Light chain-associated amyloidosis is a fatal disease characterized by the aggregation and pathologic deposition of monoclonal light chain-related fragments as amyloid fibrils in organs or tissues throughout the body. Notably, it has been observed that proteins encoded by the lambda variable light chain (V(L)) gene segment 6a are invariably associated with amyloid deposition; however, the contribution of the gene to this phenomenon has not been established. In this regard, we have determined the thermodynamic stability and kinetics of in vitro fibrillogenesis of a recombinant (r) V(L) protein, designated 6aJL2, which contains the predicted sequences encoded by the 6a and JL2 germline genes. Additionally, we studied a 6a mutant (6aJL2-Arg25Gly), that is present in approximately 25% of all amyloid-associated lambda6 light chains. Remarkably, the wild-type 6aJL2 protein was more stable than were all known amyloidogenic kappa and lambda light chains for which stability parameters are available; more importantly, it was even more so (and less fibrillogenic) than the only clinically proven nonamyloidogenic lambda6 protein, Jto. Conversely, the mutated 6aJL2-R25G molecule was considerably less stable and more fibrillogenic than was the native 6aJL2. Our data indicate that the propensity of lambda6 light chains to form amyloid can not be attributed to thermodynamic instability of the germline-encoded Vlambda6 domain, but rather, is dependent on sequence alterations that render such proteins amyloidogenic.

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Amyloid fibrils and partially unfolded intermediates may be distinguished serologically from native amyloidogenic precursor proteins or peptides. In this regard, we had previously reported that the IgG1 mAb 11-1F4, generated by immunizing mice with a thermally denatured variable region fragment of the human Igκ4 Bence Jones protein Len, reacted specifically with light chain (LC) fibrils, irrespective of κ or λ isotype but, notably, did not with native molecules (Hrncic, R. et al. (2000) Am. J. Pathol. 157, 1239Pathol. 157, -1246. To elucidate the molecular basis of this specificity, we have used a europium-linked fluorescent immunoassay, where it was demonstrated through epitope mapping that mAb 11-1F4 recognizes a conformational determinant contained within the first (Nterminal) 18 amino acids of misfolded LCs. The nature of this epitope was evidenced in competition studies where the peptide Len (1-18), but not the intact protein or other LCs, inhibited the binding of the antibody to fibrils. This unique reactivity was dependent on the structural integrity of this portion of the molecule, particularly the presence of a highly conserved prolyl residue at position 8. On the basis of our experimental data, we posit that the mAb 11-1F4 binding site found on partially denatured and fibrillar LCs involves an inducible N-terminal main chain reversal that results in the formation of a proline anchored β-turn. Our delineation of this LC fibril-associated epitope provides the rationale for the design of novel amyloid-reactive antibodies with diagnostic and therapeutic potential for patients with LC-associated and other forms of amyloidosis. Amyloidogenesis involves a process by which normally soluble proteins or peptides form nonnative intermediates that eventually assemble into fibrils (1). All types of amyloid, regardless of amino acid sequence, share common tertiary structural features, that is, they are comprised of extended β-sheets oriented perpendicularly to the long fibril axis (2,3) and possess sites that bind the dyes thioflavin T (ThT1) and Congo red (4,5). Additionally, these components and their assembly precursors, irrespective of primary structure, contain generic conformational epitopes not present on native molecules (6-12), further indicating their physical homogeneity.The common epitopes present on amyloid fibrils and their intermediates offer targets for the design of novel diagnostic and therapeutic reagents. In this regard, we have generated a murine monoclonal antibody (mAb), designated 11-1F4 (13), which reacts specifically with light chain (LC) fibrils, but not soluble proteins, and has been shown in an experimental in vivo model to accelerate the removal of amyloidomas composed of human LC fibrils, an effect independent of the κ or λ isotype or the V L subgroup (9). This mAb was generated using as immunogen a heat-aggregated suspension of the human κ4 variable domain (V L ) Len (13,14) To localize and determine the nature of the neo-antigen recognized on conformationally altered LCs by...

Although there are increasing numbers of telemedicine programmes in the USA, few have offered teleoncology services, so that the role of telemedicine in the practice of clinical oncology has yet to be fully defined. Telemedicine has been used successfully for direct patient care in Kansas. It is also a method of providing supportive care for the cancer patient, including assessments of pain and nutrition. In addition, televised tumour conferences and nursing education courses can help smaller communities develop a level of expertise that allows patients to be treated locally. Telemedicine may well be used in future for access to national and international cancer experts, and for participation in new cancer treatment protocols through cooperative group trials. When practising oncology via telemedicine, there are unique problems, including issues regarding technology (interactive video and radiograph review) and practice (patient/oncologist preferences and doctor-patient communication). Very little has been published in the area of tele-oncology so far, and studies concerning its efficacy, cost-effectiveness and the best organizational structure are still in progress. However, telemedicine appears to be a useful technique in the practice of oncology.

This small pilot study suggests that rural cancer patients may be satisfied with seeing their oncologist via telemedicine, at least on an occasional basis. Although the accrual numbers are too small to allow the results to be generalizable, the results suggest that patient acceptance is high enough to warrant further investigation of this modality in the care of rural cancer patients with limited access to cancer specialists.