Alterations in the inflammatory cells infiltrating basal cell carcinomas during immunocryosurgery.

Immunocryosurgery, the combination modality of a cryosurgery session at day 14 of a 5-week daily imiquimod treatment cycle, has shown remarkable efficacy in the treatment of basal cell carcinoma (BCC). The modality was designed to exploit synergy of antitumor effects, including the induction of immune responses, elicited by imiquimod and cryosurgery. Herein, we report on the infiltration of the BCC by selected inflammatory cell species during an immunocryosurgery treatment cycle. The density of tissue infiltrating CD68+, CD3+ and Foxp3+ cells was studied by immunohistochemistry in 56 BCC biopsies from 28 treated sites (26 patients) at baseline and at days 12, 16 or 28 during treatment. Immunocryosurgery induces statistically significant alterations in all three cell species (p < 0.003): The density of CD68+ increased already by day 12 and remained at a higher level during the treatment thereafter. The density of CD3+ cells increased significantly between days 12 and 16 of treatment. The density of Treg (Foxp3+) cells increased in the early phase of treatment (highest at day 12) to decrease significantly already 2 days after the cryosurgery session (day 16) and thereafter up to day 28 of the treatment cycle (p = 0.033). Within the tumor tissue, these alterations result in an abrupt increase in the CD3+/Foxp3+ ratio, a finding suggesting that the cryosurgical perturbation may probably play a decisive modulating role in the cellular composition of the inflammatory infiltrate during immunocryosurgery, eventually heralding the induction of an effective tumor-destructing immune response.

Hyperthermia induces therapeutic effectiveness and potentiates adjuvant therapy with non-targeted and targeted drugs in an in vitro model of human malignant melanoma.

In the present study, we have aimed to characterize the intrinsic, extrinsic and ER-mediated apoptotic induction by hyperthermia in an in vitro model of human malignant melanoma and furthermore, to evaluate its therapeutic effectiveness in an adjuvant therapeutic setting characterized by combinational treatments with non-targeted (Dacarbazine & Temozolomide) and targeted (Dabrafenib & Vemurafenib) drugs. Overall, our data showed that both low (43 °C) and high (45 °C) hyperthermic exposures were capable of inducing cell death by activating all apoptotic pathways but in a rather distinct manner. More specifically, low hyperthermia induced extrinsic and intrinsic apoptotic pathways both of which activated caspase 6 only as opposed to high hyperthermia which was mediated by the combined effects of caspases 3, 7 and 6. Furthermore, significant involvement of the ER was evident (under both hyperthermic conditions) suggesting its role in regulating apoptosis via activation of CHOP. Our data revealed that while low hyperthermia activated IRE-1 and ATF6 only, high hyperthermia induced activation of PERK as well suggesting that ultimately these ER stress sensors can lead to the induction of CHOP via different pathways of transmitted signals. Finally, combinational treatment protocols revealed an effect of hyperthermia in potentiating the therapeutic effectiveness of non-targeted as well as targeted drugs utilized in the clinical setting. Overall, our findings support evidence into hyperthermia's therapeutic potential in treating human malignant melanoma by elucidating the underlying mechanisms of its complex apoptotic induction.

Radical therapy for muscle-infiltrating bladder cancer (cystectomy or radiotherapy): does age affect the final therapeutic benefit for the patient?

PURPOSE: To evaluate the therapeutic outcome of radical cystectomy and radical radiotherapy in patients with T2N0M0 clinical stage bladder cancer in relation to their age. PATIENTS AND METHODS: Between 1995-2006, 119 patients with clinical stage T2N0M0 bladder cancer were treated with radical radiotherapy (group A) and were divided in 2 subgroups: >70 years old (A1) and 70 years old/B1 subgroup and