Inhibition of Growth and Metastasis of Tumor in Nude Mice after Intraperitoneal Injection of Bevacizumab

Objective

To explore the inhibitory effect of bevacizumab, a vascular endothelial growth factor antibody, on angiogenesis in human osteosarcoma of nude mice.

Methods

Twenty‐one nude mice were inoculated with red fluorescent protein (RFP)‐labeled human osteosarcoma cell line 143B‐RFP, that is, clones that expressed RFP in the cytoplasm, and randomly assigned to one of three groups: G1 (Control group, injected with saline solution); G2 (intraperitoneal bevacizumab 2 mg/kg twice per week) and G3 (intraperitoneal bevacizumab 5 mg/kg, twice per week). The tumor‐bearing mice were examined in a fluorescence light box that was illuminated periodically. The primary tumors were measured by fluorescence imaging weekly and their volumes calculated.

Results

The mean tumor volumes were significantly smaller in the G3 (186.4 ± 100.8 mm³) than the control group (587.0 ± 406.8 mm³) (P < 0.05) on Day 31, and again significantly smaller in the G3 (677.3 ± 461.9 mm³) than the control group (3162.6 ± 1529.2 mm³) on Day 38 (P < 0.01). The average tumor volume in the G2 group was 493.5 ± 425.4 mm³ on Day 31 and 1870.1 ± 1524.8 mm³ on Day 38. The effect on tumor volume was greater in the G3 than the G2 group. Three mice in the G2 group, four in the G3 group and four in the control group developed lung metastases that were confirmed by pathological examination; these differences were not statistically significant (P < 0.05).

Conclusions

Bevacizumab exhibits strong antiangiogenesis activity in experimental osteosarcoma in a nude mouse model but does not influence the incidence of lung metastasis. Our findings may have considerable potential for the treatment of osteosarcoma.     

Patient‐Specific Orthopaedic Implants

Patient‐specific orthopaedic implants are emerging as a clinically promising treatment option for a growing number of conditions to better match an individual's anatomy. Patient‐specific implant (PSI) technology aims to reduce overall procedural costs, minimize surgical time, and maximize patient outcomes by achieving better biomechanical implant fit. With this commercially‐available technology, computed tomography or magnetic resonance images can be used in conjunction with specialized computer programs to create preoperative patient‐specific surgical plans and to develop custom cutting guides from 3‐D reconstructed images of patient anatomy. Surgeons can then place these temporary guides or “jigs” during the procedure, allowing them to better recreate the exact resections of the computer‐generated surgical plan. Over the past decade, patient‐specific implants have seen increased use in orthopaedics and they have been widely indicated in total knee arthroplasty, total hip arthroplasty, and corrective osteotomies. Patient‐specific implants have also been explored for use in total shoulder arthroplasty and spinal surgery. Despite their increasing popularity, significant support for PSI use in orthopaedics has been lacking in the literature and it is currently uncertain whether the theoretical biomechanical advantages of patient‐specific orthopaedic implants carry true advantages in surgical outcomes when compared to standard procedures. The purpose of this review was to assess the current status of patient‐specific orthopaedic implants, to explore their future direction, and to summarize any comparative published studies that measure definitive surgical characteristics of patient‐specific orthopaedic implant use such as patient outcomes, biomechanical implant alignment, surgical cost, patient blood loss, or patient recovery.     

Is there an Upgrading to Malignancy at Surgery of Mucocele‐Like Lesions Diagnosed on Percutaneous Breast Biopsy?

Management of pure mucocele‐like lesion (MLL) diagnosed on percutaneous breast biopsy (PBB) is controversial. To assess surgical upgrade rate and clinical outcome of pure MLL obtained as sole diagnosis on PBB. Patients diagnosed with a MLL as the most advanced lesion on PBB from April 1997 to December 2010 were reviewed for radiologic presentation, biopsy technique, and pathologic and clinical outcomes. Of the 21,340 image‐guided PBB performed during the study period, 50 women with 51 MLL (0.24%) were identified. Mean age was 53.1 ± 7.7 years. Radiologic findings were mostly microcalcifications (n = 47, 92.2%). Stereotactic PBB was performed for 49 lesions (96.1%). Surgery was performed shortly after biopsy in 35 women, with benign final pathology in 33, and upgrade to ductal carcinoma in situ (DCIS) in two patients (2/35, 5.7%). Mean follow‐up was 4.2 ± 2.5 years (3.7 ± 2.1 years for surgical patients; 5.9 ± 2.9 years for follow‐up only patients); three women were lost to follow‐up (3/50). Three invasive cancers (3/47, 6.4%) were diagnosed 1.2, 1.2, and 2.8 years after biopsy: two in surgical patients, and one in a follow‐up only patient. No cancer occurred at the same site as the original MLL. Pure MLL lesion of the breast is a rare entity and is mostly associated with a benign outcome. We observed an upgrade to DCIS slightly superior to 5%, but no invasive cancer. It is therefore unclear if these lesions should be excised or clinically and radiologically followed up when such lesions are found at PBB.     

Minimization of maintenance immunosuppressive therapy after renal transplantation comparing cyclosporine A/azathioprine or cyclosporine A/mycophenolate mofetil bitherapy to cyclosporine A monotherapy: a 10‐year postrandomization follow‐up study

Long‐term outcomes in renal transplant recipients withdrawn from steroid and submitted to further minimization of immunosuppressive regimen after 1 year are lacking. In this multicenter study, 204 low immunological risk kidney transplant recipients were randomized 14.2 ± 3.7 months post‐transplantation to receive either cyclosporine A (CsA) + azathioprine (AZA; n = 53), CsA + mycophenolate mofetil (MMF; n = 53), or CsA monotherapy (n = 98). At 3 years postrandomization, the occurrence of biopsy for graft dysfunction was similar in bitherapy and monotherapy groups (21/106 vs. 26/98; P = 0.25). At 10 years postrandomization, patients’ survival was 100%, 94.2%, and 95.8% (P = 0.25), and death‐censored graft survival was 94.9%, 94.7%, and 95.2% (P = 0.34) in AZA, MMF, and CsA groups, respectively. Mean estimated glomerular filtration rate was 70.4 ± 31.1, 60.1 ± 22.2, and 60.1 ± 19.0 ml/min/1.73 m², respectively (P = 0.16). The incidence of biopsy‐proven acute rejection was 1.4%/year in the whole cohort. None of the patients developed polyomavirus‐associated nephropathy. The main cause of graft loss (n = 12) was chronic antibody‐mediated rejection (n = 6). De novo donor‐specific antibodies were detected in 13% of AZA‐, 21% of MMF‐, and 14% of CsA‐treated patients (P = 0.29). CsA monotherapy after 1 year is safe and associated with prolonged graft survival in well‐selected renal transplant recipient ( ClinicalTrials.gov number: 980654).     

Impact of de novo donor‐specific anti‐HLA antibodies on grafts outcomes in simultaneous pancreas–kidney transplantation

De novo donor‐specific antibodies (dDSA) relevance in simultaneous pancreas–kidney (SPK) transplantation has been scarcely investigated. We analyzed dDSA relationship with grafts outcomes in a long‐term follow‐up SPK‐transplanted cohort. In 150 patients that received SPK transplant between 2000 and 2013, post‐transplant anti‐human leukocyte antigen (HLA) antibodies were screened and identified using Luminex‐based assays in sera collected at 3, 6, and 12 months, then yearly. dDSA were detected in 22 (14.7%) patients at a median 3.1 years after transplant. Pretransplant anti‐HLA sensitization (OR = 4.64), full HLA‐DR mismatch (OR = 4.38), and previous acute cellular rejection (OR = 9.45) were significant risk factors for dDSA. dDSA were significantly associated with kidney (in association with acute rejection) and pancreas graft failure. In dDSA+ patients, those with at least one graft failure presented more frequently dDSA against class II or I + II (P = 0.011) and locusDQ (P = 0.043) and had a higher median dDSA number (P = 0.014) and strength (P = 0.030). Median time between dDSA emergence and pancreas and kidney graft failure was 5 and 12 months, respectively. Emergence of dDSA increased the risk of grafts failure in SPK‐transplanted patients. Full HLA‐DR mismatch was associated with dDSA emergence. dDSA characteristics might help identify patients at a higher risk of graft failure.     

Evaluation of stair motion contributes to new insights into hip osteoarthritis‐related motion pathomechanics

Stair motion in the presence of hip osteoarthritis (OA) has received less attention than level walking. Its more strenuous aspect may shed the light on different locomotor strategies when compared to walking. We, therefore, aimed to define stair motion features associated to hip OA and to evaluate whether these specific features would differ from level walking and better characterize the hip pathological condition. Principal component and linear discriminant analyses were, respectively, used as data reduction and classification techniques. Our study highlighted that most of stair motion features associated to hip OA were similar to the ones of walking. Stair descent presented with the lowest misclassification error rate, ranging from 12% to 19% (estimated by cross‐validation). But, features that may be considered as a mechanism to reduce demand on the hip abductors were found to be more important in the stair ascent condition. This was reflected by both, greater importance in the classification rule and variance compared with walking, that is, decreased hip internal rotation moment at mid‐stance (72.50% vs. 57.63%) and increased trunk lateroflexion toward affected side (56.43% vs. 29.37%). This study emphasized the importance of investigating stair motion in hip osteoarthritic population by highlighting specific locomotor strategies. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:187–196, 2016.     

Optical spectroscopic determination of human meniscus composition

This study investigates the correlation between the composition of human meniscus and its absorption spectrum in the visible (VIS) and near infrared (NIR) spectral range. Meniscus samples (n = 24) were obtained from nonarthritic knees of human cadavers with no history of joint diseases. Specimens (n = 72) were obtained from three distinct sections of the meniscus, namely; anterior, center, posterior. Absorption spectra were acquired from each specimen in the VIS and NIR spectral range (400–1,100 nm). Following spectroscopic probing, the specimens were subjected to biochemical analyses to determine the matrix composition, that is water, hydroxyproline, and uronic acid contents. Multivariate analytical techniques, including principal component analysis (PCA) and partial least squares (PLS) regression, were then used to investigate the correlation between the matrix composition and it spectral response. Our results indicate that the optical absorption of meniscus matrix is related to its composition, and this relationship is optimal in the NIR spectral range (750–1,100 nm). High correlations (R²_uronic = 86.9%, R²_water = 83.8%, R²_{hydroxyproline} = 81.7%, p < 0.0001) were obtained between the spectral predicted and measured meniscus composition, thus suggesting that spectral data in the NIR range can be utilized for estimating the matrix composition of human meniscus. In conclusion, optical spectroscopy, particularly in the NIR spectral range, is a potential method for evaluating the composition of human meniscus. This presents a promising technique for rapid and nondestructive evaluation of meniscus integrity in real‐time during arthroscopic surgery. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:270–278, 2016.