Low efficacy of thalidomide in improving response after induction in multiple myeloma patients who are candidates for high-dose therapy

Giving the impact of complete response (CR) on outcome of multiple myeloma patients addressed to high-dose melphalan, we explored the role of a pre-transplant intensification with 3 months thalidome plus dexamethasone therapy (Thal-Dex), after pulse-VAD induction. Seventy-four multiple myeloma patients (MM pts) uniformly treated, were retrospectively studied. The response rate after pulse-VAD were: CR 6%, VGPR 40%, PR 23%, MR 23%, and progression 8%. The response rate after Thal-Dex were similar: CR 11%, VGPR 39%, PR 17%, MR 9%, and progression 24%. Giving no advantage in terms of response rate with an additive toxicity, Thal-Dex does not seem useful for intensification before transplant.     

Cardiac sympathetic-vagal activity initiates a functional brain–body response to emotional arousal

A century-long debate on bodily states and emotions persists. While the involvement of bodily activity in emotion physiology is widely recognized, the specificity and causal role of such activity related to brain dynamics has not yet been demonstrated. We hypothesize that the peripheral neural control on cardiovascular activity prompts and sustains brain dynamics during an emotional experience, so these afferent inputs are processed by the brain by triggering a concurrent efferent information transfer to the body. To this end, we investigated the functional brain–heart interplay under emotion elicitation in publicly available data from 62 healthy subjects using a computational model based on synthetic data generation of electroencephalography and electrocardiography signals. Our findings show that sympathovagal activity plays a leading and causal role in initiating the emotional response, in which ascending modulations from vagal activity precede neural dynamics and correlate to the reported level of arousal. The subsequent dynamic interplay observed between the central and autonomic nervous systems sustains the processing of emotional arousal. These findings should be particularly revealing for the psychophysiology and neuroscience of emotions.

“What Is an Emotion?” by William James (1), published more than a century ago, started the scientific debate on the nature of emotions. However, a shared and definitive theory of emotions is not in place yet, and the very definition of emotions and their nature is still a matter of debate. While more “classical” theories point to emotions as “the functional states of the brain that provide causal explanations of certain complex behaviors—like evading a predator or attacking prey” (2), other theories suggest how they are constructions of the world, not reactions to it (3). Namely, emotions are internal states constructed on the basis of previous experiences as predictive schemes to react to external stimuli.The role of bodily activity in emotions is often questioned. Despite the vast literature showing bodily correlates with emotions, a long-lasting debate about the relationship between bodily states and emotions persists (4). For instance, a feeling is defined as the subjective metarepresentation and labeling of physiological changes (such as an increase in heart rate, the increase of blood pressure, or changes in peristalsis) (5) that are strictly related to the body state on the one hand and to emotions on the other. To this extent, emotions are complex psychological phenomena in which feelings are interpreted and labeled. In a particular psychopathological condition known as alexithymia, individuals experience difficulties in experiencing and understanding emotions to various degrees (6). Indeed, some of these patients can perceive the physical changes connected to a feeling but are unable to label it as emotion, so that emotional experience is described only as its physical counterpart [e.g., described an experience as “I have my heart beating too fast” instead of “I’m fearful” (7)]. From a biological point of view the way in which physical changes become feelings and emotions is based on the interplay between the central and the autonomic nervous systems.The central nervous system (CNS) communicates with the autonomic nervous system (ANS) through interoceptive neural circuits that contribute to physiological functions beyond homeostatic control, from the emotional experience and the genesis of feelings (8) to decision making (9, 10). The debate about the role of the ANS in emotions can be condensed into two views: specificity or causation (4). The specificity view is related to the James–Lange theory, which states that bodily responses precede emotions’ central processing, meaning that bodily states would be a response to the environment, followed by an interpretation carried out by the CNS that would result in the feeling felt. However, causation theories represent an updated view of the James–Lange theory, suggesting that peripheral changes influence the conscious emotional experience; from a biological point of view this may reflect the fact that autonomic nervous signals from the body do influence perceptual activity in the brain (11, 12). In this regard, subjective perception may be influenced or shaped by ascending communication from visceral inputs to the brain (13–15).Functional models of CNS and ANS interplay have described bidirectional dynamics in emotions (16–18). In particular, the functional brain–heart interplay (BHI) involves brain structures that comprise the central autonomic network (CAN), which has been described as being in charge of autonomic control (19, 20). Moreover, the default mode network (DMN) has been found to be involved in autonomic control (21) and tasks of self-related cognition and interoception (22, 23), suggesting that the DMN participates in both ascending and descending communications with the heart. Finally, the constructed emotion theory suggests how DMN together with other intrinsic networks is crucial in the genesis of emotion and emotional experience (3).Psychophysiological studies have uncovered several correlates of different autonomic signals in the brain during emotional experiences (24–27). To understand these correlations and the functional interactions between the heart and brain, various signal processing methods have been proposed to investigate functional BHI through noninvasive recordings (28). The study of emotions using these methods comprises the analysis of heartbeat-evoked potentials (29), nonlinear couplings (30), and information transfer modeling (31). However, the causative role of bodily inputs remains unknown (4) and, more specifically, the temporal and causal links between cortical and peripheral neural dynamics in both ascending and descending directions, i.e., from the brain to the body and from the body to the brain, are still to be clarified.In this study, we take a step forward in answering these scientific questions and investigate whether peripheral neural dynamics play a causal role in the genesis of emotions. We applied a mathematical model of functional BHI based on synthetic data generation (SDG) (32), estimating the directionality of the functional interplay using simultaneous electroencephalography (EEG) and electrocardiography (ECG) recordings gathered from healthy subjects undergoing emotion elicitations with video clips, the publicly available DEAP and MAHNOB datasets (33, 34). ECG series were analyzed to derive heart-rate variability (HRV) series, which result from the concurrent activity of the sympathetic and parasympathetic (vagal) branches of the ANS acting to regulate the heartbeat. We hypothesize that, from a neurobiological point of view, feelings and subsequent emotional experiences arise from the mutual interplay between brain and body, particularly in which the CNS integrates the afferent ANS information outflow, namely from-heart-to-brain interplay, which actually triggers a cascade of cortical neural activations that, in turn, modulate directed neural control onto the heart, namely from brain-to-heart interplay.     

Phase II double-blind randomized study of lonidamine and radiotherapy in epidermoid carcinoma of the lung

Patients with non metastatic squamous cell lung cancer were treated with radiotherapy (RT) plus lonidamine (LND) or placebo (PLAC), according to a randomized double-blind study design.

Treatment with lonidamine 150 mg t.i.d (27 patients) or placebo (23 patients) started 3 days before RT,lasted up to 7 months. Partial responses were observed in 14 and 6 patients respectively in the LND+RT and PLAC+RT groups. Statistical analysis of the survival curves showed no significant difference between the LND+RT (median 311 days) and PLAC+RT (median 193 days) groups.

Stage III patients survived significantly longer (p<0.05) when treated with LND+RT (median 318 days) than with PLAC+RT (median 163 days). No synergistic toxic effects between radiation and LND were noted.

To confirm these data a new and larger multicentric study is now in progress.