The role of stereotactic ablative radiotherapy in oncological and non-oncological clinical settings: highlights from the 7th Meeting of AIRO - Young Members Working Group (AIRO Giovani).

Stereotactic ablative radiotherapy is a modern cancer treatment strategy able to deliver highly focused radiation in one or a few fractions with a radical intent in several clinical settings. Young radiation oncologists need a constant and tailored update in this context to improve patient care in daily clinical practice. A recent meeting of AIRO Giovani (AIRO - Young Members Working Group) was specifically addressed to this topic, presenting state-of-the-art knowledge, based on the latest evidence in this field. Highlights of the congress are summarized and presented in this report, including thorough contributions of the speakers dealing with the role of stereotactic ablative radiotherapy in both oncological and non-oncological diseases, divided according to anatomical and clinical scenarios: intra-cranial settings (brain malignant primary tumors, metastases, benign tumors and functional disorders) and extra-cranial indications (lung primary tumors and metastases, thoracic re-irradiation, liver, lymph node and bone metastases, prostate cancer). With literature data discussed during the congress as a background, stereotactic ablative radiotherapy has proved to be a consolidated treatment approach in specific oncological and non-oncological scenarios, as well as a promising option in other clinical settings, requiring a further prospective validation in the near future. We herein present an updated overview of stereotactic ablative radiotherapy use in the clinic.

Single cell analysis reveals similar functional competence of dominant and non-dominant CD8 T-cell clonotypes

The properties of CD8 T-cells requiredfor protection from infectiousdisease and cancer are only partiallycharacterized, and only limited data isavailable regarding T-cell clonotypes.It has been proposed that dominantT-cell clonotypes may have higherprotective potential than their nondominantcounterparts. Our objectiveswere to assess memory andeffector functions, stage of differentiationand clonotype selection of tumor-reactive T lymphocytes followingpeptide vaccination in melanomapatients.We also characterized dominantversus non-dominant clonotypesto further understand the in vivo functionof these T-cells based on theirprevalence. Using a novel single-cellapproach for simultaneous ex vivomolecular and functional analysis, wereport the preferential selection andexpansion of several tumor-specificco-dominant clonotypes of intermediateto high frequencies, irrespectiveof whether native or analog peptidewas used for vaccination. Theseclonotypes made up 40 - 95% of thedifferentiated "effector-like" T-cells,but only 25% of the less-differentiated"effector-memory" cells. Bothsubsets also contained non-dominantT-cell clonotypes, but these were significantlymore frequent in the lessdifferentiatedcells. Thus, cell differentiationwas clonotype-dependent.Surprisingly however, the acquisitionof memory and effector T-cell propertieswas clonotype independent, as wefound similar functional profiles indominant and low/ non-dominantT-cell clonotypes. In contrast to analogpeptide vaccination, native peptidevaccination induced T-cell functionsthat were more comprehensive,with more pronounced effector functionscombined with memory cellproperties. In summary, this study revealsthat T-cell functions are determinedprimarily by the antigen andthe stage of T-cell differentiation, butare similar in dominant and non-dominantclonotypes participating in aCD8 T-cell response. The identifiedclonotypic basis of T-cell responsescontributes to the rational developmentof vaccines.

HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies.

OBJECTIVE: To evaluate deaths from AIDS-defining malignancies (ADM) and non-AIDS-defining malignancies (nADM) in the D:A:D Study and to investigate the relationship between these deaths and immunodeficiency. DESIGN: Observational cohort study. METHODS: Patients (23 437) were followed prospectively for 104 921 person-years. We used Poisson regression models to identify factors independently associated with deaths from ADM and nADM. Analyses of factors associated with mortality due to nADM were repeated after excluding nADM known to be associated with a specific risk factor. RESULTS: Three hundred five patients died due to a malignancy, 298 prior to the cutoff for this analysis (ADM: n = 110; nADM: n = 188). The mortality rate due to ADM decreased from 20.1/1000 person-years of follow-up [95% confidence interval (CI) 14.4, 25.9] when the most recent CD4 cell count was <50 cells/microl to 0.1 (0.03, 0.3)/1000 person-years of follow-up when the CD4 cell count was more than 500 cells/microl; the mortality rate from nADM decreased from 6.0 (95% CI 3.3, 10.1) to 0.6 (0.4, 0.8) per 1000 person-years of follow-up between these two CD4 cell count strata. In multivariable regression analyses, a two-fold higher latest CD4 cell count was associated with a halving of the risk of ADM mortality. Other predictors of an increased risk of ADM mortality were homosexual risk group, older age, a previous (non-malignancy) AIDS diagnosis and earlier calendar years. Predictors of an increased risk of nADM mortality included lower CD4 cell count, older age, current/ex-smoking status, longer cumulative exposure to combination antiretroviral therapy, active hepatitis B infection and earlier calendar year. CONCLUSION: The severity of immunosuppression is predictive of death from both ADM and nADM in HIV-infected populations.

Non-Linear and Non-Conventional Speech Processing: Alternative Techniques

This special issue aims to cover some problems related to non-linear and nonconventional speech processing. The origin of this volume is in the ISCA Tutorial and Research Workshop on Non-Linear Speech Processing, NOLISP’09, held at the Universitat de Vic (Catalonia, Spain) on June 25–27, 2009. The series of NOLISP workshops started in 2003 has become a biannual event whose aim is to discuss alternative techniques for speech processing that, in a sense, do not fit into mainstream approaches. A selected choice of papers based on the presentations delivered at NOLISP’09 has given rise to this issue of Cognitive Computation.

Integrability and non-integrability of periodic non-autonomous Lyness recurrences

This paper studies non-autonomous Lyness type recurrences of the form x_{n+2}=(a_n+x_n)/x_{n+1}, where a_n is a k-periodic sequence of positive numbers with prime period k. We show that for the cases k in {1,2,3,6} the behavior of the sequence x_n is simple(integrable) while for the remaining cases satisfying k not a multiple of 5 this behavior can be much more complicated(chaotic). The cases k multiple of 5 are studied separately.

Integrability and non-integrability of periodic non-autonomous Lyness recurrences (revised and enlarged version)

This paper studies non-autonomous Lyness type recurrences of the form xn+2 = (an+xn+1)=xn, where fang is a k-periodic sequence of positive numbers with primitive period k. We show that for the cases k 2 f1; 2; 3; 6g the behavior of the sequence fxng is simple (integrable) while for the remaining cases satisfying this behavior can be much more complicated (chaotic). We also show that the cases where k is a multiple of 5 present some di erent features.

Postprandial thermogenesis in lactating and non-lactating women from The Gambia.

Postprandial thermogenesis was assessed by indirect calorimetry in 32 Gambian women classified into three groups as follows: 12 non-pregnant non-lactating and 10 lactating women studied during the dry season and 10 lactating women studied during the rainy season. The test meal consisted of a typical Gambian breakfast and its energy content corresponded to 30% of the individual's resting metabolic rate (RMR)/24 h. During the dry season, the postprandial thermogenesis of the lactating women averaged 6.0 +/- 0.4% of the test meal energy content and was similar to that observed in the non-pregnant non-lactating women studied during the same season (5.8 +/- 0.3%). In contrast, the postprandial thermogenesis of lactating women studied during the rainy, nutritionally unfavourable season was found to be significantly lower (4.9 +/- 0.5%). There was no significant difference in the pre- and postprandial respiratory quotients among groups. This leads to the conclusion that lactation does not alter the thermogenic response to food and that the reduction in postprandial thermogenesis observed in lactating women during the wet season constitutes an adaptive response to energy deficit allowing a saving of energy in periods of food restriction.

Daily energy expenditure in free-living conditions in obese and non-obese children: comparison of doubly labelled water (2H2(18)O) method and heart-rate monitoring.

OBJECTIVE: To compare the heart-rate monitoring with the doubly labelled water (2H2(18)O) method to estimate total daily energy expenditure in obese and non-obese children. DESIGN: Cross sectional study of obese and normal weight children. SUBJECTS: 13 prepubertal children: six obese (4M, 2F, 9.1 +/- 1.5 years, 47.3 +/- 9.7 kg) and seven non-obese (3M, 4F, 9.3 +/- 0.6 years, 31.8 +/- 3.2 kg). MEASUREMENTS: Total daily energy expenditure was assessed by means of the doubly labelled water method (TEEDLW) and of heart-rate monitoring (TEEHR). RESULTS: TEEHR was significantly (P < 0.05) higher than TEEDLW in obese children (9.47 +/- 0.84 MJ/d vs 8.99 +/- 0.63 MJ/d) whereas it was not different in non-obese children (8.43 +/- 2.02 MJ/d vs 8.42 +/- 2.30 MJ/d, P = NS). The difference of TEE assessed by HR monitoring in the obese group averaged 6.2 +/- 4.7%. At the individual level, the degree of agreement (difference between TEEHR and TEEDLW +/- 2s.d.) was low both in obese (-0.36, 1.32 MJ/d) and in non-obese children (-1.30, 1.34 MJ/d). At the group level, the agreement between the two methods was good in nonobese children (95% c.i. for the bias:-0.59, 0.63 MJ/d) but not in obese children (0.04, 0.92 MJ/d). Duration of sleep and energy expenditure during resting and physical activity were not significantly different in the two groups. Patterns of heart-rate (or derived energy expenditure) during the day-time were similar in obese and non-obese children. CONCLUSION: The HR monitoring technique provides an estimation of TEE close to that assessed by the DLW method in non-obese prepubertal children. In comparison with DLW, the HR monitoring method yields a greater TEE value in obese children.

Early predictors of outcome in comatose survivors of ventricular fibrillation and non-ventricular fibrillation cardiac arrest treated with hypothermia: a prospective study

OBJECTIVES: Current indications for therapeutic hypothermia (TH) are restricted to comatose patients with cardiac arrest (CA) due to ventricular fibrillation (VF) and without circulatory shock. Additional studies are needed to evaluate the benefit of this treatment in more heterogeneous groups of patients, including those with non-VF rhythms and/or shock and to identify early predictors of outcome in this setting. DESIGN: Prospective study, from December 2004 to October 2006. SETTING: 32-bed medico-surgical intensive care unit, university hospital. PATIENTS: Comatose patients with out-of-hospital CA. INTERVENTIONS: TH to 33 +/- 1 degrees C (external cooling, 24 hrs) was administered to patients resuscitated from CA due to VF and non-VF (including asystole or pulseless electrical activity), independently from the presence of shock. MEASUREMENTS AND MAIN RESULTS: We hypothesized that simple clinical criteria available on hospital admission (initial arrest rhythm, duration of CA, and presence of shock) might help to identify patients who eventually survive and might most benefit from TH. For this purpose, outcome was related to these predefined variables. Seventy-four patients (VF 38, non-VF 36) were included; 46% had circulatory shock. Median duration of CA (time from collapse to return of spontaneous circulation [ROSC]) was 25 mins. Overall survival was 39.2%. However, only 3.1% of patients with time to ROSC > 25 mins survived, as compared to 65.7% with time to ROSC < or = 25 mins. Using a logistic regression analysis, time from collapse to ROSC, but not initial arrest rhythm or presence of shock, independently predicted survival at hospital discharge. CONCLUSIONS: Time from collapse to ROSC is strongly associated with outcome following VF and non-VF cardiac arrest treated with therapeutic hypothermia and could therefore be helpful to identify patients who benefit most from active induced cooling.

Low concentrations of 3-hydroxy glutarate leads to ammonium accumulation and non-apoptotic cell death in developing brain cells

We previously showed in a 3D rat brain cell in vitro model for glutaric aciduria type-I that repeated application of 1mM 3-hydroxy-glutarate (3-OHGA) caused ammonium accumulation, morphologic alterations and induction of non-apoptotic cell death in developing brain cells. Here, we performed a dose-response study with lower concentrations of 3- OHGA.We exposed our cultures to 0.1, 0.33 and 1mM 3-OHGA every 12h over three days at two developmental stages (DIV5-8 and DIV11-14). Ammonium accumulation was observed at both stages starting from 0.1mM 3-OHGA, in parallel with a glutamine decrease. Morphological changes started at 0.33mM with loss of MBP expression and loss of astrocytic processes. Neurons were not substantially affected. At DIV8, release of LDH in the medium and cellular TUNEL staining increased from 0.1mM and 0.33mM 3-OHGA exposure, respectively. No increase in activated caspase-3 was observed. We confirmed ammonium accumulation and non-apoptotic cell death of brain cells in our in vitro model at lower 3-OHGA concentrations thus strongly suggesting that the observed effects are likely to take place in the brain of affected patients. The concomitant glutamine decrease suggests a defect in the astrocyte ammonium buffering system. Ammonium accumulation might be the cause of non-apoptotic cell death.