Anderson Orthopaedic Clinic

Gene-expression profiling has been used to define 3 molecular subtypes of diffuse large B-cell lymphoma (DLBCL), termed germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and primary mediastinal B-cell lymphoma (PMBL). To investigate whether these DLBCL subtypes arise by distinct pathogenetic mechanisms, we analyzed 203 DLBCL biopsy samples by high-resolution, genome-wide copy number analysis coupled with gene-expression profiling. Of 272 recurrent chromosomal aberrations that were associated with gene-expression alterations, 30 were used differentially by the DLBCL subtypes (P < 0.006). An amplicon on chromosome 19 was detected in 26% of ABC DLBCLs but in only 3% of GCB DLBCLs and PMBLs. A highly up-regulated gene in this amplicon was SPIB, which encodes an ETS family transcription factor. Knockdown of SPIB by RNA interference was toxic to ABC DLBCL cell lines but not to GCB DLBCL, PMBL, or myeloma cell lines, strongly implicating SPIB as an oncogene involved in the pathogenesis of ABC DLBCL. Deletion of the INK4a/ARF tumor suppressor locus and trisomy 3 also occurred almost exclusively in ABC DLBCLs and was associated with inferior outcome within this subtype. FOXP1 emerged as a potential oncogene in ABC DLBCL that was up-regulated by trisomy 3 and by more focal high-level amplifications. In GCB DLBCL, amplification of the oncogenic mir-17-92 microRNA cluster and deletion of the tumor suppressor PTEN were recurrent, but these events did not occur in ABC DLBCL. Together, these data provide genetic evidence that the DLBCL subtypes are distinct diseases that use different oncogenic pathways.

PURPOSE: Non-small cell lung cancers carrying activating mutations in the gene for the epidermal growth factor receptor (EGFR) are highly sensitive to EGFR-specific tyrosine kinase inhibitors. However, most patients who initially respond subsequently experience disease progression while still on treatment. Part of this "acquired resistance" is attributable to a secondary mutation resulting in threonine to methionine at codon 790 (T790M) of EGFR. EXPERIMENTAL DESIGN: We sequenced exons 18 to 21 of the EGFR gene to look for secondary mutations in tumors with acquired resistance to gefitinib in 14 patients with adenocarcinomas. Subcloning or cycleave PCR was used in addition to normal sequencing to increase the sensitivity of the assay. We also looked for T790M in pretreatment samples from 52 patients who were treated with gefitinib. We also looked for secondary KRAS gene mutations because tumors with KRAS mutations are generally resistant to tyrosine kinase inhibitors. RESULTS: Seven of 14 tumors had a secondary T790M mutation. There were no other novel secondary mutations. We detected no T790M mutations in pretreatment specimens from available five tumors among these seven tumors. Patients with T790M tended to be women, never smokers, and carrying deletion mutations, but the T790M was not associated with the duration of gefitinib administration. None of the tumors had an acquired mutation in the KRAS gene. CONCLUSIONS: A secondary T790M mutation of EGFR accounted for half the tumors with acquired resistance to gefitinib in Japanese patients. Other drug-resistant secondary mutations are uncommon in the EGFR gene.

Esophageal cancer is the sixth leading cause of death from cancer and one of the least studied cancers worldwide. The global microRNA expression profile of esophageal cancer has not been reported previously. Here, for the first time, we have investigated expressed microRNAs in cryopreserved esophageal cancer tissues using advanced microRNA microarray techniques. Our microarray analyses identified seven microRNAs that could distinguish malignant esophageal cancer lesions from adjacent normal tissues. Some microRNAs could be correlated with the different clinicopathologic classifications. High expression of hsa-miR-103/107 correlated with poor survival by univariate analysis as well as by multivariate analysis. These results indicate that microRNA expression profiles are important diagnostic and prognostic markers of esophageal cancer, which might be analyzed simply using economical approaches such as reverse transcription-PCR.

A series of 1163 total hip arthroplasties (THAs) using porous-coated femoral components were roentgenographically assessed for implant fixation. For 959 primary THAs followed from two to 12 years, the femoral revision rate was 1% and the ten-year survivorship rate was 96.4%; 150 young patients had a fixation failure incidence of only 1.3% at a mean follow-up period of 6.4 years; in 204 revision THAs, the femoral re-revision rate was 4% at a mean follow-up period of 53.4 months. Failures were largely related to inadequate femoral canal filling. Because of refinements in implant design and surgical techniques, a press fit of the implant is currently achieved in 94% of cases compared to 36% during the first five years. Porous-coated femoral components have yielded results equivalent to those with cement in primary THAs. Excellent results were observed in relatively young patients and patients with revisions.

The goals of revision total hip arthroplasty (THA) are to reestablish and maintain stable implant fixation. Based upon promising early results in primary THA, porous-surfaced implants designed for bone ingrowth fixation are being increasingly used in hopes of more successfully achieving these goals than has been the case using cement. One hundred and sixty such revisions were followed for a mean of 4.4 years, with specific reference to implant fixation. Roentgenographic evaluation of implant fixation suggested four categories of femoral and acetabular components: (1) bone ingrown, (2) stable fibrous encapsulation, (3) questionable, with signs of impending instability, or (4) definitely unstable implant migration, indicative of the need for rerevision. Not surprisingly, success in achieving and maintaining stable implant fixation following revision THA is dependent upon component design, surgical technique, and preexistent bone stock damage. This classification according to bone stock damage should be borne in mind when critically evaluating the results from various revision series.

BACKGROUND: TKA is among the fastest growing interventions in medicine, with procedure incidence increasing the most in younger patients. Global knee scores have a ceiling effect and do not capture the presence of difficulty or dissatisfaction with specific activities important to patients. QUESTIONS/PURPOSES: We quantified the degree of residual symptoms and specific functional deficits in young patients who had undergone TKA. METHODS: In a national multicenter study, we quantified the degree of residual symptoms and specific functional deficits in 661 young patients (mean age, 54 years; range, 19-60 years; 61% female) at 1 to 4 years after primary TKA. To eliminate observer bias, satisfaction and function data were collected by an independent, third-party survey center with expertise in administering medical outcomes questionnaires for federal agencies. RESULTS: Overall, 89% of patients were satisfied with their ability to perform normal daily living activities, and 91% were satisfied with their pain relief. After TKA, 66% of patients indicated their knees felt normal, 33% reported some degree of pain, 41% reported stiffness, 33% reported grinding/other noises, 33% reported swelling/tightness, 38% reported difficulty getting in and out of a car, 31% reported difficulty getting in and out of a chair, and 54% reported difficulty with stairs. After recovery, 47% reported complete absence of a limp and 50% had participated in their most preferred sport or recreational activity in the past 30 days. CONCLUSIONS: When interviewed by an independent third party, about 1/3 of young patients reported residual symptoms and limitations after modern TKA. We recommend informing patients considering surgery about the high likelihood of residual symptoms and limitations after contemporary TKA, even when performed by experienced surgeons in high-volume centers, and taking specific steps to set patients' expectations to a level that is likely to be met by the procedure as it now is performed.

A study of the data on 1,318 consecutive non-cemented total hip-replacement arthroplasties revealed thirty-nine intraoperative fractures of the femur (3 per cent), only half of which were diagnosed intraoperatively. The fractures occurred in the proximal region of the femur or at the tip of the stem of the prosthesis. Most were incomplete and minimally displaced, and they did not jeopardize the stability of the femoral component. All complete proximal fractures were stabilized with a four-fifths-coated or fully coated prosthesis to provide distal fixation, and, when diagnosed intraoperatively, were fixed with cerclage wiring. When an incomplete fracture near the tip of the stem was discovered postoperatively and the posterior part of the femoral cortex was intact, a spica cast was applied, and the patient was instructed in protected weight-bearing. For a complete fracture at the tip of the stem, we recommend open reduction and internal fixation. No statistical difference was found with respect to residual pain, the score for walking, or the stability of the implant when we compared the results for the patients who had a fracture with those for the patients who did not. Modifications in surgical technique resulted in a decrease in the incidence of fractures (p less than 0.05).

To determine whether EGFR tyrosine kinase domain mutations are early events in the pathogenesis of lung adenocarcinomas, we tested for the presence of EGFR mutations in histologically normal bronchial and bronchiolar epithelia from lung adenocarcinomas bearing the common EGFR mutations. DNA was extracted from microdissected tissue obtained from 21 tumors with known EGFR mutations, 16 tumors without mutation, and 90 sites of normal bronchial and bronchiolar epithelium from the same surgical specimens. With the use of PCR and direct DNA sequencing, EGFR mutations identical to the tumors were detected in the normal respiratory epithelium in 9 of 21 (43%) patients with EGFR mutant adenocarcinomas but none in patients without mutation in the tumors. The finding of mutations being more frequent in normal epithelium within tumor (43%) than in adjacent sites (24%) suggests a localized field effect phenomenon. Our findings indicate that mutation of the tyrosine kinase domain of EGFR is an early event in the pathogenesis of lung adenocarcinomas, and suggest EGFR mutations as an early detection marker and chemoprevention target.

OBJECTIVE: To determine the causes of persistent dizziness in outpatients. DESIGN: Consecutive adult outpatients presenting with a chief complaint of dizziness. SETTING: Four clinics (internal medicine, walk-in, emergency room, and neurology) in a teaching hospital. PATIENTS: Of 185 patients presenting during the 10-month study period, 51 (28%) had minimal or no dizziness at 2-week follow-up. Of the remaining 134 patients, 100 completed the study protocol (mean age, 62 years; range, 20 to 85 years). MEASUREMENTS: Evaluation included a detailed study questionnaire, standardized physical examination, vestibular testing by a neuro-ophthalmologist, laboratory tests, audiometry, and a structured psychiatric interview. Data were abstracted onto a standard form and reviewed by three raters. Raters independently assigned diagnoses using explicit criteria, with the final cause determined by consensus. RESULTS: Primary causes of dizziness included vestibular disorders (54 patients), psychiatric disorders (16 patients), presyncope (6 patients), dysequilibrium (2 patients), and hyperventilation (1 patient); dizziness was multicausal in 13 patients and of unknown cause in 8 patients. Many of those with a single primary cause, however, had at least one other condition contributing to their dizziness; only 52% of patients had a single "pure" cause. Thirty patients had a potentially treatable primary cause, the most common being benign positional vertigo (BPV) (16%) and psychiatric disorders (6%). Central vestibulopathies detected in 10 patients were presumably vascular or idiopathic in origin. No brain tumors or cardiac arrhythmias were found. CONCLUSIONS: Vestibular disease and psychiatric disorders are the most common causes of persistent dizziness in outpatients. In about 50% of patients with dizziness, more than one factor causes or aggravates symptoms. Life-threatening causes were rare, even in our elderly population.

BACKGROUND: Solid organ transplant (SOT) recipients have been reported to be more susceptible to influenza virus. However, little is known about the clinical epidemiology and the implications of influenza viral infection among SOT recipients. METHODS: Cohort study of influenza viral infection in SOT recipients at the University of Pittsburgh Medical Center. RESULTS: Between November 1990 and April 2000, 30 cases of influenza were diagnosed in SOT recipients at our center, including influenza A (n = 22) and influenza B (n = 8). These included recipients of lung (n = 19), liver (n = 5) and kidney (n = 6) transplants. The incidence of influenza viral infection was 41.8 cases/1,000 person years (PYs), 2.8 cases/1000 PYs and 4.3 cases/ 1,000 PYs among lung, liver and renal transplant patients, respectively (p <0.0001). Symptoms were reported in all patients and included malaise, myalgia/ arthralgia, fever, cough, and shortness of breath. Secondary bacterial pneumonia occurred in five patients (17%). Other complications were seen in three SOT recipients (2 liver and 1 kidney) and included: myocarditis, myositis, and bronchiolitis obliterans. Biopsy of the transplanted organ was performed in 21 SOT recipients (18 lung, 1 liver and 2 kidney) at the time of influenza viral infection. Overall, 62% (13/21) showed variable degrees of acute allograft rejection, and included 61% (11/18) of lung, and 100% (2/2) of kidney transplant recipients. CONCLUSIONS: Influenza infection is associated with significant morbidity in different groups of SOT recipients. Studies are needed to determine if yearly chemoprophylaxis with antiviral drugs might benefit this patient population.

BACKGROUND: The pathologic TNM (pTNM) staging system was designed to aid in determining the prognosis of cancer patients and in planning and evaluating their treatment. The current pTNM classification system was not found to be predictive for patients undergoing orthotopic liver transplantation (OLTx) in the presence of hepatocellular carcinoma (HCC). Therefore, the authors examined the current system to determine whether improvements would allow the development of a more predictive system. METHODS: Three hundred seven patients with HCC underwent OLTx between 1981 and 1997. Risk factors for recurrence were identified using the Kaplan-Meier method with the log rank test. The Cox proportional hazards model was used to identify factors independently predictive of recurrence which were then used to create a new staging system. RESULTS: There was neither a direct correlation between the current pTNM system and tumor free survival nor homogeneity in outcomes for patients within certain current pTNM categories. Depth of vascular invasion, lobar distribution, lymph node status, and largest tumor size were found to be independent predictors of tumor free survival; tumor number was not found to be significant in multivariate analysis. A new staging system is proposed, which takes into account the results of the multivariate analysis in which tumor free survival correlates directly with stage. CONCLUSIONS: The proposed staging system is superior to the current pTNM staging system in predicting tumor free survival following OLTx with HCC. Further studies will determine the appropriateness of this system for staging HCC after subtotal hepatic resection.

Some somatic mutations, especially those in genes encoding tyrosine kinases, are central to the biology of specific cancers. In such instances, these “driver” mutations lead to the production of mutated enzymes, which then serendipitously serve as excellent substrates for targeted therapies.

2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS)

Postoperative wound infections following spinal fusion with instrumentation often present diagnostic and therapeutic difficulties. This article reviews 34 such infections. An infection rate of 3.7% was noted. Depending on various clinical indicators, treatment strategies included short-course antibiotics, prolonged intravenous antibiotics, or intravenous antibiotics followed by suppressive antibiotics and eventual hardware removal. To eradicate these infections, removal of instrumentation is often required; this option, however, may result in an unstable spine. Treatment algorithms were developed for treatment of postoperative spinal surgical site infections and to minimize the possibility of spine instability. All patients were cured of their infections.

BACKGROUND: Electromagnetic navigation bronchoscopy (ENB) has been widely adopted as a guidance technique for biopsy of peripheral lung nodules. However, ENB is limited by the lack of real-time confirmation of the biopsy devices. Intraprocedural cone-beam computed tomography (CBCT) imaging can be utilized to assess or confirm the location of biopsy devices. The aim of this study is to determine the safety and diagnostic yield (DY) of image fusion of intraprocedural CBCT data with live fluoroscopy (augmented fluoroscopy) during ENB-guided biopsy of peripheral lung nodules. METHODS: Data from 75 consecutive patients who underwent biopsy with ENB was collected retrospectively. Patients underwent CBCT imaging while temporarily suspending mechanical ventilation. CBCT data were acquired and 3-dimensional segmentation of nodules was performed using commercially available software (OncoSuite). During ENB, the segmented lesions were projected and fused with live fluoroscopy enabling real-time 3-dimensional guidance. RESULTS: A total of 93 lesions with a median size of 16.0 mm were biopsied in 75 consecutive patients. The overall DY by lesion was 83.7% (95% confidence interval, 74.8%-89.9%). Multivariate regression analysis showed no independent correlation between lesion size, lesion location, lesion visibility under standard fluoroscopy, and the presence of a bronchus sign with DY. Pneumothorax occurred in 3 patients (4%). CONCLUSION: Intraprocedural CBCT imaging with augmented fluoroscopy is feasible and effective and is associated with high DY during ENB-guided biopsies.

BACKGROUND: Few data exist regarding the impact of socioeconomic factors on results of current TKA in young patients. Predictors of TKA outcomes have focused primarily on surgical technique, implant details, and individual patient clinical factors. The relative importance of these factors compared to patient socioeconomic status is not known. QUESTIONS/PURPOSES: We determined whether (1) socioeconomic factors, (2) demographic factors, or (3) implant factors were associated with satisfaction and functional outcomes after TKA in young patients. METHODS: We surveyed 661 patients (average age, 54 years; range, 18-60 years; 61% female) 1 to 4 years after undergoing modern primary TKA for noninflammatory arthritis at five orthopaedic centers. Data were collected by an independent third party with expertise in collecting healthcare data for state and federal agencies. We examined specific questions regarding satisfaction, pain, and function after TKA and socioeconomic (household income, education, employment) and demographic (sex, minority status) factors. Multivariable analysis was conducted to examine the relative importance of these factors for each outcome of interest. RESULTS: Patients reporting incomes of less than USD 25,000 were less likely to be satisfied with TKA outcomes and more likely to have functional limitations after TKA than patients with higher incomes; no other socioeconomic factors were associated with satisfaction. Women were less likely to be satisfied and more likely to have functional limitations than men, and minority patients were more likely to have functional limitations than nonminority patients. Implants were not associated with outcomes after surgery. CONCLUSIONS: Socioeconomic factors, in particular low income, are more strongly associated with satisfaction and functional outcomes in young patients after TKA than demographic or implant factors. Future studies should be directed to determining the causes of this association, and studies of clinical results after TKA should consider stratifying patients by socioeconomic status.

Thirty-five patients who had had a primary total hip replacement with a porous-coated acetabular component inserted without cement had a revision procedure to treat pelvic osteolysis. The mean age at the time of the revision operation was forty-nine years (range, twenty-nine to eighty-five years). Forty-six distinct pelvic osteolytic lesions were noted radiographically around the thirty-five cups. These lesions ranged in size from 0.5 by 0.5 centimeter to 6.3 by 2.7 centimeters (mean, 2.6 by 1.7 centimeters). Fourteen of the thirty-five patients had no or only slight occasional pain at the time of diagnosis of the pelvic osteolysis, fifteen patients had pain attributed to a loose femoral component, one had pain related to a spontaneous fracture of the greater trochanter, and one had pain related to recurrent subluxation. The remaining four patients had pain in the groin despite radiographically stable implants. All of the metal-backed porous-coated acetabular components were stable according to the preoperative radiographs, and the stability was confirmed at the time of the revision. The metal shell was left in place and the acetabular liner was exchanged in all thirty-five patients. The osteolytic lesions were debrided, and thirty-four of the forty-six lesions were filled with allograft bone chips. The patients were evaluated a minimum of two years (range, two to five years; mean, 3.3 years) after the revision operation, and all thirty-five sockets were found to be radiographically stable. The bone grafts appeared to have consolidated, and none of the osteolytic defects had progressed. One-third of the lesions were no longer visible on radiographs, regardless of whether or not they had been filled with bone graft. The remaining lesions had decreased in size. It appears that, in the short-term, exchange of the liner and debridement of the granuloma, with or without use of allograft bone chips in the osteolytic defect, is a reasonable alternative to revision of the socket provided that the metal shell is solidly fixed at the time of the revision operation. If the metal shell has been markedly damaged by the femoral head, the locking mechanism for the polyethylene liner is not intact, or a satisfactory replacement liner is not available, then revision of the porous-coated acetabular component is indicated. These results must be considered preliminary. Since osteolysis may take several years to redevelop after a revision, additional follow-up is required.

Loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the development of chronic pain following inflammation or nerve injury. Inhibitory postsynaptic transmission in the adult spinal cord involves mainly glycine. Cannabidiol is a nonpsychotropic plant constituent of Cannabis sativa. As we hypothesized that non-CB receptor mechanisms of cannabidiol might contribute to its anti-inflammatory and neuroprotective effects, we investigated the interaction of cannabidiol with strychnine-sensitive alpha(1 )and alpha(1)beta glycine receptors by using the whole-cell patch clamp technique. Cannabidiol showed a positive allosteric modulating effect in a low micromolar concentration range (EC(50) values: alpha(1) = 12.3 +/- 3.8 micromol/l and alpha(1)beta = 18.1 +/- 6.2 micromol/l). Direct activation of glycine receptors was observed at higher concentrations above 100 micromol/l (EC(50) values: alpha(1) = 132.4 +/- 12.3 micromol/l and alpha(1)beta = 144.3 +/- 22.7 micromol/l). These in vitro results suggest that strychnine-sensitive glycine receptors may be a target for cannabidiol mediating some of its anti-inflammatory and neuroprotective properties.

How can voice over the Internet claim a greater share of the worldwide phone market from the voice infrastructure dominated for more than 100 years by the public-switched telephone network?

We reviewed the results an average of fifty months (range, twenty-four to 120 months) after the use of thirty-five allografts in thirty patients during primary or revision total knee replacement. Twenty-nine femoral-head allografts, five distal femoral allografts, and one proximal tibial allograft were used in conjunction with a long-stemmed implant to reconstruct large osseous defects. The patients were evaluated clinically, radiographically, and subjectively (with use of a questionnaire). Twenty-six (87 per cent) of the thirty patients had a good or excellent clinical result, and no revisions were necessary. As none of the patients had collapse of the graft, subsidence of the implant, or revision, we believe that the outcome of treatment with a femoral-head allograft, particularly in association with a component inserted with cement, is excellent. Four non-porous-coated components were placed without cement on structural allografts. Radiographically, three of those components subsided, but none of the three needed revision and two were associated with a good clinical result. Our current practice is to cement components in all arthroplasties involving grafting. Our findings suggest that the use of a stemmed component reduces the stress on the allograft, host bone, and fixation interface. In addition, such a component contributes to the longevity of a total knee replacement associated with a bone graft. Additional studies with long-term follow-up are necessary to confirm this outcome.