functional or "open" complex at a promoter, Escherichia coli RNA polymerase transiently realigns the two contacted regions of the promoter, thus stressing the intervening spacer DNA. We tested the possibility that this process plays an active role in the formation of an open complex. Two series of promoters were examined: one with spacer DNAs of 15 to 19 base-pairs and a derivative for which the promoters additionally contained a one-base gap in the spacer, so as to relieve any stress imposed on the DNA. Consistent with an active role for the stressed DNA in driving open complex formation, we have found that for promoters with a 17-base-pair spacer, the presence of a gap leads to a delay in the formation of an open complex, at a step subsequent to the initial binding of RNA polymerase to the promoter. The results with the other gapped promoters rule out direct binding of RNA polymerase to the region of the gap and indicate an increased flexibility in the gapped DNA. As not all observations with the spacer length series of gapped and ungapped promoters can be interpreted in terms of an active role of the spacer DNA without additional assumptions, such a role must still be considered tentative.

Management of burns in the wilderness.

For the practitioner working in the wilderness environment, burns represent a significant challenge. There may be a requirement for non-specialists to provide care with fewer resources than would be available in a specialist unit in the UK. In the wilderness setting, delay prior to reaching specialist care is likely to be an ever present factor. Secondary complications of the burn wound, such as respiratory problems or sepsis may therefore supervene. The paper examines certain aspects of treatment relevant to the wilderness environment, including airway injury, fluid resuscitation and local treatment of the burn wound. Escharotomy and aspects of electrical and chemical injury are also considered.

Dissections of regional lymph nodes for treatment of skin cancer: predicting annual caseloads that will optimise outcomes.

INTRODUCTION: Dissection of regional lymph nodes (RLNs) can lead to significant morbidity and a high prevalence of complications. Published guidance states that these procedures should be carried out by surgeons who are members of a specialist skin multidisciplinary team who carry out a combined minimum of 15 axillary/groin dissections per year. However, there is little evidence to guide this minimum figure of procedures. We report on the burden of service provision and prevalence of complications across the South West of England and Wales. METHODS: A 12-month review of dissections of RLNs for skin cancer was undertaken covering five Plastic Surgery Units with a collective catchment of 8.4 million people. Detailed data were collected on patient demographics, pathology, timing of surgery, and prevalence of complications. RESULTS: A total of 163 dissections were carried out. Forty-three per cent of patients experienced one or more complication. In that 12-month period, an average of 8 axillary/groin dissections was carried out per surgeon. A funnel plot demonstrated that the prevalence of complications for individual surgeons was within the limit of the plot but, in many cases, this was based only on a relatively small number of procedures per consultant. If surgeons carried out 10 procedures per year, the upper and lower limits on the plot were 73% and 11%, respectively. CONCLUSIONS: Funnel plots can provide a useful guide as to whether the prevalence of complications for procedures for individual surgeons lies within acceptable limits. Based on these results, 10 procedures per consultant per year should be sufficient to enable meaningful assessment of the prevalence of complications.

Differential distribution of insulin-like growth factors and their binding proteins within bone: relationship to bone mineral density.

To evaluate the possibility that insulin-like growth factors (IGFs) and their binding proteins (BPs) in bone play a role in regulating cortical bone formation in growing animals, we compared changes in IGF and IGF BP levels with changes in bone mineral density (BMD) at three different regions (proximal, middle, and distal) along the rabbit femoral shaft. BMD measured by dual-energy x-ray absorptiometry decreased progressively from proximal to distal regions of the shaft, from 0.449 +/- 0.005 to 0.354 +/- 0.002 g/cm2 (mean +/- SEM; n = 9), respectively; total protein concentrations also decreased toward the distal region. We extracted the IGFs and their BPs from bone by demineralization in 10% EDTA and 4 M guanidine-HCl (pH 4.5). The IGFs were then separated from their BPs by size exclusion HPLC. The pH of the extraction buffer profoundly influenced the recoveries of the IGFs and, to a lesser extent, the total protein; at least 100% more IGFs were recovered at acid (4.5) pH than at neutral (7.5) or basic (10.5) pH. The levels of IGF-I decreased markedly from proximal to distal regions, from 273 +/- 27 to 100 +/- 38 ng human IGF-I equivalent/g bone (or 103 +/- 10 to 52 +/- 11 ng human IGF-I equivalent/mg protein), respectively. IGF-II was uniformly distributed (385 +/- 17 ng human IGF-II equivalent/g bone; mean of all three regions). Levels of the predominant 28-32 kD IGF BP doublet increased by about 100% from proximal to distal segments, regardless of whether the data were expressed per unit mass or protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhanced protein fold recognition using secondary structure information from NMR.

NMR offers the possibility of accurate secondary structure for proteins that would be too large for structure determination. In the absence of an X-ray crystal structure, this information should be useful as an adjunct to protein fold recognition methods based on low resolution force fields. The value of this information has been tested by adding varying amounts of artificial secondary structure data and threading a sequence through a library of candidate folds. Using a literature test set, the threading method alone has only a one-third chance of producing a correct answer among the top ten guesses. With realistic secondary structure information, one can expect a 60-80% chance of finding a homologous structure. The method has then been applied to examples with published estimates of secondary structure. This implementation is completely independent of sequence homology, and sequences are optimally aligned to candidate structures with gaps and insertions allowed. Unlike work using predicted secondary structure, we test the effect of differing amounts of relatively reliable data.

Mephenytoin phenotyping: lack of haematologic effect and timing of urine collections.

Mephenytoin is the prototype substrate for the genetically regulated, polymorphically distributed cytochrome P450, mephenytoin hydroxylase. Mephenytoin is an anticonvulsant which has been associated with leukopenia when used chronically. The haematologic effects of a single dose of oral mephenytoin, as is typically used to determine drug metabolism phenotype for this polymorphism, have not been reported. We administered 100 mg oral racemic mephenytoin to 30 healthy male volunteers and measured complete blood count three times weekly for 23 days. The time dependency of the urinary ratio of S to R mephenytoin in five serial urine samples (0-4, 4-8, 8-16, 16-24 and 24-32 h after the dose) was evaluated. There were no significant decreases from baseline in any subject in leukocyte count, haematocrit or platelet count. Two of the 30 subjects both of Indian extraction, were poor metabolizers of mephenytoin. The S:R ratio decreased with time (p = 0.001). Using the 0-4 h urine, one subject would have been misphenotyped as a poor metabolizer; phenotype assignments were in agreement with each other based on all subsequent urine collections. We conclude that there is no evidence that single dose mephenytoin is associated with haematologic toxicity in healthy male volunteers, and that the 4-8 h post-dose urine is as reliable as the 24-32 h collection for assignment of phenotype.

Cloning of the gene encoding honeybee long-wavelength rhodopsin: a new class of insect visual pigments.

Rhodopsins (Rh), G-protein-coupled receptors with seven transmembrane (TM) helices, form the first step in visual transduction in most organisms. Although many long-wavelength (LW) vertebrate opsin sequences are known, less information is available for invertebrate LW sequences. By a combination of RT-PCR and cDNA library screening, we have cloned and sequenced the honeybee LW Rh gene. The deduced protein is composed of 378 amino acids (aa), appears to have seven TM regions, and contains many of the structures and key aa thought to be important for Rh function. Phylogenetic analysis of this sequence in relation to other invertebrate Rh reveals it to be a member of a new group of insect LW Rh.

Local tumor control in rhabdomyosarcoma following low-dose irradiation: comparison of group II and select group III patients.

PURPOSE: To determine whether low-dose irradiation (i.e., approximately 40 Gy at 1.5-1.8 Gy/fraction), which is associated with > or = 90% local control in children with initially resected rhabdomyosarcoma and microscopic residual [Intergroup Rhabdomyosarcoma (IRS) group II disease], achieves comparable results in children with locally advanced rhabdomyosarcoma (IRS group III) left with microscopic disease after induction chemotherapy with or without delayed surgery. METHODS AND MATERIALS: Among 103 patients entered on five successive studies between 1968 and 1991, 24 had evidence of microscopic residual disease after initial surgical resection (IRS group II) and received low-dose irradiation. Initial chemotherapy was used in 79 with IRS group III disease. In 28 of these 79 group III patients, chemotherapy alone (n = 16) or in combination with delayed surgery (n = 12) reduced disease to microscopic levels prior to the start of radiotherapy based upon which they received low-dose irradiation. All have a minimum 2-year follow-up and median age of 4 years. Primary tumor sites among the 24 with group II disease included: orbit (5), parameningeal (2), nonparameningeal head and neck (3), genitourinary: nonbladder/prostate (5), extremity (4), and other (5). Irradiation dose ranged from 32-50 Gy, with a median and modal dose of 40 Gy. Primary tumor sites among the 28 with group III disease selectively treated with low-dose irradiation included: orbit (1), parameningeal (6), nonparameningeal head and neck (4), genitourinary: bladder/prostate (12) and nonbladder/prostate (1), extremity (1), and other (3). Irradiation dose ranged from 33-52 Gy, with a median and modal dose of 40 Gy. RESULTS: Local disease control has been maintained in 23 of 24 patients (96%) with group II disease. Local control occurred in eight of nine (89%) group II patients receiving < 40 Gy and in all 15 receiving > or = 40 Gy (p = 0.26). Twenty (83%) are alive and free of disease. Twenty-two of the 28 patients (79%) with group III disease treated with low-dose irradiation have maintained continuous local control of disease which was not statistically different from the group II patients (p = 0.08). Local control occurred in 7 of 11 (64%) group III patients receiving < 40 Gy vs. 15 of 17 (88%) receiving > or = 40 Gy (p < = 0.14). Nineteen (68%) are alive and free of disease. Survival in these group III patients is significantly worse than that of the group II patients, with 19 (68%) alive and free of disease (p = 0.04). CONCLUSION: Children with locally advanced rhabdomyosarcoma (IRS group III) who have only microscopic disease after induction chemotherapy with or without delayed surgery have a high likelihood of achieving local control with low-dose irradiation. For this group, data suggest treatment to a dose level of at least 40 Gy.

Priming of influenza mRNA transcription is inhibited in CHO cells treated with the methylation inhibitor, neplanocin A.

Chinese hamster ovary cells were pretreated with Neplanocin A, a potent inhibitor of RNA methylation. Analysis of polyadenylated RNA from treated cells by high-pressure liquid chromatography revealed marked decreases of 2'-O-methylation within mRNA cap structures and of internal N6-methyladenosine residues. In these Neplanocin A-treated cells, influenza viral mRNA accumulation was virtually abolished. Cellular RNA from Neplanocin A-treated cells was substantially less efficient than RNA from control cells in priming cell-free influenza transcription reactions. These results suggest that the observed inhibition of influenza virus replication is due at least in part to impaired recognition of undermethylated cellular mRNA cap structures by the influenza polymerase complex.

Collection of peripheral blood stem cells after a preceding autograft: unfavorable effect of prior interferon-alpha therapy.

Eighty-eight previously autografted (78 transplanted twice and 10 once) myeloma patients who had no cryopreserved stem cells available for possible future use received G-CSF for mobilization of stem cells. One-fourth of the patients had progressive disease at the time of apheresis. All patients had received 200 mg/m2 melphalan for the first transplant. The interval between the preceding transplant and the harvest was 5-68 months (median 29). A total of 0.46-9.16 (median 3.03) x 10(6) CD34+ cells/kg were collected. More than 2 x 10(6)/kg CD34+ cells were collected in 76% of the patients, and > or = 5 x 10(6)/kg in 14%. On multivariate analysis, patients with platelet counts of > or = 200 x 10(9)/l (P < 0.0001), those who had not received any myelosuppressive chemotherapy between the last transplant and the collection (P = 0.02), and those who had received interferon-alpha for < or = 6 months (P = 0.03) had better collections. Eleven of 12 patients autografted with these cells had prompt neutrophil recovery (median 10 days to 0.5 x 10(9)/l) but recovery to 50 x 10(9)/l platelets was delayed or incomplete in 11 of 12. We conclude that it is possible to harvest peripheral blood stem cells with G-CSF stimulation in patients who have been autografted previously. Limited data suggest that platelet recovery may be suboptimal when these cells are used. These findings have practical implications for patients with malignant diseases in remission after autografting who may be candidates for future salvage therapy but have no stem cells stored, and for patients with chronic myeloid leukemia who are on long-term interferon-alpha therapy to attain cytogenetic remission for eventual collection of normal stem cells.

Salvage autologous or allogeneic transplantation for multiple myeloma refractory to or relapsing after a first-line autograft?

Forty-two patients allografted for multiple myeloma after not having attained at least a partial remission (n = 19) or after having experienced disease progression (n = 23) following one autograft were compared with 42 pair-matched controls who underwent salvage autotransplantation under identical conditions. Autografted controls were matched closely for albumin, C-reactive protein, creatinine, disease sensitivity, duration of standard therapy prior to the first transplant, Ig isotype, karyotype, LDH, and response to the first transplant, but, in comparison to allografted patients, were older, had higher beta2-microglobulin, and had a shorter interval between the two transplants. The complete remission rate was 41% after allogeneic and 33% after autologous transplantation (P = NS). The 3-year probability of event-free survival was comparable for the two groups (25 +/- 8% after autografting and 20 +/- 8% after allografting). The 3-year probability of survival was significantly higher after autologous transplantation (54 +/- 8% vs 29 +/- 9%; P = 0.01). Twenty-one patients in the autograft group were alive 11-59 months (median 32) following the second transplant, while 15 patients in the allograft group were alive at 10-53 months (median 20). The 3-year probability of disease progression was significantly lower after allogeneic transplantation (31 +/- 10% vs 72 +/- 9%, P = 0.03). The 1-year probability of transplant-related mortality was significantly higher after allografting (43 +/- 8% vs 10 +/- 5%; P = 0.0001). We conclude that while autografting appears to be superior to allografting for salvage therapy of myeloma persisting or relapsing after one previous autotransplant in terms of overall survival, event-free survival is comparable due to significantly lower disease progression after allografting. Reduction in allograft-related toxicity can potentially improve the results of allogeneic transplantation significantly.

Effects of stem length on mechanics of the femoral hip component after cemented revision.

Bone loss in the proximal femur at the time of revision hip arthroplasty for a failed primary cemented femoral component can substantially reduce the stability of the revision stem. Use of an extended-length femoral component has been suggested to aid in achieving long-term fixation; however, the optimal stem length is unknown. A three-dimensional finite element model of a Charnley-type revision femoral component in a sclerotic shell of cortical bone devoid of cancellous bone was developed, and five different stem lengths ranging from 140 to 273 mm were used. The interface between the sclerotic bone and cement mantle consisted of fibrous tissue. Distal to the sclerotic bone, bonding was allowed between the cement and bone. Relative motion between the cement and bone was reduced substantially when the stem extended beyond the original defect. Maximum principal stresses in the proximal cement mantle decreased from 7.7 to 5.5 MPa, but cement stresses near the distal tip increased from 7.9 to 10.7 MPa when the stem just bridged the defect. Further increases in stem length reduced the distal cement stresses. Increases beyond two femoral diameters had a minor effect on changes in relative motion, cement mantle stresses, and stresses across the cement-bone interface. The results suggest that a femoral component that extends beyond the area of cancellous bone defect by two femoral diameters will be most effective in minimizing stresses and motion that could be associated with clinical loosening of the cemented revision. A shorter stem that just bridges the cancellous bone defect left from the primary procedure may not provide adequate distal fixation due to high cement-bone shear stresses.

Pre-yield and post-yield shear behavior of the cement-bone interface.

Aseptic loosening of cemented total hip replacements is thought to involve mechanical failure of the cement-bone interface. However, the mechanical response of the interface, particularly the post-yield behavior, is not well understood. The purpose of this study was to determine the constitutive behavior of the cement-bone interface for loading in shear using a combination of experimental and finite element methods. A total of 55 cement-bone specimens (5 x 10 x 15-20 mm) from the proximal femur of human cadavers were loaded to failure under displacement control with use of a custom shear test jig. Finite element models of the test specimens were made and included provision for a two-parameter nonlinear interface model at the cement-bone interface. The experimental tests revealed a complicated load versus displacement response with an initial linear region and a reduction in slope until the ultimate strength (2.25+/-1.49 MPa) was reached, followed by an exponential decrease in load with increasing displacement until the entire interface debonded. Failure most often occurred at the cement-bone interface, where the cement penetrated into the bone with bone remaining in the cement in 30 specimens and with bone remaining in the cement and cement spicules remaining in the bone in 22 specimens. The adjacent bulk bone and cement did not appear to be permanently deformed. Finite element models of the test specimens revealed that failure initiated at the base of the test specimen before the peak load had been reached. The two interface parameters, interface strength (2.71+/-1.90 MPa) and interface-softening exponent (4.96+/-3.47 1/mm), could be determined directly from the experimental data and provided a good fit with the experimental structural response for a wide range of interface strengths. These results show that the cement-bone interface does not fail abruptly when the shear strength is reached but absorbs a substantial amount of energy with post-yield strain-softening behavior.

Influence of stem geometry on mechanics of cemented femoral hip components with a proximal bond.

Nonlinear, three-dimensional, finite element models of cemented femoral hip components with a proximal stem-cement bond were developed with use of a Charnley stem geometry and a modified Charnley stem geometry that had a cylindrical cross section over the distal two-thirds of the stem (Distal-Round). Peak tensile stresses in the proximal cement mantle increased 63 and 74% for the Charnley and Distal-Round stems, respectively, when the proximal stem-cement interface was debonded. The shear stresses over the stem-cement interface with a proximal bond were 29% larger for the Distal-Round stem than for the Charnley stem. After the proximal stem-cement interface was debonded, the peak tensile stresses in the cement mantle were 15% larger for the Distal-Round stem than for the Charnley stem. The results illustrate that stresses within the proximal cement mantle could be substantially reduced for both Charnley and Distal-Round stems through use of a proximal stem-cement bond. However, the risk of debonding may be higher for the Distal-Round stem because of increased shear stresses, and once debonded the risk of further loosening due to failure of the cement mantle would also be higher for the Distal-Round stem.