The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network

Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

Erratum: Sentinel Lymph Node Biopsy Status Is a Key Parameter to Stratify the Prognostic Heterogeneity of Malignant Melanoma in High-Risk Tumors >4.0 mm

<i>Background:</i> The value of sentinel lymph node biopsy (SLNB) as a useful strategy to assess the risk of future metastasis in high-risk melanomas (>4.0 mm) is controversially discussed. <i>Objectives:</i> In a single-center retrospective study, the prognostic relevance of SLNB and other risk factors in the subgroup of melanomas >4.0 mm was investigated and compared to previously published results. <i>Methods:</i> Using Kaplan-Meier estimates and Cox regressions, we assessed the prognostic relevance of SLNB in our subcohort of 87 patients with thick melanomas >4.0 mm (T4). The mean follow-up for this subgroup was 51 months. We compared SLN value as compared to ulceration. <i>Results:</i> SLN and ulceration, analyzed as separate risk factors as well as their combination, predicted a highly reduced life expectancy in terms of recurrence-free survival (RFS) in our cohort of patients. SLN, but not ulceration, also predicted overall survival (OS). <i>Conclusions:</i> Positive SLNB is an essential predictor of RFS and OS in T4 melanoma patients, whereas ulceration lacked significance with respect to OS in our cohort. Our data thus suggest the routine use of SLNB also for T4 melanoma and may therefore allow to optimize risk-stratified therapeutic regimens

Erratum: Sentinel Lymph Node Biopsy Status Is a Key Parameter to Stratify the Prognostic Heterogeneity of Malignant Melanoma in High-Risk Tumors >4.0 mm

<i>Background:</i> The value of sentinel lymph node biopsy (SLNB) as a useful strategy to assess the risk of future metastasis in high-risk melanomas (>4.0 mm) is controversially discussed. <i>Objectives:</i> In a single-center retrospective study, the prognostic relevance of SLNB and other risk factors in the subgroup of melanomas >4.0 mm was investigated and compared to previously published results. <i>Methods:</i> Using Kaplan-Meier estimates and Cox regressions, we assessed the prognostic relevance of SLNB in our subcohort of 87 patients with thick melanomas >4.0 mm (T4). The mean follow-up for this subgroup was 51 months. We compared SLN value as compared to ulceration. <i>Results:</i> SLN and ulceration, analyzed as separate risk factors as well as their combination, predicted a highly reduced life expectancy in terms of recurrence-free survival (RFS) in our cohort of patients. SLN, but not ulceration, also predicted overall survival (OS). <i>Conclusions:</i> Positive SLNB is an essential predictor of RFS and OS in T4 melanoma patients, whereas ulceration lacked significance with respect to OS in our cohort. Our data thus suggest the routine use of SLNB also for T4 melanoma and may therefore allow to optimize risk-stratified therapeutic regimens

Development of the signal in sensory rhodopsin and its transfer to the cognate transducer

The microbial phototaxis receptor sensory rhodopsin II (NpSRII, also named phoborhodopsin) mediates the photophobic response of the haloarchaeon Natronomonas pharaonis by modulating the swimming behaviour of the bacterium. After excitation by blue-green light NpSRII triggers, by means of a tightly bound transducer protein (NpHtrII), a signal transduction chain homologous with the two-component system of eubacterial chemotaxis. Two molecules of NpSRII and two molecules of NpHtrII form a 2:2 complex in membranes as shown by electron paramagnetic resonance and X-ray structure analysis. Here we present X-ray structures of the photocycle intermediates K and late M (M2) explaining the evolution of the signal in the receptor after retinal isomerization and the transfer of the signal to the transducer in the complex. The formation of late M has been correlated with the formation of the signalling state. The observed structural rearrangements allow us to propose the following mechanism for the light-induced activation of the signalling complex. On excitation by light, retinal isomerization leads in the K state to a rearrangement of a water cluster that partly disconnects two helices of the receptor. In the transition to late M the changes in the hydrogen bond network proceed further. Thus, in late M state an altered tertiary structure establishes the signalling state of the receptor. The transducer responds to the activation of the receptor by a clockwise rotation of about 15 degrees of helix TM2 and a displacement of this helix by 0.9 A at the cytoplasmic surface