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Electrical stimulation of spiral ganglion neurons in a deafened cochlea, via a cochlear implant, provides a means of investigating the effects of the removal and subsequent restoration of afferent input on the functional organization of the primary auditory cortex (AI). We neonatally deafened 17 cats before the onset of hearing, thereby abolishing virtually all afferent input from the auditory periphery. In seven animals the auditory pathway was chronically reactivated with environmentally derived electrical stimuli presented via a multichannel intracochlear electrode array implanted at 8 weeks of age. Electrical stimulation was provided by a clinical cochlear implant that was used continuously for periods of up to 7 months. In 10 long‐term deafened cats and three age‐matched normal‐hearing controls, an intracochlear electrode array was implanted immediately prior to cortical recording. We recorded from a total of 812 single unit and multiunit clusters in AI of all cats as adults using a combination of single tungsten and multichannel silicon electrode arrays. The absence of afferent activity in the long‐term deafened animals had little effect on the basic response properties of AI neurons but resulted in complete loss of the normal cochleotopic organization of AI. This effect was almost completely reversed by chronic reactivation of the auditory pathway via the cochlear implant. We hypothesize that maintenance or reestablishment of a cochleotopically organized AI by activation of a restricted sector of the cochlea, as demonstrated in the present study, contributes to the remarkable clinical performance observed among human patients implanted at a young age. J. Comp. Neurol. 512:101–114, 2009. © 2008 Wiley‐Liss, Inc.

Combination of chemotherapy with cancer vaccines is currently regarded as a potentially valuable therapeutic approach for the treatment of some metastatic tumors, but optimal modalities remain unknown. We designed a phase I/II pilot study for evaluating the effects of dacarbazine (DTIC) on the immune response in HLA-A2 1 disease-free melanoma patients who received anticancer vaccination 1 day following chemotherapy (800 mg/mq i.v.). The vaccine, consisting of a combination of HLA-A2 restricted melanoma antigen A (Melan-A/MART-1) and gp100 analog peptides (250 lg each, i.d.), was administered in combination or not with DTIC to 2 patient groups. The combined treatment is nontoxic. The comparative immune monitoring demonstrates that patients receiving DTIC 1 day before the vaccination have a significantly improved long-lasting memory CD8 1 T cell response. Of relevance, these CD8 1 T cells recognize and lyse HLA-A2 1 /Melan-A 1 tumor cell lines. Global transcriptional analysis of peripheral blood mononuclear cells (PBMC) revealed a DTIC-induced activation of genes involved in cytokine production, leukocyte activation, immune response and cell motility that can favorably condition tumor antigen-specific CD8 1 T cell responses. This study represents a proof in humans of a chemotherapyinduced enhancement of CD8 1 memory T cell response to cancer vaccines, which opens new opportunities to design novel effective combined therapies improving cancer vaccination effectiveness. '

PurposeThe VICTOR-1 study demonstrated that the all-oral metronomic combination of vinorelbine and capecitabine is highly active and well tolerated in hormone receptor-positive/HER2-negative patients. The VICTOR-2 study was designed to confirm these results.MethodsPatients received mVNR 40 mg three times a week and mCAPE 500 mg three times a day, continuously. The primary endpoint was the clinical benefit rate (CBR); secondary endpoints were toxicity, objective response rate (ORR), and progression-free survival (PFS).ResultsEighty patients were evaluable for the primary efficacy analysis. Median age was 65.3 years; most patients had HR-positive tumors (65 %). The CBR was 45.7 % (95 % CI 28.8–63.4) and 51.1 % (95 % CI 35.8–66.3) in first- and ≥ second-line therapy, respectively. The ORR was 35.5 % in first-line (95 % CI 19.2–54.6) and 25.6 % in ≥second-line (95 % CI 13.5–41.2). The median duration of response was 11.3 and 6.4 months and PFS rates at 1 year were 24.3 and 22.2 %, respectively. In triple-negative breast cancer patients (N = 28, 35 %) a lower, but clinically relevant CBR (35.7, 95 % CI 18.6–55.9) was observed. The main toxicities per cycle were non-febrile neutropenia (1.1 %), hand-foot syndrome (1.0 %), nausea and vomiting (1.0 %), leucopenia (0.8 %), fatigue (0.7 %), and diarrhea (0.4 %).ConclusionThe VICTOR-2 study confirms the clinical activity of mVNR and mCAPE in HER2-negative breast cancer patients, suggesting that the easy schedule of administration, which requires monthly blood tests and limits patients’ dependence on hospitals, and the low cost of the drugs are valuable elements, even for countries with limited access to innovative or expensive drugs.

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