Search

Purpose: It is a critical challenge to determine the risk of recurrence in early stage non–small cell lung cancer (NSCLC) patients. Accurate gene expression signatures are needed to classify patients into high- and low-risk groups to improve the selection of patients for adjuvant therapy.Experimental Design: Multiple published microarray data sets were used to evaluate our previously identified lung cancer prognostic gene signature. Expression of the signature genes was further validated with real-time reverse transcription-PCR and Western blot assays of snap-frozen lung cancer tumor tissues.Results: Our previously identified 35-gene signature stratified 264 patients with NSCLC into high- and low-risk groups with distinct overall survival rates (P < 0.05, Kaplan-Meier analysis, log-rank tests). The 35-gene signature further stratified patients with clinical stage 1A diseases into poor prognostic and good prognostic subgroups (P = 0.0007, Kaplan-Meier analysis, log-rank tests). This signature is independent of other prognostic factors for NSCLC, including age, sex, tumor differentiation, tumor grade, and tumor stage. The expression of the signature genes was validated with real-time reverse transcription-PCR analysis of lung cancer tumor specimens. Protein expression of two signature genes, TAL2 and ILF3, was confirmed in lung adenocarcinoma tumors by using Western blot analysis. These two biomarkers showed correlated mRNA and protein overexpression in lung cancer development and progression.Conclusions: The results indicate that the identified 35-gene signature is an accurate predictor of survival in NSCLC. It provides independent prognostic information in addition to traditional clinicopathologic criteria.

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 ...

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.

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.

Background: Despite the increasing global burden of stroke, there are limited data on stroke from Kenya to guide in decision-making. Stroke occurrence in sub-Saharan Africa has been associated with poor health outcomes. This study sought to establish the stroke incidence density and mortality in Kenya’s leading public tertiary hospitals for purposes of informing clinical practice and policy. Methods: This is a prospective study conducted at Kenya’s leading referral hospitals, namely, Kenyatta National Hospital (KNH) and Moi Teaching and Referral Hospital (MTRH). Adult patients with confirmed cases of stroke were recruited from February 2015 to January 2016 and followed up for a minimum period of 1 year. The WHO 2006 Stroke STEPS instrument was used to collect data on incidence and mortality at days 10 and 28 and every 3 months for 24 months. The person-time of follow-up was computed from admission to death, loss to follow-up, or the end of the study. A survival regression analysis was done using the Cox proportional hazards model. Results: A total of 719 patients were recruited (KNH: n = 406 [56.5%]; MTRH: n = 313 [43.5%]). The mean age was 58.6 ± 18.7 years, and the male-to-female ratio was 1: 1.4. Ischemic stroke accounted for 56.1% of the stroke cases. The peak age for stroke was between 50 and 69 years, when 36.3% of the cases occurred. Mortality at day 10 and day 28 was 18.4 and 26.7%, respectively. The inpatient mortality rate was 21.6%. The stroke incidence density was 507 deaths per 1,000 person-years of follow-up. The mean survival time was significantly different between inpatients (13.9 months; 95% CI: 13.0–14.7) and outpatients (18.6 months; 95% CI: 17.2–19.9) (p < 0.001). A 1-year increase in age increased the hazard by 1.8%. Inpatients had a 3.9-fold increase in hazard compared to outpatients. Conclusions: Mortality due to stroke is high, with poor survival observed in the first year after stroke. The risk of death increases with increasing age and duration of hospital stay. There is need for attention to quality of care and long-term needs of stroke patients to mitigate the high mortality rates observed. Public health initiatives aimed at early screening and diagnosis should be enhanced. Further research is recommended to establish the true burden of stroke at the community level to inform appropriate mitigation measures.

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.

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 ( 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.

Background No consensus on how to best predict for chest wall injury following SABR exists. We report our experience in chest wall dose assessment when treating peri-pleural lung lesions with stereotactic ablative radiotherapy (SABR) delivered with volumetric modulated arc therapy (VMAT). Methods 40 patients with peri-pleural peripheral lung tumors underwent SABR between July, 2012 and February, 2015. Chest wall toxicity, dose distribution, and the influence of chest wall delineation method were investigated. Results After a median follow up of 16 months, no rib fracture or skin toxicity was observed. 4 patients (10%) reported persistent chest wall pain (grade 1–2). High dose rate's association with chest wall pain trended toward statistical significance ( p =0.06). PTV exclusion and reducing chest wall expansion to 1 cm led to significant dose reduction in the chest wall dose volume parameters ( p Conclusions The risk of chest wall pain following SABR delivered with VMAT is low. High dose rate, which is 1400 MU/min with flattening filter free (FFF) beams vs. 500–600 MU/min with non-flattening filter free (non-FFF) beams, may contribute to it. Chest wall dose volume parameters may vary with PTV exclusion; while chest wall expansion of 1 cm may fail to account for some high dose regions in the chest wall.

164 Background: Chemotherapy and surgery can cause distressing symptoms, which can be a burden for health systems to address. Programs that directly engage patients, including electronic tracking of patient-reported outcomes (ePROs), can improve symptom control and decrease the need for acute care. Previous ePRO programs have relied on third party vendors with limited EHR integration, constraining their clinical utility and scalability. An integrated solution could offer distinct advantages. Methods: As part of NCI’s Moonshot-funded IMPACT consortium, 6 health systems and Epic built an electronic symptom management program (eSyM) based on the PRO-CTCAE questionnaire that is fully integrated into the EHR. The agile, user-centered design process engaged patients, clinicians, and institutions. The core functional components include: 1) symptom surveys in the postoperative period or between chemotherapy visits, 2) self-management tip sheets, 3) clinician alerts, and 4) dashboards for population management. Critical points of integration with supporting EHR functions and workflow impacts were identified; and major challenges of integration and implementation were described. Results: eSyM, which was implemented at two health systems (Baptist Memorial in Tennessee and Mississippi and West Virginia University Health) in the fall of 2019, required multiple supporting EHR functions: 1) access a secure, HIPPA-compliant patient portal/messaging system (MyChart); 2) record diagnosis, procedure and chemotherapy treatment plan data; 3) identify target populations and track metrics/events; 4) define and execute autonomous logic-based workflow rules; 5) generate reports for clinicians/patients; and 6) documentation. Major challenges included: 1) working within pre-existing EHR system standards and capabilities, which limited the ability to customize interfaces and workflows specifically for the eSyM use case; and 2) adapting to different EHR configurations and polices across multiple health systems. Conclusions: The eSyM build leveraged many existing EHR capabilities and overcame regulatory hurdles; but it required design and workflow compromise. Integration of ePRO-based symptom management programs into the EHR could help overcome barriers, consolidate clinical workflows, and foster scalability/sustainability. Ongoing efforts include launching eSyM at four more sites and evaluating its adoption, usability, and impact on clinical outcomes.

2064 Background: A standardized, validated tool for capturing symptoms from cancer patients, PRO-CTCAE, has been used to reduce symptom burden, decrease acute care needs, and preserve quality of life. The association between specific PRO-CTCAE symptom scores and single item measures of OWb and PFn were characterized to understand symptom constellations. Methods: A novel Epic-based symptom management program (eSyM) was deployed for GI, GYN, and thoracic cancer patients starting chemotherapy (Memphis Baptist) or having surgery (WVU Medicine). Patients received automated prompts to complete surveys via the patient portal (MyChart) on a fixed schedule, approximately twice/week. Each survey included one OWb item, one PFn item, and at least 6 PRO-CTCAE items (pain, nausea, vomiting, fatigue, anxiety, insomnia). The OWb and PFn items, which were created de novo, included 5 ordinal response options with corresponding pictograms (emojis from very happy to very sad for OWb; a figure walking to one prone in bed for PFn). Composite scores were generated: 0 for no symptoms, 1-2 for mild/moderate symptoms, and 3 for severe symptoms. We describe OWb and PFn and analyze associations between these items and PRO-CTCAE symptom scores. Results: Between 9/10/19-1/22/20, we collected 908 eSyM responses from 166 chemotherapy patients at Baptist (Age, M = 65), and 480 eSyM responses from 97 postoperative patients at WVU (Age, M = 57). The OWb and PFn scores demonstrated moderate correlation with PRO-CTCAE symptom scores (Baptist r = 0.63; WVU r = 0.75), and moderate correlation with mean symptom scores among surgery patients at WVU (r = 0.74); but lower correlation among chemotherapy patients at Baptist (r = 0.53-0.55). Scores improved over time following surgery, but not after initiation of chemotherapy. Among the 730 eSyM responses with none/mild values for both OWb and PFn (52.9% of all responses), only 4.5% reported any severe symptom; among 651 responses with impairment of OWb and/or PFn, 45.2% reported at least one severe symptom. Conclusions: Integration of eSyM into the Epic EHR enabled tracking of OWb, PFn, and PRO-CTCAE items. When asked alongside PRO-CTCAE symptom items, two single item OWb and PFn measures provided distinct information and correlated with symptom burden. These results demonstrate the feasibility of integrating ePRO collection into routine post-operative and medical oncology care and that PRO-CTCAE items provide information that is distinct from that obtained from global metrics of well-being. Clinical trial information: NCT03850912.

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. 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. 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

// Jino Park 1 , Michaela Schlederer 2,12 , Martin Schreiber 3 , Ryan Ice 4,5 , Olaf Merkel 6 , Martin Bilban 7 , Sebastian Hofbauer 3 , Soojin Kim 1 , Joseph Addison 4,5 , Jie Zou 8 , Chunyan Ji 8 , Silvia T. Bunting 9 , Zhengqi Wang 9 , Menachem Shoham 10 , Gang Huang 11 , Zsuzsanna Bago-Horvath 12 , Laura F. Gibson 4 , Yon Rojanasakul 4,13 , Scot Remick 4 , Alexey Ivanov 4,5 , Elena Pugacheva 4,5 , Kevin D. Bunting 9 , Richard Moriggl 2,14 , Lukas Kenner 2,12,15,* and William Tse 1,* 1 James Graham Brown Cancer Center, Division of Blood and Bone Marrow Transplantation, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA 2 Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria 3 Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria 4 Mary Babb Randolph Cancer Center, West Virginia University Health Science Center, Morgantown, WV, USA 5 Department of Biochemistry, West Virginia University School of Medicine, Morgantown, WV, USA 6 National Center for Tumor Diseases, German Cancer Research Center, Heidelberg, Germany 7 Department of Laboratory Medicine, Medical University of Vienna and Core Facility Genomics, Core Facilities, Medical University of Vienna, Vienna, Austria 8 Department of Hematology, Qilu Hospital, Shandong University School of Medicine, Jinan, Shandong, PR China 9 Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA, USA 10 Case Western University School of Medicine, Cleveland, OH, USA 11 Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA 12 Clinical Institute for Pathology, Medical University Vienna, Austria 13 Department of Pharmaceutical Science, West Virginia University School of Medicine, Morgantown, WV, USA 14 Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Medical University of Vienna, Vienna, Austria 15 Unit of Pathology of Laboratory Animals (UPLA), University of Veterinary Medicine, Vienna, Austria * These authors have contributed equally to this work Correspondence to: Lukas Kenner, email: // William Tse, email: // Keywords : AF1q, TCF7, CD44, Wnt, metastasis Received : March 02, 2015 Accepted : April 21, 2015 Published : June 07, 2015 Abstract AF1q is an MLL fusion partner that was identified from acute myeloid leukemia (AML) patients with t (1; 11) (q21; q23) chromosomal abnormality. The function of AF1q is not yet fully known, however, elevated AF1q expression is associated with poor clinical outcomes in various malignancies. Here, we show that AF1q specifically binds to T-cell-factor-7 (TCF7) in the Wnt signaling pathway and results in transcriptional activation of CD44 as well as multiple downstream targets of the TCF7/LEF1. In addition, enhanced AF1q expression promotes breast cancer cell proliferation, migration, mammosphere formation, and chemo-resistance. In xenograft models, enforced AF1q expression in breast cancer cells also promotes liver metastasis and lung colonization. In a cohort of 63 breast cancer patients, higher percentages of AF1q-positive cancer cells in primary sites were associated with significantly poorer overall survival (OS), disease-free survival (DFS), and brain metastasis-free survival (b-MFS). Using paired primary/metastatic samples from the same patients, we demonstrate that AF1q-positive breast cancer cells become dynamically dominant in the metastatic sites compared to the primary sites. Our findings indicate that breast cancer cells with a hyperactive AF1q/TCF7/CD44 regulatory axis in the primary sites may represent “metastatic founder cells” which have invasive properties.

Patients with the most common aggressive AIDS-related non-Hodgkin lymphomas can expect improved outcomes approaching those of immunocompetent patients in the contemporary era. When treated with appropriate antilymphoma therapy, these improvements apply to every subgroup of patients, including those with low CD4 counts and high-risk disease. Background We undertook the present analysis to examine the shifting influence of prognostic factors in HIV-positive patients diagnosed with aggressive non-Hodgkin lymphoma (NHL) over the last two decades. Patients and methods We carried out a pooled analysis from an existing database of patients with AIDS-related lymphoma. Individual patient data had been obtained prior from prospective phase II or III clinical trials carried out between 1990 until 2010 in North America and Europe that studied chemo(immuno)therapy in HIV-positive patients diagnosed with AIDS-related lymphomas. Studies had been identified by a systematic review. We analyzed patient-level data for 1546 patients with AIDS-related lymphomas using logistic regression and Cox proportional hazard models to identify the association of patient-, lymphoma-, and HIV-specific variables with the outcomes complete response (CR), progression-free survival, and overall survival (OS) in different eras: pre-cART (1989–1995), early cART (1996–2000), recent cART (2001–2004), and contemporary cART era (2005–2010). Results Outcomes for patients with AIDS-related diffuse large B-cell lymphoma and Burkitt lymphoma improved significantly over time, irrespective of baseline CD4 count or age-adjusted International Prognostic Index (IPI) risk category. Two-year OS was best in the contemporary era: 67% and 75% compared with 24% and 37% in the pre-cART era (P Conclusions Our results demonstrate a significant improvement of CR rate and survival for all patients with AIDS-related lymphomas. Effective HIV-directed therapies reduce the impact of HIV-related prognostic factors on outcomes and allow curative antilymphoma therapy for the majority of patients with aggressive NHL.

Risk perceptions are motivating factors for engaging in preventive health behaviors. Yet, almost one third of women attending a mobile mammography program targeted to rural and medically underserved Appalachian women respond “don’t know” to their perceived 5-year risk of breast cancer. This study used cross-sectional data from women aged ≥40 years participating in Bonnie’s Bus Mammography Screening and Preventive Care Survey from 2009 to 2011 to identify factors associated with “don’t know” responses and accuracy of perceived risk according to constructs of the health belief model and sociodemographic characteristics. Women who responded “don’t know” were more likely to be less educated, of lower income, insured by Medicaid, and less knowledgeable about breast cancer. Conversely, women who accurately perceived their risk were more likely to be of higher education, more knowledgeable about breast cancer, and have a family history of breast cancer. However, women with a high objective 5-year risk of breast cancer and older age at childbirth or were nulliparous were less likely to accurately perceive their risk. These findings suggest that women who indicate “don’t know” responses and hold inaccurate risk perceptions are a population vulnerable to health disparities and may benefit from educational interventions focused on improving breast cancer knowledge and perceptions to empower them to take an active role in their preventive health and make informed decisions based on their individual level of risk.

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.

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 non-malignant 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.

97 Background: Pediatric palliative care (PC) and end-of-life (EoL) planning and support for children, families, and providers are under-developed in Kenya. PC providers in Kenya want to build advocacy and teams to support children with life-threatening or limiting diseases and their families. Methods: KEHPCA in collaboration with UoN/KNH and US pediatric PC providers solicited applications from across the country to participate in a weeklong “train-the-trainer” workshop. The program was entirely devoted to pediatric PC and EoL care and is the “first-like” workshop to our knowledge. The program incorporated a variety of teaching and training tools that were used to support children, their families and caregivers suitable for the Kenyan setting. The cases of 7 children (7 mos. to 11 yrs) served as the focal point for training including extensive role-play scenarios. Results: The workshop convened 9-13th July 2018 in Nairobi. KEHPCA selected 31 providers from among 130 across Kenya to participate and included medical officers, nurses, pharmacists, psychosocial workers, spiritual care, and a school teacher. Expectations were identified by participants at the start, pre- and post-conference surveys were completed, and the identical survey was submitted twice to more than 5,000 physicians listed in the Kenya Board of Medicine directory. There is a lack of awareness of the importance of PC by physicians listed in the directory responding to the same survey. The workshop was well received and ways forward identified. Conclusions: There is consensus among participants that there are five critical gaps in pediatric PC in Kenya: 1) PC requires an interdisciplinary team; 2) interdisciplinary family visits are seldom done; 3) there is a need to facilitate EoL and serious illness conversations with families/guardians and children as appropriate (adolescents in particular); 4) identify ways to support the legacy of infants and young children who pass away; and 5) a clear desire to support the healthcare team. These observations will form a solid departure point for developing programs and ways forward for Kenyan children with life-threatening illnesses. [Supported in part by: KEHPCA and NIH grant nos.: D43 TW009333.]

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.

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.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.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.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.

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.

Summary Background Cardiovascular diseases are the second leading cause of morbidity and mortality in Kenya. However, there is limited clinico-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. Conclusions 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.

Non

Mobile mammography services are typically offered as a means to increase access and adherence to mammography screenings. As mobile mammography becomes a viable strategy to increase screening, a 3 year study of such a state-wide program in WV found surprisingly high rates of obesity within the study population. Thus, the objectives were to: (1) describe the demographic characteristics and comorbidities of women who utilized the WV program, and (2) determine the association between body mass index (BMI) and personal health and screening history, preventive care and wellness behaviors, nutrition and exercise behaviors, and demographics. Data collected from 1,099 women, age 40 and above, were analyzed using descriptive statistics, bivariate analyses, and a multivariate regression model. The majority (60.4 %) were married, had an income

To evaluate and compare annual and biennial mammography screening rates across age, race, and geographic location (rural-urban) and to determine mammography screening persistence over 10 years among women enrolled in the West Virginia (WV) Medicaid Fee-for-Service (FFS) program.The WV Medicaid FFS administrative claims data for women recipients aged 40-64 from 1999 to 2008 were used for study purposes. Annual and biennial screening rates and persistence with screening were determined for women who were continuously enrolled in the WV Medicaid FFS program for respective calendar years.A steady decline in the annual and biennial screening rates over a 10-year period (1999-2008) was observed among women recipients aged 40-64 years in the WV Medicaid FFS program, and screening persistence was also lower. Both annual and biennial screening rates and persistence varied by different demographic characteristics.Although mammography screening services are covered under Medicaid programs, underuse persists as a major concern. The results of this study emphasize the need to identify and address barriers to mammography screening in low-income rural populations.

Today AIDS-related non-Hodgkin’s lymphoma (AR-NHL) is a significant cause of morbidity and mortality in HIV-infected patients the world over, and especially in sub-Saharan Africa. While the overall incidence of AR-NHL since the emergence of combination antiretroviral therapy (cART) era has declined, the occurrence of this disease appears to have stabilized. In regions of the world where access to cART is challenging, the impact on disease incidence is less clear. In the resource-rich environment it is clinically well recognized that it is no longer appropriate to consider AR-NHL as a single disease entity and rather treatment of AIDS lymphoma needs to be tailored to lymphoma subtype. While intensive therapeutic strategies in the resource-rich world are clearly improving outcome, in AIDS epicenters of the world and especially in sub-Saharan Africa there is a paucity of data on treatment and outcomes. In fact, only one prospective study of dose-modified oral chemotherapy and limited retrospective studies with sufficient details provide a window into the natural history and clinical management of this disease. The scarcities and challenges of treatment in this setting provide a backdrop to review the current status and realities of the therapeutic approach to AR-NHL in sub-Saharan Africa. More pragmatic and risk-adapted therapeutic approaches are needed.

Plasmablastic lymphoma (PBL) is an aggressive CD20 negative diffuse large B cell lymphoma over-represented in patients with HIV infection. CD45 expression is weak, but immunoglobulin genes are rearranged and plasma cell markers are expressed.[1] In 1997, 95% of the cases were reported to be from HIV + patients, all with oral cavity involvement, 68% stage I. In this pre-HAART era report, 9//11 patients with follow-up died within a year of diagnosis. Most other case reports and case series have typically described poor survival for patients with PBL, particularly those infected with HIV,[2] while others were more optimistic.[3] We sought to characterize patients with PBL diagnosed and treated solely in the HAART era. We identified 12 patients with newly diagnosed PBL treated at the AIDS Malignancy Consortium (AMC) sites from 1999 to 2008. This retrospective analysis suggests these patients had better outcomes than those identified pre-HAART, perhaps due to use of aggressive chemotherapy made possible because of better supportive care and antiretroviral therapy. All AMC sites, which participated in this retrospective review were queried for cases of PBL diagnosed from 1998–2008. Two of the authors (AC and AN) reviewed the pathology reports for the criteria for plasmablastic lymphoma described in the 2008 WHO Classification.[4] Twelve cases from 9 AMC sites were included in this study. Descriptive statistics were computed for demographic and clinical characteristics. Overall survival (OS) was calculated from date of initial diagnosis to death or last follow-up. Kaplan-Meier estimates of 1-year survival were computed. All AMC sites had an Institutional Review Board waiver of authorization. Baseline clinical characteristics at study entry are presented in Table 1. The median CD4 + count at HIV diagnosis was 256 cells/uL (range 45–750) and was lower at initial PBL diagnosis with a median of 136 cells/uL (range of 2–514). Sixty-seven percent of the patients had had a prior opportunistic infection. Most (58%) of patients were not on HAART at lymphoma diagnosis, however, they had all previously taken HAART at some point. Of 7 patients not on HAART, 6 started HAART, typically at diagnosis or chemoimmunotherapy initiation. Stage at initial diagnosis was I (25%), II (25%), III (0%) and IV (50%). Four of 7 patients with extranodal disease had more than one site of involvement. Extranodal sites of disease at initial diagnosis included bone without bone marrow (4), bone marrow (1), liver (2), kidney (2), sinus (1), cerebrospinal fluid (1), colon (1), skin (1), adrenal (1), nasopharynx (1) and stomach (1). Table 1 Clinical characteristics at study entry of 12 HIV-positive patients with initial diagnosis of plasmablastic lymphoma. Surprisingly, no patients had oral involvement. LDH was elevated in 5/8 where the value was known. The International Prognostic Index could not be calculated for the group as a whole as performance status assessment data was not available in one third of the patients. Not all cases had uniform immunophenotypic data available [Table 1]. As per the definition of plasmablastic lymphoma, all 12 cases tested were negative for the B cell marker CD20. Similarly, markers of terminal B cell differentiation, CD138 and MUM-1/IFR4, were positive in 6/6 cases and in 4/4 cases tested, respectively Epstein-Barr virus (EBV) was present in 8/8 cases based on in situ hybridization (EBER). At initial diagnosis, 10/12 patients received chemotherapy, although HAART alone was attempted without success in one patient. Treatment was CHOP on a 14 day cycle (n=1) [5] or 21 day cycle (n=3), [6] (cyclophosphamide, doxorubicin, vincristine, prednisone), infusional CDE (n=1), (cyclophosphamide, doxorubicin, etoposide); [7] infusional EPOCH (n=2) (cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone),[8,9] or other (n=5). The other therapies included EPOCH with high dose methotrexate and zidovudine, either alternating (n=2), or sequential (n=2). Three patients with stage I/II disease received radiation in combination with chemotherapy. Two of the ten treated patients experienced grade 3/4 toxicity. No patient died of treatment. One patient experienced grade 3/4 fatigue, anemia, thrombocytopenia, febrile neutropenia, nausea, vomiting, diarrhea, and weight loss, and the other patient experienced renal insufficiency. Responses were complete (CR) in 7, partial (PR) in 2 and refractory in 1. CRs were seen with CHOP (n=4), EPOCH (n=2), and EPOCH alternating with high dose methotrexate and zidovudine (n=1). PRs were seen after EPOCH alternating with high dose methotrexate and zidovudine (n=2). The one patient treated with CDE had refractory disease. Overall survival is shown in Fig. 1. At a median follow up of 73 weeks (range, 40–165), the median survival was not reached. The one-year survival was 66.7% (SE, 13.6). No patients died in the follow up period after year one. Figure 1 Survival of plasmablastic lymphoma patients. We report the first case series of plasmablastic lymphoma patients, under the care of dedicated HIV malignancy oncologists in a consortium setting, diagnosed and treated exclusively in the HAART era. In this study we demonstrate relatively long disease free survival despite earlier reports showing nearly all HIV + patients with PBL were destined to die from progressive lymphoma. In the initial, pre-HAART study of PBL by Delecluse, et al.[1] 9 of the 11 patients died within 16 months of diagnosis including 3 patients with stage I disease treated with external beam radiation, poly-chemotherapy or a combination of both. In the HAART era, intensive treatment of aggressive lymphomas, such as Burkitt and diffuse large B cell lymphoma, can result in CR and long-term survival for HIV infected patients.[9–11] Cohort studies suggest that plasmablastic lymphoma has an inferior survival to Burkitt and DLBCL.[12] We demonstrate that PBL may be curable, even in patients with higher stage disease and more extranodal involvement compared to the cases described by Delecluse, et al. where the disease was primarily localized to the jaw in the majority of patients. Recently, Ibrahim et al. reported in abstract form, their single institution experience with 25 patients during the HAART era.[13] Similar to our study, only 32% were on HAART and the median CD4 + cell count was 87cells/uL. Only 76% received chemotherapy, with EPOCH being the most common treatment choice (56%), and 28% received radiotherapy. The response rate was 84% and the median OS observed in all patients who received chemotherapy was 11.6 months (range, 2–63 months). Those who were treated with EPOCH demonstrated a better median overall survival (17 months) compared to those treated with CHOP and CHOP-like regimens (7 months, p=0.04). Castillo et al. reviewed 112 cases in the literature and noted a median overall survival of 15 months with a 3 year OS of only 25%. In contrast, Cattaneo et al. reported their single institution experience of 13 patients treated during the HAART era with a 67% 3 year OS.[14] 15 patients were treated, all with CHOP or CHOP-like regiments, with involved field consolidation in seven. Five received high dose therapy with autologus stem cell transplant as first CR consolidation. The initial goal of this AMC retrospective study was to identify which first line therapy might be the most promising for HIV positive patients with plasmablastic lymphoma. The rarity of this lymphoma resulted in a very small cohort, possibly as a result of incomplete retrieval from institutional databases. In this regard, we were unable to draw specific conclusions due to the sample size, the disparate number of lymphoma regimens, and the retrospective nature of the study. However, it is notable that CR was achieved with CHOP or EPOCH based regimens. The literature on regimens more intensive than CHOP is inconsistent. Two earlier retrospective studies did not demonstrate an advantage of therapies more intensive than CHOP for PBL.[15,16] Loghavi et al. noted a series of 50 patients (20 HIV+) tended to have a better OS with CHOP than hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) (p=0.078).[17] Nonetheless, many experts do consider CHOP inadequate and favor intensive therapies including EPOCH.[18] As an aside, we cannot comment on the efficacy of HAART therapy alone, as only one patient was treated with this strategy with disease progression. In addition to intensive chemotherapy, it is probable that our patients fared better than those in the pre- HAART era due in part to better supportive care and more robust immune status. However, we cannot be certain, as the median CD4 + cell count of 256 cells/uL at initial PBL diagnosis was relatively low. Moreover, 59% had had a prior opportunistic infection and only 29% were on HAART at PBL diagnosis. Currently Clinical Trials Support Unit (CTSU) 9177 is prospectively studying EPOCH therapy for patients diagnosed with PBL irrespective of HIV status. Given the biologic similarity to multiple myeloma, drug classes like immune modulatory agents (IMiDs) and protease inhibitors [19] might also be promising agents for future study. The nearly ubiquitous finding of Epstein Barr in tumor tissue (11of 12 evaluable cases in our study) may provide a rationale for viral-based strategies. Finally, the role for autologous stem cell transplant in the setting of relapsed/refractory disease is also worthy of exploration.

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.

The purpose of this study was to determine the prevalence, medical services and treatment utilization, and costs associated with breast cancer in a socioeconomically underprivileged population covered by a state Medicaid fee-for-service (FFS) program.We analyzed the West Virginia (WV) Medicaid FFS administrative claims data for women recipients 21-64 years of age enrolled continuously in the program during the calendar year 2005. Breast cancer-related medical services and treatment use and costs were calculated for women recipients with breast cancer. The excess burden of breast cancer was calculated by comparing the all-cause healthcare utilization and costs among women recipients with breast cancer to a matched control group of women recipients without breast cancer. Healthcare costs incurred during the 1-year study period were calculated from the perspective of state Medicaid. Cost estimates in the study excluded out-of-pocket expenses and indirect costs of breast cancer.In 2005, the prevalence of breast cancer in the WV Medicaid FFS program was 22.7/1000. More than 98% of breast cancer-related medical services utilization occurred in the office setting. Approximately 73% of women recipients with breast cancer had at least one claim for breast cancer treatment, with hormone therapy being the most common (55.1%) treatment. The all-cause healthcare costs were significantly higher for women recipients with breast cancer compared to those without breast cancer ($16,345 vs. $13,027, p0.001).Consistent with our expectations, breast cancer diagnosis among women recipients in the WV Medicaid FFS program was found to be associated with higher all-cause healthcare use and costs compared to women recipients in the matched control group. The excess cost burden associated with breast cancer could be attributed to higher office visit, emergency room visit, and prescription medication use among recipients with breast cancer.

To determine the toxicities, pharmacokinetics, pharmacodynamics, and maximum tolerated dose of bortezomib in patients with renal impairment and to develop dosing guidelines for such a patient population.Sixty-two adult cancer patients received intravenous bortezomib at 0.7-1.5 mg/m(2) on days 1, 4, 8, and 11 every 3 weeks. Patients were stratified by 24-h creatinine clearance (CrCl) normalized to body surface area (BSA) 1.73 m(2) into five cohorts: normal renal function (≥ 60 ml/min/1.73 m(2)); mild dysfunction (40-59 ml/min/1.73 m(2)); moderate dysfunction (20-39 ml/min/1.73 m(2)); severe dysfunction (20 ml/min/1.73 m(2)); and dialysis. Dose escalation was planned for the four cohorts with renal dysfunction. Plasma bortezomib concentrations and blood 20S proteasome inhibition were assayed.Bortezomib escalation to the standard 1.3 mg/m(2) dose was well tolerated in all patients with CrCl ≥ 20 ml/min/1.73 m(2); 0.7 mg/m(2) was tolerated in three patients with severe renal dysfunction (20 ml/min/1.73 m(2)). Bortezomib dose escalation was well tolerated in nine dialysis patients, including to 1.3 mg/m(2) in four patients. Decreased CrCl did not affect bortezomib pharmacokinetics or pharmacodynamics. Bortezomib-related side-effects were neither more common nor severe in patients with renal dysfunction versus those with normal renal function.Bortezomib 1.3 mg/m(2) is well tolerated, and dose reductions are not necessary in patients with renal dysfunction. Extrapolation from clinical and pharmacologic data suggests patients with severe renal dysfunction, including dialysis patients, can receive bortezomib at the full dose established to be clinically effective in the general patient population.

We evaluated the impact of busulfan dose intensity in patients undergoing reduced toxicity/intensity conditioning allogeneic transplantation in a multicenter retrospective study of 112 consecutive patients. Seventy-five patients were conditioned with busulfan (0.8 mg/kg/dose IV × 8 doses), fludarabine (30 mg/m(2) /day, days -7 to -3), and 6 mg/kg of ATG [reduced intensity conditioning (RIC) group], while 37 patients received a more-intense conditioning with busulfan (130 mg/m(2) /day IV, days -6 to -3), fludarabine (40 mg/m(2) /day, days -6 to -3) and 6 mg/kg of ATG [reduced toxicity conditioning (RTC) group]. At baseline both groups were matched for median age, unrelated donor allografts, and human leukocyte antigen-mismatched allografts. More patients in RIC group had high-risk disease, and higher median comorbidity index. There were no graft rejections. Median time to neutrophil (17 days vs. 15 days; p = 0.003) and platelet engraftment (16 days vs. 11 days; p 0.001) was significantly longer in the RIC group. RTC group had significantly more bacterial (62.2% vs. 32%; p = 0.004) and fungal infections (13.5% vs. 1.3% p = 0.01). For RIC and RTC groups rates of grades II-IV acute GVHD (34% vs. 40%; p-value = 0.54), and chronic GVHD (45% vs. 57%; p-value = 0.30) were not significantly different. In similar order at 1 year the cumulative-incidence of non-relapse mortality (NRM; 12% vs. 21%; p-value = 0.21) and relapse rates (38% vs. 39%; p = 0.96) were not significantly different. Patients in RIC and RTC groups had similar 1-year overall survival (61% vs. 50%, p = 0.11) and progression-free survival (50% vs. 36%, p-value = 0.39). Our data suggest that the merits of higher busulfan dose intensity in the context of fludarabine/busulfan-based RTC may be offset by higher early morbidity.

MN-029 (denibulin HCl) is a novel vascular-disrupting agent that reversibly inhibits microtubule assembly, resulting in disruption of the cytoskeleton of tumor vascular endothelial cells. This study determined the safety, pharmacokinetics, and acute anti-vascular effects of MN-029.Patients were treated with escalating doses of MN-029 (4.0-225 mg/m(2)) administered IV at 3-week intervals. This first-in-human study followed an accelerated titration design, with intra-patient dose escalation. Plasma samples were assayed to determine PK parameters. DCE-MRI scans were acquired at baseline and at 6-8 h post-dose.Thirty-four patients received 151 infusions of MN-029. The most common toxicities of MN-029 included nausea and vomiting (which appeared to be dose related), diarrhea, fatigue, headache, and anorexia. No clinically significant myelotoxicity, stomatitis or alopecia was observed. There was no evidence of cumulative toxicity in patients receiving multiple courses of therapy. The cohort at 180 mg/m(2) was expanded to six patients due to a reversible episode of acute coronary ischemia, without sequelae and with preservation of myocardial function. Two dose-limiting toxicities occurred at 225 mg/m(2), a transient ischemic attack and grade 3 transaminitis, thus ending dose escalation. Pharmacokinetic data indicated dose-related increases in C (max) and AUC values, although substantial inter-subject variability was observed. No objective responses were noted; however, five patients had stable disease ≥6 months. A significant linear correlation was found between reduction in K (trans) and exposure to MN-029.MN-029 was generally well tolerated and showed decrease in tumor vascular parameters. The maximum tolerated dose was 180 mg/m(2).

Combretastatin A4 phosphate (CA4P) is the lead compound of a relatively new class of agents termed vascular disrupting agents that target existing tumor blood vessels. Rapid tumor blood flow shutdown has been demonstrated in preclinical models and patients by various techniques such as dynamic contrast-enhanced MRI, perfusion computed tomography and PET scans following CA4P infusion. CA4P typically induces rapid tumor necrosis in the center of the tumor and leaves a rim of viable cells in the periphery. In oncology, CA4P does not appear to be that active by itself, but may be more efficacious when combined with chemotherapy, antiangiogenic therapy and radiation therapy. Studies are currently underway, which combine CA4P with antiangiogenic agents. Side effects have included hypertension, tumor pain and occasional cardiovascular toxicity, without any significant myelosuppression or disabling systemic symptoms. The utility of CA4P for conditions other than cancer, which involves neovascularization such as macular degeneration, is also being explored.

e18108Background: Anaplastic thyroid cancer (ATC) is considered a systemic disease at the time of diagnosis and has a poor prognosis. A long-term survivor (Case #1) treated with combretastatin (fos...

Myocardial stunning, known as stress cardiomyopathy, broken-heart syndrome, transient left ventricular apical ballooning, and Takotsubo cardiomyopathy, has been reported after many extracardiac stressors, but not following chemotherapy. We report 2 cases with characteristic electrocardiographic and echocardiographic features following combined modality therapy with combretastatin, a vascular-disrupting agent being studied for treatment of anaplastic thyroid cancer. In 1 patient, an ECG performed per protocol 18 hours after drug initiation showed deep, symmetric T-wave inversions in limb leads I and aVL and precordial leads V2 through V6. Echocardiography showed mildly reduced overall left ventricular systolic function with akinesis of the entire apex. The patient had mild elevations of troponin I. Coronary angiography revealed no epicardial coronary artery disease. The electrocardiographic and echocardiographic abnormalities resolved after several weeks. The patient remains stable from a cardiovascular standpoint and has not had a recurrence during follow-up. An electrocardiogram performed per protocol in a second patient showed deep, symmetric T-wave inversions throughout the precordial leads and a prolonged QT interval. Echocardiography showed mildly reduced left ventricular function with hypokinesis of the apical-septal wall. Acute coronary syndrome was ruled out, and both the electrocardiographic and echocardiographic changes resolved at follow-up. Although the patient remained pain-free without recurrence of anginal symptoms during long-term follow-up, the patient developed progressive malignancy and died. Copyright © 2009 Wiley Periodicals, Inc.

This study evaluated the pharmacokinetic and safety profiles of arsenic trioxide given twice per week in adult cancer patients with advanced malignancies and varying degrees of renal function. Patients received intravenous arsenic trioxide 0.15 mg/kg twice weekly for 4 weeks, followed by a 2-week rest period. The pharmacokinetic profiles of the pharmacologically active arsenical species, arsenious acid (AsIII), and its metabolites, monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV), were evaluated during the first cycle for 72 h following doses on days 1 and 22. Safety assessments were made at each treatment visit. Twenty patients received an average of 11 doses. Compared with normal renal function, mild to severe renal impairment decreased urinary excretion of AsIII and increased exposure to MMAV and DMAV 1.4- to 8-fold after multiple dose administration. Only severe renal impairment substantially increased exposure to AsIII (AUC0–t increased by 18% after a single dose and 40% after multiple doses). The safety profile of arsenic trioxide after limited treatment on a twice-per-week schedule was comparable across all renal function groups. Renal impairment did increase the systemic exposure to arsenic and its methylated metabolites following standard daily dosing of arsenic trioxide. The data from the limited number of patients with severe renal dysfunction did not suggest that severe renal impairment affected the safety profile of arsenic trioxide in cancer patients who received limited treatment with arsenic trioxide.

Objective: To report a case of probable bendamustine-related hemolytic anemia. Case Summary: A 64-year-old white female had recently received treatment with bendamustine for stage III follicular lymphoma. After her fourth cycle, she was admitted to an outside facility with severe right upper quadrant pain across her back and findings consistent with obstructive jaundice. She was found to have pancytopenia and elevations in total bilirubin, alkaline phosphatase, and transaminase levels. A bone marrow biopsy showed no evidence of lymphoma and presence of megakaryocytes on 2 occasions. Upon transfer to West Virginia University Hospitals, her haptoglobin was found to be undetectable, total bilirubin 10.3 mg/dL (unconjugated bilirubin 4.9 mg/dL), reticulocyte count 21.4% (reticulocyte index ≥2%), alkaline phosphatase 1125 U/L, and lactate dehydrogenase 421 U/L. The peripheral smear showed evidence of spherocytes and very rare schistocytes. Based on these findings, the woman was diagnosed with hemolytic anemia secondary to bendamustine exposure. She was started on prednisone 1 mg/kg (60 mg) daily and, soon after, her platelets and hemoglobin stabilized. Discussion: Drug-induced hemolytic anemia is an acquired or extrinsic process that results in antibody-mediated red blood cell destruction. The patient was not taking any medications commonly associated with hemolytic anemia; however, her laboratory test results were consistent with hemolytic anemia. Based on bendamustine's structural similarity to fludarabine and fludarabine s association with causing hemolytic anemia, we considered exposure to bendamustine to be the most likely contributory factor for her diagnosis. According to the Naranjo probability scale, a probable likelihood was reflected in bendamustine causing the hemolytic anemia. Conclusions: Continued monitoring of postmarketing data is necessary to correlate this occurrence of hemolytic anemia with bendamustine therapy.

Rebeccamycin analog (RA) is an antitumor antibiotic with both topoisomerase I and II inhibiting activity. Topoisomerase inhibitors have demonstrated synergy with platinum agents. We performed a phase I trial of combination RA with oxaliplatin in patients with refractory solid tumors. RA was administered as a 1-hour infusion daily on days 1-5 with oxaliplatin administered on day 5. Cycles were repeated every 21 days. A total of 17 patients were enrolled. The MTD for RA was 80 mg/m(2)/d for five days along with oxaliplatin 130 mg/m(2) on day 5. Myelosuppression was a common occurrence but was mild except in one instance. Dose limiting toxicities included atrial fibrillation and hypophosphatemia. There was evidence of antitumor activity including 3 partial responses in patients with esophageal, gallbladder and hepato-cellular carcinoma; 5 additional patients had stable disease. Thus, the combination of RA and oxaliplatin is both tolerable and has evidence of clinical activity, but given the lack of significant activity for single agent RA across a variety of disease sites, it is unlikely to proceed to phase II development.

Purpose Information is limited as to how we should treat invasive anal squamous cell carcinoma (SCC) in patients with chronic immunosuppression, since the majority of clinical studies to date have excluded such patients. The objective of this study is to compare treatment outcomes in immunocompetent (IC) versus immunodeficient (ID) patients with invasive anal SCC treated similarly with combined modality therapy. Methods and Materials Between January 1999 and March 2007, a total of 36 consecutive IC and ID patients received concurrent chemoradiotherapy using three-dimensional conformal radiotherapy with infusional 5-fluorouracil and mitomycin C. The IC and ID groups consisted of 19 and 17 patients, respectively, with 14 human immunodeficiency virus–positive (HIV+) and 3 post–solid organ transplant ID patients. There were no significant differences in tumor size, T stage, N stage, chemotherapy doses, or radiation doses between the two groups. Results With a median follow-up of 3.1 years, no differences were found in overall survival, disease-specific survival, and colostomy-free survival. Three-year overall survival was 83.6% (95% CI = 68.2–100) and 91.7% (95% CI = 77.3–100) in the IC and ID groups, respectively. In addition, there were no differences in acute and late toxicity profiles between the two groups. In the human immunodeficiency virus–positive patients, Cox modeling showed no difference in overall survival by pretreatment CD4 counts (hazard ratio = 0.994, 95% CI = 0.98–1.01). No correlation was found between CD4 counts and the degree of acute toxicities. Conclusion Our data suggest that standard combined modality therapy with three-dimensional conformal radiotherapy and 5-fluorouracil plus mitomycin C is as safe and effective for ID patients as for IC patients.

Bryostatin 1, isolated from a marine bryozoan, enhances the efficacy of cytotoxic agents through modulation of the protein kinase C pathway and is active in combination with vincristine for diffuse large B-cell lymphoma. Further, the apoptotic frequency of peripheral blood T lymphocytes as determined by flow cytometry may predict which patients will respond to this combination. We tested the efficacy and safety of bryostatin 1 50 microg/m(2) given over 24 hr and vincristine 1.4 mg/m(2) on days 1 and 15 every 28 days in aggressive B-cell non-Hodgkin lymphoma (NHL) relapsing after autologous stem cell transplantation. End points included tumor response, toxicity, and survival. Responses were correlated with an increase in apoptotic frequency of CD5+ cells by flow cytometry using annexin V staining. Fourteen patients were enrolled with 13 being evaluable for a response. The overall response rate was 31% with two patients achieving a complete response. The most common toxicities were Grade 3 lymphopenia (seven patients), Grade 3 to 4 neutropenia (two patients), and Grade 3 hypophosphatemia (two patients). Median progression-free and overall survivals for all patients were 5.7 and 21.4 months, respectively. One patient demonstrated an increase in T-cell apoptotic frequency, also achieving a complete response. Bryostatin 1 and vincristine have efficacy in select patients with aggressive NHL. Future investigations of agents targeting the protein kinase C pathway may benefit from early response assessment using flow cytometry to evaluate T-cell apoptosis.

Purpose Africa is burdened by the AIDS epidemic and attendant increase in HIV/AIDS-related malignancies. Pragmatic approaches to therapeutic intervention could be of great value. Dose-modified oral chemotherapy for AIDS-related non-Hodgkin's lymphoma is one such approach. Patients and Methods The oral regimen consisted of lomustine 50 mg/m2 on day 1 (cycle 1 only), etoposide 100 mg/m2 on days 1 to 3, and cyclophosphamide/procarbazine 50 mg/m2 each on days 22 to 26 at 6-week intervals (one cycle) for two total cycles in HIV-infected patients with biopsy-proven non-Hodgkin's lymphoma. Results Forty-nine patients (21 in Uganda and 28 in Kenya) were treated. The majority of patients were female (59%) and had a poor performance status (63%); 69% of patients had advanced-stage disease; and 18 patients (37%) had access to antiretroviral therapy. In total, 79.5 cycles of therapy were administered. The regimen was well tolerated, had modest effects (decline) on CD4+ lymphocyte counts (P = .077), and had negligible effects on HIV-1 viral replication. Four febrile neutropenia episodes and three treatment-related deaths (6% mortality rate) occurred. The overall objective response rate was 78% (95% CI, 62% to 88%); median follow-up time was 8.2 months (range, 0.1 to 71 months); median event-free and overall survival times were 7.9 months (95% CI, 3.3 to 13.0 months) and 12.3 months (95% CI, 4.9 to 32.4 months), respectively; and 33% of patients survived 5 years. Conclusion Dose-modified oral chemotherapy is efficacious, has comparable outcome to that in the United States in the pre–highly active antiretroviral therapy setting, has an acceptable safety profile, and is pragmatic in sub-Saharan Africa. The international collaboration has been highly successful, and subsequent projects should focus on strategies to optimize combination antiretroviral therapy and chemotherapy and follow-up tissue correlative studies.

Purpose: It is a critical challenge to determine the risk of recurrence in early stage non–small cell lung cancer (NSCLC) patients. Accurate gene expression signatures are needed to classify patients into high- and low-risk groups to improve the selection of patients for adjuvant therapy. Experimental Design: Multiple published microarray data sets were used to evaluate our previously identified lung cancer prognostic gene signature. Expression of the signature genes was further validated with real-time reverse transcription-PCR and Western blot assays of snap-frozen lung cancer tumor tissues. Results: Our previously identified 35-gene signature stratified 264 patients with NSCLC into high- and low-risk groups with distinct overall survival rates (P < 0.05, Kaplan-Meier analysis, log-rank tests). The 35-gene signature further stratified patients with clinical stage 1A diseases into poor prognostic and good prognostic subgroups (P = 0.0007, Kaplan-Meier analysis, log-rank tests). This signature is independent of other prognostic factors for NSCLC, including age, sex, tumor differentiation, tumor grade, and tumor stage. The expression of the signature genes was validated with real-time reverse transcription-PCR analysis of lung cancer tumor specimens. Protein expression of two signature genes, TAL2 and ILF3, was confirmed in lung adenocarcinoma tumors by using Western blot analysis. These two biomarkers showed correlated mRNA and protein overexpression in lung cancer development and progression. Conclusions: The results indicate that the identified 35-gene signature is an accurate predictor of survival in NSCLC. It provides independent prognostic information in addition to traditional clinicopathologic criteria.

Purpose Cytotoxic and anti-angiogenic drugs are efficacious in malignancies. This trial was undertaken to evaluate the toxicity of a novel regimen combining docetaxel and lenalidomide. Patients and methods Patients with advanced solid tumors were eligible. Docetaxel was administered on day 1, and lenalidomide was given on days 1–14 of each 21-day cycle. Since significant myelosuppression occurred, pegfilgrastim was added on day 2. Dose limiting toxicity (DLT) was defined as ≥grade 3 non-hematologic toxicity, grade 4 neutropenia with fever, or grade 4 anemia or thrombocytopenia. Results Thirty-three patients were enrolled. DLTs included neutropenia, nausea/vomiting, and dyspnea. Of the evaluable patients, 69% had stable disease, and 3% had partial response. Conclusions This regimen was well tolerated and provided stable disease in the majority of advanced cancer patients. The recommended phase II dosing is docetaxel 75 mg/m2 on day 1, lenalidomide 25 mg on days 1–14, and pegfilgrastim 6 mg on day 2, given every 3 weeks.