Outcomes, Prognostic Factors and Salvage Treatment for Recurrent Chordoma After Pencil Beam Scanning Proton Therapy at the Paul Scherrer Institute.

AIMS: The outcome of chordoma patients with local or distant failure after proton therapy is not well established. We assessed the disease-specific (DSS) and overall survival of patients recurring after proton therapy and evaluated the prognostic factors affecting DSS. MATERIALS AND METHODS: A retrospective analysis was carried out of 71 recurring skull base (n = 36) and extracranial (n = 35) chordoma patients who received adjuvant proton therapy at initial presentation (n = 42; 59%) or after post-surgical recurrence (n = 29; 41%). The median proton therapy dose delivered was 74 GyRBE (range 62-76). The mean age was 55 ± 14.2 years and the male/female ratio was about one. RESULTS: The median time to first failure after proton therapy was 30.8 months (range 3-152). Most patients (n = 59; 83%) presented with locoregional failure only. There were only 12 (17%) distant failures, either with (n = 5) or without (n = 7) synchronous local failure. Eight patients (11%) received no salvage therapy for their treatment failure after proton therapy. Salvage treatments after proton therapy failure included surgery, systemic therapy and additional radiotherapy in 45 (63%), 20 (28%) and eight (11%) patients, respectively. Fifty-three patients (75%) died, most often from disease progression (47 of 53 patients; 89%). The median DSS and overall survival after failure was 3.9 (95% confidence interval 3.1-5.1) and 3.4 (95% confidence interval 2.5-4.4) years, respectively. On multivariate analysis, extracranial location and late failure (≥31 months after proton therapy) were independent favourable prognostic factors for DSS. CONCLUSION: The survival of chordoma patients after a treatment failure following proton therapy is poor, particularly for patients who relapse early or recur in the skull base. Although salvage treatment is administered to most patients with uncontrolled disease, they will ultimately die as a result of disease progression in most cases.

Mature neurons: equipped for survival.

Neurons completely transform how they regulate cell death over the course of their lifetimes. Developing neurons freely activate cell death pathways to fine-tune the number of neurons that are needed during the precise formation of neural networks. However, the regulatory balance between life and death shifts as neurons mature beyond early development. Mature neurons promote survival at all costs by employing multiple, often redundant, strategies to prevent cell death by apoptosis. This dramatic shift from permitting cell death to ensuring cellular survival is critical, as these post-mitotic cells must provide neuronal circuitry for an organism's entire lifetime. Importantly, as many neurodegenerative diseases afflict adult neuronal populations, the survival mechanisms in mature neurons are likely to be either reversed or circumvented during neurodegeneration. Examining the adaptations for inhibiting apoptosis during neuronal maturation is key to comprehending not just how neurons survive long term, but may also provide insight for understanding how neuronal toxicity in various neurodegenerative diseases may ultimately lead to cell death.