Evaluation of Therapeutics for Advanced-Stage Heart Failure and Other Severely-Debilitating or Life-Threatening Diseases.

Severely-debilitating or life-threatening (SDLT) diseases include conditions in which life expectancy is short or quality of life is greatly diminished despite available therapies. As such, the medical context for SDLT diseases is comparable to advanced cancer and the benefit vs. risk assessment and development of SDLT disease therapeutics should be similar to that of advanced cancer therapeutics. A streamlined development approach would allow patients with SDLT conditions earlier access to therapeutics and increase the speed of progression through development. In addition, this will likely increase the SDLT disease therapeutic pipeline, directly benefiting patients and reducing the economic and societal burden of SDLT conditions. Using advanced-stage heart failure (HF) as an example that illustrates the concepts applicable to other SDLT indications, this article proposes a streamlined development paradigm for SDLT disease therapeutics and recommends development of aligned global regulatory guidance.

Histopathologic and immunophenotypic characterization of extramedullary plasmacytomas in nine cats.

To contribute to the existing body of knowledge in the literature on the apparently rare extramedullary plasmacytoma in cats, lymphoid tumors with plasmacytic cellular morphology taken from nine cats were examined. The paraffin-embedded material was investigated by standard hematoxylin and eosin, and special staining techniques (Giemsa, Congo-red, and periodic acid-Schiff reaction). The tumors also were examined immunohistochemically for the presence of immunoglobulin G, immunoglobulin A, immunoglobulin M, immunoglobulin light chains (lambda, kappa), various amyloid proteins, and FeLV-antigen (p27 protein). An immunoglobulin-producing tumor of plasmacellular origin (extramedullary plasmacytoma [EMP]) could be diagnosed in all cases on the basis of immunohistochemical light-chain expression. All but one of the neoplasms occurred in the skin of older, predominantly male cats. As in humans and dogs, the following types could be identified according to their morphologic features: mature type (two), cleaved type (two), asynchronous type (four), and polymorphous type (one). The tumor tissue of three cats revealed amyloid deposits, which were immunohistochemically diagnosed as ALlambda-amyloid in all three cases.

Prognostic value of histopathological grading in canine extramedullary plasmacytomas.

The canine extramedullary plasmacytoma (cEMP) has recently been the subject of numerous investigations, indicating that the histomorphologic diagnosis is often difficult because of the variety of morphologic features. Therefore, the objective of this study was to establish a subclassification scheme for cEMPs and to evaluate correlations between the types and malignancy. Retrospectively, 117 cEMPs, all immunohistochemically characterized by a monoclonal immunoglobulin light-chain expression, were collected and assigned to morphologic types. These types were compared using data from a follow-up study on metastasis and tumor recurrence, then compared by proliferation rate, determined by immunohistochemical detection of the antigen Ki-67. Histopathologic typing revealed five different types of cEMPs, ranging from the mature type with typical plasma cells to the polymorphous-blastic type. Between these two forms, three additional types were established: hyaline, cleaved, and asynchronous. Most of the cEMPs were of the cleaved and asynchronous types. In all cEMPs, mononuclear and multinuclear giant cells were present to varying degrees. Although the results of cell proliferation and the follow-up study indicated less benign behavior by the polymorphous-blastic type, the proliferation rate revealed no statistically significant differences among the cEMP types. The clinical data therefore confirmed previous findings that the risk of tumor recurrence and metastasis in general can be classed as low. The established cEMP typing system is probably a very helpful diagnostic tool, although the types cannot be used for a tumor grading system.

Identification of lambda light chain amyloid in eight canine and two feline extramedullary plasmacytomas.

Amyloid deposition in varying amounts and with variable patterns of distribution (focal or diffuse) was demonstrated in eight canine and two feline extramedullary plasmacytomas expressing lambda light chains. Frequently, the neoplastic plasma cells had been displaced by the amyloid deposits. Foreign-body giant cells were regularly detected in the vicinity of the amyloid. In all 10 cases, Congo-red staining of the amyloid was resistant to potassium permanganate oxidation. Immunohistochemically, the amyloid reacted positively with cross-reacting antibodies against human and equine A lambda amyloids. Extramedullary plasmacytomas accompanied by localized AL amyloidosis have so far been described in human beings, dogs, cats and horses.