Chitosan Sponges to Locally Deliver Amikacin and Vancomycin: A Pilot In Vitro Evaluation

Background

Open orthopaedic wounds are ideal sites for infection. Preventing infection in these wounds is critical for reducing patient morbidity and mortality, controlling antimicrobial resistance and lowering the cost of treatment. Localized drug delivery has the potential to overcome the challenges associated with traditional systemic dosing. A degradable, biocompatible polymer sponge (chitosan) that can be loaded with clinician-selected antibiotics at the point of care would provide the patient and clinician with a desirable, adjunctive preventive modality.

Questions/purposes

We asked (1) if an adaptable, porous chitosan matrix could absorb and elute antibiotics for 72 hours for potential use as an adjunctive therapy to débridement and lavage; and (2) if the sponges could elute levels of antibiotic that would inhibit growth of Staphylococcus aureus and Pseudomonas aeruginosa?

Methods

We fabricated a degradable chitosan sponge that can be loaded with antibiotics during a 60-second hydration in drug-containing solution. In vitro evaluation determined amikacin and vancomycin release from chitosan sponges at six time points. Activity tests were used to assess the release of inhibitory levels of amikacin and vancomycin.

Results

Amikacin concentration was 881.5 μg/mL after 1 hour with a gradual decline to 13.9 μg/mL after 72 hours. Vancomycin concentration was 1007.4 μg/mL after 1 hour with a decrease to 48.1 μg/mL after 72 hours. Zone of inhibition tests were used to verify inhibitory levels of drug release from chitosan sponges. A turbidity assay testing activity of released amikacin and vancomycin indicated inhibitory levels of elution from the chitosan sponge.

Clinical Relevance

Chitosan sponges may provide a potential local drug delivery device for preventing musculoskeletal infections.     

Liposomal Formulation Decreases Toxicity of Amphotericin B In Vitro and In Vivo

Background

Liposomal amphotericin B is locally delivered to treat fungal orthopaedic infections but little is known about local tissue toxicity, if any, that might be associated with local delivery.

Questions/purposes

(1) Is liposomal amphotericin B cytotoxic in vitro? (2) Is locally delivered liposomal amphotericin B toxic to tissue in vivo?

Methods

Mouse fibroblasts (BA LB/3T3 A31) and osteoblasts (MC3T3) were exposed to two formulations of amphotericin B (liposomal and deoxycholate) at concentrations of 0, 1, 5, 10, 100, 500, and 1000 μg/mL. Cell viability was determined by MTT assay after 1, 3, and 5 hours of exposure and a proliferation assay after 1, 4, and 7 days of exposure and then after 3 recovery days without drug. Tissue exposure occurred by local delivery of liposomal amphotericin B, 200 or 800 mg/batch antifungal-loaded bone cement (ALBC), or amphotericin B deoxycholate, 800 mg/batch ALBC in rat paraspinal muscles. White blood cell count (WBC) and serum amphotericin B levels were obtained on Days 1 and 3. Rats were euthanized at 2 and 4 weeks and semiqualitative histopathology was performed.

Results

Liposomal amphotericin B is cytotoxic in vitro but not toxic to tissues in vivo. All cells survived concentrations up to 1000 μg/mL for 5 hours, 100% ± 0%, but none survived ≥ 100 μg/mL for 7 days, 0% ± 0%. Fibrosis was seen adjacent to ALBC without inflammation or necrosis, indistinguishable from controls for both liposomal amphotericin B doses. Amphotericin B serum levels were all less than 1 µg/mL and WBC counts were all normal.

Conclusions

In vitro cytotoxicity to liposomal amphotericin B occurred but no adverse tissue reaction was seen in vivo.

Clinical Relevance

Local delivery of liposomal amphotericin B in ALBC was well tolerated by mouse tissue; however, clinical studies are needed to confirm this finding in humans.     

Lower-Dose Mepivacaine Plus Fentanyl May Improve Spinal Anesthesia for Knee Arthroscopy

Background

Previous work indicates that 30 mg isobaric mepivacaine 1.5% plus 10 μg fentanyl produces reliable anesthesia for knee arthroscopy with a more rapid recovery profile than 45 mg mepivacaine.

Questions/Purposes

This randomized controlled trial compared plain mepivacaine to three reduced doses of mepivacaine with 10 μg fentanyl for spinal anesthesia.

Methods

Following written informed consent, subjects undergoing outpatient knee arthroscopy were prospectively randomized into one of four groups: mepivacaine 37.5 mg (M37.5); mepivacaine 30 mg plus fentanyl 10 μg (M30/F10); mepivacaine 27 mg plus fentanyl 10 μg (M27/F10); and mepivacaine 24 mg plus fentanyl 10 μg (M24/F10). The spinal was evaluated by the blinded anesthetist and surgeon. In the post-anesthesia care unit, sensory and motor block resolution was assessed. Subjects rated their satisfaction with the overall experience.

Results

Group M30/F10 (n = 6) had two “fair” anesthetics, and group M27/F10 (n = 10) had one “fair” and one “inadequate” anesthetic. Both groups were eliminated from further enrollment per study protocol. The recovery profiles showed little difference between groups M37.5 and M30/F10, except for motor block resolution (median (25th percentile, 75th percentile): 171 (135, 195) and 128 (120, 135), respectively). Groups M27/F10 and M24/F10 demonstrated recovery profiles that were faster than group M37.5. Patient satisfaction was 10/10 for all groups.

Conclusions

Adding fentanyl 10 μg to a lower dose of mepivacaine 1.5% can lead to quicker recovery profiles. However, this advantage of a quicker recovery must be weighed against the likelihood of an incomplete anesthetic.

Electronic supplementary material

The online version of this article (doi:10.1007/s11420-015-9454-8) contains supplementary material, which is available to authorized users.     

Rifamycin Derivatives Are Effective Against Staphylococcal Biofilms In Vitro and Elutable From PMMA

Background

Local antimicrobial delivery through polymethylmethacrylate beads (PMMA), commonly vancomycin, is used for the treatment of contaminated open fractures but has limited activity against Staphylococcus aureus biofilms, which occur commonly in such fractures. Rifamycins have activity against biofilms and are an effective treatment for osteoarticular infections involving staphylococcal biofilms, but there are limited studies evaluating the activity of rifamycin derivatives, other than rifampin, against biofilms of S. aureus and evaluating incorporation of these drugs into PMMA for treatment of contaminated open fractures.

Questions/purposes

(1) Are rifamycin derivatives effective against established biofilms of clinical isolates of S. aureus? (2) Can PMMA be used as a carrier for rifamycin derivatives?

Methods

Biofilms were developed and evaluated for susceptibility to a panel of antimicrobials in vitro using the minimum biofilm eradication concentration high-throughput model. Susceptibility was assessed by measuring bacterial recovery at 6 and 24 hours after antimicrobial treatment. Activity of rifamycin derivatives against intracellular bacteria was also evaluated using a gentamicin protection assay. Evaluation of PMMA as a carrier for rifampin and rifamycin derivatives was determined by assessing the curing time subsequent to loading of rifamycins and characterizing the release kinetics of rifamycins at daily intervals for 14 days from PMMA by performing bioassays.

Results

Rifamycin derivatives between 1 and 8 µg/mL reduced bacteria within biofilms 5- to 9-logs and prevented bacterial recovery up to 24 hours post-treatment, indicating near to complete eradication of biofilms. Rifamycin derivatives at 32 µg/mL had activity against intracellular staphylococci, significantly reducing the number of internalized bacteria with limited effects on osteoblast viability. Rifampin was the only rifamycin observed to have a suitable release profile from PMMA, releasing 49% of the total antibiotic and maintaining a sustained released profile up to 14 days at a mean 28 ± 6 μg/mL.

Conclusions

Rifampin can be incorporated into PMMA and eluted at concentrations effective against biofilms and intracellular staphylococci.

Clinical Relevance

Our in vitro findings suggest that local delivery of rifampin may be an effective strategy for the prevention and/or treatment of open fractures where S. aureus biofilms might develop. Clinical studies are needed to characterize what role this approach might have in the prevention and treatment of infections involving biofilms.

Electronic supplementary material

The online version of this article (doi:10.1007/s11999-015-4300-3) contains supplementary material, which is available to authorized users.     

Voriconazole Is Cytotoxic at Locally Delivered Concentrations: A Pilot Study

Background

Fungal infections are rare but major problems when they involve orthopaedic implants. Preferred treatment in North America is two-staged: resection and then delayed reconstruction, with local delivery of an antifungal between stages. The effect of voriconazole, a hydrophobic antifungal, on local tissues and wound healing is unclear.

Questions/purposes

We asked: (1) Is voriconazole cytotoxic to fibroblasts or osteoblasts at target concentrations for local delivery? And (2) if cytotoxic, can fibroblasts or osteoblasts resume proliferation after voriconazole is removed?

Methods

We exposed 5000 fibroblasts or osteoblasts/well to voriconazole concentrations of 0, 1, 5, 10, 25, 100, 500, 1000, 5000, 10,000, and 20,000 μg/mL (n = 4 wells/concentration) in 24-well plates. At 3 and 7 days, cell growth was assessed with alamarBlue^® and light microscopy. After Day 7, exposure to voriconazole was stopped and incubation continued for 4 days in medium with no voriconazole. On Day 11, cell growth (recovery) was assessed with alamarBlue^® and light microscopy.

Results

Increasing voriconazole concentration to more than 100 μg/mL decreased osteoblast and fibroblast growth. Cell growth recovered after 7 days’ exposure to 1000 μg/mL or less.

Conclusions

Voriconazole is cytotoxic to osteoblasts and fibroblasts, but cell growth recovers over 4 days after exposure to 1000 μg/mL or less.

Clinical Relevance

Cytotoxicity seen from voriconazole to mouse osteoblasts and fibroblasts occurs at concentrations achievable clinically from local delivery. It may be prudent to limit the dose of voriconazole in antibiotic-loaded bone cement.     

Accuracy of medical models made by consumer-grade fused deposition modelling printers

BACKGROUND:

Additive manufacturing using fused deposition modelling (FDM) has become widely available with the development of consumer-grade three-dimensional printers. To be useful in maxillofacial surgery, models created by these printers must accurately reproduce the craniofacial skeleton.

OBJECTIVE:

To determine the accuracy of consumer-grade FDM printers in the production of medical models compared with industrial selective laser sintering (SLS) printers.

METHODS:

Computed tomography images of a dry skull were manipulated using OsiriX (OsiriX, Switzerland) and ZBrush (Pixologic, USA) software. Models were fabricated using a consumer-grade FDM printer at 100 μm, 250 μm and 500 μm layer heights and an industrial SLS printer. Seven linear measurements were made on the models and compared with the corresponding dry skull measurements using an electronic caliper.

RESULTS:

A dimensional error of 0.30% was observed for the SLS models and 0.44%, 0.52% and 1.1% for the 100 μm, 250 μm and 500 μm FDM models, respectively.

CONCLUSION:

Consumer-grade FDM printers can produce medical models with sufficient dimensional accuracy for use in maxillofacial surgery. With this technology, surgeons can independently produce low-cost maxillofacial models in an office setting.     

Renal and functional outcomes following cystectomy and neobladder reconstruction

Background:

Orthotopic reconstruction following cystectomy has evolved in an attempt to restore anatomy and function to as close as possible to the preoperative state. We review the renal and functional outcomes of patients who underwent cystectomy and neobladder reconstruction at our institution.

Methods:

Between December 2003 and October 2007, 31 patients underwent cystectomy with Studer neobladder reconstruction at the Ottawa Hospital, Ottawa, Ontario, Canada. Follow-up data were obtained regarding renal function (serum creatinine, μmol/L), continence, urinary flow rates and post-void residual (PVR) at 3, 6 and 12 months after surgery. Change in creatinine from preoperative baseline was calculated and analyzed by student t-test to determine if there was a significant rise in creatinine.

Results:

There was a statistically significant increase in creatinine from preoperative baseline, with an average increase of 17.3 μmol/L, 21.8 μmol/L and 26.3 μmol/L at 3, 6 and 12 months, respectively. Six patients developed hydronephrosis. Excluding patients with hydronephrosis, there continued to be a statistically significant rise in creatinine with an average increase of 11.9 μmol/L, 14.7 μmol/L and 19.4 μmol/L at 3, 6 and 12 months, respectively. At 1 year, daytime continence was achieved by 89% of patients; 70% were continent at night.

Interpretation:

Orthotopic neobladders have excellent functional outcomes with low rates of incontinence, which improved throughout follow-up. A significant proportion of patients developed hydronephrosis, highlighting the need for close follow-up to prevent reversible renal deterioration. Creatinine increased during follow-up irrespective of the development of hydronephrosis, but the clinical significance is unknown.     

Early detection of prostate cancer local recurrence by urinary prostate-specific antigen

Purpose:

We assessed the role of urinary prostate-specific antigen (uPSA) in the follow-up of prostate cancer after retropubic radical prostatectomy (RRP) for the early detection of local recurrences.

Methods:

We recruited 50 patients previously treated for prostate cancer with RRP and who had not experienced a prostate-specific antigen (PSA) recurrence within their first postoperative year into a cross-sectional laboratory assessment and prospective 6-year longitudinal follow-up study. We defined biochemical failure as a serum PSA (sPSA) of 0.3 μg/L or greater. Patients provided blood samples and a 50-mL sample of first-voided urine. We performed Wilcoxon rank-sum and Fisher exact tests for statistical analysis.

Results:

The median sPSA was 0.13 μg/L. The median uPSA was 0.8 μg/L, and was not significantly different when comparing Gleason scores or pathological stages. Of the 50 patients, 27 initially had a nondetectable sPSA but a detectable uPSA, and 11 patients experienced sPSA failure after 6 years. Six patients had detectable sPSA and uPSA initially. Fifteen patients were negative for both sPSA and uPSA, and 13 remained sPSA-free after 6 years. The odds ratio (OR) of having sPSA failure given a positive uPSA test was 4.5 if sPSA was undetectable, but was reduced to 2.6 if sPSA was detectable. The pooled Mantel–Haenszel OR of 4.2 suggested that a detectable uPSA quadrupled the risk of recurrence, independent of whether sPSA was elevated or not. The sensitivity of uPSA for detecting future sPSA recurrences was 81% and specificity was 45%.

Conclusion:

Urinary PSA could contribute to an early detection of local recurrences of prostate cancer after a radical prostatectomy.     

Novel Antibiotic-loaded Point-of-care Implant Coating Inhibits Biofilm

Background

Orthopaedic biomaterials are susceptible to biofilm formation. A novel lipid-based material has been developed that may be loaded with antibiotics and applied as an implant coating at point of care. However, this material has not been evaluated for antibiotic elution, biofilm inhibition, or in vivo efficacy.

Questions/purposes

(1) Do antibiotic-loaded coatings inhibit biofilm formation? (2) Is the coating effective in preventing biofilm in vivo?

Methods

Purified phosphatidylcholine was mixed with 25% amikacin or vancomycin or a combination of 12.5% of both. A 7-day elution study for coated titanium and stainless steel coupons was followed by turbidity and zone of inhibition assays against Staphylococcus aureus and Pseudomonas aeruginosa. Coupons were inoculated with bacteria and incubated 24 hours (N = 4 for each test group). Microscopic images of biofilm were obtained. After washing and vortexing, attached bacteria were counted. A mouse biofilm model was modified to include coated and uncoated stainless steel wires inserted into the lumens of catheters inoculated with a mixture of S aureus or P aeruginosa. Colony-forming unit counts (N = 10) and scanning electron microscopy imaging of implants were used to determine antimicrobial activity.

Results

Active antibiotics with colony inhibition effects were eluted for up to 6 days. Antibiotic-loaded coatings inhibited biofilm formation on in vitro coupons (log-fold reductions of 4.3 ± 0.4 in S aureus and 3.1 ± 0 for P aeruginosa in phosphatidylcholine-only coatings, 5.6 ± 0 for S aureus and 3.1 ± 0 for P aeruginosa for combination-loaded coatings, 5.5 ± 0.3 for S aureus in vancomycin-loaded coatings, and 3.1 ± 0 for P aeruginosa for amikacin-loaded coatings (p < 0.001 for all comparisons of antibiotic-loaded coatings against uncoated controls for both bacterial strains, p < 0.001 for comparison of antibiotic-loaded coatings against phosphatidylcholine only for S aureus, p = 0.54 for comparison of vancomycin versus combination coating in S aureus, P = 0.99 for comparison of antibiotic- and unloaded phosphatidylcholine coatings in P aeruginosa). Similarly, antibiotic-loaded coatings reduced attachment of bacteria to wires in vivo (log-fold reduction of 2.54 ± 0; p < 0.001 for S aureus and 0.83 ± 0.3; p = 0.112 for P aeruginosa).

Conclusions

Coatings deliver active antibiotics locally to inhibit biofilm formation and bacterial growth in vivo. Future evaluations will include orthopaedic preclinical models to confirm therapeutic efficacy.

Clinical Relevance

Clinical applications of local drug delivery coating could reduce the rate of implant-associated infections.     

Limited adequacy of thyroid cancer patient follow-up at a Canadian tertiary care centre

Background

We sought to evaluate the adequacy of follow-up of thyroid cancer patients at a Canadian centre.

Methods

We mailed a survey to the family physicians of thyroid cancer patients and analyzed the findings relative to follow-up guidelines published by the American Thyroid Association (ATA). Statistical significance between early and late follow-up patterns was analyzed using the χ² test.

Results

Our survey response rate was 56.2% (91 of 162). The time from operation ranged from 1.24–7.13 (mean 3.96) years, and 87.9% of patients had undergone a physical exam within the previous year. Only 37.4% and 14% of patients had a serum thyroglobulin measurement within 6 and between 6 and 12 months before the survey, respectively. Thyroid simulating hormone (TSH) levels were measured within the prior 6 months in 67% of patients and between 6 and 12 months in 13.2%. The TSH levels were suppressed (< 0.1 μIU/L) in 24.2% of patients, 0.1–2 μIU/L in 44% and greater than 2 μIU/L in 17.6%. Ultrasonography was the most common imaging test performed.

Conclusion

There is significant variation in the follow-up patterns of patients with thyroid cancer, and there is considerable deviation from current ATA guidelines.     

Antimicrobial Distribution From Local Delivery Depends on Dose

Background

Tissue distribution after local delivery has been quantified over a period of 5 hours on 7-T MRI in a rabbit model using gadolinium-labeled diethylenetriamine pentaacetic acid (Gd-DTPA) as an antimicrobial surrogate; however, it is unknown how the Gd-DTPA load in a local depot will affect the duration of high-concentration Gd-DTPA in local tissues after surgical débridement.

Questions/purposes

We determined whether the Gd-DTPA load in bone cement affected its local tissue distribution over a period of 1 month after local delivery.

Methods

A 1-cm³ soft tissue dead space was created in the quadriceps of seven rabbits and filled with gadolinium-loaded bone cement. At 7, 14, and 33 days, the volume of tissue with a Gd-DTPA concentration of more than 14 μg/mL was calculated from T1-weighted images using 7-T MRI. Differences in volumes of distribution were analyzed with ANOVA.

Results

The volume of tissue with more than 14 μg/mL Gd-DTPA was much larger from higher gadolinium loads on Day 7 (p = 0.02) (2121 mm³ for 10 g and 665 mm³ for 1 g) and smaller with time for the 10-g formulation (2121 mm³ on Day 7 and 1241 mm³ on Day 14).

Conclusions

Volume of distribution and duration of Gd-DTPA after local delivery increased with increasing load in the cement and decreased with time.

Clinical Relevance

For local delivery, high antimicrobial concentrations would be expected in greater volumes of tissue, for longer durations, when higher antimicrobial loads are used.     

Nosocomial Transmission of Highly Resistant Microorganisms on a Spinal Cord Rehabilitation Ward

Background/Objective:

To study the mechanism of nosocomial transmission of highly resistant microorganisms (HRMOs).

Design:

A prospective observational study.

Setting:

A spinal cord ward of a rehabilitation center.

Participants:

Patients admitted to the spinal cord rehabilitation ward.

Outcome Measures:

HRMOs present in urine and feces. HRMOs, Enterobacteriaceae: (1) that produced an extended-spectrum β-lactamase (ESBL), (2) that were resistant to carbapenems, (3) that fluoroquinolones and aminoglycosides (for Escherichia coli and Klebsiella species), or other Enterobacteriaceae species that were resistant to 2 of 3 of the following types of antibiotics (fluoroquinolones, aminoglycosides, cotrimoxazole).

Methods:

Bacterial growth, identification and sensitivity were tested in urine cultures of 46 patients and faeces cultures of 15 patients. Data were collected on demographic characteristics, underlying diseases, reason and date of admission, room number, method of catheterization (suprapubic, clean intermittent catheterization or indwelling Foley catheter) and antibiotic use.

Results:

Nine different HRMOs (7 E coli, 1 Enterobacter cloacae, and 1 Citrobacter koseri) were isolated in urine samples from 15 patients. E coli resistant to gentamicin, tetracycline, amoxicillin, cotrimoxazole, and ciprofloxacin were isolated from 8 patients during the study (cluster 1). One strain of multiresistant E coli found before the start of the study was not found during the study period (cluster 2). E coli strains producing an ESBL and resistant to tetracycline, cotrimoxazole, and ciprofloxacin were isolated from urine samples of 3 patients (cluster 3). Ciprofloxacin-resistant E coli were present in feces of 3 patients (2 in cluster 1). Catheterization was found to be significantly more prevalent in patients with HRMOs. Most of the patients in cluster 1 were treated with antibiotics before the first isolation of the strain.

Conclusions:

HRMOs from urine samples were strongly correlated with the use of catheterization. A close correlation was found between prior use of antibiotics and colonization of the urinary tract on the level of the individual patient, which has been rarely described in the literature.     

Dietary habits and prostate cancer detection: a case–control study

Background

Many studies have suggested that nutritional factors may affect prostate cancer development. The aim of our study was to evaluate the relationship between dietary habits and prostate cancer detection.

Methods

We studied 917 patients who planned to have transrectal ultrasonography–guided prostatic biopsy based on an elevated serum prostate-specific antigen (PSA) level, a rising serum PSA level or an abnormal digital rectal examination. Before receiving the results of their biopsy, all patients answered a self-administered food frequency questionnaire. In combination with pathology data we performed univariable and multivariable logistic regression analyses for the predictors of cancer and its aggressiveness.

Results

Prostate cancer was found in 42% (386/917) of patients. The mean patient age was 64.5 (standard deviation [SD] 8.3) years and the mean serum PSA level for prostate cancer and benign cases, respectively, was 13.4 (SD 28.2) μg/L and 7.3 (SD 4.9) μg/L. Multivariable analysis revealed that a meat diet (e.g., red meat, ham, sausages) was associated with an increased risk of prostate cancer (odds ratio [OR] 2.91, 95% confidence interval [CI] 1.55–4.87, p = 0.027) and a fish diet was associated with less prostate cancer (OR 0.54, 95% CI 0.32–0.89, p = 0.017). Aggressive tumours were defined by Gleason score (≥ 7), serum PSA level (≥ 10 μg/L) and the number of positive cancer cores (≥ 3). None of the tested dietary components were found to be associated with prostate cancer aggressivity.

Conclusion

Fish diets appear to be associated with less risk of prostate cancer detection, and meat diets appear to be associated with a 3-fold increased risk of prostate cancer. These observations add to the growing body of evidence suggesting a relationship between diet and prostate cancer risk.     

Long-term follow-up and metal ion trend of patients with metal-on-metal total hip arthroplasty

Purpose

Long-term studies are required to support the use of metal-on-metal (MoM) bearings in total hip arthroplasty (THA) given the concern about systemic metal ion release and reports of adverse local soft tissue reactions. The purpose of this study was to report the seven to 13-year clinical, radiographic, and metal ion results in patients following MoM THA.

Methods

We studied 163 prostheses after second-generation MoM THA between July 1997 and November 2003. Cobalt and chromium metal ions were collected using whole and analysed by inductively-coupled plasma-mass spectrometry.

Results

The mean follow-up was 8.87 years (range, 7–13 years). Four hips (2.5 %) were revised. The Kaplan-Meier survivorship was 91.3 % for revision for all causes, and 97.5 % when excluding the hips revised for a manufacturer’s defect. Median whole blood cobalt levels peaked at a value of 2.87 μg/L at four years (p < 0.0001 vs. pre-operative) and subsequently decreased to 2.0 μg/L after nine years (p = 0.002 vs. four years). Median chromium levels maximally increased up to 0.75 μg/L after five years (p < 0.0001 vs. pre-operative) and tended to decrease thereafter to values of 0.56 μg/L after seven years.

Conclusions

This seven to 13-year follow-up study indicates that the clinical and radiological results following MoM THA are satisfactory with low revision rates. Cobalt and chromium ion levels peaked at four and five years, respectively, and gradually decreased thereafter.     

Neuroprotective therapy using granulocyte colony-stimulating factor for patients with worsening symptoms of compression myelopathy, part 1: a phase I and IIa clinical trial

Objective

Based on the neuroprotective effects of granulocyte colony-stimulating factor (G-CSF) on experimental spinal cord injury, we initiated a clinical trial that evaluated the safety and efficacy of neuroprotective therapy using G-CSF for patients with worsening symptoms of compression myelopathy.

Methods

We obtained informed consent from 15 patients, in whom the Japanese Orthopaedic Association (JOA) score for cervical myelopathy decreased two points or more during a recent 1-month period. G-CSF (5 or 10 μg/kg/day) was intravenously administered for five consecutive days. We evaluated motor and sensory functions of the patients and the presence of adverse events related to G-CSF therapy.

Results

G-CSF administration suppressed the progression of myelopathy in all 15 patients. Neurological improvements in motor and sensory functions were obtained in all patients after the administration, although the degree of improvement differed among the patients. Nine patients in the 10-μg group (n = 10) underwent surgical treatment at 1 month or later after G-CSF administration. In the 10-μg group, the mean JOA recovery rates 1 and 6 months after administration were 49.9 ± 15.1 and 59.1 ± 16.3%, respectively. On the day following the start of G-CSF therapy, the white blood cell count increased to more than 22,700 cells/mm³. It varied from 12,000 to 50,000 and returned to preadministration levels 3 days after completing G-CSF treatment. No serious adverse events occurred during or after treatment.

Conclusion

The results indicate that G-CSF administration at 10 μg/kg/day is safe for patients with worsening symptoms of compression myelopathy and may be effective for their neurological improvement.     

Does Vitamin E-blended UHMWPE Prevent Biofilm Formation?

Background

Biofilm-related periprosthetic infections are catastrophic to patients and clinicians. Data suggest the addition of vitamin E to UHMWPE may have the ability to reduce biofilm formation on the surface of UHMWPE; however, previous studies were performed using stagnant broth solutions that may not have simulated a physiologic environment. In addition, the observed differences in levels of bacterial attachment, though statistically significant, may not be clinically significant.

Questions/purposes

We blended vitamin E with UHMWPE material and tested it for the ability to resist biofilm formation using a clinical isolate of methicillin-resistant Staphylococcus aureus (MRSA). Three additional materials were tested for comparison: highly crosslinked UHMWPE, compression-molded UHMWPE, and polyetheretherketone. We also determined whether the surface roughness of these materials facilitated biofilm formation.

Methods

Using a flow cell system, samples of each material type were placed into separate chambers. A 10% solution of brain-heart infusion broth containing 10⁵ colony-forming units (CFUs)/mL was flowed through the flow cell over 48 hours. The number of bacteria that adhered to the surface was quantified and biofilm formation was observed qualitatively using scanning electron microscopy. Optical profilometry was used to determine the surface roughness of each material type.

Results

Vitamin E-blended UHMWPE did not reduce biofilm formation of a clinically relevant strain of MRSA compared to materials that did not have vitamin E. More specifically, vitamin E-blended materials had similar amounts of biofilm formation (~ 8 log₁₀ CFUs/cm²) compared to materials not containing vitamin E (~ 8.1 log₁₀ CFUs/cm²) (p > 0.4). The roughness of vitamin E-blended material surfaces (mean ± SD: 1.85 ± 0.46 µm) compared to that of materials without vitamin E (2.06 ± 1.24 µm) did not appear to influence biofilm formation.

Conclusions

Under physiologically relevant conditions, vitamin E-blended UHMWPE did not have the ability to reduce the formation of biofilms by MRSA.

Clinical Relevance

These data indicate that the addition of vitamin E to UHMWPE may not reduce clinically relevant rates of biofilm-related periprosthetic infections of total joint arthroplasty devices.     

Fast-Track Management of Patients Undergoing Proximal Pancreatic Resection

INTRODUCTION

To avoid the risk of complications of biliary drainage, a feasibility study was carried out to determine whether it might be possible to fast-track surgical treatment, with resection before biliary drainage, in jaundiced patients with proximal pancreatic/peri-ampullary malignancy.

PATIENTS AND METHODS

Over an 18-month period, based on their presenting bilirubin levels and other logistical factors, all jaundiced patients who might be suitable for fast-track management were identified. Data on complications and hospital stay were compared with those patients in whom a conventional pathway (with biliary drainage) was used during the same time period. Data were also compared with a group of patients from the preceding 6 months.

RESULTS

Nine patients were fast-tracked and 49 patients treated in the conventional pathway. Fast-track patients mean (SD) serum bilirubin level was 265 μmol/l (81.6) at the time of the operation compared to 43 μmol/l (51.3; P ≥ 0.0001) in conventional patients. Mean (SD) of time from referral to operation, 14 days (9) versus 59 days (36.9), was significantly shorter in fast-track patients than conventional patients (P ≤ 0.0001). Length of hospital stay mean (SD) at 17 (6) days versus 22 days (19.6; P = 0.2114), surgical complications and mortality in fast-track patients were similar to conventional patients. Prior to surgery, the 49 conventional patients underwent a total of 73 biliary drainage procedures resulting in seven major complications. Comparison with the group of patients from the previous 6 months indicated that the conventional group were not disadvantaged.

CONCLUSIONS

Fast-track management by resection without biliary drainage of selected patients with distal biliary strictures is safe and has the potential to reduce the waiting time to surgery, overall numbers of biliary drainage procedures and the complications thereof.     

Low dose short duration pulsed electromagnetic field effects on cultured human chondrocytes: An experimental study

Background:

Pulsed electromagnetic field (PEMF) is used to treat bone and joint disorders for over 30 years. Recent studies demonstrate a significant effect of PEMF on bone and cartilage proliferation, differentiation, synthesis of extracellular matrix (ECM) and production of growth factors. The aim of this study is to assess if PEMF of low frequency, ultralow field strength and short time exposure have beneficial effects on in-vitro cultured human chondrocytes.

Materials and Methods:

Primary human chondrocytes cultures were established using articular cartilage obtained from knee joint during joint replacement surgery. Post characterization, the cells were exposed to PEMF at frequencies ranging from 0.1 to 10 Hz and field intensities ranging from 0.65 to 1.95 μT for 60 min/day for 3 consecutive days to analyze the viability, ECM component synthesis, proliferation and morphology related changes post exposure. Association between exposure doses and cellular effects were analyzed with paired''t’ test.

Results:

In-vitro PEMF exposure of 0.1 Hz frequency, 1.95 μT and duration of 60 min/day for 3 consecutive days produced the most favorable response on chondrocytes viability (P < 0.001), ECM component production (P < 0.001) and multiplication. Exposure of identical chondrocyte cultures to PEMFs of 0.65 μT field intensity at 1 Hz frequency resulted in less significant response. Exposure to 1.3 μT PEMFs at 10 Hz frequency does not show any significant effects in different analytical parameters.

Conclusions:

Short duration PEMF exposure may represent a new therapy for patients with Osteoarthritis (OA).     

Who’s too old to screen? Prostate cancer in elderly men

Introduction:

Prostate cancer is the most common nonskin malignancy affecting men and is the second leading cause of cancer-related death in North America. The incidence of prostate cancer increases dramatically with age. However, many health authorities advocate the cessation of routine prostate cancer testing in men older than 75 because of the belief that most patients will have a clinically insignificant cancer and will not benefit from therapy. The true prevalence of clinically significant prostate cancer in elderly men is not known.

Methods:

We analyzed 1446 needle biopsies of the prostate in men aged 75 or older. All pathological reviews were conducted by the pathology department at the Methodist Hospital in Houston, Tex. Data were collected from pathology reports, hospital and clinic databases, and medical records when available. Data obtained included age at biopsy, serum prostate-specific antigen (PSA) levels, number of positive core biopsies and Gleason grade. Statistical analysis was performed using Stata. Clinically significant cancer was defined by the pathological presence of Gleason grade 6 adenocarcinoma in more than 1 biopsy core or the presence of any Gleason 4 or 5 component in the biopsy.

Results:

The median age of the patients included in the study was 78.8 and 95% of the patients were between the ages of 75 and 85. The mean serum PSA level for patients biopsied was 10.4 μg/L. Of all biopsies reviewed, 53% were positive for prostate cancer and 78% of these would be defined as clinically significant cancer. Regression analysis revealed age to be a significant (p < 0.05) factor for increased Gleason grade in positive biopsies. Logistic regression revealed age as a significant factor (p < 0.05) for clinically significant prostate cancer even when controlling for PSA. A serum PSA threshold value of 6.5 μg/L would have missed 38% of significant cancers and a threshold of 4.0 μg/L would have missed 8% of significant cancers.

Conclusion:

Our findings suggest that the prevalence of clinically significant prostate cancer in the elderly population may be higher than previously thought. As the population continues to live longer and healthier lives, it will become more common to confront prostate cancer morbidity in the eldery population. Using higher serum PSA thresholds to eliminate unnecessary biopsies in older men does not appear to help identify patients at greater risk of having clinically significant prostate cancer. Patients with prostate cancer having aggressive clinical features may benefit from treatment of their prostate cancer well into their eighth and ninth decades of life. Testing and diagnostic recommendations should reflect the potential benefit of identifying patients with aggressive prostate cancer even after age 75.