A Retrospective Case Series of Synovial Sarcoma of the Upper Extremity.

PURPOSE: Previous studies have grouped the treatment of axial and appendicular synovial sarcomas. The purpose of this study was to assess the prognostic variables of upper extremity synovial sarcomas (UESS) and compare the outcomes of those who underwent a nononcologic or inadvertent excision prior to definitive resection to those who underwent an initial oncologic resection. METHODS: We reviewed the records of 23 UESS treated with definitive surgery at our institution between 1990 and 2014. There were 13 women and 10 men with a median age of 30 years (6-60) and median follow-up of 63 months (15-248). Prognostic variables, recurrence-free survival (RFS), and overall survival (OS) were then assessed. RESULTS: Fifteen patients (65%) had a prior unplanned excision. Five patients required an amputation to obtain local control of disease. There were 3 observed local recurrences and 2 distant metastases at a median of 45 months from presentation. We found no difference in need for amputation, RFS, or OS between those who had undergone a planned excision and those who had an unplanned excision. CONCLUSION: While we were unable to find a significant difference in outcomes or amputation rates between those who underwent reexcision of a previously unplanned excision and those who underwent an initial planned resection, the high rate of unplanned excision is troubling and should remind practitioners to consider sarcoma in the differential of all upper extremity masses.

Treatment of Dupuytren's contracture: a systematic review.

Aims: Dupuytren's contracture is a benign, myoproliferative condition affecting the palmar fascia that results in progressive contractures of the fingers. Despite increased knowledge of the cellular and connective tissue changes involved, neither a cure nor an optimum form of treatment exists. The aim of this systematic review was to summarize the best available evidence on the management of this condition. Materials and Methods: A comprehensive database search for randomized controlled trials (RCTs) was performed until August 2017. We studied RCTs comparing open fasciectomy with percutaneous needle aponeurotomy (PNA), collagenase clostridium histolyticum (CCH) with placebo, and CCH with PNA, in addition to adjuvant treatments aiming to improve the outcome of open fasciectomy. A total of 20 studies, involving 1584 patients, were included. Results: PNA tended to provide higher patient satisfaction with fewer adverse events, but had a higher rate of recurrence compared with limited fasciectomy. Although efficacious, treatment with CCH had notable recurrence rates and a high rate of transient adverse events. Recent comparative studies have shown no difference in clinical outcome between patients treated with PNA and those treated with CCH. Conclusion: Currently there remains limited evidence to guide the management of patients with Dupuytren's contracture. Cite this article: Bone Joint J 2018;100-B:1138-45.

Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016

Tumor budding is a well-established independent prognostic factor in colorectal cancer but a standardized method for its assessment has been lacking. The primary aim of the International Tumor Budding Consensus Conference (ITBCC) was to reach agreement on an international, evidence-based standardized scoring system for tumor budding in colorectal cancer. The ITBCC included nine sessions with presentations, a pre-meeting survey and an e-book covering the key publications on tumor budding in colorectal cancer. The 'Grading of Recommendation Assessment, Development and Evaluation' method was used to determine the strength of recommendations and quality of evidence. The following 10 statements achieved consensus: tumor budding is defined as a single tumor cell or a cell cluster consisting of four tumor cells or less (22/22, 100%). Tumor budding is an independent predictor of lymph node metastases in pT1 colorectal cancer (23/23, 100%). Tumor budding is an independent predictor of survival in stage II colorectal cancer (23/23, 100%). Tumor budding should be taken into account along with other clinicopathological features in a multidisciplinary setting (23/23, 100%). Tumor budding is counted on H&E (19/22, 86%). Intratumoral budding exists in colorectal cancer and has been shown to be related to lymph node metastasis (22/22, 100%). Tumor budding is assessed in one hotspot (in a field measuring 0.785 mm2) at the invasive front (22/22, 100%). A three-tier system should be used along with the budding count in order to facilitate risk stratification in colorectal cancer (23/23, 100%). Tumor budding and tumor grade are not the same (23/23, 100%). Tumor budding should be included in guidelines/protocols for colorectal cancer reporting (23/23, 100%). Members of the ITBCC were able to reach strong consensus on a single international, evidence-based method for tumor budding assessment and reporting. It is proposed that this method be incorporated into colorectal cancer guidelines/protocols and staging systems.

Ulnar head replacement and sigmoid notch resurfacing arthroplasty with a lateral meniscal allograft: 'calamari procedure'.

We report the outcomes of ulnar head replacement with concomitant resurfacing of the sigmoid notch with a lateral meniscal allograft that attempted to recreate the palmar and dorsal radioulnar ligaments in four patients. Patients' ranges of motion, grip strength, postoperative complications and radiographs were assessed. The mean follow-up was 20 (range 12-28) months. There was an increase in postoperative range of motion with an average increase in grip strength of 43% to the unaffected extremity. All patients experienced marked reduction in their postoperative pain. No patients reported symptoms of implant instability. Distal ulna implant arthroplasty with a lateral meniscal allograft gives favourable short-term outcomes. LEVEL OF EVIDENCE: IV.

Phlpp1 facilitates post-traumatic osteoarthritis and is induced by inflammation and promoter demethylation in human osteoarthritis.

OBJECTIVE: Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability. OA is characterized by articular chondrocyte deterioration, subchondral bone changes and debilitating pain. One strategy to promote cartilage regeneration and repair is to accelerate proliferation and matrix production of articular chondrocytes. We previously reported that the protein phosphatase Phlpp1 controls chondrocyte differentiation by regulating the activities of anabolic kinases. Here we examined the role of Phlpp1 in OA progression in a murine model. We also assessed PHLPP1 expression and promoter methylation. DESIGN: Knee joints of WT and Phlpp1(-/-) mice were surgically destabilized by transection of the medial meniscal ligament (DMM). Mice were assessed for signs of OA progression via radiographic and histological analyses, and pain assessment for mechanical hypersensitivity using the von Frey assay. Methylation of the PHLPP1 promoter and PHLPP1 expression were evaluated in human articular cartilage and chondrocyte cell lines. RESULTS: Following DMM surgeries, Phlpp1 deficient mice showed fewer signs of OA and cartilage degeneration. Mechanical allodynia associated with DMM surgeries was also attenuated in Phlpp1(-/-) mice. PHLPP1 was highly expressed in human articular cartilage from OA patients, but was undetectable in cartilage specimens from femoral neck fractures (FNFxs). Higher PHLPP1 levels correlated with less PHLPP1 promoter CpG methylation in cartilage from OA patients. Blocking cytosine methylation or treatment with inflammatory mediators enhanced PHLPP1 expression in human chondrocyte cell lines. CONCLUSION: Phlpp1 deficiency protects against OA progression while CpG demethylation and inflammatory cytokines promote PHLPP1 expression.

Putting the baby back in the bathwater: the interpretation of randomised trials in surgery.

Recently, several high impact randomised controlled trials have been published suggesting no greater benefit from orthopaedic surgery over conservative treatment, or limited surgical intervention. These studies can have profound effects on clinical practice, leading to the abandonment of previously widely-used operations. How do surgeons who believe these operations are beneficial over conservative treatment rationalise these findings, and justify their use with hospital administrators and health care funders who require evidence for the value and efficacy of surgical treatment?

MUC4 regulates cellular senescence in head and neck squamous cell carcinoma through p16/Rb pathway.

The limited effectiveness of therapy for patients with advanced stage head and neck squamous cell carcinoma (HNSCC) or recurrent disease is a reflection of an incomplete understanding of the molecular basis of HNSCC pathogenesis. MUC4, a high molecular weight glycoprotein, is differentially overexpressed in many human cancers and implicated in cancer progression and resistance to several chemotherapies. However, its clinical relevance and the molecular mechanisms through which it mediates HNSCC progression are not well understood. This study revealed a significant upregulation of MUC4 in 78% (68/87) of HNSCC tissues compared with 10% positivity (1/10) in benign samples (P=0.006, odds ratio (95% confidence interval)=10.74 (2.0-57.56). MUC4 knockdown (KD) in SCC1 and SCC10B HNSCC cell lines resulted in significant inhibition of growth in vitro and in vivo, increased senescence as indicated by an increase in the number of flat, enlarged and senescence-associated ß-galactosidase (SA-ß-Gal)-positive cells. Decreased cellular proliferation was associated with G0/G1 cell cycle arrest and decrease expression of cell cycle regulatory proteins like cyclin E, cyclin D1 and decrease in BrdU incorporation. Mechanistic studies revealed upregulation of p16, pRb dephosphorylation and its interaction with histone deacetylase 1/2. This resulted in decreased histone acetylation (H3K9) at cyclin E promoter leading to its downregulation. Orthotopic implantation of MUC4 KD SCC1 cells into the floor of the mouth in nude mice resulted in the formation of significantly smaller tumors (170±18.30 mg) compared to those (375±17.29 mg) formed by control cells (P=0.00007). In conclusion, our findings showed that MUC4 overexpression has a critical role by regulating proliferation and cellular senescence of HNSCC cells. Downregulation of MUC4 may be a promising therapeutic approach for treating HNSCC patients.

Linked distal radioulnar joint arthroplasty: an analysis of the APTIS prosthesis.

Painful radioulnar convergence following resection of the distal ulna can produce substantial disability and prove a challenging surgical problem, particularly in the revision setting. The purpose of this study was to evaluate the outcome of a series of patients with chronic distal radioulnar joint instability or multiple prior procedures treated with linked distal radioulnar joint arthroplasty with the APTIS prosthesis. A series of ten patients were identified with a mean follow up of 4.0 years. At final follow-up nine of ten implants survived free from revision or removal, with patients experiencing good pain relief and functional outcomes, with reasonable overall satisfaction in all seven patients who returned the questionnaires. Despite the medium-term follow-up and small number of patients, our results suggest the linked distal radioulnar joint arthroplasty may be a viable option for treating painful radioulnar convergence following multiple failed procedures at the distal radioulnar joint.

Indian-born patients attending a sexual health clinic in Australia have differing characteristics to their Australian-born counterparts.

We report a retrospective cross-sectional study from Western Sydney that assessed the sexual health characteristics of Indian-born patients attending sexual health services compared with Australian-born controls. The sexual health needs of Indian-born patients differed significantly from controls with those born in India reporting more sexual dysfunction and controls having more sexually transmitted infections (STI). These issues should be considered when delivering services to people from culturally and linguistically diverse backgrounds.

Survey of hand surgeons regarding their perceived needs for an expanded upper extremity fellowship.

PURPOSE: To survey practicing hand surgeons regarding their perceived need for an expanded upper extremity fellowship. METHODS: Electronic surveys were sent to 248 surgeons who had completed a hand surgery fellowship between 2008 and 2010. The survey was structured to ascertain whether there was a need for expanded education encompassing the entire upper extremity. Four separate mailings were made. Of the 248 surgeons who were sent the survey, 131 (53%) responded. Of the respondents, 74% (97) were trained in orthopedics, 16% (21) in plastic surgery, and 10% (13) in general surgery. RESULTS: Of the 131 respondents, 7% (9) felt that 1 year of specialty training was insufficient, 48% (63) had sought shoulder and elbow training in their fellowship, and 52% (68) did not have dedicated plastic surgery rotations. Microsurgical experience was variable: 8% (10) of respondents had not been exposed to replantation, 23% (30) had not been exposed to free flap surgery, 32% (42) had not participated in brachial plexus surgery, and 17% (22) had not done a vascularized bone graft. Fifty-six percent (73) of respondents had not had dedicated time for research during their fellowship. Eleven percent (15) had obtained additional training after their fellowship, including shoulder and elbow, microsurgery, pediatrics, and peripheral nerve surgery. When asked if they would have applied to a 2-year hand and upper extremity fellowship, 60% (79) of respondents would have applied. CONCLUSIONS: Based on the results of this survey, 1 year of hand fellowship training has been perceived as inadequate by 7% (9) of respondents, with exposure insufficient in shoulder and elbow, microsurgery, pediatrics, and clinical research. Further critical review of hand fellowship education should be considered, with the availability of extended fellowship tracks for those requesting an increased breadth of upper extremity surgical training.

PTTG induces EMT through integrin αVß3-focal adhesion kinase signaling in lung cancer cells.

Pituitary tumor transforming gene (PTTG) is a well-studied oncogene for its role in tumorigenesis and serves as a marker of malignancy in several cancer types including lung. In the present study, we defined the role of PTTG in actin cytoskeleton remodeling, cell migration and induction of epithelial mesenchymal transition (EMT) through the regulation of integrin α(V)ß(3)-FAK (focal adhesion kinase) signaling pathway. Overexpression of PTTG through an adenovirus vector resulted in a significant increase in the expression of integrins α(V) and ß(3), a process that was reversed with the downregulation of PTTG expression through the use of an adenovirus expressing PTTG-specific small interfering RNA (siRNA). Western blot analysis of cells infected with adenovirus PTTG cDNA resulted in increased FAK and enhanced expression of adhesion complex molecules paxillin, metavincullin, and talin. Furthermore, downstream signaling genes Rac1, RhoA, Cdc42 and DOCK180 showed upregulation upon PTTG overexpression. This process was dependent on integrin α(V), as blockage by antagonist echistatin (RGD peptide) or α(V)-specific siRNA resulted in a decrease in FAK and subsequent adhesion molecules. Actin cytoskeleton disruption was detected as a result of integrin-FAK signaling by PTTG as well as enhanced cell motility. Taken together, our results suggest for the first time an important role of PTTG in regulation of integrins α(V) and ß(3) and adhesion-complex proteins leading to induction of EMT.

Vascularized medial femoral condyle corticoperiosteal flaps for the treatment of recalcitrant humeral nonunions.

BACKGROUND: Several methods have been used in the management of humeral nonunions. With the advent of modern microsurgical techniques, vascularized bone grafting is becoming increasingly used to improve local biology. We report our experience in the use of a vascularized corticoperiosteal bone flap from the medial femoral supracondylar region in the treatment of recalcitrant humeral nonunions. METHODS: A retrospective review was performed of all patients treated with this technique over a 4-year period within our institution. Patient demographics, nonunion characteristics, complications, and long-term outcomes were analyzed. RESULTS: Six patients underwent vascularized periosteal graft reconstruction. Prior to this, all had failed an average of three procedures with the length of nonunion ranging from 6 to 68 months. All six nonunions healed by an average of 6.8 months (range 2-12 months). Two patients required additional secondary procedures. Functional outcome improved in all patients as adjudged by disabilities of the arm, shoulder, and hand, Mayo elbow performance, and Constant Murley scores. CONCLUSIONS: The vascularized medial femoral condyle corticoperiosteal flap provides an additional treatment option for the management of humeral nonunions.

Vascularized bone grafting from the dorsal distal radius for Kienböck's disease: technique, indications and review of the literature.

The goals of surgical procedures in Kienböck's disease are to preserve wrist function, revascularize the necrotic lunate and maintain normal wrist kinematics when possible. Of the various treatment options, pedicled vascularized bone grafts from the dorsal distal radius permit the transfer of vascularized osseous tissue to the necrotic lunate in order to revascularize it. Vascularized bone grafting is an attractive alternative to conventional bone grafting by improving the local biological environment and thereby promoting revascularization. Recent advances in the anatomy and physiology of vascularized pedicled bone grafts have increased our ability to apply them to the treatment of Kienböck's disease. The purpose of this article is to describe the detailed vascular anatomy of the dorsal distal radius, the surgical technique, indications as well as contraindications of our preferred method of pedicled vascularized bone grafts of Kienböck's disease.

Chlamydia trachomatis causing neonatal conjunctivitis in a tertiary care center.

Chlamydia trachomatis is considered a major aetiological agent of conjunctivitis in newborns. The objective of the present study was to determine the aetiology of neonatal conjunctivitis and clinico-epidemiological correlates of chlamydial ophthalmia neonatorum. Fifty-eight newborns with signs and symptoms of conjunctivitis were studied. Conjunctival specimens were subjected to Gram staining, routine bacteriological culture, culture for Neisseria gonorrhoeae and direct fluorescent antibody (DFA) staining for diagnosis of C. trachomatis infection. C. trachomatis was detected in 18 (31%) neonates. Findings suggest that since C. trachomatis is the most common cause of neonatal conjunctivitis, routine screening and treatment of genital C. trachomatis infection in pregnant women and early diagnosis and treatment of neonatal Chlamydial conjunctivitis may be considered for its prevention and control.

Histological patterns in drug-induced liver disease.

The diagnosis of drug-induced liver injury (DILI) is a challenging problem, often confounded by incomplete clinical information and the difficulty of eliciting exposure to herbal products, over-the-counter agents and toxins. The task is further rendered difficult on biopsy, as drugs can mimic all the patterns found in primary liver disease. Acute hepatitis, with or without cholestasis, is the most common histological pattern of DILI, and drugs such as acetaminophen are the leading causes of acute liver failure. Most cases of DILI resolve on discontinuation of the drug, but recovery can take months or rarely the disease can progress despite drug withdrawal. Drugs such as methotrexate can lead to chronic hepatitis and cirrhosis, while others such as minocycline, nitrofurantoin and methyldopa are implicated in autoimmune hepatitis. Prolonged cholestasis and ductopenia resembling primary chronic biliary disease can occur. Drug-induced steatohepatitis is also an uncommon pattern, but is well described with drugs such as amiodarone and irinotecan. In the presence of risk factors such as obesity and diabetes, some drugs such as tamoxifen, oestrogens and nifedipine can precipitate or exacerbate steatohepatitis. Other observed patterns include granulomatous hepatitis, vascular injury (eg, sinusoidal obstruction syndrome), Ito cell lipidosis and neoplasms (eg, adenomas).

Pharmacodynamic and pharmacokinetic characterisation of RBx 7796: a novel 5-lipoxygenase inhibitor.

OBJECTIVE: RBx 7796, a 5-lipoxygenase inhibitor, was evaluated in in vivo efficacy models, in vitro ADME and in vivo pharmacokinetic models. METHOD: RBx 7796 was evaluated for inhibition of 5-lipoxygenase enzyme and release of LTB4 from isolated rat and human neutrophils. RBx 7796 was tested in allergic bronchoconstriction model in Balb/c mice and LPS induced airway hyperreactivity model in rats. RBx 7796 was evaluated for metabolic stability in liver microsomes and cytochrome P450 inhibition potential. Pharmacokinetic profile of RBx 7796 was also determined in rat and dog. RESULTS: RBx 7796 inhibited 5-lipoxygenase enzyme and inhibited release of LTB4 from neutrophils. RBx 7796 also inhibited early and late airway reactivity following allergen challenge in mouse model. LPS induced increase in airway reactivity was blocked by RBx 7796. Compound was found to be stable in liver microsomes and devoid of major cytochrome P450 inhibition potential. The oral bioavailability of RBx 7796 in rat and dog was 83 % and 47 %, respectively. Following repeated daily administration, compound did not exhibit any sign of accumulation and/or tendency to induce its own metabolism. CONCLUSION: The results suggest that RBx 7796 is an inhibitor of 5-lipoxygenase enzyme that is orally efficacious in two different models of airway reactivity. The molecule also demonstrated acceptable pharmacokinetic profile warranting further development.

LHRH receptor targeted therapy for breast cancer.

Breast cancer remains the most common cancer among women, with an estimated 212,920 new cases and 40,970 deaths in the United States in 2006. The present work extends the studies of nanoparticles targeted to the luteinizing hormone-releasing hormone (LHRH) receptor which is overexpressed in breast, ovarian, endometrial and prostate cancer cells. In contrast, LHRH receptors are not expressed, or expressed at a low level in most visceral organs. In our studies, we conjugated Fe3O4 nanoparticles (20-30 nm) with [D-Trp6]LHRH (Triptorelin), a decapeptide analog of LHRH currently used for treatment of sex-hormone-dependent tumors. Conjugation of [D-Trp6]LHRH to Fe3O4 particles retained its binding affinity and biological activity for the LHRH receptor. Treatment of two separate breast tumor cell lines (MCF-7 and MDA-MB231) with these conjugated nanoparticles resulted in 95-98% cell death and loss of viability within 24 h whereas no change in cell proliferation or cell apoptosis was observed in cells treated with equal amounts of either [D-Trp6]LHRH or unconjugated Fe3O4 nanoparticles. These studies provide critical and important information regarding use of LHRH receptor targeted therapy for breast cancer.

Sexing of human hip bones of Indian origin by discriminant function analysis.

The present study was carried out in terms of discriminant analysis and was conducted on 100 human hip bones (of unknown sex) of Indian origin. Based on morphological features, each of the hip bone was rated on a scale of 1-3 for sexing. Twelve measurements and five indices were recorded. The results of discriminant function analysis showed that the acetabular height (vertical diameter) and indices 1 (total pelvic height/acetabular height), 2 (midpubic width/acetabular height) and 3 (pubic length/acetabular height) were very good measures for discriminating sexes. Pelvic brim depth, minimum width of ischiopubic ramus and indices 4 (pelvic brim chord x pelvic brim depth) and 5 (pubic length x 100/ischial length) were also good discriminators of sex. The remaining parameters were not significant as they showed a lot of overlap between male and female categories. The results indicated that one exclusive criterion for sexing was index 3 (pubic length/acetabular height). In comparison with the morphological criteria, the abovementioned index caused 25% and 10.25% increase in the hip bones of female and male category, respectively.