What Factors Are Associated With Local Metastatic Lesion Progression After Intramedullary Nail Stabilization?

BACKGROUND: Pathologic fracture of the long bones is a common complication of bone metastases. Intramedullary nail stabilization can be used prophylactically (for impending fractures) or therapeutically (for completed fractures) to preserve mobility and quality of life. However, local disease progression may occur after such treatment, and there is concern that surgical instrumentation and the intramedullary nail itself may seed tumor cells along the intramedullary tract, ultimately leading to loss of structural integrity of the construct. Identifying factors associated with local disease progression after intramedullary nail stabilization would help surgeons predict which patients may benefit from alternative surgical strategies. QUESTIONS/PURPOSES: (1) Among patients who underwent intramedullary nail stabilization for impending or completed pathologic fractures of the long bones, what is the risk of local progression, including progression of the existing lesion and development of a new lesion around the nail? (2) Among patients who experience local progression, what proportion undergo reoperation? (3) What patient characteristics and treatment factors are associated with postoperative local progression? (4) What is the difference in survival rates between patients who experienced local progression and those with stable local disease? METHODS: Between January 2013 and December 2019, 177 patients at our institution were treated with an intramedullary nail for an impending or completed pathologic fracture. We excluded patients who did not have a pathologic diagnosis of metastasis before fixation, who were younger than 18 years of age, who presented with a primary soft tissue mass that eroded into bone, and who experienced nonunion from radiation osteitis or an avulsion fracture rather than from metastasis. Overall, 122 patients met the criteria for our study. Three fellowship-trained orthopaedic oncology surgeons involved in the care of these patients treated an impending or pathologic fracture with an intramedullary nail when a long bone lesion either fractured or was deemed to be of at least 35% risk of fracture within 3 months, and in patients with an anticipated duration of overall survival of at least 6 weeks (fractured) or 3 months (impending) to yield palliative benefit during their lifetime. The most common primary malignancy was multiple myeloma (25% [31 of 122]), followed by lung carcinoma (16% [20 of 122]), breast carcinoma (15% [18 of 122]), and renal cell carcinoma (12% [15 of 122]). The most commonly involved bone was the femur (68% [83 of 122]), followed by the humerus (27% [33 of 122]) and the tibia (5% [6 of 122]). A competing risk analysis was used to determine the risk of progression in our patients at 1 month, 3 months, 6 months, and 12 months after surgery. A proportion of patients who ultimately underwent reoperation due to progression was calculated. A univariate analysis was performed to determine whether lesion progression was associated with various factors, including the age and sex of the patient, use of adjuvant therapies (radiation therapy at the site of the lesion, systemic therapy, and antiresorptive therapy), histologic tumor type, location of the lesion, and fracture type (impending or complete). Patient survival was assessed with a Kaplan-Meier curve. A p value < 0.05 was considered significant. RESULTS: The cumulative incidence of local tumor progression (with death as a competing risk) at 1 month, 3 months, 6 months, and 12 months after surgery was 1.9% (95% confidence interval 0.3% to 6.1%), 2.9% (95% CI 0.8% to 7.5%), 3.9% (95% CI 1.3% to 8.9%), and 4.9% (95% CI 1.8% to 10.3%), respectively. Of 122 patients, 6% (7) had disease progression around the intramedullary nail and 0.8% (1) had new lesions at the end of the intramedullary nail. Two percent (3 of 122) of patients ultimately underwent reoperation because of local progression. The only factors associated with progression were a primary tumor of renal cell carcinoma (odds ratio 5.1 [95% CI 0.69 to 29]; p = 0.03) and patient age (difference in mean age 7.7 years [95% CI 1.2 to 14]; p = 0.02). We found no associations between local disease progression and the presence of visceral metastases, other skeletal metastases, radiation therapy, systemic therapy, use of bisphosphonate or receptor activator of nuclear factor kappa-B ligand inhibitor, type of fracture, or the direction of nail insertion. There was no difference in survivorship curves between those with disease progression and those with stable local disease (= 0.36; p = 0.54). CONCLUSION: Our analysis suggests that for this population of patients with metastatic bone disease who have a fracture or impeding fracture and an anticipated survival of at least 6 weeks (completed fracture) or 3 months (impending fracture), the risk of experiencing local progression of tumor growth and reoperations after intramedullary nail stabilization seems to be low. Lesion progression was not associated with the duration of survival, although this conclusion is limited by the small number of patients in the current study and the competing risks of survival and local progression. Based on our data, patients who present with renal cell carcinoma should be cautioned against undergoing intramedullary nailing because of the risk of postoperative lesion progression. LEVEL OF EVIDENCE: Level III, therapeutic study.

Bisphosphonate Therapy for Treating Osteonecrosis in Pediatric Leukemia Patients: A Systematic Review.

BACKGROUND: Despite improved outcomes in children with leukemia, complications such as osteonecrosis are common. We conducted a systematic review to investigate the role of bisphosphonates in reducing pain, improving mobility, and stabilizing lesions in pediatric leukemia survivors. METHODS: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched the PubMed, Embase, Cochrane, Web of Science, Scopus, CINAHL, and ClinicalTrials.gov databases. Five of 221 articles retrieved met our inclusion criteria. RESULTS: Bisphosphonates, especially when combined with dietary calcium and vitamin D supplements and physical therapy (supplements/PT) were associated with improved pain and mobility in 54% and 50% of patients, respectively. A significantly greater proportion of patients treated with bisphosphonates (83%) reported mild/moderate pain or no pain compared with those with supplements/PT alone (36%) (P<0.001). Sixty-six percent of patients treated with bisphosphonates achieved improved/full mobility compared with 27% of those treated with supplements/PT alone (P=0.02). However, 46% of patients showed progressive joint destruction despite bisphosphonate therapy. No adverse events were reported, except for acute phase reactions to intravenous therapies. CONCLUSIONS: Bisphosphonates, when combined with supplements/PT, were associated with less pain and improved mobility, but not prevention of joint destruction in pediatric leukemia patients with osteonecrosis.

Adjuvant MRI-guided percutaneous cryoablation treatment for aneurysmal bone cyst.

Aneurysmal bone cysts are benign, expansile, lytic bone lesions that behave in a locally aggressive manner. Although radiography and computed tomography (CT) can detect the lesion, magnetic resonance imaging (MRI) is ideal for the demonstration of characteristic fluid-fluid levels, extent, and margins. Treatment typically consists of open surgical curettage with the addition of local adjuvants and bone grafting. Residual or recurring lesions may be treated using percutaneous cryoablation. Although CT guidance is often employed for image guidance, visualization and targeting of smaller clusters can be challenging in young children, secondary to the partially mineralized bone matrix in the immature skeleton. In such cases, the higher contrast resolution of interventional MRI affords direct visualization and targeting of small aneurysmal bone cysts, accurate monitoring of the extent of the growing ice ball beyond the lesion's margin, and avoidance of exposure to ionizing radiation. We report a case of a 5-year-old boy with recurrent or remaining aneurysmal bone cysts of the scapula after surgical excision and embolization, which were successfully treated using MRI-guided cryoablation.

Simulation model to predict the fate of ciprofloxacin in the environment after wastewater treatment.

The extent hospital effluent contributes to antimicrobial presence in the environment and its impact on resistance dissemination remains unknown. To investigate the fate of the antimicrobial ciprofloxacin in hospital effluent a Monte Carlo simulation model was developed to model levels from hospital use to wastewater treatment plant (WWTP) effluent release, in addition to modeling resistance formation potential, hazard quotient (HQ) and swimmer exposure. The mean predicted concentration (PC) of ciprofloxacin in hospital effluent, urban effluent, WWTP effluent, sludge, soil and sea water was 579, 6.06, 2.59, 3.48, 0.006 and 0.15 mg/m(3), respectively. A parallel surveillance study confirmed levels of ciprofloxacin above or below the limit of detection. The model predicted levels would never exceed the ECOSAR toxicity value. The model predicted a 98% probability of ciprofloxacin exhibiting a HQ > 1 (low toxicity concern). The mean ciprofloxacin PC in WWTP effluent was less than the minimum inhibitory concentration (MIC). The probability of conditions in WWTP effluent being favorable for resistance at 20% and 80% of the MIC was 3% and 72%, respectively. In all instances, when the MIC was bound, the probability for resistance formation within soil and sea water was < 1%. The probability of a swimmer being exposed to a level of ciprofloxacin greater than the acceptable daily intake was negligible. The study concluded that release of hospital effluent into the environment may lead to concentrations of ciprofloxacin which are of low toxicity concern but may be conducive to resistance formation and allow for the dissemination of resistance.

Characterization and in vitro immunomodulatory screening of fructo-oligosaccharides of Asparagus racemosus Willd.

Asparagus racemosus Linn. (Fam. Liliaceae) is an ethno-pharmacologically acclaimed Ayurvedic medicinal plant. In the present study, aqueous extract of A. racemosus (ARC) was fractionated and screened for the polysaccharide fraction (ARP). The characterization was done by enzymatic, Size Exclusion, gas chromatography with flame ionization detector (GC-FID), high pressure anion exchange chromatography (HPAEC) and thin layer chromatographic analyses. Phyto-chemical evaluation confirmed the presence of 26.7% of 2→1 linked fructo-oligosaccharides (FOS). They have a degree of polymerization (DP) of nearly 7-8. Cytotoxicity evaluation on P388 cell lines was consistent with low cytotoxicity of the extracts. In vitro Natural Killer (NK) cell activity was evaluated using human peripheral blood mononuclear cells (PBMC) isolated from whole blood on a ficoll-hypaque density gradient. K562 a myeloid leukemia cell line, were used as target cells. ARC, tested over the range 0.2-50 µg/ml, showed a dose-related stimulation of NK cell activity with a peak increase of 16.9±4.4% at 5.6 µg/ml. However, ARP demonstrated a higher stimulatory activity of 51.8±1.2% at 25 µg/ml. The results indicate that the FOS from A. racemosus potentiates the NK cell activity and this could be an important mechanism underpinning the 'Rasayana' properties of this plant.

Immunomodulatory Polysaccharide from Chlorophytum borivilianum Roots.

Chlorophytum borivilianum Santapau & Fernandes (Liliaceae) is an ayurvedic Rasayana herb with immunostimulating properties. The polysaccharide fraction (CBP) derived from hot water extraction of C. borivilianum (CB), comprising of ∼31% inulin-type fructans and ∼25% acetylated mannans (of hot water-soluble extract), was evaluated for its effect on natural killer (NK) cell activity (in vitro). Human peripheral blood mononuclear cells (PBMCs), isolated from whole blood on a Ficoll-Hypaque density gradient, were tested in the presence or absence of varying concentrations of each C. borivilianum fraction for modulation of NK cell cytotoxic activity toward K562 cells. Preliminary cytotoxicity evaluation against P388 cells was performed to establish non-cytotoxic concentrations of the different fractions. Testing showed the observed significant stimulation of NK cell activity to be due to the CBP of C. borivilianum. Furthermore, in vivo evaluation carried out on Wistar strain albino rats for humoral response to sheep red blood cells (SRBCs) and immunoglobulin-level determination using enzyme-linked immunosorbent assay (ELISA), exhibited an effectiveness of C. borivilianum aqueous extract in improving immune function. Present results provide useful information for understanding the role of CBP in modulating immune function.

A combined Phase I and II open-label study on the immunomodulatory effects of seaweed extract nutrient complex.

BACKGROUND: Isolated fucoidans from brown marine algae have been shown to have a range of immune-modulating effects. This exploratory study aimed to determine whether a seaweed nutrient complex containing a blend of extracts from three different species of brown algae plus nutrients is safe to administer and has biological potential as an immune modulator. The study was undertaken as an open-label combined Phase I and II study. METHODS: Participants (n = 10) were randomized to receive the study medication at either a 100 mg (n = 5) or 1000 mg (n = 5) dose over 4 weeks. The primary outcome measurement was in vivo changes in lymphocyte subsets. The secondary outcome measures were ex vivo changes in T-lymphocyte (CD4 and CD8) activation, phagocytosis of granulocytes and monocytes, T helper 1/T helper 2 cytokines, and serum oxygen radical absorbance capacity. RESULTS: The preparation was found to be safe over the 4 weeks at both doses tested. There were no clinically relevant changes to blood measurements of hemopoietic, hepatic, or renal function. Immunomodulatory measurements showed no dose response between the two doses. The combined results from the two doses demonstrated a significant increase in cytotoxic T cell numbers and phagocytic capacity in monocytes, and a significant decrease in levels of the inflammatory cytokine interleukin 6. A separate analysis of the 100 mg dose (n = 5) alone showed a significant linear component over time (P < 0.05) for phagocytosis by both granulocytes and monocytes. CONCLUSION: The seaweed nutrient complex was safe to use when taken orally over 4 weeks. The preparation was demonstrated to have potential as an immune modulator, and this bioactivity deserves further exploration.

A forced titration study of the antioxidant and immunomodulatory effects of Ambrotose AO supplement.

BACKGROUND: Oxidative stress plays a role in acute and chronic inflammatory disease and antioxidant supplementation has demonstrated beneficial effects in the treatment of these conditions. This study was designed to determine the optimal dose of an antioxidant supplement in healthy volunteers to inform a Phase 3 clinical trial. METHODS: The study was designed as a combined Phase 1 and 2 open label, forced titration dose response study in healthy volunteers (n = 21) to determine both acute safety and efficacy. Participants received a dietary supplement in a forced titration over five weeks commencing with a no treatment baseline through 1, 2, 4 and 8 capsules. The primary outcome measurement was ex vivo changes in serum oxygen radical absorbance capacity (ORAC). The secondary outcome measures were undertaken as an exploratory investigation of immune function. RESULTS: A significant increase in antioxidant activity (serum ORAC) was observed between baseline (no capsules) and the highest dose of 8 capsules per day (p = 0.040) representing a change of 36.6%. A quadratic function for dose levels was fitted in order to estimate a dose response curve for estimating the optimal dose. The quadratic component of the curve was significant (p = 0.047), with predicted serum ORAC scores increasing from the zero dose to a maximum at a predicted dose of 4.7 capsules per day and decreasing for higher doses. Among the secondary outcome measures, a significant dose effect was observed on phagocytosis of granulocytes, and a significant increase was also observed on Cox 2 expression. CONCLUSION: This study suggests that Ambrotose AO(R) capsules appear to be safe and most effective at a dosage of 4 capsules/day. It is important that this study is not over interpreted; it aimed to find an optimal dose to assess the dietary supplement using a more rigorous clinical trial design. The study achieved this aim and demonstrated that the dietary supplement has the potential to increase antioxidant activity. The most significant limitation of this study was that it was open label Phase 1/Phase 2 trial and is subject to potential bias that is reduced with the use of randomization and blinding. To confirm the benefits of this dietary supplement these effects now need to be demonstrated in a Phase 3 randomised controlled trial (RCT). TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Register: ACTRN12605000258651.

A combined phase I and II open label study on the effects of a seaweed extract nutrient complex on osteoarthritis.

BACKGROUND: Isolated fucoidans from brown marine algae have been shown to have a range of anti-inflammatory effects. PURPOSE: This present study tested a Maritech((R)) extract formulation, containing a blend of extracts from three different species of brown algae, plus nutrients in an open label combined phase I and II pilot scale study to determine both acute safety and efficacy in osteoarthritis of the knee. PATIENTS AND METHODS: Participants (n = 12, five females [mean age, 62 +/- 11.06 years] and seven males [mean age, 57.14 +/- 9.20 years]) with a confirmed diagnosis of osteoarthritis of the knee were randomized to either 100 mg (n = 5) or 1000 mg (n = 7) of a Maritech((R)) extract formulation per day. The formulation contained Maritech((R)) seaweed extract containing Fucus vesiculosis (85% w/w), Macrocystis pyrifera (10% w/w) and Laminaria japonica (5% w/w) plus vitamin B6, zinc and manganese. Primary outcome was the average comprehensive arthritis test (COAT) score which is comprised of four sub-scales: pain, stiffness, difficulty with physical activity and overall symptom severity measured weekly. Safety measures included full blood count, serum lipids, liver function tests, urea, creatinine and electrolytes determined at baseline and week 12. All adverse events were recorded. RESULTS: Eleven participants completed 12 weeks and one completed 10 weeks of the study. Using a multilevel linear model, the average COAT score was reduced by 18% for the 100 mg treatment and 52% for the 1000 mg dose at the end of the study. There was a clear dose response effect seen between the two treatments (P

Bovine lactoferrin supplementation supports immune and antioxidant status in healthy human males.

Dietary supplements of bovine lactoferrin are purported in consumer literature to enhance and support the immune system response through their antioxidant, antibacterial, and antiviral properties. Our aim was to investigate more fully the potential immune modulating properties and antioxidant activity of an oral supplementation of bovine lactoferrin in humans. Using an intraindividual repeated measure design, 8 healthy males aged 30 to 55 years, self-administered daily for 21 days, one capsule of placebo for 7 days, followed by 100 mg of lactoferrin for 7 days, followed by 200 mg of lactoferrin for 7 days. Peripheral blood lymphocyte subset counts, T-cell activation, natural killer (NK) cell cytotoxicity, serum cytokine levels (tumor necrosis factor [TNF]-alpha, interferon [IFN]-gamma, interleukin [IL]-2, IL-4, IL-6, and IL-10), and serum hydrophilic, lipophilic, and total antioxidant capacity were repeatedly measured before and after each progressive supplementation. Statistically significant increases were found between presupplementation levels and levels after 200 mg of supplementation in total T-cell activation (as measure by CD3(+)) (P < .001), helper T-cell activation (as measure by CD4(+)) (P < .001), cytotoxic T-cell activation (as measured by CD8(+)) (P < .001), and hydrophilic antioxidant capacity (P < .05). No significant changes were seen in the other parameters measured. These results support the proposal that oral supplements of bovine lactoferrin may be a useful adjunct toward modulation of immune activity, in particular T-cell activation and antioxidant status.

Lymphatic spread of pagetic osteogenic sarcoma detected by bone scan.

Bone scans are widely utilized for detection of metastases from bone sarcomas. Technetium methylene diphosphonate scan ([(99m)Tc]MDP) is one of the most popular radiotracers used for that purpose. Lymphatic spread of bone sarcomas is unusual and often difficult to diagnose. Unfortunately, bone scans are not as sensitive in demonstrating lymphatic spread of sarcomas as they are at demonstrating hematogenous spread. A bone scan will often fail to demonstrate lymph nodes metastases until there is mineralization at the affected node. In this report, we highlight an interesting case of a patient with secondary osteogenic sarcoma (OS) from Paget's disease in the distal femur with non-ossified inguinal nodal metastasis diagnosed with [(99m)Tc]MDP. Lymph node involvement was not appreciated on plain radiographs or computed tomography (CT).

Prospective identification of risk factors for wound infection after lower extremity oncologic surgery.

BACKGROUND: Surgical site infections (SSI) are frequent causes of morbidity and mortality after orthopaedic oncologic procedures. This study was conducted to identify the surgical site infection rate following a lower extremity or pelvic procedure and assess the risk factors for acquiring SSI by direct observation of orthopaedic oncology patients' wounds at a comprehensive cancer center. METHODS: One hundred ten consecutive patients were prospectively studied. The surveillance of surgical site infections was carried out by a surgeon-trained nurse from the Infectious Disease Service. Nineteen variables were analyzed as risk factors. RESULTS: The overall SSI rate was 13.6% (15 of 110). Excluding those patients with known preoperative infections, the SSI rate was 9.5% (10 of 105). Two statistically significant risk factors for surgical site infection in these patients emerged in the multivariate analysis: blood transfusion (P =.007) and obesity (P =.016). Procedure category was significant in univariate analysis only. Preoperative length of stay, length of procedure, prior adjuvant treatment (chemotherapy or radiotherapy), prior surgery, and use of an implant or allograft were not statistically significant risk factors for wound infection. Antibiotic usage patterns did not influence SSI rate. CONCLUSIONS: Blood transfusion and obesity should be considered individual risk factors for the development of wound infection in patients having orthopaedic oncologic procedures.