Use of light activated intramedullary device for revision of a proximal humerus fracture: a case study.

BACKGROUND: Post-operative non-compliance is a risk factor for fracture fixation failure and presents a challenge for revision surgery planning. We present a patient who underwent revision surgery for a proximal humerus fracture with lateral locked plating augmented with a UV light activated intramedullary implant. CASE: A 45-year-old woman with a history of alcoholism presented with a proximal humerus fracture. After undergoing open reduction internal fixation with a lateral locking plate, the patient suffered a fall secondary to delirium tremens. New radiographs demonstrated displacement of the fracture with failure of screws. Revision surgery consisting of removal of the initial construct as well as open reduction internal fixation via lateral locking plate, augmented with a UV-activated intramedullary cement implant, was performed. CONCLUSION: This is the first case report describing the use of a UV-activated intramedullary cement implant to augment the use of lateral locked plating for proximal humerus fractures. This case illustrates the successful management using UV-activated intramedullary cement to augment fixation, specifically in a patient with risk factors and post-operative non-compliance that predispose to fixation failure.

Heterotopic ossification in the knee following retrograde nailing of a femur fracture.

BACKGROUND: Heterotopic ossification (HO) is a pathologic bone formation in extra skeletal tissue and articular space. This was an objection to nailing of femur fractures across the knee; however, this has not been the case in many thousands of cases. Nonetheless, we present a patient in who placement of a retrograde nail resulted in calcification in the knee requiring excision. CASE PRESENTATION: A 42-year-old male presented to the clinic complaining of pain, popping, clicking, and mocking in the right knee, especially in the patellar region. Nine months prior he suffered an ipsilateral femur fracture that was treated with a retrograde intramedullary nail. X-ray and CT scan were used to confirm the presentation of a heterotopic bone mass in the Hoffa area of the right knee. The patient underwent an arthrotomy for excision of the bone mass. The bone mass was excised, but bone in the ACL was not removed. The patient experienced pain relief and improved range of motion following excision. CONCLUSION: Intraarticular heterotopic ossification is an infrequent event. We present a case of heterotopic ossification in the knee following retrograde nailing. The patient experienced improved symptoms and range of motion after excision of the intraarticular heterotopic bone mass.

Intramedullary nailing of concurrent ipsilateral fractures of the tibia and femur: primary synchronous nailing versus staged osteosynthesis with temporizing external fixation.

INTRODUCTION: The optimal timing to definitive osteosynthesis in the polytraumatized patient remains an unanswered question. Early total care, damage control orthopaedics, and early appropriate care have been described to manage the fractures in these patients, but there is a paucity of literature specific to ipsilateral tibial and femoral fractures. We sought the perioperative outcomes of primary simultaneous intramedullary nailing (IMN) versus temporizing external fixation (EF) of both fractures. METHODS: A chart review of all patients who sustained fractures of the ipsilateral femur and tibia that were definitively treated with (IMN) from January 2010 to December 2020 was performed. Patients who underwent initial EF and those that were primarily treated with IMNs were examined. RESULTS: IMNs and EF were the initial treatment in 23 and 16 patients, respectively. The mean (range) injury severity score (ISS) was 23.3 (33) in the EF group vs. 18.5 (34) in the IMN group, (p = 0.0686). The EF group had a higher total transfused units of packed red blood cells 7.4 vs. 2.8, the mean initial operative time was 236 vs. 282.6 (min), (p = 0.7399), a longer mean total operative time 601.78 vs. 236 (min), and longer mean length of stay 15.6 vs. 11 (days), (p < 0.5). Rates of complications were not significantly different between groups. CONCLUSION: Primary IMN is as safe as provisional EF in the adequately resuscitated patient with ipsilateral femoral and tibial fractures. This implies the fixation of both fractures into a single surgery without increasing perioperative complications, and decreasing total hospital stay in patients with sufficient preoperative resuscitation.

Histone acetylation regulates intracellular pH.

Differences in global levels of histone acetylation occur in normal and cancer cells, although the reason why cells regulate these levels has been unclear. Here we demonstrate a role for histone acetylation in regulating intracellular pH (pH(i)). As pH(i) decreases, histones are globally deacetylated by histone deacetylases (HDACs), and the released acetate anions are coexported with protons out of the cell by monocarboxylate transporters (MCTs), preventing further reductions in pH(i). Conversely, global histone acetylation increases as pH(i) rises, such as when resting cells are induced to proliferate. Inhibition of HDACs or MCTs decreases acetate export and lowers pH(i), particularly compromising pH(i) maintenance in acidic environments. Global deacetylation at low pH is reflected at a genomic level by decreased abundance and extensive redistribution of acetylation throughout the genome. Thus, acetylation of chromatin functions as a rheostat to regulate pH(i) with important implications for mechanism of action and therapeutic use of HDAC inhibitors.

Does an antibiotic nail made in a lubricated tube release antibiotic?

INTRODUCTION: The treatment of long-bone osteomyelitis has long been a difficult problem. Recently, antibiotic-impregnated intramedullary rods for the treatment of infected long-bone fractures have been gaining popularity but they are quite difficult to fabricate. Recently, a new technique that utilizes mineral oil to coat the inside of a chest tube mold prior to introduction of cement has been proven to ease fabrication. We hypothesized that the use of mineral oil would alter the elution characteristics of tobramycin from the intramedullary device. METHODS: Two groups of antibiotic nails were fabricated under sterile conditions. The control group utilized a chest tube mold. The study group utilized a chest tube that was coated with mineral oil prior to cement injection. Each intramedullary nail was placed in pooled human serum and incubated under physiologic conditions. The level of tobramycin in each sample was measured at timepoints 0, 1, 6, and 24 h. RESULTS: There was no significant difference when comparing control with the experimental group at any timepoint. Antibiotic nails eluted tobramycin at a rapid rate in the first 6 h of exposure to serum, regardless of their preparation with oil or without oil. The rate of elution fell precipitously between 6 and 24 h. CONCLUSION: We believe that although this study, as with any study, cannot perfectly recreate in vivo conditions, we have clearly shown that mineral oil has no significant effect on elution of tobramycin from antibiotic nails.

Rifampin and tobramycin combination with PMMA antibiotic cement.

Rifampin is a powerful antibiotic used in the treatment of biofilm-forming bacteria with studies supporting its use in PMMA cement. However, it has not been widely accepted for its use in PMMA cement due to a perception that it is unable to solidify in a timely manner. The technique described consists of ratio of aminoglycoside and rifampin that reduces time to solidification to approximately 15-20 min.

Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles.

Therapeutics that are designed to engage RNA interference (RNAi) pathways have the potential to provide new, major ways of imparting therapy to patients. Long, double-stranded RNAs were first shown to mediate RNAi in Caenorhabditis elegans, and the potential use of RNAi for human therapy has been demonstrated by the finding that small interfering RNAs (siRNAs; approximately 21-base-pair double-stranded RNA) can elicit RNAi in mammalian cells without producing an interferon response. We are at present conducting the first in-human phase I clinical trial involving the systemic administration of siRNA to patients with solid cancers using a targeted, nanoparticle delivery system. Here we provide evidence of inducing an RNAi mechanism of action in a human from the delivered siRNA. Tumour biopsies from melanoma patients obtained after treatment show the presence of intracellularly localized nanoparticles in amounts that correlate with dose levels of the nanoparticles administered (this is, to our knowledge, a first for systemically delivered nanoparticles of any kind). Furthermore, a reduction was found in both the specific messenger RNA (M2 subunit of ribonucleotide reductase (RRM2)) and the protein (RRM2) levels when compared to pre-dosing tissue. Most notably, we detect the presence of an mRNA fragment that demonstrates that siRNA-mediated mRNA cleavage occurs specifically at the site predicted for an RNAi mechanism from a patient who received the highest dose of the nanoparticles. Together, these data demonstrate that siRNA administered systemically to a human can produce a specific gene inhibition (reduction in mRNA and protein) by an RNAi mechanism of action.

Antibiotic-laden PMMA bead chains for the prevention of infection in compound fractures: current state of the art.

Antibiotic-laden PMMA bead chains are a valuable method of local antibiotic treatment in the prevention of infection in open fractures. When used in this setting, they provide high concentrations of broad-spectrum antibiotics to the area of the highest risk which may not be well perfused or reached by systemic antibiotics, while also eliminating dead space. In this article, the historical and current state of antibiotic-laden bead chains is discussed. The literature provides evidence that antibiotic-laden bead chains are a useful adjuvant with systemic antibiotics in the prevention of infection in open fractures. These bead chains can be sterilely prepared in the operating room or manufactured, and they maintain their elution and antimicrobial properties for a considerable time period. The bead chains also allow a high local concentration of antibiotics without risk of systemic toxicity or fear of clinically significant growth or persistence of bacteria on the beads. Bead chains are a practical method of local antibiotic therapy when the wounds can be closed.

Medial malleolus screws: out in one view and out.

Cartilage damage or mechanical blocking from screw penetration into intra-articular cartilage can reduce the chances of successful outcomes during medial malleolus fixation. There have been diverging opinions among surgeons concerning the reliability of radiographic assessment of fracture fixation and malleolus screw positioning. Therefore, this radiographic study examines the location of medial malleolus lag screws relative to the ankle mortise articular surface. In three Sawbones models, Kirschner wires were overdrilled with a 4.0-mm cannulated cortical screw simulating screws that would be intra- and extra-articular when performing open reduction and internal fixation of a medial malleolar fracture. Under fluoroscopy, images were evaluated to determine whether known intra-articular screws appeared extra-articular in any radiographic view. No image from models with known intra-articular penetration appeared extra-articular in any view or under "live" fluoroscopy. At 20° internal rotation, a screw with a known extra-articular position appeared to be within the cartilage. Intra-operative fluoroscopy is necessary to ensure proper extra-articular placement of screws. If a screw is pictured extra-articular in any radiograph, then it can be assumed that the screw is indeed out of the joint.

Complications of operative treatment of clavicle fractures in a Level I Trauma Center.

Traditionally, the belief is that the clavicle heals readily and with nonoperative treatment. Since evidence suggests that many clavicles benefit from operative care, the aim of this study was to find the incidence of complications after operative treatment of clavicle fractures. This retrospective study includes 56 patients (41 male and 15 female) who were treated operatively for clavicle fractures between 2010 and 2012. The indications were displacement more than 20 mm, comminution, tenting of the skin, floating shoulder, and open fractures. Seventy-five percent of the fractures occurred in the midshaft and 25 % in the lateral third of the clavicle. There were no fractures of the medial third. The midshaft fractures were either plated with 3.5 mm reconstruction plates or anatomical locking plates. For internal fixation of the lateral fractures, we used acromioclavicular hook plates. The mean follow-up period was 4.6 months (range 1.0-28.0). Three patients did not participate in the follow-up. There were 12 patients with complications (21 %). Five of them required reoperations. Two patients were reoperated due to clavicle nonunions, two patients due to traumatic refracture of the plated clavicle, and one because of pain caused by the plate. Four cases developed superficial infections, and there was one patient with a deep tissue infection. None of the patients showed signs of neurovascular impairment postoperatively. None of the patients complained about decreased range of motion or loss of muscle strength postoperatively. Plating of clavicle fractures is a procedure that results in lower rates of malunion, nonunion, and functional impairment compared with nonoperative treatment. Nonetheless, one case in ten has a complicated course. Attention to technique and careful follow-up may prevent these problems.

Reconstruction of the Medial Malleolus With Iliac Crest Autograft After Traumatic Loss: A Case Report.

CASE: A 19-year-old woman sustained an open ankle fracture with complete destruction of the left medial malleolus and significant soft-tissue loss. After temporizing external fixation and coverage with a rotational posterior tibial artery perforator flap, the medial malleolus was reconstructed with an autologous iliac crest bone graft and direct repair of the deltoid ligament. The patient achieved excellent improvement in functional outcomes at 21 months with adequate restoration of ankle motion. CONCLUSION: This case shows reconstruction of the medial malleolus with autologous iliac crest bone graft after traumatic loss can be a viable treatment option for young patients.

Laterally Based External Fixation for Pott's Fractures.

In this article, we describe the construction and appropriate use of a lateral-based fixator for ankle fractures. This lateral-based frame is useful for treating Pott's fractures. With lateral ankle dislocations, the lateral frame places the hindfoot in alignment with the leg. Soft tissue trauma has been recognized as an early limiting factor in patients with ankle fractures, in addition to the need for obtaining and maintaining anatomic position. A kickstand is added for heel and medial soft tissue offloading. The lateral frame is a quick and reproducible technique with satisfactory results.Level of Evidence: Level V: Surgical Technique.

Smoking negatively impacts renal cell carcinoma overall and cancer-specific survival.

BACKGROUND: Tobacco use is a leading cause of premature death, yet few studies have investigated the effect of tobacco exposure on the outcome of patients with renal cell carcinoma (RCC). The authors of this report retrospectively studied the impact of smoking on clinicopathologic factors, survival outcomes, and p53 expression status in a large cohort of patients with RCC. METHODS: Eight hundred-two patients (457 nonsmokers and 345 smokers) who had up to 232 months of follow-up were compared for differences in their clinicopathologic features and survival outcomes. Immunohistochemical differences in p53 expression were correlated with smoking status. RESULTS: Smokers presented more commonly with pulmonary comorbidities (P < .0001) and cardiac comorbidities (P = .014) and with a worse performance status (P = .031) than nonsmokers. Smoking was associated significantly with tumor multifocality (P = .022), higher pathologic tumor classification (P = .037), an increased risk of bulky lymph node metastases (P = .031), and the presence of distant metastases (P < .0001), especially lung metastases (P < .0001). Both overall survival (OS) (62.37 months vs 43.64 months; P = .001) and cancer-specific survival (CSS) (87.43 months vs 56.57 months; P = .005) were significantly worse in patients who smoked. The number of pack-years was retained as an independent predictor of CSS and OS in patients with nonmetastatic disease. Mean expression levels of p53 were significantly higher in current smokers compared with former smokers and nonsmokers (P = .012). CONCLUSIONS: In patients with RCC, a history of smoking was associated with worse pathologic features and survival outcomes and with an increased risk of having mutated p53. Further investigation of the genetic and molecular mechanisms associated with decreased CSS in patients with RCC who have a history of smoking is indicated.

Expression of thyroid transcription factor-1 in normal endometrium is associated with risk of endometrial cancer development.

Thyroid transcription factor-1 (TTF-1) is a DNA-binding protein that is mainly expressed in thyroid and lung tissue, but has also been found in gynecologic tissue. Recent studies have suggested that TTF-1 has tumor suppressor function in lung adenocarcinoma models. In the current study, we examined whether expression of TTF-1 in benign endometrium and endometrial hyperplasia might impact on the risk of developing endometrial cancer. Formalin-fixed paraffin-embedded endometrial tissues obtained from 535 cases were used to construct an endometrial tissue microarray. One hundred fifty of 207 patients had multiple serial endometrial specimens including 46 patients who progressed to endometrial cancer. The tissue microarray included a range of histopathologies including benign endometrium (n=231), simple hyperplasia (n=105), complex hyperplasia (n=36), simple atypical hyperplasia (n=10), complex atypical hyperplasia (n=44), and endometrial carcinoma (n=109). Expression of TTF-1 by immunohistochemistry in benign endometrium and endometrial hyperplasia was correlated with progression to cancer and clinical features known to be associated with increased risk of developing endometrial cancer. Carcinoma specimens showed a significantly greater expression of TTF-1 compared with benign endometrium and non-atypical hyperplasia (P=0.0007 and P=0.05). Presence of TTF-1 expression in benign endometrium was associated with a significantly decreased risk of cancer development (P=0.003, hazards ratio=0.104, 95% CI: 0.024-0.455). TTF-1 expression in hyperplasia did not significantly correlate with progression to cancer. The data from our study show that TTF-1 expression in normal endometrium is associated with a reduced risk of endometrial cancer development. This observation suggests that TTF-1 might function as a tumor suppressor in endometrial tissue. TTF-1 expression in normal endometrium could potentially provide clinically useful information as a biomarker for the risk of endometrial cancer.

Inflation osteoplasty: in vitro evaluation of a new technique for reducing depressed intra-articular fractures of the tibial plateau and distal radius.

BACKGROUND: Anatomic reduction of intra-articular fractures of the tibial plateau and distal radius can be difficult to achieve. Treatment goals are centered on restoring the native anatomy and articular congruency. Several surgeons in the USA have begun using an inflatable bone tamp to reduce these fracture patterns. The concept is built on the success of the tamp in kyphoplasty of the spine, but it has yet to be tested in the lab for use in the extremities. We performed an investigation into the safety and efficacy of using an inflatable bone tamp for intra-articular fracture reduction of the tibial plateau and distal radius. MATERIALS AND METHODS: Paired cadaveric specimens were obtained for a total of six proximal tibias and six distal radii. Intra-articular depression-type fractures were created in all specimens. The inflatable bone tamp was then used to reduce the depression. For comparison, the tibias were fractured on the medial and lateral side and a conventional metal tamp was used on the contralateral side of the balloon. Fine-cut micro-computed tomography (CT) scans were performed on all intact specimens, which were then fractured, and again after fracture reduction. CT data was used to measure the amount of restoration of the normal anatomy and to compare the effectiveness of the balloon to conventional methods. RESULTS: The inflatable bone tamp was equivalent to conventional methods in large, minimally displaced fracture fragments and proved superior when comminution was present at the articular surface. No instances of overreduction or penetration into the joint were encountered with the balloon, whereas this was a common occurrence with conventional metal tamps. The inflatable tamp was successful in reducing all distal radius fractures without complication. CONCLUSION: Anatomic reduction of impacted articular fractures should be the goal of any treating surgeon. In our cadaveric models, we have shown the inflatable bone tamp to be safe and effective in reducing depressed articular fractures around the tibial plateau and distal radius. The balloon offers the advantage of being minimally invasive and creating a symmetric, contained defect to hold bone filler for subchondral support.

Pathological, immunohistochemical and cytogenetic features of papillary renal cell carcinoma with clear cell features.

PURPOSE: Papillary renal cell carcinoma is characterized histologically by tumors with cells arranged in a papillary pattern. Typically the cells have a chromophilic appearance but areas may show cells with clear cytoplasm, similar to those in clear cell renal cell carcinoma. MATERIALS AND METHODS: We re-reviewed the histological slides of 148 patients with papillary renal cell carcinoma who underwent nephrectomy for the presence of clear cells. Results were correlated with other pathological features, immunohistochemical expression of 22 protein markers, cytogenetic analysis and overall survival. RESULTS: Papillary renal cell carcinoma with clear cells was identified in 57 patients (39%). Clear cells were associated with higher T classification and grade, vascular invasion and type 2 papillary renal cell carcinoma. On immunohistochemistry these tumors revealed higher expression of epithelial vascular endothelial growth factor receptor-2 than papillary renal cell carcinoma without clear cells. All papillary renal cell carcinomas with clear cells expressed α-methylacyl-coenzyme A racemase and 76% expressed cytokeratin 7. Six of 8 tumors (75%) with chromosome 3p loss had clear cell features. The presence of clear cells was retained as an independent prognostic factor on multivariate analysis. In cases of papillary renal cell carcinoma with clear cells the loss of 3p material and absent cytokeratin 7 expression were associated with a worse outcome. CONCLUSIONS: Papillary renal cell carcinoma with clear cells is a novel entity with a unique clinical, immunohistochemical and cytogenetic phenotype. The presence of clear cells is associated with aggressive pathological characteristics and poorer prognosis.

Global histone modification patterns predict risk of prostate cancer recurrence.

Aberrations in post-translational modifications of histones have been shown to occur in cancer cells but only at individual promoters; they have not been related to clinical outcome. Other than being targeted to promoters, modifications of histones, such as acetylation and methylation of lysine and arginine residues, also occur over large regions of chromatin including coding regions and non-promoter sequences, which are referred to as global histone modifications. Here we show that changes in global levels of individual histone modifications are also associated with cancer and that these changes are predictive of clinical outcome. Through immunohistochemical staining of primary prostatectomy tissue samples, we determined the percentage of cells that stained for the histone acetylation and dimethylation of five residues in histones H3 and H4. Grouping of samples with similar patterns of modifications identified two disease subtypes with distinct risks of tumour recurrence in patients with low-grade prostate cancer. These histone modification patterns were predictors of outcome independently of tumour stage, preoperative prostate-specific antigen levels, and capsule invasion. Thus, widespread changes in specific histone modifications indicate previously undescribed molecular heterogeneity in prostate cancer and might underlie the broad range of clinical behaviour in cancer patients.

Tibial pilon fractures: a review of incidence, diagnosis, treatment, and complications.

Tibial pilon fractures are challenging to treat, as they are typically intra-articular and associated with extensive soft tissue damage. We briefly review the anatomy of the distal tibia, as well as the pathophysiology of pilon fractures. The treatment of tibial pilon fractures is still controversial in the literature, and we present some of the available options. Consideration is also given to peri-operative complications, such as preoperative oedema and blistering and late postoperative traumatic arthritis. Finally, we propose a treatment algorithm (used in our institution), taking into account the level of associated soft tissue injuries. The use of a 2-phase treatment protocol is recommended; however, to date, no absolute treatment protocol exists for these injuries.

Global levels of histone modifications predict prognosis in different cancers.

Cancer cells exhibit alterations in histone modification patterns at individual genes and globally at the level of single nuclei in individual cells. We demonstrated previously that lower global/cellular levels of histone H3 lysine 4 dimethylation (H3K4me2) and H3K18 acetylation (ac) predict a higher risk of prostate cancer recurrence. Here we show that the cellular levels of both H3K4me2 and H3K18ac also predict clinical outcome in both lung and kidney cancer patients, with lower levels predicting significantly poorer survival probabilities in both cancer groups. We also show that lower cellular levels of H3K9me2, a modification associated with both gene activity and repression, is also prognostic of poorer outcome for individuals with either prostate or kidney cancers. The predictive power of these histone modifications was independent of tissue-specific clinicopathological variables, the proliferation marker Ki-67, or a p53 tumor suppressor mutation. Chromatin immunoprecipitation experiments indicated that the lower cellular levels of histone modifications in more aggressive cancer cell lines correlated with lower levels of modifications at DNA repetitive elements but not with gene promoters across the genome. Our results suggest that lower global levels of histone modifications are predictive of a more aggressive cancer phenotype, revealing a surprising commonality in prognostic epigenetic patterns of adenocarcinomas of different tissue origins.

Absent CD44v6 expression is an independent predictor of poor urothelial bladder cancer outcome.

PURPOSE: CD44v6 is a cell surface protein involved in cell migration, cell adhesion, tumor progression and metastatic spread. We evaluated its role as a molecular marker for urothelial bladder cancer. MATERIALS AND METHODS: A tissue microarray was constructed containing 410 primary urothelial bladder cancers, each in triplicate. Immunohistochemical staining was done with a commercially available antibody. The percent of tumor cells staining positive for CD44v6 was evaluated and we assessed associations with stage, grade and survival. RESULTS: CD44v6 expression was higher in noninvasive (Ta, Tis) vs invasive (T1-T4) tumors (p <0.001). It decreased with increasing grade (p <0.001). In patients who underwent transurethral bladder resection absent CD44v6 expression was associated with a 2.3-fold increased risk of recurrence (95% CI 1.28 to 4.08). Median time to recurrence for tumors with vs without CD44v6 expression was 23 vs 9 months (p = 0.003). In a multivariate Cox model absent CD44 expression was an independent adverse prognostic factor for tumor recurrence (HR 2.33, p = 0.006). In cystectomy cases median overall survival for CD44v6 nonexpression vs expression was 30 vs 75 months (p = 0.0027) and CD44v6 expression was retained as an independent prognostic factor for overall survival (HR 1.54, p = 0.042). CONCLUSIONS: Absent CD44v6 expression is an independent adverse predictor of urothelial bladder cancer recurrence and overall survival. Routine evaluation of CD44v6 expression may allow the identification of high risk patients who require more intensive surveillance or aggressive therapy. Targeting of CD44v6 with monoclonal antibodies may provide new avenues for urothelial bladder cancer imaging and treatment.