Mesorectal failure after chemoradiotherapy for squamous cell carcinoma of the anus: is sphincter-saving surgery reasonable?

BACKGROUND: Abdominoperineal resection (APR) is today the standard treatment for improving survival in case of mesorectal failure without anal canal recurrence after chemoradiotherapy (CRT) for squamous cell carcinoma of the anus (SCC). The aim of this study was to assess if a sphincter-saving surgery is a safe alternative to classical salvage APR in these patients. METHODS: A retrospective study was conducted on all patients who had total mesorectal excision (TME) with sphincter-saving surgery either with coloanal or low colorectal anastomosis, for mesorectal failure after CRT for SCC between 2012 and 2020 at our institution. The main endpoint of our study was oncological results at the end of follow-up. Postoperative morbidity and mortality were secondary endpoints. RESULTS: There were 10 patients, (8 women, median age 55 years [range 45-61 years]). On TME specimens, R0 resections were noted in five (50%), R1 resection in four (40%) and R2 resection in one (10%). After a median follow-up of 42 months (4-74 months), five patients were alive, and four (40%) were alive at 5-year follow-up. During follow-up, locoregional failure after TME was noted in two patients (20%), distant relapse in three patients (30%) and both locoregional plus distant failure in two patients (20%). Only two patients (20%) had anal recurrence, one in the anal canal, the other in the peri-anastomotic area. Long- term local control was achieved in 2 of the 5 patients (40%) who underwent R0 resection versus only 1/4 patients (25%) with R1 resection. CONCLUSIONS: Our preliminary study suggested that sphincter-saving surgery could be proposed in selected patients with SCC presenting mesorectal failure after CRT, providing a feasible R0 resection.

Two-site interaction of nuclear factor of activated T cells with activated calcineurin.

Transcription factors belonging to the nuclear factor of activated T cells (NFAT) family regulate the expression of cytokine genes and other inducible genes during the immune response. The functions of NFAT proteins are directly controlled by the calcium- and calmodulin-dependent phosphatase calcineurin. Here we show that the binding of calcineurin to NFAT is substantially increased when calcineurin is activated with calmodulin and calcium. FK506.FKBP12 drug-immunophilin complexes inhibited the interaction of NFAT with activated calcineurin much more effectively than they inhibited the interaction with inactive calcineurin, suggesting that part of the interaction with activated calcineurin involved the enzyme active site. We have previously shown that NFAT is targeted to inactive calcineurin at a region distinct from the calcineurin active site (Aramburu, J., Garcia-Cozar, F. J., Raghavan, A., Okamura, H., Rao, A., and Hogan, P. G. (1998) Mol. Cell 1, 627-637); this region is also involved in NFAT binding to activated calcineurin, since binding is inhibited by an NFAT peptide spanning the calcineurin docking site on NFAT. The interacting surfaces are located on the catalytic domain of the calcineurin A chain and on an 86-amino acid fragment of the NFAT regulatory domain. NFAT binding to the calcineurin catalytic domain was inhibited by the calcineurin autoinhibitory domain and the RII substrate peptide, which bind in the calcineurin active site, as well as by the NFAT docking site peptide, which binds to a region of calcineurin distinct from the active site. We propose that, in resting cells, NFAT is targeted to a region of the calcineurin catalytic domain that does not overlap the calcineurin active site. Upon cell activation, displacement of the autoinhibitory domain by calmodulin binding allows NFAT to bind additionally to the calcineurin active site, thus positioning NFAT for immediate dephosphorylation at functional phosphoserine residues.

Antibodies against a peptide representative of a conserved region of human IFN-alpha. Differential effects on the antiviral and antiproliferative effects of IFN.

mAb generated from mice immunized with a synthetic peptide representative of a conserved region (amino acids 133 to 147) of human IFN-alpha are described. Antisera from mice immunized with the peptide coupled to keyhole limpet hemocyanin were able to specifically bind to the peptide and also to bind and precipitate human IFN-alpha. Binding of the antibodies to IFN-alpha was inhibited by the immunizing peptide, but not by an unrelated peptide. Immunized mice were used to obtain three hybridomas producing mAb able to recognize both the immunizing peptide and human IFN-alpha, as determined by RIA and immunoprecipitation. These antibodies also neutralized the antiviral effect of human leukocyte IFN. In contrast, none of the mAb significantly affected the inhibition of Daudi cell proliferation induced by IFN-alpha.