Targeting the secreted RGDKGE collagen fragment reduces PD­L1 by a proteasome­dependent mechanism and inhibits tumor growth.

Structural alterations of collagen impact signaling that helps control tumor progression and the responses to therapeutic intervention. Integrins represent a class of receptors that include members that mediate collagen signaling. However, a strategy of directly targeting integrins to control tumor growth has demonstrated limited activity in the clinical setting. New molecular understanding of integrins have revealed that these receptors can regulate both pro­ and anti­tumorigenic functions in a cell type­dependent manner. Therefore, designing strategies that block pro­tumorigenic signaling, without impeding anti­tumorigenic functions, may lead to development of more effective therapies. In the present study, evidence was provided for a novel signaling cascade in which ß3­integrin­mediated binding to a secreted RGDKGE­containing collagen fragment stimulates an autocrine­like signaling pathway that differentially governs the activity of both YAP and (protein kinase­A) PKA, ultimately leading to alterations in the levels of immune checkpoint molecule PD­L1 by a proteasome dependent mechanism. Selectively targeting this collagen fragment, reduced nuclear YAP levels, and enhanced PKA and proteasome activity, while also exhibiting significant antitumor activity in vivo. The present findings not only provided new mechanistic insight into a previously unknown autocrine­like signaling pathway that may provide tumor cells with the ability to regulate PD­L1, but our findings may also help in the development of more effective strategies to control pro­tumorigenic ß3­integrin signaling without disrupting its tumor suppressive functions in other cellular compartments.

National Recommendations against Prostate Specific Antigen Screening versus Statewide Medicaid Expansion Initiatives: A Battle of the Titans.

PURPOSE: Medicaid expansion under the Patient Protection and Affordable Care Act occurred almost concurrently with 2012 U.S. Preventive Services Task Force recommendations against prostate specific antigen screening. Here the relative influence on prostate specific antigen screening rates by 2 concurrent and opposing system-level policy initiatives is investigated: improved access to care and change in clinical practice guidelines. MATERIALS AND METHODS: Behavioral Risk Factor Surveillance System data from years 2012 to 2018 were analyzed for trends in self-reported prostate specific antigen screening and insurance coverage. Subanalyses included state Medicaid expansion status and respondent federal poverty level. Multivariable logistic regression was performed to evaluate factors associated with prostate specific antigen screening. RESULTS: From 2012 to 2018 prostate specific antigen screening predominantly declined with a notable exception of an increase of 7.3% for men at <138% federal poverty level between 2011 and 2013 in early expansion states. Initial increases did not continue, and screening trends mirrored those of nonexpansion states by 2018. Notably, 2014 planned expansions states did not follow this trend with minimal change between 2015 and 2017 compared to declines in early expansion states and nonexpansion states (-0.4% vs -6.7% and -8.6%, respectively). CONCLUSIONS: Medicaid expansion was associated with increased rates of insured men at <138% federal poverty level from 2012 to 2018 in early expansion states. In this group, initial increases in prostate specific antigen screening were not durable and followed the trend of reduced screening seen across the United States. In planned expansions states the global drop in prostate specific antigen screening from 2016 to 2018 was offset in men at <138% federal poverty level by expanding access to care. Nonexpansion states showed a steady decline in prostate specific antigen screening rates. This suggests that policy such as U.S. Preventive Services Task Force recommendations against screening competes with and often outmatches access to care.

Challenges of HIV Lymphoma Clinical Trials in Africa: Lessons From the AIDS Malignancy Consortium 068 Study.

The purpose of this article is to describe lessons from the first lymphoma clinical trial conducted by the AIDS Malignancy Consortium (AMC) in sub-Saharan Africa (SSA). AMC-068 was a randomized phase II comparison of intravenous versus oral chemotherapy for HIV-positive diffuse large B-cell lymphoma. Opening in 2016, AMC-068 planned to enroll 90 patients (45 per arm) in Kenya, Malawi, Uganda, and Zimbabwe over 24 months and follow patients for 24 months to assess overall survival. In 2018, the study closed after screening 42 patients but enrolling only 7. Challenges occurred during protocol development, pre-activation, and postactivation. During protocol development (2011-2012), major obstacles were limited baseline data to inform study design; lack of consensus among investigators and approving bodies regarding appropriateness of the oral regimen and need for randomized comparison with cyclophosphamide, doxorubicin, vincristine, and prednisone; and heterogeneity across sites in local standards for diagnosis, staging, and treatment. During pre-activation (2012-2016), challenges included unexpected length and layers of regulatory approval across multiple countries, need to upgrade pathology capacity at sites, need to augment existing chemotherapy infusion capacity at sites, and procurement issues for drugs and supplies. Finally, during postactivation (2016-2018), challenges included long delays between symptom onset and screening entry for many patients, leading to compromised performance status and organ function; other patient characteristics that frequently led to exclusion, including high tumor proliferative index or other pathologic features that were disallowed; and costs of routine diagnostic procedures often being borne by patients, which also contributed to pre-enrollment delays. Lessons from AMC-068 are being applied to the design and conduct of new AMC lymphoma trials in SSA, and the study has contributed to a strong operational foundation that will support innovative clinical trials in the future.

Disability-Adjusted Life-Years Due to Stroke in Kenya.

BACKGROUND: There is little information on stroke morbidity in Kenya to inform health care planning. The disability-adjusted life-years (DALYs) are a time-based measure of health status that incorporates both disability and mortality. METHODS: This was a multicenter prospective study in Kenya's public tertiary hospitals conducted in 2015-2017. Data on sex, age, and global disability outcome were collected and used to calculate the sum of years of life lost prematurely due to stroke (YLL), the years of healthy life lost due to disability (YLD), and the DALYs. RESULTS: Up to 719 adult stroke patients participated in the study. The peak age group for stroke was 60-64 years, with ischemic stroke accounting for 56.1% of the stroke cases. After 1-year follow-up, the YLD were 2,402.50, YLL were 5,335.99, and the DALYs were 7,738.49. YLD contributed 31% of the total DALYs. The DALYs varied by sex (male: 2,835.79; female: 4,902.70 years) and by stroke type (ischemic stroke: 4,652.98; hemorrhagic stroke: 3,085.51). The young age group (< 45 years) bore a greater burden accounting for 35.6% of the total DALYs. CONCLUSION: The YLD, YLL, and DALYs observed reinforce the need for targeted prevention of risk factors and comprehensive stroke care initiatives in Kenya.

Prostate cancer navigation: initial experience and association with time to care.

OBJECTIVE: To evaluate factors associated with use of patient navigation in a prostate cancer population and identify whether navigation is associated with prolonged time to care. Cancer patient navigation has been shown to improve access to cancer screening, diagnosis, and treatment, but little is known about patient navigation in prostate cancer care. METHODS: All men diagnosed with localized prostate cancer between 2009 and 2015 were abstracted from the MaineHealth multi-specialty tumor registry. Regression analyses controlling for patient-, disease-, and system-level factors evaluated characteristics associated with navigation utilization. The association between navigation utilization, barriers to care, and longer time to treatment was assessed with Cox proportional hazards regression. RESULTS: Of the patient population (n = 1587), 85% of men were navigated. Navigation use was associated with earlier year of diagnosis, treatment by a high-volume urologist, and lower risk disease (p < 0.05). Treatment delay was associated with low-risk disease (vs: intermediate OR 0.62, 95% CI 0.46-0.85 and high OR 0.16, 95% CI 0.1-0.25) and receipt of navigation services (OR 1.65, 95% CI 1.12-2.45) but not distance to care, insurance, or treatment choice. CONCLUSIONS: We observed that patients with low-risk prostate cancer were more likely to utilize navigation, but traditional barriers to care were not associated with utilization. Navigation was associated with longer time to treatment, which likely reflects clinically appropriate delays associated with greater shared decision making. Time to treatment may not be the ideal metric for evaluating navigation in prostate cancer; shared decision making, patient satisfaction, and psychosocial outcomes may be more appropriate.

Stroke distribution patterns and characteristics in Kenya's leading public health tertiary institutions: Kenyatta National Hospital and Moi Teaching and Referral Hospital.

BACKGROUND: Cardiovascular diseases are the second leading cause of morbidity and mortality in Kenya. However, there is limited clinic-epidemiological data on stroke to inform decision making. This study sought to establish stroke distribution patterns and characteristics in patients seeking care at Kenyatta National Hospital (KNH) and Moi Teaching and Referral Hospital (MTRH), with the ultimate aim of establishing the first national stroke registry in Kenya. METHODS: This was a prospective multicentre cohort study among stroke patients. The study used a modified World Health Organisation STEP-wise approach to stroke surveillance tool in collecting data on incidence, major risk factors and mortality rate. The Cochran's Mantel-Haenszel chisquared test of conditional independence was used with p-value set at 0.05. RESULTS: A total of 691 patients with confirmed stroke were recruited [KNH 406 (males: 40.9%; females: 59.1%); MTRH 285 (males: 44.6%; females: 55.4%) ] and followed over a 12-month period. Overall, ischaemic stroke accounted for 55.6% of the stroke cases, with women being the most affected (57.5%). Mortality rate at day 10 was 18.0% at KNH and 15.5% at MTRH, and higher in the haemorrhagic cases (20.3%). The most common vascular risk factors were hypertension at 77.3% (males: 75.7%; females: 78.5%), smoking at 16.1% (males: 26.6% females: 8.3%) and diabetes at 14.9% (males: 15.7%; females: 14.4%). Ischaemic stroke was conditionally independent of gender after adjusting for age. CONCLUSION: To our knowledge this is the first pilot demonstration establishing a stroke registry in sub-Saharan Africa and clearly establishes feasibility for this approach. It also has utility to both inform and potentially guide public policy and public health measures on stroke in Kenya. Important and unexpected observations included the preponderance of women affected by cerebrovascular disease and that cigarette smoking was the second most common risk factor. The latter, over time, will further impact on the clinico-epidemiological profile of cerebrovascular disease in Kenya.

Definitive Upfront Stereotactic Ablative Radiotherapy Combined with Image-Guided, Intensity Modulated Radiotherapy (IG-IMRT) or IG-IMRT Alone for Locally Advanced Non-Small Cell Lung Cancer.

BACKGROUND: Image-guided (IG) intensity-modulated radiotherapy (IMRT) enables maximal tumor margin reduction for the sparing of organs at risk (OARs) when used to treat locally advanced non-small cell lung cancer (NSCLC) with definitive chemo-radiation. It also allows for the incorporation of stereotactic ablative radiotherapy (SABR) into the treatment regimen. Here, we describe our initial experience in combining definitive upfront SABR to the primary lesion with chemo-radiation delivered with conventionally fractionated IG-IMRT to the remaining regional disease; along with clinical outcome following chemo-radiation with conventionally fractionated IG-IMRT alone in the treatment of locally advanced NSCLC. METHODS: The clinical outcome of 29 patients with locally advanced NSCLC who underwent conventionally fractionated IG-IMRT, or definitive upfront SABR followed by IG-IMRT combined with chemotherapy (induction, concurrent, or both) was retrospectively reviewed. RESULTS: After a median follow up of 23.7 months, the median overall survival (OS) and progression-free survival (PFS) were 19.8 and 11.3 months, respectively. The 2 year local, regional, and distant control was 60%, 62%, and 38%, respectively. No local failure was observed in 3 patients following SABR + IG-IMRT while 6/26 patients failed locally following IG-IMRT alone. SABR + IG-IMRT was well tolerated. No ≥ grade 3 radiation-related toxicity was observed. CONCLUSION: Definitive upfront SABR followed by IG-IMRT in selected patients with locally advanced NSCLC warrants further investigation in future clinical trials, while chemo-radiation with IG-IMRT alone was well tolerated.

MLLT11/AF1q boosts oncogenic STAT3 activity through Src-PDGFR tyrosine kinase signaling.

Constitutive STAT3 activation by tyrosine phosphorylation of mutated or amplified tyrosine kinases (pYSTAT3) is critical for cancer initiation, progression, invasion, and motility of carcinoma cells. We showed that AF1q is associated with STAT3 signaling in breast cancer cells. In xenograft models, enhanced AF1q expression activated STAT3 and promoted tumor growth and metastasis in immunodeficient NSG mice. The cytokine secretory phenotype of MDA-MB-231LN breast cancer cells with altered AF1q expression revealed changes in expression of platelet-derived growth factor subunit B (PDGF-B). AF1q-induced PDGF-B stimulated motility, migration, and invasion of MDA-MB-231LN cells, and AF1q up-regulated platelet-derived growth factor receptor (PDGFR) signaling. Further, AF1q-induced PDGFR signaling enhanced STAT3 activity through Src kinase activation, which could be blocked by the Src kinase inhibitor PP1. Moreover, AF1q up-regulated tyrosine kinase signaling through PDGFR signaling, which was blockable by imatinib. In conclusion, we demonstrated that enhanced AF1q expression contributes to persistent and oncogenic pYSTAT3 levels in invasive carcinoma cells by activating Src kinase through activation of the PDGF-B/PDGFR cascade. Therefore, AF1q plays an essential role as a cofactor in PDGF-B-driven STAT3 signaling.

Factors influencing survival among Kenyan children diagnosed with endemic Burkitt lymphoma between 2003 and 2011: A historical cohort study.

Discovering how to improve survival and establishing clinical reference points for children diagnosed with endemic Burkitt lymphoma (eBL) in resource-constrained settings has recaptured international attention. Using multivariate analyses, we evaluated 428 children with eBL in Kenya for age, gender, tumor stage, nutritional status, hemoglobin, lactate dehydrogenase (LDH), Epstein-Barr virus (EBV) and Plasmodium falciparum prior to induction of chemotherapy (cyclophosphamide, vincristine, methotrexate and doxorubicin) to identify predictive and prognostic biomarkers of survival. During this 10 year prospective study period, 22% died in-hospital and 78% completed six-courses of chemotherapy. Of those, 16% relapsed or died later; 31% achieved event-free-survival; and 31% were lost to follow-up; the overall one-year survival was 45%. After adjusting for covariates, low hemoglobin (<8 g/dL) and high LDH (>400 mU/ml) were associated with increased risk of death (adjusted Hazard Ratio (aHR) = 1.57 [0.97-2.41]) and aHR = 1.84, [0.91-3.69], respectively). Anemic children with malaria were 3.55 times more likely to die [1.10-11.44] compared to patients without anemia or malarial infection. EBV load did not differ by tumor stage nor was it associated with survival. System-level factors can also contribute to poor outcomes. Children were more likely to die when inadvertently overdosed by more than 115% of the correct dose of cyclophosphamide (a HR = 1.43 [0.84-2.43]) or doxorubicin (a HR = 1.25, [0.66-2.35]), compared with those receiving accurate doses of the respective agent in this setting. This study codifies risk factors associated with poor outcomes for eBL patients in Africa and provides a benchmark by which to assess improvements in survival for new chemotherapeutic approaches.

Cancer treatment-related cardiotoxicity: current state of knowledge and future research priorities.

Cardiotoxicity resulting from direct myocyte damage has been a known complication of cancer treatment for decades. More recently, the emergence of hypertension as a clinically significant side effect of several new agents has been recognized as adversely affecting cancer treatment outcomes. With cancer patients living longer, in part because of treatment advances, these adverse events have become increasingly important to address. However, little is known about the cardiovascular pathogenic mechanisms associated with cancer treatment and even less about how to optimally prevent and manage short- and long-term cardiovascular complications, leading to improved patient safety and clinical outcomes. To identify research priorities, allocate resources, and establish infrastructure required to address cardiotoxicity associated with cancer treatment, the National Cancer Institute (NCI) and National Heart, Lung and Blood Institute (NHLBI) sponsored a two-day workshop, "Cancer treatment-related cardiotoxicity: Understanding the current state of knowledge and future research priorities," in March 2013 in Bethesda, MD. Participants included leading oncology and cardiology researchers and health professionals, patient advocates and industry representatives, with expertise ranging from basic to clinical science. Attendees were charged with identifying research opportunities to advance the understanding of cancer treatment-related cardiotoxicity across basic and clinical science. This commentary highlights the key discussion points and overarching recommendations from that workshop.

Strategies of dose escalation in the treatment of locally advanced non-small cell lung cancer: image guidance and beyond.

Radiation dose in the setting of chemo-radiation for locally advanced non-small cell lung cancer (NSCLC) has been historically limited by the risk of normal tissue toxicity and this has been hypothesized to correlate with the poor results in regard to local tumor recurrences. Dose escalation, as a means to improve local control, with concurrent chemotherapy has been shown to be feasible with three-dimensional conformal radiotherapy in early phase studies with good clinical outcome. However, the potential superiority of moderate dose escalation to 74 Gy has not been shown in phase III randomized studies. In this review, the limitations in target volume definition in previous studies; and the factors that may be critical to safe dose escalation in the treatment of locally advanced NSCLC, such as respiratory motion management, image guidance, intensity modulation, FDG-positron emission tomography incorporation in the treatment planning process, and adaptive radiotherapy, are discussed. These factors, along with novel treatment approaches that have emerged in recent years, are proposed to warrant further investigation in future trials in a more comprehensive and integrated fashion.

Developing clinical strength-of-evidence approach to define HIV-associated malignancies for cancer registration in Kenya.

BACKGROUND: Sub-Saharan Africa cancer registries are beset by an increasing cancer burden further exacerbated by the AIDS epidemic where there are limited capabilities for cancer-AIDS match co-registration. We undertook a pilot study based on a "strength-of-evidence" approach using clinical data that is abstracted at the time of cancer registration for purposes of linking cancer diagnosis to AIDS diagnosis. METHODS/FINDINGS: The standard Nairobi Cancer Registry form was modified for registrars to abstract the following clinical data from medical records regarding HIV infection/AIDS in a hierarchal approach at time of cancer registration from highest-to-lowest strength-of-evidence: 1) documentation of positive HIV serology; 2) antiretroviral drug prescription; 3) CD4+ lymphocyte count; and 4) WHO HIV clinical stage or immune suppression syndrome (ISS), which is Kenyan terminology for AIDS. Between August 1 and October 31, 2011 a total of 1,200 cancer cases were registered. Of these, 171 cases (14.3%) met clinical strength-of-evidence criteria for association with HIV infection/AIDS; 69% (118 cases were tumor types with known HIV association - Kaposi's sarcoma, cervical cancer, non-Hodgkin's and Hodgkin's lymphoma, and conjunctiva carcinoma) and 31% (53) were consistent with non-AIDS defining cancers. Verifiable positive HIV serology was identified in 47 (27%) cases for an absolute seroprevalence rate of 4% among the cancer registered cases with an upper boundary of 14% among those meeting at least one of strength-of-evidence criteria. CONCLUSIONS/SIGNIFICANCE: This pilot demonstration of a hierarchal, clinical strength-of-evidence approach for cancer-AIDS registration in Kenya establishes feasibility, is readily adaptable, pragmatic, and does not require additional resources for critically under staffed cancer registries. Cancer is an emerging public health challenge, and African nations need to develop well designed population-based studies in order to better define the impact and spectrum of malignant disease in the backdrop of HIV infection.

Dicycloplatin, a novel platinum analog in chemotherapy: synthesis of chinese pre-clinical and clinical profile and emerging mechanistic studies.

Dicycloplatin (DCP) has better solubility and stability than both cisplatin and carboplatin. Pre-clinical and phase I studies demonstrated significant antitumor activity and fewer adverse events than carboplatin. Phase II clinical trials in advanced non-small cell lung cancer found efficacy and safety of DCP-plus-paclitaxel comparable to carboplatin-plus-paclitaxel but better tolerability. This article summarizes and reviews pre-clinical and clinical data for dicycloplatin from the Chinese medical literature. We also report on new mechanistic findings in our laboratory in West Virginia, USA. Patient blood samples were collected for DCP-prototype determination by liquid chromatography mass spectrometry (LC-MS/MS). Molecular studies of ovarian cancer cells treated with DCP or cisplatin were carried out for gene-signature profiling using immunoblotting. Pharmacokinetic mass-spectrometry showed different spectrum profiles of DCP and carboplatin in plasma. Plasma concentration of DCP prototype was 17.1 µg/ml 2h after administration, with a peak concentration of 26.9 µg/ml at 0.5 h. Immunoblotting showed DCP-induced activation of DNA damage pathways, including double-phosphorylated checkpoint kinase 2 (CHK2) and breast cancer 1 (BRCA1) and triple-phosphorylated p53, compared to controls. Cisplatin produced a similar profile, with increased p53 protein. DCP and cisplatin activate DNA-damage response through similar pathways. DCP may be more soluble and stable, and better-tolerated.

Breaking and entering into the CNS: clues from solid tumor and nonmalignant models with relevance to hematopoietic malignancies.

Various malignancies invade the CNS sanctuary site, accounting for the vast majority of CNS neoplastic foci and contributing to significant morbidity as well as mortality. The blood-brain barrier (BBB) exhibits considerable impermeability to chemotherapeutic agents, severely limiting therapeutic options available for patients developing metastatic CNS involvement, accounting for poor outcomes. The mechanisms by which malignant cells breach the highly exclusive BBB and subsequently survive in this unique anatomical site remain poorly understood, with most of the current knowledge stemming from nonmalignant and solid malignancy models. While solid and hematologic malignancies may face different challenges once within the CNS (e.g., solid tumor parenchymal metastasis compared to masses/nodules/leptomeningeal disease in hematologic malignancies), commonality exists in the process of migrating across the BBB from the circulation. Specifically considering this last point, this review aims to survey the current mechanistic knowledge regarding malignant migration across the BBB, necessarily emphasizing the better studied solid tumor and nonmalignant models with the intention of highlighting both the current knowledge gap and additional work required to effectively consider how hematopoietic malignancies breach the CNS.

Sorafenib and thyroid cancer.

The emergence of serine-threonine small molecule, multi-targeted kinase inhibitors over the past decade is greatly impacting the therapeutic armamentarium for numerous malignancies, especially thyroid carcinoma. Chief among them are a class of agents referred to as vascular endothelial growth factor signal pathway inhibitors. Sorafenib is a lead compound that has been recently approved by the US FDA for radioactive iodine-refractory differentiated thyroid cancer (DTC). Sorafenib clearly is altering the natural history of DTC. In the largest randomized Phase III study ever conducted in DTC, sorafenib significantly improved progression-free survival compared to placebo (10.8 vs 5.8 months) and had an acceptable and manageable safety profile, though commonly attributed side effects of hand-foot skin reaction, diarrhea and hypertension were more frequent than in other settings. This agent represents a new treatment option for patients with progressive radioactive iodine-refractory DTC.

Randomized safety and efficacy study of fosbretabulin with paclitaxel/carboplatin against anaplastic thyroid carcinoma.

BACKGROUND: Anaplastic thyroid cancer (ATC), a rare highly vascularized tumor, has a dismal outcome. We conducted an open-label study of doublet carboplatin/paclitaxel chemotherapy with or without fosbretabulin in patients with ATC. METHODS: Patients were randomly assigned in a 2:1 ratio to 6 cycles of paclitaxel 200 mg/m(2) followed by carboplatin AUC 6 on day 1 every 3 weeks (CP), or these drugs were given on day 2 after fosbretabulin 60 mg/m(2) (CP/fosbretabulin) on days 1, 8 and 15. After 6 cycles, patients on the fosbretabulin arm without progression could continue to receive fosbretabulin on days 1 and 8 of a 3-week schedule until progression. The primary end point was overall survival (OS). RESULTS: Eighty patients were assigned (planned, 180) when enrollment was stopped due to rarity of disease and very low accrual. Median OS was 5.2 months [95% confidence interval (CI) 3.1, 9.0] for the CP/fosbretabulin arm (n=55; hazard ratio 0.73 [95% CI 0.44, 1.21]) and 4.0 months [95% CI 2.8, 6.2] for the CP arm (n=25; p=0.22 [log rank test]). One-year survival for CP/fosbretabulin versus CP was 26% versus 9%, respectively. There was no significant difference in progression-free survival between the two arms. Grade 1-2 hypertension and grade 3-4 neutropenia were more common with CP/fosbretabulin. There were no significant adverse cardiovascular side effects. CONCLUSIONS: Although the study did not meet statistical significance in improvement in OS with the addition of fosbretabulin to carboplatin/paclitaxel, it represents the largest prospective randomized trial ever conducted in ATC. The regimen is well tolerated, with AEs and deaths primarily related to ATC and disease progression.

Sibling donor and recipient immune modulation with atorvastatin for the prophylaxis of acute graft-versus-host disease.

PURPOSE: Graft-versus-host disease (GVHD) is major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Atorvastatin is a potent immunomodulatory agent that holds promise as a novel and safe agent for acute GVHD prophylaxis. PATIENTS AND METHODS: We conducted a phase II trial to evaluate the safety and efficacy of atorvastatin administration for GVHD prophylaxis in both adult donors and recipients of matched sibling allogeneic HCT. Atorvastatin (40 mg per day orally) was administered to sibling donors, starting 14 to 28 days before the anticipated first day of stem-cell collection. In HCT recipients (n = 30), GVHD prophylaxis consisted of tacrolimus, short-course methotrexate, and atorvastatin (40 mg per day orally). RESULTS: Atorvastatin administration in healthy donors and recipients was not associated with any grade 3 to 4 adverse events. Cumulative incidence rates of grade 2 to 4 acute GVHD at days +100 and +180 were 3.3% (95% CI, 0.2% to 14.8%) and 11.1% (95% CI, 2.7% to 26.4%), respectively. One-year cumulative incidence of chronic GVHD was 52.3% (95% CI, 27.6% to 72.1%). Viral and fungal infections were infrequent. One-year cumulative incidences of nonrelapse mortality and relapse were 9.8% (95% CI, 1.4% to 28%) and 25.4% (95% CI, 10.9% to 42.9%), respectively. One-year overall survival and progression-free survival were 74% (95% CI, 58% to 96%) and 65% (95% CI, 48% to 87%), respectively. Compared with baseline, atorvastatin administration in sibling donors was associated with a trend toward increased mean plasma interleukin-10 concentrations (5.6 v 7.1 pg/mL; P = .06). CONCLUSION: A novel two-pronged strategy of atorvastatin administration in both donors and recipients of matched sibling allogeneic HCT seems to be a feasible, safe, and potentially effective strategy to prevent acute GVHD.

Treatment factors affecting outcomes in HIV-associated non-Hodgkin lymphomas: a pooled analysis of 1546 patients.

Limited comparative data exist for the treatment of HIV-associated non-Hodgkin lymphoma. We analyzed pooled individual patient data for 1546 patients from 19 prospective clinical trials to assess treatment-specific factors (type of chemotherapy, rituximab, and concurrent combination antiretroviral [cART] use) and their influence on the outcomes complete response (CR), progression free survival (PFS), and overall survival (OS). In our analysis, rituximab was associated with a higher CR rate (odds ratio [OR] 2.89; P < .001), improved PFS (hazard ratio [HR] 0.50; P < .001), and OS (HR 0.51; P < .0001). Compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), initial therapy with more dose-intense regimens resulted in better CR rates (ACVBP [doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisolone]: OR 1.70; P < .04), PFS (ACVBP: HR 0.72; P = .049; "intensive regimens": HR 0.35; P < .001) and OS ("intensive regimens": HR 0.54; P < .001). Infusional etoposide, prednisone, infusional vincristine, infusional doxorubicin, and cyclophosphamide (EPOCH) was associated with significantly better OS in diffuse large B-cell lymphoma (HR 0.33; P = .03). Concurrent use of cART was associated with improved CR rates (OR 1.89; P = .005) and trended toward improved OS (HR 0.78; P = .07). These findings provide supporting evidence for current patterns of care where definitive evidence is unavailable.

Phase II trial of sorafenib in patients with advanced anaplastic carcinoma of the thyroid.

BACKGROUND: Anaplastic thyroid cancer (ATC) is a rare but highly aggressive malignancy with a median survival of 3-5 months. The BRAF oncogene is mutated to its active form in up to 24% of ATC cases. Sorafenib is a tyrosine kinase inhibitor that acts on the RAF-1 serine/threonine kinase. In preclinical mouse models, sorafenib inhibits the growth of ATC xenografts and improves survival. No study of sorafenib in ATC has been conducted. We conducted a multi-institutional phase II trial of sorafenib in patients with ATC who had failed up to two previous therapies. METHODS: The primary endpoint of the trial was the Response Evaluation Criteria In Solid Tumors (RECIST)-defined imaging response rate. Twenty patients with ATC were treated with sorafenib 400 mg twice daily. RESULTS: Two of the 20 patients had a partial response (10%) and an additional 5 of 20 (25%) had stable disease. The duration of response in the two responders was 10 and 27 months, respectively. For the patients with stable disease, the median duration was 4 months (range 3-11 months). The overall median progression-free survival was 1.9 months with a median and a 1-year survival of 3.9 months and 20%, respectively. Toxicity was manageable and as previously described for sorafenib, including hypertension and skin rash. CONCLUSION: Sorafenib has activity in ATC, but at a low frequency and similar to our previous experience with fosbretabulin. One patient with a response had previously progressed on fosbretabulin. Toxicities were both predictable and manageable.