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Abstract Background: We had previously piloted thalidomide treatment in MMM and showed an approximately 20% response in terms of both anemia and splenomegaly (Elliott et al. BJH2002;117:288). Encouraged by this experience, we undertook the current phase II study to explore the therapeutic activity of the more potent as well as less neurotoxic immunomodulatory drug, lenalidomide (CC-5013). Methods: The study group comprised a consecutive series of patients with MMM that fulfilled protocol entry criteria that included hemoglobin level ≤ 10 g/dL, platelet count ≥ 100 x 109/L, and neutrophil count ≥ 1 x 109/L. The treatment program consisted of daily oral lenalidomide (10 mg/day) for 3 consecutive 28-day cycles with a plan to continue with additional 3 cycles in case of response. Results: i. Pretreatment patient information Twenty-seven patients (median age, 66 years; range, 40–78) were accrued between March 5, 2004 and June 15, 2005. Median duration of disease prior to protocol treatment was 30 months (range, 1–245). Previous therapy was documented in all but 2 patients. Twenty patients were RBC transfusion-dependent. Baseline median (range) values for palpable spleen size, leukocyte count, platelet count, CD34 cell count, and serum lactate dehydrogenase (LDH) were 16 cm (0–31), 8.4 x 109/L (1.8–84.4), 299 x 109/L (124–831), 166.1 x 106/L (2.8–5176.4), and 778 U/L (267–1725), respectively. Cytogenetic abnormalities were detected in 13 patients (48%). JAK2 V617F mutation analysis was performed in 21 patients and revealed homozygous, heterozygous, and wild-type alleles in 3, 8, and 10 patients, respectively. ii. Adverse events Adverse events (any/grade 3 or 4) with definite, probable, or possible attributions to the drug included fatigue (52%/12%), neutropenia (40%/24%), pruritus (36%/0%), thrombocytopenia (28%/8%), anemia (16%/8%), rash (12%/8%), and respiratory distress with hypoxia (8%/8%). To date, 7 deaths have been reported, all occuring after discontinuation of protocol therapy, and none were directly linked to the drug. iii. Response The median post-treatment follow up is now 16 months (range 1–17 months). During this period, 6 patients (22%) have experienced either a major (3 patients normalized their hemoglobin level), minor (2 patients became transfusion-independent), or marginal response in anemia. The median time to response and response duration were 2 and 7 months, respectively. Two of the 3 major responders had a baseline der(1;18)(q10;q10) or del(5)(q13q33) cytogenetic abnormality, the latter one of which displayed a major cytogenetic remission. In the patient with der(1;18)(q10;q10), the hemoglobin level increased to a level of 19.1 g/dL from being transfusion-dependent at the start of lenalidomide therapy. Interestingly, the particular patient was homozygous for the JAK2 V617F mutation. Responses were also recorded for palpable splenomegaly (26%), constitutional symptoms (67%), and serum LDH level (70%). Seven patients normalized their LDH. Conclusion: Lenalidomide therapy improved anemia in at least 20% of patients with MMM. Some of the responses were spectacular and appeared to be associated with specific cytogenetic abnormalities. The documentation of a positive drug effect on LDH, constitutional symptoms, and splenomegaly in patients not showing early response in anemia suggests the possibility of an even higher response rate with a longer treatment schedule.

Abstract Background: In essential thrombocythemia (ET), homozygosity for the JAK2 V617F mutant allele is rare despite the frequent (23–57%) occurrence of the heterozygous state. This is in direct contrast with the situation in polycythemia vera (PV) where homozygosity for the mutation is seen in 25–33% of the cases. The particular observation is consistent with what has been observed in vitro as well as in animal studies where JAK2 V617F has been associated with induction of erythropoietin hypersensitivity in cell lines and erythrocytosis in mice (James et al. Nature2005;434:1144). Therefore, regardless of whether or not JAK2 V617F represents a primary event in myeloproliferative disorders, it is probable that it promotes a PV phenotype. In the current study, we explore this hypothesis as well as investigate the long-term prognostic relevance of the mutation in a well defined cohort of patients with ET seen at a single institution. Methods: The diagnosis of ET was according to the WHO classification of tumors (Jaffe ES et al. Lyon, IARC press, 2001). All patients were seen at the Mayo Clinic and patient characteristics and subsequent clinical events were determined both retrospectively (chart review) and prospectively (by means of a questionnaire sent both to patients and their primary doctors). In addition date and cause of death were confirmed by probing both the social security index and the national death index. DNA for mutation screening was derived and sequenced from either archived unsorted cells from the bone marrow or prospectively collected peripheral blood granulocytes according to previously published methods (Levine et al. Cancer Cell, 2005;7:387). Results: The study cohort consisted of 150 consecutive patients with ET including 99 females and 51 males (median age 49.8 years; range 16.8–98). Overall, JAK2 V617F was detected in 73 patients (48.7%) but none were homozygous for the mutant allele. At diagnosis, ET patients with JAK2 V617F were significantly older (median age of 53.5 vs. 42.3; p=0.02) and also displayed higher readings of both hemoglobin level (p=0.0002) and leukocyte count (p=0.005). All study patients have now been followed for a median of 11.4 years from diagnosis (range 0–32.7) and follow-up period was similar between the two mutational categories (p=0.53). During this period, 32 patients have died and the median survival for the entire group was 19.3 years; 21.9 and 17.7 years in the absence and presence of the mutation, respectively (p=0.09). Disease transformation into acute leukemia, myelofibrosis, and PV occurred in 6 (4%), 15 (10%), and 8 (5.3%) patients, respectively, and the only significant difference between the two mutational categories in this regard was the higher incidence of transformation into PV in patients with the mutation (p=0.02). Multivariate analysis identified age, hemoglobin level, and thrombosis history at diagnosis but not JAK2 V617F mutational status as independent risk factors for survival. Conclusion: Although the presence of JAK2 V617F in ET appears to promote a PV phenotype, it might not carry treatment-relevant information.

Deborah Doniach MD, FRCP was born in Geneva, Switzerland in 1912. She attended high school at the Lycée Molière and medical school at the Sorbonne in Paris. Deborah married Israel (Sonny) Doniach in 1933. After the births of their two children, she resumed her studies at the Royal Free Hospital Medical School in London, graduating in 1945. After additional training in Immunopathology and Endocrinology, Dr. Doniach joined the faculty in the Department of Immunology at the Middlesex Hospital and rose to become Honorary Consultant Immunopathologist and full Professor of Clinical Immunology. During her career, Deborah enjoyed a long and fruitful collaboration with the chemist and immunologist Ivan Roitt. From their partnership sprang the seminal discovery that Hashimoto's thyroiditis is an autoimmune disease in which circulating antibodies target thyroglobulin, a normal thyroid protein. In addition, they demonstrated a separate antibody cytotoxic to thyrocytes, later found to target thyroid peroxidase. These novel insights ran counter to the prevailing scientific dogma contending that antibodies target only nonself antigens. Thus, the field of research into thyroid autoimmunity, and indeed into autoimmune diseases in general, was born. This work spawned a cadre of future investigators whose studies define our current understanding of thyroid autoimmunity and the broader spectrum of autoimmune disease. In her private life, Deborah was a free thinker who defied conventional norms of the day. She was vivacious, warm, and genuinely interested in everybody and everything. Deborah Doniach died on New Year's Day, 2004 at the age of 91.

Importance Black individuals are more likely than white individuals to develop dementia. Whether higher blood pressure (BP) levels in black individuals explain differences between black and white individuals in dementia risk is uncertain. Objective To determine whether cumulative BP levels explain racial differences in cognitive decline. Design, Setting, and Participants Individual participant data from 5 cohorts (January 1971 to December 2017) were pooled from the Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, and Northern Manhattan Study. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represented a 0.1-SD difference in cognition. The median (interquartile range) follow-up was 12.4 (5.9-21.0) years. Analysis began September 2018. Main Outcomes and Measures The primary outcome was change in global cognition, and secondary outcomes were change in memory and executive function. Exposures Race (black vs white). Results Among 34 349 participants, 19 378 individuals who were free of stroke and dementia and had longitudinal BP, cognitive, and covariate data were included in the analysis. The mean (SD) age at first cognitive assessment was 59.8 (10.4) years and ranged from 5 to 95 years. Of 19 378 individuals, 10 724 (55.3%) were female and 15 526 (80.1%) were white. Compared with white individuals, black individuals had significantly faster declines in global cognition (−0.03 points per year faster [95% CI, −0.05 to −0.01]; P = .004) and memory (−0.08 points per year faster [95% CI, −0.11 to −0.06]; P < .001) but significantly slower declines in executive function (0.09 points per year slower [95% CI, 0.08-0.10]; P < .001). Time-dependent cumulative mean systolic BP level was associated with significantly faster declines in global cognition (−0.018 points per year faster per each 10–mm Hg increase [95% CI, −0.023 to −0.014]; P < .001), memory (−0.028 points per year faster per each 10–mm Hg increase [95% CI, −0.035 to −0.021]; P < .001), and executive function (−0.01 points per year faster per each 10–mm Hg increase [95% CI, −0.014 to −0.007]; P < .001). After adjusting for cumulative mean systolic BP, differences between black and white individuals in cognitive slopes were attenuated for global cognition (−0.01 points per year [95% CI, −0.03 to 0.01]; P = .56) and memory (−0.06 points per year [95% CI, −0.08 to −0.03]; P < .001) but not executive function (0.10 points per year [95% CI, 0.09-0.11]; P < .001). Conclusions and Relevance These results suggest that black individuals’ higher cumulative BP levels may contribute to racial differences in later-life cognitive decline.

Background Frailty increases risk for complications after total joint arthroplasty (TJA). Whether this association is influenced by anesthetic administered is unknown. We hypothesized that use of neuraxial (spinal or epidural) anesthesia is associated with better outcomes compared with general anesthesia, and that the effect of anesthesia type on outcomes differs by frailty status. Methods This single-institution cohort study included all patients (≥50 years) from January 2005 through December 2016 undergoing unilateral, primary and revision TJA. Using multivariable Cox regression, we assessed relationships between anesthesia type, a preoperative frailty deficit index (FI) categorized as non-frail (FI <0.11), vulnerable (FI 0.11 to 0.20), and frail (FI >0.20), and complications (mortality, infection, wound complications/hematoma, reoperation, dislocation, and periprosthetic fracture) within 1 year after surgery. Interactions between anesthesia type and frailty were tested, and stratified models were presented when an interaction (p<0.1) was observed. Results Among 18 458 patients undergoing TJA, more patients were classified as frail (21.5%) and vulnerable (36.2%) than non-frail (42.3%). Anesthesia type was not associated with complications after adjusting for age, joint, and revision type. However, in analyzes stratified by frailty, vulnerable patients under neuraxial block had less mortality (HR=0.49; 95% CI 0.27 to 0.89) and wound complications/hematoma (HR=0.71; 95% CI 0.55 to 0.90), whereas no difference in risk by anesthesia type was observed among patients found non-frail or frail. Conclusions Neuraxial anesthesia use among vulnerable patients was associated with improved survival and less wound complications. Calculating preoperative frailty prior to TJA informs perioperative risk and enhances shared-decision making for selection of anesthesia type.

Several new systemic therapy options have become available for patients with metastatic breast cancer, which have led to improvements in survival. In addition to patient and clinical factors, the treatment selection primarily depends on the tumor biology (hormone-receptor status and HER2-status). The NCCN Guidelines specific to the workup and treatment of patients with recurrent/stage IV breast cancer are discussed in this article.

Abstract Background Intrathecal opioids are routinely administered during spinal anesthesia for postcesarean analgesia. The effectiveness of intrathecal morphine for postcesarean analgesia is well established, and the use of intrathecal hydromorphone is growing. No prospective studies have compared the effectiveness of equipotent doses of intrathecal morphine versus intrathecal hydromorphone as part of a multimodal analgesic regimen for postcesarean analgesia. The authors hypothesized that intrathecal morphine would result in superior analgesia compared with intrathecal hydromorphone 24 h after delivery. Methods In this single-center, double-blinded, randomized trial, 138 parturients undergoing scheduled cesarean delivery were randomized to receive 150 µg of intrathecal morphine or 75 µg of intrathecal hydromorphone as part of a primary spinal anesthetic and multimodal analgesic regimen; 134 parturients were included in the analysis. The primary outcome was the numerical rating scale score for pain with movement 24 h after delivery. Static and dynamic pain scores, nausea, pruritus, degree of sedation, and patient satisfaction were assessed every 6 h for 36 h postpartum. Total opioid consumption was recorded. Results There was no significant difference in pain scores with movement at 24 h (intrathecal hydromorphone median [25th, 75th] 4 [3, 5] and intrathecal morphine 3 [2, 4.5]) or at any time point (estimated difference, 0.5; 95% CI, 0 to 1; P = 0.139). Opioid received in the first 24 h did not differ between groups (median [25th, 75th] oral morphine milligram equivalents for intrathecal hydromorphone 30 [7.5, 45.06] vs. intrathecal morphine 22.5 [14.0, 37.5], P = 0.769). From Kaplan–Meier analysis, the median time to first opioid request was 5.4 h for hydromorphone and 12.1 h for morphine (log-rank test P = 0.200). Conclusions Although the hypothesis was that intrathecal morphine would provide superior analgesia to intrathecal hydromorphone, the results did not confirm this. At the doses studied, both intrathecal morphine and intrathecal hydromorphone provide effective postcesarean analgesia when combined with a multimodal analgesia regimen. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background and Purpose— Cerebral small vessel disease (SVD) is associated with increased stroke risk and poor stroke outcomes. We aimed to evaluate whether chronic SVD burden is associated with poor recruitment of collaterals in large-vessel occlusive stroke. Methods— Consecutive patients with middle cerebral artery or internal carotid artery occlusion presenting within 6 hours after stroke symptom onset who underwent thrombectomy from 2012 to 2017 were included. The prespecified primary outcome was poor collateral flow, which was assessed on baseline computed tomographic angiography (poor, ≤50% filling; good, >50% filling). Markers of chronic SVD on brain magnetic resonance imaging were rated for the extent of white matter hyperintensities, enlarged perivascular spaces, chronic lacunar infarctions and cerebral microbleeds using the Standards for Reporting Vascular Changes on Neuroimaging criteria. Severity of SVD was quantified by adding the presence of each SVD feature, with a total possible score of 0 to 4; each SVD type was also evaluated separately. Multivariable logistic regression analyses were performed to evaluate the relationships between SVD and poor collaterals, with adjustment for potential confounders. Results— Of the 100 eligible patients, the mean age was 65±16 years, median National Institutes of Health Stroke Scale score was 15, and 68% had any SVD. Poor collaterals were observed in 46%, and those with SVD were more likely to have poor collaterals than patients without SVD (aOR, 1.9 [95% CI, 1.1–3.2]). Of the SVD types, poor collaterals were significantly associated with white matter hyperintensities (aOR, 2.9 per Fazekas increment [95% CI, 1.6–5.3]) but not with enlarged perivascular spaces (adjusted odds ratio [aOR], 1.3 [95% CI, 0.4–4.0]), lacunae (aOR, 2.1 [95% CI, 0.6–7.1]), or cerebral microbleeds (aOR, 2.1 [95% CI, 0.6–7.8]). Having a greater number of different SVD markers was associated with a higher odds of poor collaterals (crude trend P <0.001; adjusted P =0.056). There was a dose-dependent relationship between white matter hyperintensity burden and poor collaterals: adjusted odds of poor collaterals were 1.5, 3.0, and 9.7 across Fazekas scores of 1 to 3 ( P trend=0.015). No patient with an SVD score of 4 had good collaterals. Conclusions— Chronic cerebral SVD is associated with poor recruitment of collaterals in large vessel occlusive stroke. A prospective study to elucidate the potential mechanism of how SVD may impair the recruitment of collaterals is ongoing.

High stage and recurrent ovarian clear cell carcinoma (OCC) are associated with poor prognosis and resistance to chemotherapy. A distinguishing histological feature of OCC is abundant cytoplasmic stores of glucose, in the form of glycogen, that can be mobilized for cellular metabolism. Here, we report the effect on preclinical models of OCC of disrupting glycogen utilization using the glucose analogue 2-deoxy-D-glucose (2DG). At concentrations significantly lower than previously reported for other cancers, 2DG markedly improves the efficacy in vitro of carboplatin chemotherapy against chemo-sensitive TOV21G and chemo-resistant OVTOKO OCC cell lines, and this is accompanied by the depletion of glycogen. Of note, 2DG doses—of more than 10-fold lower than previously reported for other cancers—significantly improve the efficacy of carboplatin against cell line and patient-derived xenograft models in mice that mimic the chemo-responsiveness of OCC. These findings are encouraging, in that 2DG doses, which are substantially lower than previously reported to cause adverse events in cancer patients, can safely and significantly improve the efficacy of carboplatin against OCC. Our results thus justify clinical trials to evaluate whether low dose 2DG improves the efficacy of carboplatin in OCC patients.

AbstractThe scope of pharmacy practice in global health has expanded over the past decade creating additional education and training opportunities for students, residents and pharmacists. There has also been a shift from short‐term educational and clinical experiences to more sustainable bidirectional partnerships between high‐income countries (HICs) and low‐ to middle‐income countries (LMICs). As more institutional and individual partnerships between HICs and LMICs begin to form, it is clear that there is a lack of guidance for pharmacists on how to build meaningful, sustainable, and mutually beneficial programs. The aim of this paper is to provide guidance for pharmacists in HICs to make informed decisions on global health partnerships and identify opportunities for engagement in LMICs that yield mutually beneficial collaborations. This paper uses the foundations of global health principles to identify five pillars of global health engagement when developing partnerships: (a) sustainability, (b) shared leadership, (c) mutually beneficial partnerships, (d) local needs‐based care and (e) host‐driven experiential and didactic education. Finally, this paper highlights ways pharmacists can use the pillars as a framework to engage and support health care systems, collaborate with academic institutions, conduct research, and interface with governments to improve health policy.