Integrating Function‐Directed Treatments into Palliative Care

The growing acceptance of palliative care has created opportunities to increase the use of rehabilitation services among populations with advanced disease, particularly those with cancer. Broader delivery has been impeded by the lack of a shared definition for palliative rehabilitation and a mismatch between patient needs and established rehabilitation service delivery models. We propose the definition that, in the advanced cancer population, palliative rehabilitation is function‐directed care delivered in partnership with other clinical disciplines and aligned with the values of patients who have serious and often incurable illnesses in contexts marked by intense and dynamic symptoms, psychological stress, and medical morbidity to realize potentially time‐limited goals. Although palliative rehabilitation is most often delivered by inpatient physical medicine and rehabilitation consultation/liaison services and by physical therapists in skilled nursing facilities, outcomes in these settings have received little scrutiny. In contrast, outpatient cancer rehabilitation programs have gained robust evidentiary support attesting to their benefits across diverse settings. Advancing palliative rehabilitation will require attention to historical barriers to the uptake of cancer rehabilitation services, which include the following: patient and referring physicians’ expectation that effective cancer treatment will reverse disablement; breakdown of linear models of disablement due to presence of concurrent symptoms and psychological distress; tension between reflexive palliation and impairment‐directed treatment; palliative clinicians’ limited familiarity with manual interventions and rehabilitation services; and challenges in identifying receptive patients with the capacity to benefit from rehabilitation services. The effort to address these admittedly complex issues is warranted, as consideration of function in efforts to control symptoms and mood is vital to optimize patients’ autonomy and quality of life. In addition, manual rehabilitation modalities are effective and drug sparing in the alleviation of adverse symptoms but are markedly underused. Realizing the potential synergism of integrating rehabilitation services in palliative care will require intensification of interdisciplinary dialogue.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146938/1/pmr2s335.pd

Metal Depletion and Warm H2 in the Brown Dwarf 2M1207 Accretion Disk

We present new far-ultraviolet observations of the young M8 brown dwarf 2MASS J12073346-3932539, which is surrounded by an accretion disk. The data were obtained using the Hubble Space Telescope-Cosmic Origins Spectrograph. Moderate resolution spectra (R~17,000-18,000) obtained in the 1150-1750 A and 2770-2830 A bandpasses reveal H2 emission excited by HI Ly$\alpha$ photons, several ionization states of carbon (CI - CIV), and hot gas emission lines of HeII and NV (T ~ 10^4-5 K). Emission from some species that would be found in a typical thermal plasma at this temperature (SiII, SiIII, SiIV, and MgII) are not detected. The non-detections indicate that these refractory elements are depleted into grains, and that accretion shocks dominate the production of the hot gas observed on 2MASS J12073346-3932539. We use the observed CIV luminosity to constrain the mass accretion rate in this system. We use the kinematically broadened H2 profile to confirm that the majority of the molecular emission arises in the disk, measure the radius of the inner hole of the disk (R_{hole}~3R_{*}), and constrain the physical conditions of the warm molecular phase of the disk (T(H2)~2500-4000 K). A second, most likely unresolved H2 component is identified. This feature is either near the stellar surface in the region of the accretion shock or in a molecular outflow, although the possibility that this Jovian-like emission arises on the day-side disk of a 6 M_{J} companion (2M1207b) cannot be conclusively ruled out. In general, we find that this young brown dwarf disk system is a low-mass analog to classical T Tauri stars that are observed to produce H2 emission from a warm layer in their disks, such as the well studied TW Hya and DF Tau systems.Comment: ApJ, accepted. 12 pages, 10 figures. 3 tables

Proof-of-Concept Trial with the Neurosteroid Pregnenolone Targeting Cognitive and Negative Symptoms in Schizophrenia

The neurosteroid pregnenolone and its sulfated derivative enhance learning and memory in rodents. Pregnenolone sulfate also positively modulates NMDA receptors and could thus ameliorate hypothesized NMDA receptor hypofunction in schizophrenia. Furthermore, clozapine increases pregnenolone in rodent hippocampus, possibly contributing to its superior efficacy. We therefore investigated adjunctive pregnenolone for cognitive and negative symptoms in patients with schizophrenia or schizoaffective disorder receiving stable doses of second-generation antipsychotics in a pilot randomized, placebo-controlled, double-blind trial. Following a 2-week single-blind placebo lead-in, patients were randomized to pregnenolone (fixed escalating doses to 500 mg/day) or placebo, for 8 weeks. Primary end points were changes in BACS and MCCB composite and total SANS scores. Of 21 patients randomized, 18 completed at least 4 weeks of treatment (n = 9/group). Pregnenolone was well tolerated. Patients receiving pregnenolone demonstrated significantly greater improvements in SANS scores (mean change = 10.38) compared with patients receiving placebo (mean change = 2.33), p = 0.048. Mean composite changes in BACS and MCCB scores were not significantly different in patients randomized to pregnenolone compared with placebo. However, serum pregnenolone increases predicted BACS composite scores at 8 weeks in the pregnenolone group (rs = 0.81, p = 0.022). Increases in allopregnanolone, a GABAergic pregnenolone metabolite, also predicted BACS composite scores (rs = 0.74, p = 0.046). In addition, baseline pregnenolone (rs = −0.76, p = 0.037), pregnenolone sulfate (rs = − 0.83, p = 0.015), and allopregnanolone levels (rs = −0.83, p = 0.015) were inversely correlated with improvements in MCCB composite scores, further supporting a possible role for neurosteroids in cognition. Mean BACS and MCCB composite scores were correlated (rs = 0.74, p <0.0001). Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for cognitive symptoms in schizophrenia

Physiological Correlates of Volunteering

We review research on physiological correlates of volunteering, a neglected but promising research field. Some of these correlates seem to be causal factors influencing volunteering. Volunteers tend to have better physical health, both self-reported and expert-assessed, better mental health, and perform better on cognitive tasks. Research thus far has rarely examined neurological, neurochemical, hormonal, and genetic correlates of volunteering to any significant extent, especially controlling for other factors as potential confounds. Evolutionary theory and behavioral genetic research suggest the importance of such physiological factors in humans. Basically, many aspects of social relationships and social activities have effects on health (e.g., Newman and Roberts 2013; Uchino 2004), as the widely used biopsychosocial (BPS) model suggests (Institute of Medicine 2001). Studies of formal volunteering (FV), charitable giving, and altruistic behavior suggest that physiological characteristics are related to volunteering, including specific genes (such as oxytocin receptor [OXTR] genes, Arginine vasopressin receptor [AVPR] genes, dopamine D4 receptor [DRD4] genes, and 5-HTTLPR). We recommend that future research on physiological factors be extended to non-Western populations, focusing specifically on volunteering, and differentiating between different forms and types of volunteering and civic participation

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Posterior Reversible Encephalopathy Syndrome due to High Dose Corticosteroids for an MS Relapse

Increased blood pressure is a known adverse effect associated with corticosteroids but little is published regarding the risk with the high doses used in multiple sclerosis (MS). A 53-year-old female with known relapsing remitting MS presented with a new brainstem relapse. Standard of care treatment for an acute MS relapse, 1250 mg of oral prednisone for 5 days, was initiated. She developed an occipital headache and dizziness and felt generally unwell. These symptoms persisted after treatment was complete. On presentation to medical attention, her blood pressure was 199/110 mmHg, although she had no history of hypertension. MRI changes were consistent with posterior reversible encephalopathy syndrome (PRES), demonstrating abnormal T2 signal in both thalami, the posterior occipital and posterior parietal white matter with mild sulcal effacement. As her pressure normalized with medication, her symptoms resolved and the MRI changes improved. No secondary cause of hypertension was found. This is the first reported case of PRES secondary to high dose corticosteroid use for an MS relapse without a history of hypertension and with no other secondary cause of hypertension identified. This rare complication should be considered in MS patients presenting with a headache or other neurological symptoms during treatment for a relapse