Use of MicroRNA biomarkers to distinguish enchondroma from low-grade chondrosarcoma.

Establishing a definitive diagnosis between benign enchondroma versus low-grade chondrosarcoma presents a potential challenge to both clinicians and pathologists. microRNAs (small non-coding RNAs) have proven to be effective biomarkers for the identification of tumors and tumor progression. We present analysis, both array and quantitative PCR, that shows consistently and substantially increased expression of two microRNAs, miRs-181a and -138, in low-grade chondrosarcomas compared with enchondromas. The data suggest these microRNAs would provide an analytical distinction between the chondrosarcoma and benign neoplasms that can be performed in formalin-fixed paraffin-embedded specimens. Together with recent publications, these data indicate that miRs-181a and -138 also play a role in tumor development and homeostasis and may provide new targets for the development of much needed therapeutic intervention.

Malignant and benign bone tumors that you are likely to see.

Although primary malignancies of bone are rare, thousands of benign bone tumors are diagnosed annually. It is important to be able to distinguish benign lesions from malignant lesions and differentiate those lesions that can be watched versus lesions that require further treatment and referral to an orthopaedic oncologist. Learning to distinguish these entities and their appropriate treatment or triage will positively affect the patient and the surgeon's practice.

2011 Mid-America Orthopaedic Association Dallas B. Phemister Physician in Training Award: Can musculoskeletal tumors be diagnosed with ultrasound fusion-guided biopsy?

BACKGROUND: Percutaneous biopsy for musculoskeletal tumors commonly relies on imaging adjuncts including ultrasound (US), CT, or MRI. These modalities however have disadvantages (US) or are cumbersome, not universally available, and costly (CT and MRI). US fusion is a novel technique that fuses previously obtained CT or MRI data with real-time US, which allows biopsies to be performed in an US suite. It has proven useful in various body systems but musculoskeletal applications remain scarce. Our goal is to evaluate the fusion technology and determine its ability to diagnose musculoskeletal tumors. QUESTIONS/PURPOSES: We determined whether biopsies performed via US fusion compared with CT guidance provide equivalent diagnostic yield and accuracy and allow quicker biopsy scheduling and procedure times. METHODS: Forty-seven patients were assigned to undergo either US fusion (with MR, n = 16 or CT, n = 15) or CT-guided biopsies (n = 16). We evaluated adequacy of the histologic specimen (diagnostic yield) and correlation with surgical pathology (diagnostic accuracy). We determined scheduling times and lengths of the biopsy. RESULTS: US fusion and CT-guided biopsy groups had comparable diagnostic yields (CT = 94%; US/MRI = 94%; US/CT = 93%) and accuracy (CT = 83%; US/MRI = 90%; US/CT = 100%). US fusion biopsies were faster to schedule and perform. All procedures were safe with minimal complications. CONCLUSIONS: US fusion provides a high diagnostic yield and accuracy comparable to CT-guided biopsy while performed in the convenience of an US suite. This may have resulted in the observed faster scheduling and biopsy times. LEVEL OF EVIDENCE: Level II, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence.

Imaging interpretation of oncologic musculoskeletal conditions.

There is considerable overlap in the clinical and imaging presentation of general orthopaedic conditions and musculoskeletal neoplasms. At centers that treat orthopaedic oncologic conditions, it is not uncommon to see patients with spine and extremity tumors previously treated for presumed general orthopaedic ailments. It is important for orthopaedic surgeons to understand how to interpret commonly ordered radiographic studies (radiographs, MRIs, and CT scans) as they relate to bone and soft-tissue tumors, to be familiar with the imaging appearance of common musculoskeletal lesions in the extremities and spine, and to understand what imaging findings should trigger a referral to an orthopaedic oncologist.

The AOA: A Comprehensive House with Compassionate Leaders. Presidential Address to the AOA, June 15, 2020: AOA Critical Issues.

ABSTRACT: The American Orthopaedic Association (AOA) is the world's oldest orthopaedic association and it has been responsible for the founding of many prominent organizations as well as The Journal of Bone & Joint Surgery. While the AOA has traditionally focused on academic orthopaedic leadership, the time has come to expand our horizons and look to include all orthopaedic leaders from the wide variety of leadership roles in which they currently serve.Orthopaedic surgeons who demonstrate compassionate leadership will find that they create stronger, more successful teams. Compassionate leadership is a skill that can be learned, and investing the energy to develop this skill will have a profound impact on our success as orthopaedic surgeons and leaders.

Tumors for the general orthopedist: how to save your patients and practice.

It is likely that most orthopaedic surgeons will see a patient with a benign or malignant musculoskeletal tumor sometime during their career. However, because of the rarity of these entities, many surgeons may benefit from a review of how to evaluate a patient with a bone lesion or soft-tissue mass. A logical approach is necessary in evaluating imaging studies as well as in the workup of children and adults with a possible tumor. It is important to have a good working relationship with a musculoskeletal radiologist to assist in interpreting the images. If the treatment algorithms lead to a conclusive diagnosis of a benign bone tumor, benign soft-tissue mass, or metastatic bone disease, the orthopaedic surgeon may choose to definitively treat the patient. If the workup indicates an indeterminate lesion, it may be prudent to discuss the situation with an orthopaedic oncologist or transfer the care of the patient to a physician with more specialized knowledge. A careful, logical workup is needed prior to surgery to limit risks to the patient and optimize the chances for a favorable outcome.

Operative Experience During Orthopaedic Residency Compared with Early Practice in the U.S.

BACKGROUND: The goal of surgical education is to prepare the trainee for independent practice; however, the relevance of the current residency experience to practice remains uncertain. The purpose of this study was to identify the surgical procedures most frequently performed in orthopaedic residency and in early surgical practice and to identify surgical procedures performed more often or less often in orthopaedic residency compared with early surgical practice. METHODS: This retrospective cohort study included American Medical Association (AMA) Current Procedural Terminology (CPT) codes (n = 4,329,561 procedures) reported by all U.S. orthopaedic surgery residents completing residency between 2010 and 2012 (n = 1,978) and AMA CPT codes for all procedures (n = 413,370) reported by U.S. orthopaedic surgeons who took the American Board of Orthopaedic Surgery Part II certifying examination between 2013 and 2015 (n = 2,205). Relative rates were determined for AMA CPT codes and AMA CPT code categories for adult and pediatric surgeries that had frequencies of ≥0.1% for both practitioners and residents. RESULTS: The top 25 adult AMA CPT code categories contributed 82.1% of the total case volume for residents and 82.4% for practitioners. Knee and shoulder arthroscopy were the most frequently performed procedures in adults in both residency and early practice. Humerus/elbow fracture and/or dislocation procedures and "other musculoskeletal-introduction or removal" procedures were the most frequently performed procedures in pediatric cases in both residency and early practice. Of the total 78 adult and 82 pediatric code categories included in our analysis that had a frequency of >1% in residency or early practice, there were 4 adult and 6 pediatric code categories demonstrating 44% to 1,164% greater frequency in residency than in early practice, and there were 8 adult and 7 pediatric code categories demonstrating 26% to 73% less frequency in residency than in early practice. CONCLUSIONS: Similarity between residency and early practice experience is generally strong. However, we identified several AMA CPT code categories and individual CPT codes for which the level of exposure during residency varied substantially from early practice experience. These findings can help residencies ensure adequate trainee exposure to procedures performed commonly in early practice.

PARP-1 regulates DNA repair factor availability.

PARP-1 holds major functions on chromatin, DNA damage repair and transcriptional regulation, both of which are relevant in the context of cancer. Here, unbiased transcriptional profiling revealed the downstream transcriptional profile of PARP-1 enzymatic activity. Further investigation of the PARP-1-regulated transcriptome and secondary strategies for assessing PARP-1 activity in patient tissues revealed that PARP-1 activity was unexpectedly enriched as a function of disease progression and was associated with poor outcome independent of DNA double-strand breaks, suggesting that enhanced PARP-1 activity may promote aggressive phenotypes. Mechanistic investigation revealed that active PARP-1 served to enhance E2F1 transcription factor activity, and specifically promoted E2F1-mediated induction of DNA repair factors involved in homologous recombination (HR). Conversely, PARP-1 inhibition reduced HR factor availability and thus acted to induce or enhance "BRCA-ness". These observations bring new understanding of PARP-1 function in cancer and have significant ramifications on predicting PARP-1 inhibitor function in the clinical setting.

Intraosseous hemangioblastoma of the cervical spine: case report.

A 69-year-old woman presented with bilateral upper-extremity radiculopathy and neck pain after a mechanical fall. Admission CT and MRI of the cervical spine demonstrated a pathological C-4 fracture. Subsequent malignancy workup was negative. A CT-guided biopsy of the lesion showed intraosseous hemangioblastoma. Hemangioblastoma is a highly vascular, slow-growing tumor of the CNS; intraosseous location of this tumor is extremely rare. The authors review the diversity of its presentation and the treatment techniques of this rare tumor in an extremely rare location.

Intratumoral heterogeneity analysis reveals hidden associations between protein expression losses and patient survival in clear cell renal cell carcinoma.

Intratumoral heterogeneity (ITH) is a prominent feature of kidney cancer. It is not known whether it has utility in finding associations between protein expression and clinical parameters. We used ITH that is detected by immunohistochemistry (IHC) to aid the association analysis between the loss of SWI/SNF components and clinical parameters.160 ccRCC tumors (40 per tumor stage) were used to generate tissue microarray (TMA). Four foci from different regions of each tumor were selected. IHC was performed against PBRM1, ARID1A, SETD2, SMARCA4, and SMARCA2. Statistical analyses were performed to correlate biomarker losses with patho-clinical parameters. Categorical variables were compared between groups using Fisher's exact tests. Univariate and multivariable analyses were used to correlate biomarker changes and patient survivals. Multivariable analyses were performed by constructing decision trees using the classification and regression trees (CART) methodology. IHC detected widespread ITH in ccRCC tumors. The statistical analysis of the "Truncal loss" (root loss) found additional correlations between biomarker losses and tumor stages than the traditional "Loss in tumor (total)". Losses of SMARCA4 or SMARCA2 significantly improved prognosis for overall survival (OS). Losses of PBRM1, ARID1A or SETD2 had the opposite effect. Thus "Truncal Loss" analysis revealed hidden links between protein losses and patient survival in ccRCC.

Imported platelets demonstrate decreased pH and glucose by reagent strip testing when compared to locally derived platelets.

The most common infectious risk from blood transfusion in the United States is bacterial contamination of platelet components. Although detection of bacterially contaminated platelet components is best achieved with a culture system, AABB standards permit alternatives including the use of staining methods or reagent strips. In this study, 13,216 consecutive platelet components were screened using reagent strips for evidence of the presence of bacteria. Testing was performed immediately prior to release of the platelet components for transfusion; 10,836 were collected locally and 2,380 were imported from other blood banks. A mix of whole-blood-derived and apheresis products was included. If either the glucose concentration was <250 mg/ml or the pH was <7.0, the platelet component was quarantined and a specimen was obtained for Gram's stain and culture. Every transfused platelet component that was associated with a reported transfusion reaction was also tested by Gram's stain and culture. Overall, 1.47% of imported platelet components were reactive while only 0.12% of locally collected platelets were reactive. Of 48 reactive platelet components, 44 were tested by Gram's stain and culture. None was found to be bacterially contaminated. In summary, imported platelet components were significantly more likely to be falsely reactive by reagent strip screening as compared to locally prepared platelet components.

Ewing Sarcoma in the Fifth Metacarpal of an Adult Woman: A Case Report.

CASE: Atypical presentations of Ewing sarcoma (ES) can lead to misdiagnosis and delays in treatment. We present a rare case of ES in the hand of an adult woman who underwent multiple interventions prior to referral to our institution. At 22 months after definitive treatment, the patient remained pleased with the result and had no evidence of recurrence. CONCLUSION: To our knowledge, ES of the hand in an adult woman has not yet been reported in the literature, and a lack of recognition of this condition might be secondary to the absence of features traditionally associated with malignant bone neoplasms. A broader differential diagnosis after intervention failures offers the opportunity for diagnosis and appropriate treatment.

Immunohistochemistry Successfully Uncovers Intratumoral Heterogeneity and Widespread Co-Losses of Chromatin Regulators in Clear Cell Renal Cell Carcinoma.

Recent studies have shown that intratumoral heterogeneity (ITH) is prevalent in clear cell renal cell carcinoma (ccRCC), based on DNA sequencing and chromosome aberration analysis of multiple regions from the same tumor. VHL mutations were found to be universal throughout individual tumors when it occurred (ubiquitous), while the mutations in other tumor suppressor genes tended to be detected only in parts of the tumors (subclonal). ITH has been studied mostly by DNA sequencing in limited numbers of samples, either by whole genome sequencing or by targeted sequencing. It is not known whether immunohistochemistry (IHC) can be used as a tool to study ITH. To address this question, we examined the protein expression of PBRM1, and PBRM1-related proteins such as ARID1A, SETD2, BRG1, and BRM. Altogether, 160 ccRCC (40 per stage) were used to generate a tissue microarray (TMA), with four foci from each tumor included. Loss of expression was defined as 0-5% of tumor cells with positive nuclear staining in an individual focus. We found that 49/160 (31%), 81/160 (51%), 23/160 (14%), 24/160 (15%), and 61/160 (38%) of ccRCC showed loss of expression of PBRM1, ARID1A, SETD2, BRG1, and BRM, respectively, and that IHC could successfully detect a high prevalence of ITH. Phylogenetic trees were constructed that reflected the ITH. Striking co-losses among proteins were also observed. For instance, ARID1A loss almost always accompanied PBRM1 loss, whereas BRM loss accompanied loss of BRG1, PBRM1 or ARID1A. SETD2 loss frequently occurred with loss of one or more of the other four proteins. Finally, in order to learn the impact of combined losses, we compared the tumor growth after cells acquired losses of ARID1A, PBRM1, or both in a xenograft model. The results suggest that ARID1A loss has a greater tumor-promoting effect than PBRM1 loss, indicating that xenograft analysis is a useful tool to investigate how these losses impact on tumor behavior, either alone or in combination.

Umbilical cord stricture: a cause of recurrent fetal death.

BACKGROUND: Umbilical cord stricture is a recognized cause of fetal demise, but the exact etiology remains unknown. The risk of recurrence has generally been thought to be low. CASE: Three of 4 fetuses of a single patient died between 28 and 30 weeks of gestation; all were found to have stricture of the umbilical cord at the fetal insertion. Her one surviving infant was delivered emergently at 25 weeks. All infants were growth restricted but had no anatomic abnormalities. CONCLUSION: Umbilical cord stricture was diagnosed as the cause of all 3 fetal deaths. Patients with a demise attributed to umbilical cord stricture should be counseled that the risk of recurrent cord stricture is undetermined.

Cutaneous metastasis of micropapillary urothelial carcinoma.

A 59-year-old man presented with persistent skin rash found to be cutaneous metastasis from micropapillary urothelial carcinoma status post right radical nephroureterectomy and adjuvant chemotherapy. The skin metastasis appeared 2 months after postchemotherapy imaging demonstrated complete radiographic response. Cutaneous metastases from primary genitourinary malignancies are very rare clinical entities associated with poor prognosis. Cutaneous metastases do not have distinctive gross appearance and are often misdiagnosed as common dermatologic disorders. It is imperative that urologists have high index of suspicion for metastasis in patients with persistent skin rash in the setting of advanced genitourinary malignancies.

Evaluation and staging of musculoskeletal neoplasia.

Musculoskeletal neoplasia are rare and can present in a highly variable fashion. Maintaining an index of suspicion for the presence of neoplasia is important. A standard approach to evaluation with history, physical, and appropriate imaging studies is mandatory. This information then can be synthesized to properly stage the lesion, which in turn facilitates an appropriate treatment plan. This article discusses the systematic approach to the evaluation and staging of musculoskeletal lesions.

Musculoskeletal neoplasia: helping the orthopaedic surgeon establish the diagnosis.

Encountering musculoskeletal neoplasia in the clinical practice of orthopaedic surgery is a rather uncommon event but can be an anxiety-provoking experience when it occurs. Using a systematic approach to imaging these lesions includes evaluation via plain radiographs and other modalities such as bone scintigraphy (BS), computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET). By applying specific imaging characteristics obtained from these different modalities, the radiologist and orthopaedic surgeon can jointly create an appropriate differential diagnosis. The radiologist plays a key role as part of the diagnostic team, including providing crucial support for biopsy and staging. This article discusses a systematic approach in the evaluation and staging of musculoskeletal neoplasia from the perspective of supporting the orthopaedic surgeon.