A Case of Perianal Mucinous Adenocarcinoma Arising from an Anorectal Fistula Successfully Resected after Preoperative Radiotherapy

A case of mucinous adenocarcinoma arising on a long-standing anorectal fistula is described. A 60-year-old man with a long history of mucinous discharge, pain and perianal induration underwent a biopsy of the external opening of the fistula that showed a mucinous infiltrating adenocarcinoma. Due to the large size of the tumor and the fact that it had extended into the surrounding tissue, preoperative radiotherapy was performed. Radiotherapy was given with 40 Gy in 25 fractions for 5 weeks through posterior and bilateral portals. After radiotherapy the tumor was markedly shrunk and the serum level of carcinoembryonic antigen was also improved. Abdominoperineal resection was performed 8 weeks after the termination of radiotherapy. Histological examination of the resected specimen revealed that the invasion of the tumor remained within the sphincter muscle and that no cancer cells were present on the surgical margin. The histological effect of radiotherapy was judged as grade 1b. This treatment can result in downstaging and R0 resection, which also has a possibility to prevent local recurrence. This case suggests that preoperative radiotherapy may play an important role in the definitive treatment of locally advanced perianal mucinous adenocarcinoma

Decreased Amyloidogenicity Caused by Mutational Modulation of Surface Properties of the Immunoglobulin Light Chain BRE Variable Domain

Amyloid formation by immunoglobulin light chain (LC) proteins is associated with amyloid light chain (AL) amyloidosis. Destabilization of the native state of the variable domain of the LC (V_L) is known to be one of the critical factors in promoting the formation of amyloid fibrils. However, determining the key residues involved in this destabilization remains challenging, because of the existence of a number of intrinsic sequence variations within V_L. In this study, we identified the key residues for destabilization of the native state of amyloidogenic V_L in the LC of BRE by analyzing the stability of chimeric mutants of BRE and REI V_L; the latter immunoglobulin is not associated with AL amyloidosis. The results suggest that the surface-exposed residues N45 and D50 are the key residues in the destabilization of the native state of BRE V_L. Point mutations at the corresponding residues in REI V_L (K45N, E50D, and K45N/E50D) destabilized the native state and increased amyloidogenicity. However, the reverse mutations in BRE V_L (N45K, D50E, and N45K/D50E) re-established the native state and decreased amyloidogenicity. Thus, analyses using chimeras and point mutants successfully elucidated the key residues involved in BRE V_L destabilization and increased amyloidogenic propensity. These results also suggest that the modulation of surface properties of wild-type V_L may improve their stability and prevent the formation of amyloid fibrils