Understanding rural pharmacists' perspectives: lived experiences and insights associated with rural recruitment and retention.

INTRODUCTION: Pharmacists serve an important role in rural communities, and in some cases they may be the only health professional available. Their recruitment and retention is a major concern for rural communities and health services; however, a deeper understanding regarding the advantages and challenges of sustaining a rural pharmacy workforce is somewhat limited. The aim of this study was to develop a deeper understanding of pharmacists' perspectives about factors influencing pharmacist recruitment and retention to rural and remote communities. METHODS: The exploratory study, carried out in rural Tasmania and rural Western Victoria, used a qualitative descriptive design. Structured interviews, lasting between 30-60 minutes, were conducted by a single researcher using the Pharmacist Community Apgar Questionnaire via face-to-face, telephone or videoconferencing technology. Data were analysed thematically using verbatim transcription, extraction of significant statements and identification of similarities in formulated meanings, grouping the similar meanings and significant statements that pertained to the phenomena of interest. Specifically, qualitative data were used to provide a deeper understanding of factors identified as key assets, capabilities, or those most challenging for pharmacist recruitment and retention. RESULTS: The advantages and disadvantages rural communities face in recruiting and retaining pharmacists are presented. These insights are linked to the advantages of financial income, incentives and moving allowance. Further advantages include the degree of practice autonomy, breadth of tasks, the perception of the community, loyalty to the pharmacy and its pharmacists, along with community recognition. Challenges associated with the recruitment and retention of pharmacists centred on the need for spousal or partner employment opportunities, having greater proximity to schools, access to social or cultural opportunities, along with good transport connections. Further challenges included housing, the cost of schooling for children, having adequate locum or peer coverage and opportunities to host interns. DISCUSSION: The study provides a deeper exploration of the meaning and experiences of factors that previous research has shown are considered advantageous or challenging to the recruitment and retention of pharmacists in rural areas. Through the voices of pharmacists living and working in a rural area, the findings further enlighten our understanding regarding how the multifaceted and complex nature of health workforce planning may be addressed. As such, greater pharmacist recruitment and retention is enabled through adequate financial compensation and incentives, along with additional tax incentives for business and health services. Further, innovation is required to enhance economic sustainability. Locum coverage and intern opportunities also require innovative approaches to address concerns among potential candidates. Lastly, efforts to enable and support social connections such as schooling and spousal employment, while building community connection and a sense of rural community belonging, remain essential to recruit and retain pharmacists. CONCLUSION: Rural pharmacist recruitment and retention is complex, requiring a multi-pronged approach to implement practical solutions. Given this complexity and the unique features of each rural community, solutions require whole-of-community ownership to create innovative solutions. Recognition of specific advantages and challenges can address key driving factors for pharmacist recruitment and retention in rural communities.

Sustaining rural pharmacy workforce understanding key attributes for enhanced retention and recruitment.

OBJECTIVE: To pilot the Pharmacist Community Apgar Questionnaire (PharmCAQ) and evaluate its usability and capacity to develop a greater understanding of the unique factors that impact the rural recruitment and retention of pharmacists. DESIGN: Cross-sectional design involving face-to-face, telephone or video conferencing interviews. SETTING: Twelve rural communities across Tasmania and Western Victoria, Australia. PARTICIPANTS: Participants (n = 24) included pharmacists, a Director of Clinical Services, pharmacy practice managers and senior pharmacy assistants. MAIN OUTCOME MEASURES: Interviews enabled the completion of the PharmCAQ, which assigns quantitative values to 50 key factors to ascertain a community's strengths and challenges associated with recruitment and retention and their relative importance to the pharmacist workforce. RESULTS: The cumulative PharmCAQ scores indicated the tool was sensitive enough to differentiate high- and low-performing communities. Overall, the highest-rated factors considered most vital to pharmacist recruitment and retention were the reputation of the pharmacy, the ability of the pharmacist to be independent and autonomous, the loyalty of the community to the pharmacy, the level and stability of monetary compensation and the breadth of tasks available to a pharmacist. CONCLUSIONS: This study identified the strengths and challenges of participating communities and provided an insight into the shared factors to consider in recruiting and retaining pharmacists. Further, each community has unique strengths that can further be promoted in recruitment, flagging where limited resources are best used to address site specific challenges. This is more likely to ensure the matching of the right candidate with the right community.

The Pharmacy Community Apgar Questionnaire: a modified Delphi technique to develop a rural pharmacist recruitment and retention tool.

INTRODUCTION: An adequate healthcare workforce remains essential for the health of rural communities. Strategies to address rural health workforce challenges have often centred on the medical and nursing workforce; however, addressing the rural pharmacist workforce also remains critical as they are often the first point of contact for health advice. Initiatives have increased pharmacist supply; however, key issues such as poor attraction, recruitment, and retention to rural areas remain. The aim of this study was to support the recruitment and retention of pharmacists in rural areas of Australia through the development of the Pharmacy Community Apgar Questionnaire (PharmCAQ). METHODS: A modified Delphi technique was employed to develop the PharmCAQ. A panel of experts were purposively selected. Eight representatives were from organisations with rural experience relevant to the study including the Society of Hospital Pharmacists of Australia, the Pharmaceutical Society of Australia, the Pharmacy Guild of Australia, the Pharmacy Board of Australia, and a representative of a government health agency, who also leads a hospital pharmacy. Three additional participants included local and international academics with health policy and rural health workforce expertise. All participants participated in three separate focus groups of 45-60 minutes duration, where the review and refinement of factors that drive recruitment and retention of pharmacist were discussed. Face and content validity was achieved through the representatives, while internal consistency was achieved when the tool was piloted among 10 rural pharmacists in rural Victoria. RESULTS: Fifty key factors that impact the recruitment and retention of pharmacists were identified, developed and succinctly described. All factors were grouped into five classifications: (1) geographic, (2) economic and resources, (3) practice and scope of practice, (4) practice environment and (5) community practice support. After final consensus, the factors and their definitions formed the final questionnaire. Lastly, the reliability of PharmCAQ was determined, with a Cronbach's alpha coefficient of 0.852. CONCLUSION: While the development and use of the Apgar questionnaire for the recruitment and retention of health professionals is not a novel idea, seeking to specifically focus on pharmacists is unique. However, 10 factors were similar to factors associated with rural recruitment and retention of both physicians and nurses; they encompassed geographic, community support, and economic and resource factors. Regardless of similarities or differences between health professions in terms of recruitment and retention, as a mechanism for addressing the worsening health professional shortage currently experienced in rural areas, the PharmCAQ was developed to support the recruitment and retention of the pharmacist workforce in rural areas.

Factors contributing to the recruitment and retention of rural pharmacist workforce: a systematic review.

BACKGROUND: Recruiting and retaining medical, nursing, and allied health professionals in rural and remote areas is a worldwide challenge, compromising continuity of care and population health outcomes in these locations. Specifically, pharmacists play an essential and accessible frontline healthcare role, and are often the first point of contact for health concerns. Despite several incentives, there remains a maldistribution and undersupply of pharmacists in rural and remote areas across many parts of the world. Although current systematic reviews have focussed on factors affecting pharmacists' retention generally, literature specifically focused on rural pharmacist workforce in a global context remains limited. The aim of this systematic review is to identify factors associated with recruitment and retention of the pharmacist workforce in rural and remote settings. Better understanding of these contributors will inform more effective interventional strategies to resolve pharmacist workforce shortages. METHODS: A systematic search of primary studies was conducted in online databases, including Medline, Embase, CINAHL, Scopus, Web of Science and PsycINFO, and by hand-searching of reference lists. Eligible studies were identified based on predefined inclusion/exclusion criteria and methodological quality criteria, utilising the Critical Appraisal Skills Programme (CASP) and Good Reporting of A Mixed Methods Study (GRAMMS) checklists. RESULTS: The final review included 13 studies, with quantitative, qualitative, or mixed methods research design. Study-specific factors associated with recruitment and retention of pharmacists in rural practice were identified and grouped into five main themes: geographic and family-related, economic and resources, scope of practice or skills development, the practice environment, and community and practice support factors. CONCLUSIONS: The results provide critical insights into the complexities of rural recruitment and retention of pharmacists and confirms the need for flexible yet multifaceted responses to overcoming rural pharmacist workforce challenges. Overall, the results provide an opportunity for rural communities and health services to better identify key strengths and challenges unique to the rural and remote pharmacist workforce that may be augmented to guide more focussed recruitment and retention endeavours.

'The public rely on me a lot': Rural pharmacists' perspectives on their roles in oral health care.

OBJECTIVE: To examine rural pharmacists' perspectives on their roles in oral health in rural communities and collaborations with dental practitioners. DESIGN: A qualitative research study using face-to-face, semistructured interviews. Interview data were thematically analysed with the assistance of Nvivo 10. SETTING: Eleven rural communities across rural Tasmania. PARTICIPANTS: Twenty community pharmacists. RESULTS: Five major themes emerged: (i) barriers for patients to access dental services; (ii) oral health presentations to rural pharmacies; (iii) roles of pharmacists in oral health care (subthemes: advice; health promotion; and referrals); (iv) collaborations with dental practitioners; and (v) oral health education and training. CONCLUSION: This study suggests that rural community pharmacists had advisory and referral roles in oral health and acknowledged that they could play a greater role in oral health promotion. It was suggested that oral health could be incorporated into existing pharmacy health promotion and surveillance activities. There was a lack of collaboration between pharmacists and dentists or dental services and limited oral health education and training provided to pharmacists. Stronger collaboration between pharmacists and dental practitioners and better oral health training for pharmacists may enhance their role in promoting oral health within rural communities.

Exercise for reducing falls in people living with and beyond cancer.

BACKGROUND: Current treatment modalities for cancer have been successful in achieving improved survivorship; however, they come with a number of long-term adverse effects. Accidental falls are a common and clinically significant adverse event in people living with and beyond cancer and rates are higher than in the rest of the population. OBJECTIVES: To assess the effects of prescribed or provided exercise for reducing accidental falls, and falls risk factors of strength, flexibility and balance, in people living with and beyond cancer. SEARCH METHODS: We searched the following electronic databases from inception to 10 July 2018, with no restrictions: CENTRAL, MEDLINE, Embase, and seven other databases. We searched clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform (ICTRP) for ongoing trials, and reference lists of reviews and retrieved articles for additional studies. SELECTION CRITERIA: We included all randomised controlled trials investigating exercise interventions versus no treatment, usual care or non-exercise interventions on falls incidence or falls risk factors in adults living with and beyond cancer (18 years of age or older at diagnosis). We excluded cross-over studies and studies in acute or inpatient hospice care. DATA COLLECTION AND ANALYSIS: At least two review authors independently completed data extraction for included papers. We used Covidence software to manage screening, data collection and extraction. We assessed evidence using GRADE and presented results in a 'Summary of findings' table. MAIN RESULTS: Eleven studies (835 participants) compared exercise to usual care. No studies compared exercise with no treatment or non-exercise interventions. The quality of the evidence was very low for the primary outcome rates of falls, and very low to low for the secondary outcomes. We downgraded the evidence due to study limitations (risk of bias), and issues of imprecision due to small sample sizes, inconsistency and indirectness. All studies were at high risk of bias for blinding of participants and personnel due to inability to blind participants to an exercise intervention. Risk of bias was generally low or unclear for other categories.There was generally little information on the important outcomes comparing exercise to usual care.Rates of falls and number of fallers: one study (223 participants) measured accidental falls, but reported neither the rate of falls or the number of fallers; there was no difference in the number of falls between exercise and usual care (very low-quality evidence).Strength: 10 studies (813 participants) reported on strength outcomes. Two analyses favoured exercise over usual care: quadriceps strength (2 studies, 72 participants; mean difference (MD) 8.99 kg, 95% confidence interval (CI) 1.29 to 16.70; low-quality evidence), and leg press (4 studies, 388 participants; MD 21.1 kg, 95% CI 8.47 to 33.74; low-quality evidence). In one analysis of the Sit-to-Stand Test, there was no difference between exercise and usual care (4 studies, 214 participants; standardised mean difference (SMD) -0.45, 95% CI -1.05 to 0.14; very low-quality evidence).Flexibility: one study (21 participants) reported on flexibility for Sit-and-Reach Distance (MD 2.05 cm, 95% CI 0.59 to 3.51; very low-quality evidence).Balance: five studies (350 participants) measured three different balance outcomes. Two analyses favoured exercise over usual care: postural balance (4 studies, 127 participants; standardised mean difference (SMD) 0.44, 95% CI 0.08 to 0.79; very low-quality evidence), and Backward Walk Test (2 studies, 280 participants; SMD -0.24, 95% CI -0.48 to -0.01; low-quality evidence). There was no difference between exercise and usual care for the Timed Up-and-Go Test (1 study, 15 participants; MD -0.35 seconds, 95% CI -1.47 to 0.77; low-quality evidence).Number of people sustaining a fall-related fracture: the quality of the evidence for exercise reducing fall-related fractures was very low.Adverse events: a single study (223 participants) noted some temporary muscle soreness on initiation of exercise or when there was an increase in the weight lifted. As no occurrence data were reported, we could not assess this variable further. No studies reported musculoskeletal injury. Analysis indicated that there was very low-quality evidence that exercise did not increase fatigue. AUTHORS' CONCLUSIONS: There is a paucity of evidence for exercise training to reduce fall rates in people living with and beyond cancer. Exercise training may improve strength, flexibility and balance for people in this population, but the evidence is very low quality.

Romidepsin in peripheral and cutaneous T-cell lymphoma: mechanistic implications from clinical and correlative data.

Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T-cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long-term disease control and the ability to retreat patients relapsing off-therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving romidepsin as third-line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3.5 months to 10 years; in four of six patients, re-initiation of treatment led to clear benefit. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24 h. These data argue against cell death occurring as a result of an epigenetics-mediated gene induction programme. Together this work supports the safety and activity of romidepsin in T-cell lymphoma, but suggests a complex mechanism of action.

A phase II study of vorinostat and rituximab for treatment of newly diagnosed and relapsed/refractory indolent non-Hodgkin lymphoma.

This study examines the activity and tolerability of a regimen combining vorinostat and rituximab in patients with indolent B-cell non-Hodgkin lymphoma. A total of 28 patients with newly diagnosed or relapsed/refractory follicular, marginal zone, or mantle cell lymphoma, with 4 or less prior therapies were eligible for this open-label phase II study. Oral vorinostat 200 mg was administered twice daily on days 1-14 along with 375 mg/m(2) of intravenous rituximab on day 1 of a 21-day cycle, continuing until disease progression or unacceptable toxicity. Primary end point was objective response rate, with secondary end points of progression-free survival, time to progression, duration of response, safety, and tolerability. Median follow up was 25.6 months and median number of vorinostat cycles was 11.5. Overall response rate was 46% for all patients, 67% for previously untreated, and 41% for relapsed/refractory patients. Median progression-free survival was 29.2 months for all patients, 18.8 months for previously treated patients, and not reached for untreated patients. The regimen was well tolerated over long treatment periods with the most common grade 3/4 adverse events being asymptomatic thrombosis, neutropenia, thrombocytopenia, lymphopenia, and fatigue. The vorinostat/rituximab combination exhibits activity in indolent B-cell non-Hodgkin lymphoma with an acceptable safety profile and durable responses. Re-treatment was effective in 2 of 3 relapsing responders. This phase II clinical trial was registered at clinicaltrials.gov identifier: 00720876.

A phase 1 clinical trial of vorinostat in combination with decitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome.

Patients with acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) may respond to treatment with epigenetic-modifying agents. Histone deacetylase inhibitors may synergize with hypomethylating agents. This phase 1 dose-escalation study was designed to determine the maximum tolerated dose, recommended phase 2 dose, safety and tolerability of vorinostat plus decitabine in patients with relapsed/refractory AML, newly-diagnosed AML, or intermediate- to high-grade MDS. Thirty-four patients received concurrent therapy with decitabine plus vorinostat and 37 received sequential therapy with decitabine followed by vorinostat. Twenty-nine patients had relapsed/refractory AML, 31 had untreated AML and 11 had MDS. The target maximum administered dose (MAD) of decitabine 20 mg/m(2) daily for 5 d plus vorinostat 400 mg/d for 14 d was achieved for concurrent and sequential schedules, with one dose-limiting toxicity (Grade 3 QTc prolongation) reported in the sequential arm. Common toxicities were haematological and gastrointestinal. Responses were observed more frequently at the MAD on the concurrent schedule compared with the sequential schedule in untreated AML (46% vs. 14%), relapsed/refractory AML (15% vs. 0%) and MDS (60% vs. 0%). Decitabine plus vorinostat given concurrently or sequentially appears to be safe and well-tolerated. Concurrent therapy shows promising clinical activity in AML or MDS, warranting further investigation.

Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma.

Romidepsin (depsipeptide or FK228) is a histone deacetylase inhibitor, one of a new class of agents active in T-cell lymphoma. A phase 2 trial was conducted in cutaneous (CTCL) and peripheral (PTCL) T-cell lymphoma. Major and durable responses in CTCL supported the approval of romidepsin for CTCL. Forty-seven patients with PTCL of various subtypes including PTCL NOS, angioimmunoblastic, ALK-negative anaplastic large cell lymphoma, and enteropathy-associated T-cell lymphoma were enrolled. All patients had received prior therapy with a median of 3 previous treatments (range 1-11); 18 (38%) had undergone stem-cell transplant. All patients were evaluated for toxicity; 2 patients discovered to be ineligible were excluded from response assessment. Common toxicities were nausea, fatigue, and transient thrombocytopenia and granulocytopenia. Complete responses were observed in 8 and partial responses in 9 of 45 patients, for an overall response rate of 38% (95% confidence interval 24%-53%). The median duration of overall response was 8.9 months (range 2-74). Responses were observed in various subtypes, with 6 responses among the 18 patients with prior stem-cell transplant. The histone deacetylase inhibitor romidepsin has single agent clinical activity associated with durable responses in patients with relapsed PTCL.

A phase I study in adults of clofarabine combined with high-dose melphalan as reduced-intensity conditioning for allogeneic transplantation.

Clofarabine is a novel purine nucleoside analog with immunosuppressive and antileukemia activity. We performed a phase I study of the combination of clofarabine plus melphalan as a reduced-intensity conditioning regimen for allogeneic stem cell transplantation in patients with acute myelogenous leukemia. Patients over age 18 in complete remission or with active disease (up to 50% marrow blasts) who had a matched related or unrelated donor were eligible. The conditioning regimen consisted of escalating doses of clofarabine plus melphalan, followed by allogeneic stem cell transplantation. Sixteen patients (median age, 63 years) were treated at 3 dose levels; 4 of these patients had primary induction failure, and 3 were in first relapse. One patient at dose level 2 and 1 patient at dose level 3 died of multiorgan toxicity; no other dose-limiting toxicities were seen. All other patients at both doses of clofarabine studied demonstrated complete engraftment by day 30, with a median time to absolute neutrophil count recovery of 14 days, and 16 days for platelet recovery. With a median follow-up of 17 months, only 2 patients relapsed, and 4 patients died. Clofarabine plus melphalan at dose level 2 is a well-tolerated conditioning regimen with activity in patients with advanced acute myelogenous leukemia.

HDAC inhibitor reduces cytokine storm and facilitates induction of chimerism that reverses lupus in anti-CD3 conditioning regimen.

In allogeneic hematopoietic cell transplantation (HCT), donor T cell-mediated graft versus host leukemia (GVL) and graft versus autoimmune (GVA) activity play critical roles in treatment of hematological malignancies and refractory autoimmune diseases. However, graft versus host disease (GVHD), which sometimes can be fatal, remains a major obstacle in classical HCT, where recipients are conditioned with total body irradiation or high-dose chemotherapy. We previously reported that anti-CD3 conditioning allows donor CD8(+) T cells to facilitate engraftment and mediate GVL without causing GVHD. However, the clinical application of this radiation-free and GVHD preventative conditioning regimen is hindered by the cytokine storm syndrome triggered by anti-CD3 and the high-dose donor bone marrow (BM) cells required for induction of chimerism. Histone deacetylase (HDAC) inhibitors such as suberoylanilide hydroxamic acid (SAHA) are known to induce apoptosis of cancer cells and reduce production of proinflammatory cytokines by nonmalignant cells. Here, we report that SAHA inhibits the proliferative and cytotoxic activity of anti-CD3-activated T cells. Administration of low-dose SAHA reduces cytokine production and ameliorates the cytokine storm syndrome triggered by anti-CD3. Conditioning with anti-CD3 and SAHA allows induction of chimerism with lower doses of donor BM cells in old nonautoimmune and autoimmune lupus mice. In addition, conditioning with anti-CD3 and SAHA allows donor CD8(+) T cell-mediated GVA activity to reverse lupus glomerulonephritis without causing GVHD. These results indicate that conditioning with anti-CD3 and HDAC inhibitors represent a radiation-free and GVHD-preventative regimen with clinical application potential.

The novel histone deacetylase inhibitor, LBH589, induces expression of DNA damage response genes and apoptosis in Ph- acute lymphoblastic leukemia cells.

We investigated the mechanism of action of LBH589, a novel broad-spectrum HDAC inhibitor belonging to the hydroxamate class, in Philadelphia chromosome-negative (Ph(-)) acute lymphoblastic leukemia (ALL). Two model human Ph(-) ALL cell lines (T-cell MOLT-4 and pre-B-cell Reh) were treated with LBH589 and evaluated for biologic and gene expression responses. Low nanomolar concentrations (IC(50): 5-20 nM) of LBH589 induced cell-cycle arrest, apoptosis, and histone (H3K9 and H4K8) hyperacetylation. LBH589 treatment increased mRNA levels of proapoptosis, growth arrest, and DNA damage repair genes including FANCG, FOXO3A, GADD45A, GADD45B, and GADD45G. The most dramatically expressed gene (up to 45-fold induction) observed after treatment with LBH589 is GADD45G. LBH589 treatment was associated with increased histone acetylation at the GADD45G promoter and phosphorylation of histone H2A.X. Furthermore, treatment with LBH589 was active against cultured primary Ph(-) ALL cells, including those from a relapsed patient, inducing loss of cell viability (up to 70%) and induction of GADD45G mRNA expression (up to 35-fold). Thus, LBH589 possesses potent growth inhibitory activity against including Ph(-) ALL cells associated with up-regulation of genes critical for DNA damage response and growth arrest. These findings provide a rationale for exploring the clinical activity of LBH589 in the treatment of patients with Ph(-) ALL.

Use of failure mode and effects analysis for proactive identification of communication and handoff failures from organ procurement to transplantation.

A multidisciplinary team from the University of Wisconsin Hospital and Clinics transplant program used failure mode and effects analysis to proactively examine opportunities for communication and handoff failures across the continuum of care from organ procurement to transplantation. The team performed a modified failure mode and effects analysis that isolated the multiple linked, serial, and complex information exchanges occurring during the transplantation of one solid organ. Failure mode and effects analysis proved effective for engaging a diverse group of persons who had an investment in the outcome in analysis and discussion of opportunities to improve the system's resilience for avoiding errors during a time-pressured and complex process.

Sorafenib inhibits signal transducer and activator of transcription 3 signaling associated with growth arrest and apoptosis of medulloblastomas.

Medulloblastomas are the most frequent malignant brain tumors in children. Sorafenib (Nexavar, BAY43-9006), a multikinase inhibitor, blocks cell proliferation and induces apoptosis in a variety of tumor cells. Sorafenib inhibited proliferation and induced apoptosis in two established cell lines (Daoy and D283) and a primary culture (VC312) of human medulloblastomas. In addition, sorafenib inhibited phosphorylation of signal transducer and activator of transcription 3 (STAT3) in both cell lines and primary tumor cells. The inhibition of phosphorylated STAT3 (Tyr(705)) occurs in a dose- and time-dependent manner. In contrast, AKT (protein kinase B) was only decreased in D283 and VC312 medulloblastoma cells and mitogen-activated protein kinases (extracellular signal-regulated kinase 1/2) were not inhibited by sorafenib in these cells. Both D-type cyclins (D1, D2, and D3) and E-type cyclin were down-regulated by sorafenib. Also, expression of the antiapoptotic protein Mcl-1, a member of the Bcl-2 family, was decreased and correlated with apoptosis induced by sorafenib. Finally, sorafenib suppressed the growth of human medulloblastoma cells in a mouse xenograft model. Together, our data show that sorafenib blocks STAT3 signaling as well as expression of cell cycle and apoptosis regulatory proteins, associated with inhibition of cell proliferation and induction of apoptosis in medulloblastomas. These findings provide a rationale for treatment of pediatric medulloblastomas with sorafenib.

A Phase I Study of the Combination of Rituximab and Ipilimumab in Patients with Relapsed/Refractory B-Cell Lymphoma.

PURPOSE: Based on the potential for ipilimumab (I) to augment T-cell activation, we hypothesize that ipilimumab would augment the efficacy of rituximab (R) in patients with relapsed/refractory (R/R) CD20+non-Hodgkin's lymphoma (NHL). This phase I study aimed to identify a recommended phase 2 dose, document toxicities, and preliminarily assess efficacy and potential predictive biomarkers. PATIENTS AND METHODS: Thirty-three patients with R/R CD20+B-cell lymphoma received R at 375 mg/m2weekly for 4 weeks and I at 3 mg/kg on day 1 and every 3 weeks for four doses. Responding patients went on to maintenance with each agent given every 12 weeks. To facilitate correlative analysis, the expansion phase randomized patients to simultaneous R+I versus R with I delayed 2 weeks. RESULTS: Toxicity was manageable; no dose-limiting toxicity was observed at the doses studied. When considering the entire cohort, efficacy was modest, with an objective response rate (ORR) of 24% and median progression-free survival (PFS) of 2.6 months. However, in follicular lymphoma patients, the ORR was 58% with a median PFS of 5.6 months. The randomized comparison of R with R+I demonstrated that R+I resulted in more effective B-cell depletion (BCD). Both B-cell depletion and the ratio of CD45RA-regulatory T cell (Treg) to Treg were associated with response at all time points. CONCLUSIONS: The combination of R+I has manageable toxicity and encouraging efficacy in R/R follicular lymphoma. The ratio of CD45RA-Tregs to total Tregs, and peripheral BCD should be studied further as potential predictors of response.

Adverse drug reactions in primary care: a scoping review protocol.

REVIEW QUESTION/OBJECTIVE: The objective of the scoping review is to examine the types of adverse drug reactions experienced by patients in the primary care setting and to map the classes of medications associated with adverse drug reactions.

A sequential treatment of depsipeptide followed by 5-azacytidine enhances Gadd45beta expression in hepatocellular carcinoma cells.

BACKGROUND: DNA methylation can influence histone modification and gene expression. The growth-arrest DNA damage inducible gene 45beta (Gadd45beta) has been reported as a potential diagnostic marker for aggressive hepatocellular carcinoma. In this study, the synergistic effect of the histone deacetylase inhibitor depsipeptide and the DNA methyltransferase inhibitor 5-azacytidine on the Gadd45beta gene expression in human liver cells was examined. MATERIALS AND METHODS: The effects of depsipeptide and 5-azacytidine in CL-48, HepG2 and Hep3B cells were examined by PCR, cell viability test, Western blot and chromatin immunoprecipitation assay. RESULTS: Two microM depsipeptide reactivated Gadd45beta gene expression considerably within 4 h in HepG2 cells, but not in CL-48 or Hep3B cells. Up to 10 microM 5-azacytidine had no reactivation effect on Gadd45beta. A sequential treatment of depsipeptide+5-azacytidine (but not 5-azacytidine+depsipeptide) exhibited a synergistic effect on Gadd45beta gene reactivation in the HepG2 cells. CONCLUSION: The results show for the first time that histone acetylation in sequence with hypermethylation can override transcriptional repression. Our results provide a novel insight into the epigenetics-based strategy for treating human liver cancer.