Integrating Palliative Care Into Physiatric Care: Perspective of the Association of Academic Physiatrists Physiatry Palliative Care Task Force.

ABSTRACT: There are opportunities for physiatrists to apply a palliative care lens within clinical encounters across rehabilitation settings. The expanding population of patients with serious illness and injury cared for by physiatrists and the anticipated shortage of specialty palliative care clinicians make it important that physiatrists hone and apply basic palliative care skills as part of comprehensive physiatric care. In this article, four clinical vignettes highlight relevant palliative care communication skills and demonstrate the value of integrating these skills within physiatry encounters. Resources to support physiatrists in applying basic palliative skills are provided throughout.

Large branchial arch cyst excision using superficial and deep cervical plexus blocks in a patient with severe comorbidities.

Branchial arches are embryologic structures that develop between the fourth and seventh gestational week. Anomalies may form if these structures fail to develop. The majority of cases are diagnosed during childhood, with surgical excision recommended to prevent risk of infection, growth or malignancy. We report an unusual case of a 72-year-old man with severe cardiac comorbidities who presented with a large second branchial arch cyst extending into the oropharynx. General anaesthesia to facilitate surgical excision was deemed too risky. Therefore, we performed successful ultrasound-guided superficial and deep cervical plexus blocks as a sole mode of anaesthesia. This case highlights how regional anaesthesia can be utilised to facilitate surgery in high-risk patients, as well as presenting an alternative for general anaesthesia.

A comparison of the effects of clozapine and its metabolite norclozapine on metabolic dysregulation in rodent models.

RATIONALE: The second generation antipsychotic drug clozapine is a psychotherapeutic agent with superior efficacy for treatment-resistant schizophrenia. Clozapine is associated with a low likelihood of neurological side-effects, but a high propensity to induce weight gain and metabolic dysregulation. The primary metabolite of clozapine is norclozapine (N-Desmethylclozapine), which has psychoactive properties itself, but its effects on metabolic function remains unknown. The goal of the present study was to determine whether directly administered norclozapine could cause metabolic dysregulation, similar to clozapine. METHODS: Adult female rats were treated with a range of doses of clozapine and norclozapine (0.5, 2, 8 & 20 mg/kg, i.p.) and then subjected to the intraperitoneal glucose tolerance test (IGTT), where glucose levels were recorded for 2 h following a glucose challenge. In parallel, rats were tested with two doses of clozapine and norclozapine (2 & 20 mg/kg, i.p.) in the hyperinsulinemic-euglycemic clamp (HIEC), to measure whole body insulin resistance. RESULTS: In the IGTT, clozapine demonstrated dose-dependent effects on fasting glucose levels and total glucose area-under-the-curve following the glucose challenge, with the two highest doses strongly increasing glucose levels. Only the highest dose of norclozapine increased fasting glucose levels, and caused a non-significant increase in glucose levels following the challenge. By contrast, both doses of clozapine and norclozapine caused a potent and long-lasting decrease in the glucose infusion rate in the HIEC, indicating that both compounds cause whole body insulin resistance. ABSTRACT: While not as potent as its parent compound, norclozapine clearly exerts acute metabolic effects, particularly on insulin resistance. This article is part of the issue entitled 'Special Issue on Antipsychotics'.

A pilot randomized trial of adjuvanted influenza vaccine in adult allogeneic hematopoietic stem cell transplant recipients.

The annual influenza vaccine is recommended for hematopoietic stem cell transplant (HSCT) patients although studies have shown suboptimal immunogenicity. Influenza vaccine containing an oil-in-water emulsion adjuvant (MF59) may lead to greater immunogenicity in HSCT recipients. We randomized adult allogeneic HSCT patients to receive the 2015-2016 influenza vaccine with or without MF59 adjuvant. Preimmunization and 4-week post-immunization sera underwent strain-specific hemagglutination inhibition assay. We randomized 73 patients and 67 (35 adjuvanted; 32 non-adjuvanted) had paired samples available at follow-up. Median age was 54 years (range 22-74) and time from transplant was 380 days (range 85-8107). Concurrent graft-versus-host disease was seen in 42/73 (57.5%). Geometric mean titers increased significantly after vaccination in both groups. Seroconversion to at least one of three influenza antigens was present in 62.9% vs 53.1% in adjuvanted vs non-adjuvanted vaccine (P=0.42). Factors associated with lower seroconversion rates were use of calcineurin inhibitors (P<0.001) and shorter duration from transplantation (P=0.001). Seroconversion rates were greater in patients who got previous year influenza vaccination (82.6% vs 45.5%, P=0.03). Adjuvanted vaccine demonstrated similar immunogenicity to non-adjuvanted vaccine in the HSCT population and may be an option for some patients.

The clonal origins of leukemic progression of myelodysplasia.

The genetics behind the progression of myelodysplasia to secondary acute myeloid leukemia (sAML) is poorly understood. In this study, we profiled somatic mutations and their dynamics using next generation sequencing on serial samples from a total of 124 patients, consisting of a 31 patient discovery cohort and 93 patients from two validation cohorts. Whole-exome analysis on the discovery cohort revealed that 29 of 31 patients carry mutations related to at least one of eight commonly mutated pathways in AML. Mutations in genes related to DNA methylation and splicing machinery were found in T-cell samples, which expand at the initial diagnosis of the myelodysplasia, suggesting their importance as early disease events. On the other hand, somatic variants associated with signaling pathways arise or their allelic burdens expand significantly during progression. Our results indicate a strong association between mutations in activated signaling pathways and sAML progression. Overall, we demonstrate that distinct categories of genetic lesions play roles at different stages of sAML in a generally fixed order.

A multicenter trial of myeloablative clofarabine and busulfan conditioning for relapsed or primary induction failure AML not in remission at the time of allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic cell transplantation (HCT) may produce long-term survival in AML after relapse or primary induction failure (PIF). However, outcomes of HCT performed for AML not in remission are historically poor given high relapse rates and transplant-related mortality. Preliminary studies suggest conditioning with clofarabine and myeloablative busulfan (CloBu4) may exert significant anti-leukemic effects without excessive toxicity in refractory hematologic malignancies. A prospective multicenter phase II trial was conducted to determine the efficacy of CloBu4 for patients proceeding directly to HCT with AML not in remission. Seventy-one patients (median age: 56 years) received CloBu4. At day 30 after HCT, 90% achieved morphologic remission. The incidence of non-relapse mortality and relapse at 2 years was 25% and 55%, respectively. The 2-year overall survival (OS) and event-free survival (EFS) were 26% and 20%, respectively. Patients entering HCT in PIF had significantly greater EFS than those in relapse (34% vs 8%; P<0.01). Multivariate analysis comparing CloBu4 with a contemporaneous cohort (Center for International Blood and Marrow Transplantation Research) of AML not in remission receiving other myeloablative conditioning (n=105) demonstrated similar OS (HR: 1.33, 95% confidence interval: 0.92-1.92; P=0.12). HCT with myeloablative CloBu4 is associated with high early response rates and may produce durable remissions in select patients with AML not in remission.

Relationship between neurocognitive functioning and medication management ability over the first 6 months following allogeneic stem cell transplantation.

Although neurocognitive impairment has been established as a major issue among cancer survivors, the real-world consequences of this impairment are unclear. This study investigated the relationship between neurocognitive functioning and medication management ability over time among 58 patients treated with allogeneic hematopoietic stem cell transplantation (HCT). Participants completed a neuropsychological test battery and a simulated medication management task at three time points: pre-transplant (T0), Day 100 (T1) and 6 months post transplant (T2). Neurocognitively impaired participants performed worse on the medication management task than neurocognitively normal participants at each time point, and were more likely to score in the impaired range of medication management ability post transplant (72% vs 20%, P<0.001 at T1; 67% vs 23%, P=0.013 at T2). In multivariate analyses, worse performance in executive functioning/working memory consistently predicted impaired medication management ability, even when controlling for sociodemographic and clinical confounders (odds ratio=0.89, 95% confidence interval (0.80, 0.98), P=0.023). Lower physical symptom distress also predicted impaired medication management ability, but this effect decreased over time. Self-reported cognitive problems were not correlated with medication management ability at any time point. Findings suggest that poor neurocognitive functioning, particularly in the domain of executive functioning/working memory, is associated with worse medication management ability within the first 6 months after allogeneic HCT.

Clonal dynamics in a single AML case tracked for 9 years reveals the complexity of leukemia progression.

Most types of cancers are made up of heterogeneous mixtures of genetically distinct subclones. In particular, acute myeloid leukemia (AML) has been shown to undergo substantial clonal evolution over the course of the disease. AML tends to harbor fewer mutations than solid tumors, making it challenging to infer clonal structure. Here, we present a 9-year, whole-exome sequencing study of a single case at 12 time points, from the initial diagnosis until a fourth relapse, including 6 remission samples in between. To the best of our knowledge, it covers the longest time span of any data set of its kind. We used these time series data to track the hierarchy and order of variant acquisition, and subsequently analyzed the evolution of somatic variants to infer clonal structure. From this, we postulate the development and extinction of subclones, as well as their anticorrelated expansion via varying drug responses. In particular, we show that new subclones started appearing after the first complete remission. The presence and absence of different subclones during remission and relapses implies differing drug responses among subclones. Our study shows that time series analysis contrasting remission and relapse periods provides a much more comprehensive view of clonal structure and evolution.

Patient age, remission status and HCT-CI in a combined score are prognostic for patients with AML undergoing allogeneic hematopoietic cell transplantation in CR1 and CR2.

For AML, older age, advanced disease and increased hematopoietic cell transplant comorbidity index (HCT-CI) are associated with worse prognosis following allogeneic hematopoietic cell transplantation (HCT). This single-center retrospective study investigated the influence of pre-transplant characteristics on outcomes of 387 patients undergoing allogeneic HCT for AML in CR1 and CR2. The multivariable analysis model for overall survival (OS) included age (hazard ratio (HR)=2.24 for ages 31-64 years and HR=3.23 for age ⩾65 years compared with age ⩽30 years, P=0.003), remission status (HR=1.49 for CR2 compared with CR1, P=0.005) and HCT-CI score (HR=1.47 for ⩾3 compared with <3, P=0.005). Transplant year was significantly associated with OS (P=0.001) but this did not influence the model. A weighted score was developed with age ⩽30, CR1 and HCT-CI score <3 receiving 0 points each, and CR2 and HCT-CI score ⩾3 receiving 1 point each. Ages 31-64 received 2 points, age ⩾65 received 3 points. Scores were grouped as follows: scores 0-1 (low risk, n=36), score 2 (intermediate-low risk, n=147), score 3 (intermediate-high risk, n=141) and scores 4-5 (high risk, n=63) with 3-year OS of 71%, 55%, 42% and 29% for scores 0-1, 2, 3 and 4-5, respectively (P<0.0001). The score predicted nonrelapse mortality (P=0.03) but not cumulative incidence of relapse (P=0.18). This model should be validated for the pre-HCT assessment of AML patients in CR1 and CR2.

Comparable outcomes post allogeneic hematopoietic cell transplant for patients with de novo or secondary acute myeloid leukemia in first remission.

Secondary AML (sAML) has a poor prognosis with conventional chemotherapy alone. Allogeneic hematopoietic cell transplantation (HCT) is beneficial for high-risk AML. Data comparing outcomes of transplants for patients with de novo and sAML are limited. We compared outcomes of patients transplanted for de novo and sAML in first complete remission and investigated the effect of age, HCT comorbidity index (HCT-CI) and karyotype in both groups. A total of 264 patients with de novo (n=180) and sAML (n=84) underwent allogeneic HCT between 1999 and 2013. Median age at transplant was 51 years (range 18-71), median follow-up of survivors was 77 months. Evaluation of all patients demonstrated no significant difference between de novo and sAML for overall survival (P=0.18), leukemia-free survival (P=0.17), cumulative incidence of relapse (P=0.51) and non-relapse mortality (P=0.42). Multivariable and propensity score analyses confirmed the comparable outcomes between de novo and sAML post transplant. Although sAML demonstrates outcomes inferior to de novo AML treated with chemotherapy alone, outcomes following allogeneic HCT are comparable between the two groups.

Efficacy and safety of beloranib for weight loss in obese adults: a randomized controlled trial.

AIM: To assess the efficacy, safety and tolerability of beloranib treatment for obesity. METHODS: This phase II, double-blind, randomized study investigated the effects of beloranib suspension (0.6, 1.2 and 2.4 mg) or placebo, administered subcutaneously, for 12 weeks in 147 participants (primarily white women) with obesity. No diet or exercise advice was administered. RESULTS: At week 12, beloranib resulted in dose-dependent progressive weight loss of -5.5 ± 0.5, -6.9 ± 0.6 and -10.9 ± 1.1 kg for the 0.6, 1.2 and 2.4 mg beloranib doses, respectively, compared with -0.4 ± 0.4 kg with placebo (all p < 0.0001 vs placebo). Weight loss with beloranib was associated with corresponding reductions in waist circumference and body fat mass, as well as improvements in lipids, high-sensitivity C-reactive protein and blood pressure. Sleep disturbance and gastrointestinal adverse events were more common with beloranib than with placebo; these were generally mild to moderate, transient and dose-related, and led to more early study withdrawals in participants in the group with the highest dose of beloranib. CONCLUSIONS: In this 12-week phase II study, beloranib produced clinically and statistically significant weight loss and corresponding improvements in cardiometabolic risk factors. Beloranib appeared safe, and the 0.6 and 1.2 mg doses were generally well tolerated. The 2.4 mg dose was associated with increased sleep latency and mild to moderate gastrointestinal adverse events over the first month of treatment. These findings represent a novel mechanism for producing clinically meaningful weight loss.

Risk model incorporating donor IL6 and IFNG genotype and gastrointestinal GVHD can discriminate patients at high risk of steroid refractory acute GVHD.

Steroid refractory acute GVHD (SR aGVHD) is associated with high morbidity and mortality. This study attempted to generate a risk model for SR aGVHD using 259 single nucleotide polymorphisms (SNPs) in 53 genes of recipients and donors. A total of 268 patients with aGVHD who were treated with systemic steroids were included. Patients were randomly divided into training (n=180) and validation sets (n=88). Clinical risk factors were also evaluated. In the training set, 85 (47.2%) developed SR aGVHD. Gastrointestinal involvement (P<0.0001) and donor genotypes of IL6 (rs1800797; P=6.2 × 10(-4)) and IFNG (rs2069727; P=4.4 × 10(-4)) were significant risk factors. Scores were assigned to the above risk factors. Patients were divided into low (score 0, n=74) vs high risk (scores 1-3; n=106) in risk model. Higher incidence of SR aGVHD was noted in the high risk (61.3%) vs the low-risk group (27%; P<0.0001, odds ratio (OR) 4.28). Predictive effect of risk model was replicated in the validation set (P=0.0045, OR 3.74). This risk model was associated with response to therapy, overall and GVHD-specific survival and non-relapse mortality. Our study suggested that this risk model could identify patients at high risk of SR aGVHD with donor genotype of IL6 (rs1800797) and IFNG (rs2069727) along with gastrointestinal involvement of aGVHD.

The risk of polyomavirus BK-associated hemorrhagic cystitis after allogeneic hematopoietic SCT is associated with myeloablative conditioning, CMV viremia and severe acute GVHD.

Hemorrhagic cystitis (HC) is a common complication after allogeneic hematopoietic SCT (allo-HSCT). Several risk factors have been suggested including BU-containing myeloablative conditioning, unrelated donors and GVHD, but these have not been consistently reported. We conducted a retrospective study including 339 allo-HSCT recipients between 2009 and 2012. Of 339 patients, 79 (23.3%) developed HC with 2-year cumulative incidence of 24.0% (95% confidence interval, 19.4-28.9). The median onset time was 45 days (range, 16-430) after allo-HSCT. Sixty-two patients (84%) out of 74 evaluated for urine BK virus PCR testing showed a positive result (mean 2.0 × 10(10) copies of DNA per mL). In univariate analysis, myeloablative conditioning, HLA-mismatched donor, CMV viremia and acute GVHD (aGVHD) grade 3-4 were significantly associated with the risk of HC. Multivariate analysis confirmed all associating factors identified in univariate analysis except for HLA-mismatched donor: myeloablative conditioning (hazard ratio (HR) 2.63, P=0.003), CMV viremia (HR 1.88, P=0.014) and aGVHD grade 3-4 (HR 1.71, P=0.029). HC did not affect OS or non-relapse mortality. Symptomatic HC is a frequent complication following allo-HSCT, with a 2-year cumulative incidence of 24.0%. Three clinical factors associated with HC were identified including myeloablative conditioning, CMV viremia and severe aGVHD.

Novel inactivating mutation of the calcium-sensing receptor in a young woman with mild hypercalcaemia.

A young woman with mild hypercalcaemia and an inappropriately normal serum parathyroid hormone had parathyroid scintigraphy suggestive of an active ectopic parathyroid tissue in the superior mediastinum. Urinary calcium to creatinine clearance ratio was low, and a subsequent genetic analysis confirmed a novel mutation (Q164K) in the calcium sensing receptor gene, consistent with familial hypocalciuric hypercalcaemia. We propose that this mutation accounts for her clinical and investigational findings, although a double pathology of Q164K and an ectopic parathyroid adenoma is also conceivable.

The effect of protein and calorie intake on prealbumin, complications, length of stay, and function in the acute rehabilitation inpatient with stroke.

BACKGROUND: Nutrition's impact on stroke rehabilitation outcomes is controversial. Existing studies utilize albumin without correcting for inflammation in nutritional assessments. Here, prealbumin was used and inflammation assessed to determine if nutrition impacts rehabilitation outcomes. OBJECTIVE: Determine the effect of dietary intake on prealbumin level, number of complications, length of stay, and Functional Independence Measure (FIM) efficiency in rehabilitation stroke inpatients. METHODS: Patients had admission and discharge prealbumin and C-reactive protein (CRP) levels drawn; and, weekly protein and calorie counts obtained. Patients were followed for number of complications, length of stay, and FIM efficiency. RESULTS: Mean protein and calorie intake was 57.6 ± 16.2 g/d and 1452.2 ± 435.8 kcal/d, respectively. 77.6% of patients had normal prealbumin on admission with 94.9% on discharge. Prealbumin increased significantly from admission to discharge (22.3 ± 6.2 mg/dL vs. 24.6 mg/dL ± 5.1 mg/dL, P = 0.007). Number of complications and length of stay were predicted by CRP in regression models. Total, motor, and cognitive FIM efficiencies were not universally affected by prealbumin levels, protein intake, or calorie intake. CONCLUSIONS: Nearly all hypoprealbuminemic stroke rehabilitation inpatients correct their levels eating a non-supplemented diet. Number of complications, length of stay, and functional outcomes in this patient are not affected by prealbumin levels, protein intake, or calorie intake.

Duration of first remission, hematopoietic cell transplantation-specific comorbidity index and patient age predict survival of patients with AML transplanted in second CR.

Allo-SCT is potentially curative for patients with AML. Patients transplanted in CR2 tend to experience inferior survival compared with those in CR1. We retrospectively investigated the impact of pretransplant variables on the outcome of patients transplanted with AML in CR2. Ninety-four patients with AML in CR2 received a transplant between 1999 and 2011 with myeloablative (MA, n=65) or reduced-intensity conditioning regimens (RIC, n=29). Variables investigated included cytogenetic risk at diagnosis (SWOG), hematopoietic cell transplantation-specific comorbidity index (HCT-CI), CMV status, duration of CR1 and age. Median age of all patients was 47 years (range 18-70). Multivariable analysis for OS identified three prognostically significant categories: a favorable risk group included patients with duration of CR1 ≥6 months, age <55 years and HCT-CI score 0-3, an intermediate risk group with duration of CR1 ≥6 months, age <55 years and HCT-CI score 4-5 and a high-risk group with duration of CR1 <6 months or age ≥55 years (P=0.0001) with 5-year survivals of 53%, 31% and 6%, respectively. Acute and chronic GVHD did not influence this risk stratification. The stated risk factors discriminate patients with different OS and may assist in decision making for allo-SCT.

Ascending dose-controlled trial of beloranib, a novel obesity treatment for safety, tolerability, and weight loss in obese women.

OBJECTIVE: Evaluate the safety and tolerability of beloranib, a fumagillin-class methionine aminopetidase-2 (MetAP2) inhibitor, in obese women over 4 weeks. DESIGN AND METHODS: Thirty-one obese (mean BMI 38 kg/m2) women were randomized to intravenous 0.1, 0.3, or 0.9 mg/m2 beloranib or placebo twice weekly for 4 weeks (N = 7, 6, 9, and 9). RESULTS: The most frequent AEs were headache, infusion site injury, nausea, and diarrhea. Nausea and infusion site injury occurred more with beloranib than placebo. The most common reason for discontinuation was loss of venous access. There were no clinically significant abnormal laboratory findings. In subjects completing 4 weeks, median weight loss with 0.9 mg/m2 beloranib was -3.8 kg (95% CI -5.1, -0.9; N = 8) versus -0.6 kg with placebo (-4.5, -0.1; N = 6). Weight change for 0.1 and 0.3 mg/m2 beloranib was similar to placebo. Beloranib (0.9 mg/m2) was associated with a significant 42 and 18% reduction in triglycerides and LDL-cholesterol, as well as improvement in C-reactive protein and reduced sense of hunger. Changes in ß-hydroxybutyrate, adiponectin, leptin, and fibroblast growth factor-21 were consistent with the putative mechanism of MetAP2 inhibition. Glucose and blood pressure were unchanged. CONCLUSIONS: Beloranib treatment was well tolerated and associated with rapid weight loss and improvements in lipids, C-reactive protein, and adiponectin.