The influence of posterior acromial morphology on outcomes and return to pushups in young patients undergoing arthroscopic posterior capsulolabral repair.

Background: Prior evidence has identified specific posterior acromial morphology as significantly associated with unidirectional posterior shoulder instability. The purpose of this study is to determine the influence of posterior acromial morphology on the outcomes of arthroscopic posterior capsulolabral repair (APCLR) for unidirectional posterior shoulder instability. Additionally, we sought to determine the influence of posterior acromial morphology on the rate and time to return to pushups following APCLR. Methods: We performed a retrospective review of prospectively collected data. The study included consecutive patients undergoing APCLR. Data collected included demographics, radiographic measurements including posterior acromial height (PAH) and posterior acromial tilt on preoperative scapular-Y radiographs, and patient-reported outcome measures at the preoperative and postoperative visits. In addition, starting at 6 months postoperative, patients were asked if they could perform pushups defined as at least 10 repetitions. At the final follow-up, we collected the number of pushups patients were able to perform. Results: Thirty-two consecutive patients underwent APCLR with a mean follow-up of 26 months (range, 12-41). Significant improvement from preoperative to 2 years postoperative was demonstrated in Subjective Shoulder Value (50-85), VAS (6-2.5), American Shoulder and Elbow Surgeons (48 to 83), and Western Ontario Shoulder Instability (WOSI) (1437-777), P = .001. The recurrent instability rate was 3/32 (9%). Patients with PAH > 23 (N = 17) had a recurrent instability rate of 18% (3/17) versus PAH ≤ 23 (N = 15) 0% (0/15), worse WOSI scores (P = .41), and a lower number of pushups (P = .48). The percentage of patients reporting the ability to perform pushups was (6 months/1 year/2 years) (50%/78%/95%). The mean number of pushups reported at the final follow-up was 33 (range, 1-60). Discussion: Following APCLR, approximately 50% of patients resume pushups at 6 months postoperatively, and 80% return at 1 year. Patients reported performing a mean of 33 pushups following APCLR at the final follow-up. Patients with a PAH greater than 23 on preoperative scapular-Y radiographs had a higher rate of recurrent posterior instability, worse WOSI scores, and lower return to pushups; however, the results did not meet statistical significance. Therefore, future larger studies are needed to determine if posterior acromial morphology is independently associated with worse outcomes and increased recurrent instability rates following APCLR.

Arthroscopic Removal of Extra-Articular Foreign Bodies From the Shoulder: Inside-Out Technique.

Arthroscopic shoulder surgery can be performed for retrieval of bullets and retained metallic fragments in the glenohumeral and subacromial spaces. Previous case reports and case series have demonstrated the effectiveness of an arthroscopic approach over an open procedure, as it is less invasive, allows for improved inspection and documentation of the joint surfaces and periarticular structures, and potentially leads to a faster recovery. An arthroscopic approach for extracting foreign bodies from both the quadrilateral space and the posterior extra-articular space by first accessing the glenohumeral space has yet to be described. This inside-out technique may afford surgeons the potential for improved visualization and less morbidity compared with a traditional open posterior approach. We report a technique for an arthroscopic inside-out approach for removal of extra-articular foreign bodies retained in either the quadrilateral space or the posterior extra-articular space.

Hip Arthroscopy: A Social Media Analysis of Patient Perception.

BACKGROUND: The rate of hip arthroscopy has increased significantly in recent years, although understanding of patient perception remains limited. PURPOSE: To analyze posts shared on Instagram and Twitter referencing hip arthroscopy to evaluate perspective, tone, timing, content, visibility, and location. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A search of public posts on Instagram and Twitter was performed over a 1-year period, selected through use of the following hashtags: #hiparthroscopy, #hipscope, and #labralrepair. A total of 1850 Instagram posts and 163 Twitter posts were included in the analysis. A categorical classification system was used for media format (picture or video), perspective (patient, family or friend, physician, hospital or physical therapy group, professional organization, news media, or industry), timing (preoperative, postoperative, nonoperative), perioperative period (within 1 week before or after surgery), tone (positive, negative, or neutral), and content (surgical site, hospital or surgeon, imaging, rehabilitation, activities of daily living (ADLs), return to work, surgical instruments, or education). Post popularity (number of likes) and geographic location were also recorded. RESULTS: Of the 1850 Instagram posts analyzed, 91.2% were made by patients, and 52.9% were positive. The most common content included in Instagram posts was rehabilitation, ADLs, and hospital or surgeon. A total of 163 Twitter posts were analyzed, with 59.0% of posts made by physicians. A majority of posts had a positive tone, and the most frequently referenced themes included education, hospital or surgeon, and rehabilitation. Overall, posts originated from 24 different countries. CONCLUSION: The majority of patients who undergo hip arthroscopy have a positive tone when discussing their procedure. Posts commonly focused on rehabilitation, ADLs, hospital or surgeon, and education. This analysis provides insight into patient perspectives toward hip arthroscopy.

Elucidating the Catalytic Power of Glutamate Racemase by Investigating a Series of Covalent Inhibitors.

The application of covalent inhibitors has experienced a renaissance within drug discovery programs in the last decade. To leverage the superior potency and drug target residence time of covalent inhibitors, there have been extensive efforts to develop highly specific covalent modifications to decrease off-target liabilities. Herein, we present a series of covalent inhibitors of an antimicrobial drug target, glutamate racemase, discovered through structure-based virtual screening. A combination of enzyme kinetics, mass spectrometry, and surface-plasmon resonance experiments details a highly specific 1,4-conjugate addition of a small-molecule inhibitor with a catalytic cysteine of glutamate racemase. Molecular dynamics simulations and quantum mechanics-molecular mechanics geometry optimizations reveal the chemistry of the conjugate addition. Two compounds from this series of inhibitors display antimicrobial potency similar to ß-lactam antibiotics, with significant activity against methicillin-resistant S. aureus strains. This study elucidates a detailed chemical rationale for covalent inhibition and provides a platform for the development of antimicrobials with a novel mechanism of action against a target in the cell wall biosynthesis pathway.

Treatment of iatrogenic V2 segment vertebral artery pseudoaneurysm using Pipeline flow-diverting stent.

BACKGROUND: Iatrogenic injury to the vertebral artery is a rare but potential complication of cervical spine surgery. Previous authors have commented on the use of flow-diverting stents for treatment of aneurysms of the V3 segment of the vertebral artery. CASE DESCRIPTION: Here, we report a case in which injury occurred at the V2 segment of the vertebral artery with the development of a pseudoaneurysm, which was found on angiography. After decompressing the spinal cord from an epidural hematoma, the pseudoaneurysm was treated by deploying two Pipeline flow-diverting stents (Medtronic, Minneapolis, MN). Obliteration of the pseudoaneurysm was noted on follow-up angiography 4 days after the treatment. CONCLUSION: This case highlights a unique treatment at a region which, to our knowledge, has not been mentioned in the literature.

Tumor transcriptome reveals the predictive and prognostic impact of lysosomal protease inhibitors in non-small-cell lung cancer.

PURPOSE: Insight into clinical response to platinum-based chemotherapy (PBC) in non-small-cell lung cancer (NSCLC). METHODS: Matched tumor and nontumor lung tissues from PBC-treated NSCLC patients (four nonresponders and four responders) and tumor tissue from an independent test set (four nonresponders and four responders), were profiled using microarrays. Lysosomal protease inhibitors SerpinB3 and cystatin C were highly correlated with clinical response and were further evaluated by immunohistochemistry in PBC-treated patients (36 prechemotherapy and 13 postchemotherapy). Investigation of the pathogenic and prognostic significance of SerpinB3 was performed in 251 primary tumors, with 64 regional lymph node pairs, from chemotherapy-naïve NSCLC patients using immunohistochemistry. RESULTS: Bioinformatic analyses of gene expression in the training set identified a gene set (n = 17) that separated all patients in the training and test sets (n = 16) according to response in hierarchical clustering. Transcriptome profiling revealed that SerpinB3 mRNA was highly correlated with degree of response (r = -0.978; P < .0001) and was a clear outlier (nonresponders:responders > 50-fold). SerpinB3 protein expression was correlated with clinical response in PBC-treated NSCLC patients (P = .045). Expression of SerpinB3 and cystatin C, relative to the target, protease cathepsin B, was independently predictive of response (odds ratio, 17.8; 95% CI, 2.0 to 162.4; P = .01), with an accuracy of 72%. High SerpinB3 expression levels, invariably associated with chemoresistance, had contrasting prognostic impact in untreated squamous cell carcinomas (hazard ratio [HR], 0.43; 95% CI, 0.18 to 0.93) or adenocarcinomas (HR, 2.09; 95% CI, 1.03 to 4.72). CONCLUSION: This provides the first comprehensive molecular characterization of clinical responsiveness to PBC in NSCLC and reveals the predictive and prognostic impact of two lysosomal protease inhibitors, potentially representing novel targets for NSCLC therapeutics.

Profiling cytochrome P450 expression in ovarian cancer: identification of prognostic markers.

PURPOSE: The cytochromes P450 are a multigene family of enzymes with a central role in the oxidative metabolism of a wide range of xenobiotics, including anticancer drugs and biologically active endogenous compounds. The purpose of this study was to define the cytochrome P450 profile of ovarian cancer and identify novel therapeutic targets and establish the prognostic significance of expression of individual cytochrome P450s in this type of cancer. EXPERIMENTAL DESIGN: Immunohistochemistry for a panel of 23 cytochrome P450s and cytochrome P450 reductase was done on an ovarian cancer tissue microarray consisting of 99 primary epithelial ovarian cancers, 22 peritoneal metastasis, and 13 normal ovarian samples. The intensity of immunoreactivity in each sample was established by light microscopy. RESULTS: In primary ovarian cancer, several P450s (CYP1B1, CYP2A/2B, CYP2F1, CYP2R1, CYP2U1, CYP3A5, CYP3A7, CYP3A43, CYP4Z1, CYP26A1, and CYP51) were present at a significantly higher level of intensity compared with normal ovary. P450 expression was also detected in ovarian cancer metastasis and CYP2S1 and P450 reductase both showed significantly increased expression in metastasis compared with primary ovarian cancer. The presence of low/negative CYP2A/2B (log rank = 7.06, P = 0.008) or positive CYP4Z1 (log rank = 6.19, P = 0.01) immunoreactivity in primary ovarian cancer were each associated with poor prognosis. Both CYP2A/2B and CYP4Z1 were also independent markers of prognosis. CONCLUSIONS: The expression profile of individual P450s has been established in ovarian cancer. Several P450s show increased expression in ovarian cancer and this provides the basis for developing P450-based therapeutics in ovarian cancer. Expression of CYP2A/2B or CYP4Z1 in primary ovarian cancer were independent markers of prognosis.

Multiplex quantitative real-time PCR of laser microdissected tissue.

This chapter describes a method for the rapid assessment of gene copy number in laser microdissected material using multiplex real-time polymerase chain reaction (PCR). Here a putative oncogene (ZNF217) was evaluated in a series of colon tumors, but the method is applicable to any locus for which a nucleic acid sequence is available. The preparation, laser microdissection, and optimum storage of snap-frozen tumor material from freshly resected tissue is described. A set of guidelines specific for real-time PCR assays is included to assist with optimum primer and probe design. In this assay multiplex real-time PCR was performed and our experience has demonstrated that a multiplex reaction allows for a more accurate assessment of gene copy number than a "singleplex" assay because it removes the need for an external control.

Laser capture microdissection and PCR for analysis of human papilloma virus infection.

Human papilloma virus (HPV) infection is considered one of the main factors involved in the pathogenesis of endocervical adenocarcinoma. However, the cellular location of HPV in this type of tumor is controversial. We have developed a method to determine the presence of HPV type 16 in endocervical cancer cells using laser capture microdissection followed by DNA extraction and qualitative polymerase chain reaction. Our results show that HPV type 16 is present in endocervical adenocarcinoma cells.

Cytochrome p450 profile of colorectal cancer: identification of markers of prognosis.

PURPOSE: The cytochromes P450 (P450) are a multigene family of enzymes with a central role in the oxidative metabolism of a wide range of xenobiotics, including anticancer drugs, carcinogens, and endogenous compounds. The purpose of this study was to define the P450 profile of colorectal cancer and establish the prognostic significance of expression of individual P450s in colorectal cancer. EXPERIMENTAL DESIGN: Immunohistochemistry for a panel of 23 P450s was done on a colorectal cancer tissue microarray consisting of 264 primary colorectal cancers, 91 lymph node metastasis, and 10 normal colorectal samples. The intensity of immunoreactivity in each sample was established by light microscopy. RESULTS: The most frequently expressed form of P450 in normal colon was CYP3A4. In primary colorectal cancer, several P450s (CYP1B1, CYP2S1, CYP2U1, CYP3A5, and CYP51) were present at a significantly higher level of intensity compared with normal colon. P450 expression was also detected in lymph node metastasis and the presence of several P450s (CYP1B1, CYP2A/2B, CYP2F1, CYP4V2, and CYP39) in the lymph node metastasis strongly correlated with their presence in corresponding primary tumors. The presence of strong CYP51 (log-rank = 12.11, P = 0.0005) or strong CYP2S1 (log-rank = 6.72, P = 0.0095) immunoreactivity were associated with poor prognosis. CYP51 was also an independent marker of prognosis (P = 0.009). CONCLUSIONS: The expression of individual P450s has been established in colorectal cancer. Several P450s show increased expression in colorectal cancer. High expression of CYP51 or CYP2S1 were associated with poor prognosis and CYP51 is an independent marker of prognosis.

Mortalin is over-expressed by colorectal adenocarcinomas and correlates with poor survival.

Using comparative proteomic analysis we have identified over-expression of mortalin in colorectal adenocarcinomas. Mortalin, also known as mitochondrial heat-shock protein 70 (mhsp 70), is involved in cell cycle regulation with important roles in cellular senescence and immortalization pathways. It is known to bind to and inactivate wild-type tumour suppressor protein p53 and influences the Ras-Raf-MAPK pathway. By immunostaining a colorectal cancer tissue microarray linked to a patient database, we further found that mortalin over-expression correlates with poor patient survival and, in multivariate analysis, is independent of standard prognostic variables (p = 0.04). Our findings demonstrate that mortalin over-expression may predict outcome in colorectal cancer and suggest that this protein is involved in colorectal neoplasia. Our experimental approach emphasises the analytical power of combining proteomics with tissue microarray analysis in the context of a well-defined tumour database.

The candidate oncogene ZNF217 is frequently amplified in colon cancer.

In this study we have defined the changes in gene copy number of the candidate oncogene ZNF217 during colon cancer development and progression. This gene is mapped to chromosome 20q and lies within 20q13.2, a region which we have previously shown to be highly amplified in colorectal cancer by comparative genomic hybridization. The gene copy number of ZNF217 was assessed in 100 colon carcinomas (19 Dukes' A, 42 Dukes' B and 39 Dukes' C), 13 colonic adenomas and 10 normal colon samples. DNA extracted from laser microdissected cells was amplified by multiplex real-time PCR at two distinct gene loci--ZNF217 and beta-globin (control gene)--on an ABI7700 sequence detection system. Of the 100 colon cancers studied, 61 showed some level of amplification of ZNF217, 15 had loss of ZNF217, while 24 were diploid. All the adenomas except one were diploid. In this study we have found that ZNF217 amplification is a frequent event in colon cancer and that the extent of its amplification varies markedly between tumours (range 3-13 copies). There was a trend toward poorer survival in patients whose cancers had either gain or loss of ZNF217.

Quantitative analysis of the Ah receptor/cytochrome P450 CYP1B1/CYP1A1 signalling pathway.

Cytochrome P450 (CYP) drug metabolising enzymes CYP1A1 and CYP1B1 are regulated through the ligand-activated aryl hydrocarbon (Ah) receptor. Differential expression of CYP1A1 and CYP1B1 mRNA and protein has previously been reported in human tissues with the presence of the message often extrapolated to indicate the presence of protein. The aim of this study was to clarify these potentially misleading findings, by analysing components of the Ah receptor pathway (CYP1B1, CYP1A1, Ah receptor and ARNT) using a combination of quantitative real-time RT-PCR and immunoblotting. Three human cell lines (MOG-G-CCM, MCF7 and HEPG2) known to differentially express CYP1A1 and CYP1B1 mRNA and protein were exposed to the Ah receptor agonist 3-MC, and basal and inducible levels of CYP1A1, CYP1B1, Ah receptor and ARNT were determined. The key finding of this study was the demonstration of equivalent levels of CYP1B1 mRNA in both the treated and untreated MOG-G-CCM cell lines, with expression of the corresponding CYP1B1 protein only after exposure to an Ah receptor agonist. This finding suggests that a post-transcriptional mechanism is involved in the regulation of CYP1B1. In addition, the expression pattern of CYP1B1 mRNA and protein in the MOG-G-CCM cells highlights this cell line as a potential model for studying CYP1B1 expression in human tissue.

CYP3A4 promoter variant is associated with prostate cancer risk in men with benign prostate hyperplasia.

Prostate cancer (PRCa) is one of the most common causes of cancer death in men and determinants of PRCa risk remain largely unidentified. Benign prostatic hyperplasia (BPH) is found in the majority of ageing men and has been linked with PRCa. CYP3A4 may influence PRCa through its role in testosterone metabolism. This nested case-control study assessed a CYP3A4 single nucleotide polymorphism as a risk factor for developing PRCa in patients with BPH. The CYP3A4 variant allele identified men with BPH who are at increased risk of progressing to PRCa (odds ratio 6.3, 95% CI 2.3-17.3), providing a potential tool to assist prediction strategies for this disease.