Translational development of an ADAMTS-5 antibody for osteoarthritis disease modification.

OBJECTIVE/METHOD: Aggrecanase activity, most notably ADAMTS-5, is implicated in pathogenic cartilage degradation. Selective monoclonal antibodies (mAbs) to both ADAMTS-5 and ADAMTS-4 were generated and in vitro, ex vivo and in vivo systems were utilized to assess target engagement, aggrecanase inhibition and modulation of disease-related endpoints with the intent of selecting a candidate for clinical development in osteoarthritis (OA). RESULTS: Structural mapping predicts the most potent mAbs employ a unique mode of inhibition by cross-linking the catalytic and disintegrin domains. In a surgical mouse model of OA, both ADAMTS-5 and ADAMTS-4-specific mAbs penetrate cartilage following systemic administration, demonstrating access to the anticipated site of action. Structural disease modification and associated alleviation of pain-related behavior were observed with ADAMTS-5 mAb treatment. Treatment of human OA cartilage demonstrated a preferential role for ADAMTS-5 inhibition over ADAMTS-4, as measured by ARGS neoepitope release in explant cultures. ADAMTS-5 mAb activity was most evident in a subset of patient-derived tissues and suppression of ARGS neoepitope release was sustained for weeks after a single treatment in human explants and in cynomolgus monkeys, consistent with high affinity target engagement and slow ADAMTS-5 turnover. CONCLUSION: This data supports a hypothesis set forth from knockout mouse studies that ADAMTS-5 is the major aggrecanase involved in cartilage degradation and provides a link between a biological pathway and pharmacology which translates to human tissues, non-human primate models and points to a target OA patient population. Therefore, a humanized ADAMTS-5-selective monoclonal antibody (GSK2394002) was progressed as a potential OA disease modifying therapeutic.

Aggressive surgical treatment of digital papillary adenocarcinoma.

The case of a 38-year-old white man with digital papillary adenocarcinoma is presented. It is a lesion of the skin often occurring in the digits of the hand or of the feet. This disease is rare and has not been reported in the plastic surgical or orthopedic literature to date. A case report is presented here along with our rationale for aggressive surgical treatment consisting of amputation.

Tetrasomy 21 in megakaryoblastic leukemia.

A 23-month-old female evaluated for profound anemia proved to have megakaryoblastic leukemia. The diagnosis is based on examination of bone marrow morphology, cytochemical characteristics, and immunophenotype. The chromosome complement of unstimulated blast cells in peripheral blood and bone marrow was 48,XX,+21,+21. Tetrasomy 21 is the sole clonal cytogenetic abnormality in this patient with megakaryoblastic leukemia. The constitutional complement of the patient is normal female, 46,XX.

Beta-thalassemia resulting from a single nucleotide substitution in an acceptor splice site.

Beta-globin gene mutations which alter normal globin RNA splicing have confirmed the necessity of invariant nucleotides GT at donor splice sites. Functional consequences of point mutations in the invariant AG acceptor splice site have not been determined. We have isolated and characterized a beta-globin gene from a Black patient with beta-thalassemia intermedia which has an A-G transition at the usual intervening sequence 2 (IVS2) acceptor splice site. Functional analysis of transcripts produced by this mutant gene in a transient expression vector indicates that the mutation inactivates the normal acceptor splice site and results in some utilization of a cryptic splice site near position 580 of IVS2. This mutation would be expected to produce a beta-globin gene which results in no normal beta-globin mRNA.

Surgical treatment of subcutaneous calcifications of polymyositis or dermatomyositis.

The "tumoral" calcifications seen with polymyositis and dermatomyositis are frequently large and painful. Many surgeons believe such calcifications should not be removed surgically, arguing that the surgical trauma induces further calcification that is probably ever more severe. However, we believe that surgical removal of these large masses is less traumatic than cyclical, spontaneous extrusion of the calcium with secondary healing. We present 2 patients in whom chronically draining and painful dystrophic calcifications were treated surgically without recurrence.

Butterfly correction of webbed-neck deformity in Turner's syndrome.

A posterior approach is proposed for correction of the webbed-neck deformity of Turner's syndrome. In this approach, a butterfly-shaped portion of redundant skin is excised posteriorly and the lateral, superior and inferior flaps joined in a double Y midline suture line. This approach avoids the unnatural hairline and noticeable scars characteristic of a lateral approach. We believe that the revision required in the case reported here can be avoided by employing an X-shaped, rather than a double inverted Y-shaped, suture line.

Use of the latissimus dorsi myocutaneous island flap for reconstruction in the head and neck area: case report.

Cadaver dissection indicated that a large amount of tissue could be transferred in one stage to the head and neck by a latissimus dorsi myocutaneous island flap tunneled beneath a pectoral skin bridge. A clinical trial of this flap (for one-stage reconstruction of a patient after excision of a recurrent mandibular carcinoma and a neck dissection) was successful. Previous investigators have found the myocutaneous latissimus dorsi flap to be dependable and adaptable in reconstructions of the chest wall, breast, and shoulder. It is evident now that the flap also has value in reconstructions of the head and neck.

Microvascular anastomosis: an experimental model utilizing the rabbit ear.

Using the rabbit ear as an experimental model, a composite flap based on an anastomosed central artery and vein can be created and its viability determined. This inexpensive model can be used to train plastic surgical residents in microsurgery and in further investigations of the microcirculation of flaps and their survival.

Malignant pleural mesothelioma. Report of 19 cases.

Malignant pleural mesothelioma may be composed of sarcomatous, epitheliomatous or mixed cell types. They can be differentiated from localized, benign mesothelioma. Malignant pleural mesothelioma is a rapidly fatal tumor that poses serious diagnostic and therapeutic problems. A series of 19 cases was compiled at the North Carolina Baptist Hospital, and data from these cases were compared to those of other series. The average survival time was 10 months. The most common symptoms were dyspnea, chest pain, pleural effusion, and weight loss. Three patients had a definite history of exposure to asbestos; in 6 more there was a questionable exposure. The most helpful investigative screening tool was the chest roentgenogram, in that it demonstrated an intrathoracic abnormality; however, mesothelioma could not be differentiated from inflammatory reaction or bronchogenic carcinoma with pleural effusion. Sputum cytology as well as pleural effusion cytology was only suggestive of malignancy. Bronchoscopy was not helpful. Needle biopsy yielded malignant cells in 3 of 8 patients. Exploratory thoracotomy was the most accurate means of diagnosis but was frequently followed by seeding into the incision and severe, intractable incisional pain. Therapy proved to be palliative at best. Thoracotomy did not alter the course of the disease; in fact, the production of severe incisional pain was deleterious to the patient's well-being. Cordotomy done in 3 patients brought no relief. Neither radiation therapy nor chemotherapy had a significant effect on survival time or palliation.