Pilot study of a Spanish language measure of financial toxicity in underserved Hispanic cancer patients with low English proficiency.

Background: Financial toxicity (FT) reflects multi-dimensional personal economic hardships borne by cancer patients. It is unknown whether measures of FT-to date derived largely from English-speakers-adequately capture economic experiences and financial hardships of medically underserved low English proficiency US Hispanic cancer patients. We piloted a Spanish language FT instrument in this population. Methods: We piloted a Spanish version of the Economic Strain and Resilience in Cancer (ENRICh) FT measure using qualitative cognitive interviews and surveys in un-/under-insured or medically underserved, low English proficiency, Spanish-speaking Hispanics (UN-Spanish, n = 23) receiving ambulatory oncology care at a public healthcare safety net hospital in the Houston metropolitan area. Exploratory analyses compared ENRICh FT scores amongst the UN-Spanish group to: (1) un-/under-insured English-speaking Hispanics (UN-English, n = 23) from the same public facility and (2) insured English-speaking Hispanics (INS-English, n = 31) from an academic comprehensive cancer center. Multivariable logistic models compared the outcome of severe FT (score > 6). Results: UN-Spanish Hispanic participants reported high acceptability of the instrument (only 0% responded that the instrument was "very difficult to answer" and 4% that it was "very difficult to understand the questions"; 8% responded that it was "very difficult to remember resources used" and 8% that it was "very difficult to remember the burdens experienced"; and 4% responded that it was "very uncomfortable to respond"). Internal consistency of the FT measure was high (Cronbach's α = 0.906). In qualitative responses, UN-Spanish Hispanics frequently identified a total lack of credit, savings, or income and food insecurity as aspects contributing to FT. UN-Spanish and UN-English Hispanic patients were younger, had lower education and income, resided in socioeconomically deprived neighborhoods and had more advanced cancer vs. INS-English Hispanics. There was a higher likelihood of severe FT in UN-Spanish (OR = 2.73, 95% CI 0.77-9.70; p = 0.12) and UN-English (OR = 4.13, 95% CI 1.13-15.12; p = 0.03) vs. INS-English Hispanics. A higher likelihood of severely depleted FT coping resources occurred in UN-Spanish (OR = 4.00, 95% CI 1.07-14.92; p = 0.04) and UN-English (OR = 5.73, 95% CI 1.49-22.1; p = 0.01) vs. INS-English. The likelihood of FT did not differ between UN-Spanish and UN-English in both models (p = 0.59 and p = 0.62 respectively). Conclusion: In medically underserved, uninsured Hispanic patients with cancer, comprehensive Spanish-language FT assessment in low English proficiency participants was feasible, acceptable, and internally consistent. Future studies employing tailored FT assessment and intervention should encompass the key privations and hardships in this population.

Enhancing the utilization of healthy living interventions among cancer survivors in historically underserved populations and communities.

PURPOSE: This study aimed to describe the clinical characteristics and wellness programming preferences of cancer survivors from Acres Homes, a historically Black neighborhood in Houston, Texas, with areas of persistent poverty. The goal of this study was to identify opportunities to increase cancer survivor utilization of healthy eating and active living interventions aligned to cancer center community outreach and engagement efforts. METHODS: This multiple methods study included a retrospective review of electronic health record data (n = 413) and qualitative interviews with cancer survivors (n = 31) immediately preceding initiation of healthy eating, active living programming in Acres Homes. RESULTS: This study found Acres Homes survivors have high rates of co-occurrent cardiometabolic disease including obesity (45.0%), diabetes (30.8%), and other related risk factors as well as treatment-related symptoms. Four major concepts emerged from interviews: (1) Factors that influence survivors' ability to eat well and exercise, (2) Current usage of community resources, (3) Interest in relevant programming, and (4) Specific programming preferences. Opportunities for current and future health promotion programming for cancer survivors were explored. CONCLUSION: Strategically tailoring community resources for cancer survivors can provide a more robust network of support to promote healthy eating and active living in this population. This work informed community implementation of evidence-based health interventions in Acres Homes and may support future projects aiming to enhance community-led cancer prevention efforts in historically underserved communities.

A systematic review and meta-analysis of e-cigarette use among cancer survivors.

PURPOSE: We conducted a systematic review and meta-analysis to determine the use of e-cigarettes among cancer survivors, factors associated with their use, and prevalence of e-cigarette use as a quit attempt. METHODS: We searched five electronic databases until June 2022. Two authors independently selected studies, appraised their quality, and collected data. RESULTS: Twenty-three publications from eight data sources (national surveys) met our eligibility criteria. The pooled rate of lifetime e-cigarette use among cancer survivors was 15% (95% CI 6-27%); current use was 3% (95% CI 0-8%). Among survivors who currently used traditional cigarettes, 63% (95% CI 57-69%) also used e-cigarettes. The reported rates of weighted lifetime e-cigarette use differed between age groups (18-44 years, up to 46.7%; 45-64, up to 27.2%; ≥65, up to 24.8%). Nine publications reported factors associated with lifetime e-cigarette use (i.e., active use of traditional cigarettes; heavy drinking; poor mental health; younger age; being male, non-Hispanic White, or single; having less than high school education or income ≤$25,000 USD; and living in the South regions of the US or urban areas). E-cigarettes were used as a quit resource by 75% of survivors reporting dual use of electronic and traditional cigarettes (95% CI 63%, 85%). CONCLUSION: More than two-thirds of survivors currently using traditional cigarettes also use e-cigarettes. Higher use rates of e-cigarettes were reported among young cancer survivors compared to older survivors. Future studies are needed to assess the impact of e-cigarettes on long-term health and improve screening of smoking behaviors. IMPLICATIONS FOR CANCER SURVIVORS: Our study provides an overview of the prevalence of e-cigarette use and sociodemographic risk factors associated with e-cigarette use among cancer survivors. The findings can assist providers in supporting attempts to quit among cancer survivors.

Effect of dexamethasone on dyspnoea in patients with cancer (ABCD): a parallel-group, double-blind, randomised, controlled trial.

BACKGROUND: Systemic corticosteroids are commonly prescribed for palliation of dyspnoea in patients with cancer, despite scarce evidence to support their use. We aimed to assess the effect of high-dose dexamethasone versus placebo on cancer-related dyspnoea. METHODS: The parallel-group, double-blind, randomised, controlled ABCD (Alleviating Breathlessness in Cancer Patients with Dexamethasone) trial was done at the at the University of Texas MD Anderson Cancer Center and the general oncology clinic at Lyndon B Johnson General Hospital (both in Houston, TX, USA). Ambulatory patients with cancer, aged 18 years or older, and with an average dyspnoea intensity score on an 11-point numerical rating scale (NRS; 0=none, 10=worst) over the past week of 4 or higher were randomly assigned (2:1) to receive dexamethasone 8 mg orally every 12 h for 7 days followed by 4 mg orally every 12 h for 7 days, or matching placebo capsules for 14 days. Pharmacists did permuted block randomisation with a block size of six, and patients were stratified by baseline dyspnoea score (4-6 vs 7-10) and study site. Patients, research staff, and clinicians were masked to group assignment. The primary outcome was change in dyspnoea NRS intensity over the past 24 h from baseline to day 7 (±2 days). Analyses were done by modified intention-to-treat (ie, including all patients who were randomly assigned and started the study treatment, regardless of whether they completed the study). Enrolment was stopped after the second preplanned interim analysis, when the futility criterion was met. This study is registered with ClinicalTrials.gov (NCT03367156) and is now completed. FINDINGS: Between Jan 11, 2018, and April 23, 2021, we screened 2867 patients, enrolled 149 patients, and randomly assigned 128 to dexamethasone (n=85) or placebo (n=43). The mean change in dyspnoea NRS intensity from baseline to day 7 (±2 days) was -1·6 (95% CI -2·0 to -1·2) in the dexamethasone group and -1·6 (-2·3 to -0·9) in the placebo group, with no significant between-group difference (mean 0 [95% CI -0·8 to 0·7]; p=0·48). The most common all-cause grade 3-4 adverse events were infections (nine [11%] of 85 patients in the dexamethasone group vs three [7%] of 43 in the placebo group), insomnia (seven [8%] vs one [2%]), and neuropsychiatric symptoms (three [4%] vs none [0%]). Serious adverse events, all resulting in hospital admissions, were reported in 24 (28%) of 85 patients in the dexamethasone group and in three (7%) of 43 patients in the placebo group. No treatment-related deaths occurred in either group. INTERPRETATION: High-dose dexamethasone did not improve dyspnoea in patients with cancer more effectively than placebo and was associated with a higher frequency of adverse events. These data suggest that dexamethasone should not be routinely given to unselected patients with cancer for palliation of dyspnoea. FUNDING: US National Cancer Institute.

Short-form adaptive measure of financial toxicity from the Economic Strain and Resilience in Cancer (ENRICh) study: Derivation using modern psychometric techniques.

OBJECTIVES: This study sought to evaluate advanced psychometric properties of the 15-item Economic Strain and Resilience in Cancer (ENRICh) measure of financial toxicity for cancer patients. METHODS: We surveyed 515 cancer patients in the greater Houston metropolitan area using ENRICh from March 2019 to March 2020. We conducted a series of factor analyses alongside parametric and non-parametric item response theory (IRT) assessments using Mokken analysis and the graded response model (GRM). We utilized parameters derived from the GRM to run a simulated computerized adaptive test (CAT) assessment. RESULTS: Among participants, mean age was 58.49 years and 278 (54%) were female. The initial round factor analysis results suggested a one-factor scale structure. Negligible levels of differential item functioning (DIF) were evident between eight items. Three items were removed due to local interdependence (Q3>+0.4). The original 11-point numerical rating scale did not function well, and a new 3-point scoring system was implemented. The final 12-item ENRICh had acceptable fit to the GRM (p<0.001; TLI = 0.94; CFI = 0.95; RMSEA = 0.09; RMSR = 0.06) as well as good scalability and dimensionality. We observed high correlation between CAT version scores and the 12-item measure (r = 0.98). During CAT, items 2 (money you owe) and 4 (stress level about finances) were most frequently administered, followed by items 1 (money in savings) and 5 (ability to pay bills). Scores from these four items alone were strongly correlated with that of the 12-item ENRICh (r = 0.96). CONCLUSION: These CAT and 4-item versions provide options for quick screening in clinical practice and low-burden assessment in research.

Financial toxicity impact on younger versus older adults with cancer in the setting of care delivery.

BACKGROUND: Young adults and other working-age adults with cancer are at risk for cancer-related financial toxicity (FT), including material hardships, depletion of coping resources, and psychological burden. This study compares FT domains in young adults (18-39 years old) (YAs), other working-age adults (40-64 years old), and older adults (≥65 years old) receiving cancer care. METHODS: A total of 311 adults were surveyed using the multi-domain Economic Strain and Resilience in Cancer instrument measuring FT (0-10 score indicating least to greatest FT; score ≥5 severe FT). Participants were receiving ambulatory care from March-September 2019. Associations of age with overall FT and material hardship, coping resource depletion, and psychological burden FT domains were tested using Kruskal-Wallis and χ2 tests and multivariable generalized linear models with gamma distribution. RESULTS: YAs (median age, 31.5 years) comprised 9.6% of the sample; other working-age adults comprised 56.9%. Overall, material, coping, and psychological FT scores were worse in younger age adults versus older adults (P < .001 in all multivariable models). Compared with older adults, younger age adults demonstrated worse material hardship (median scores, 3.70 vs 4.80 vs 1.30 for YAs, other working-age, and older adults, respectively; P < .001), coping resource depletion (4.50 vs 3.40 vs 0.80; P < .001), and psychological burden (6.50 vs 7.00 vs 1.00; P < .001). Fifty percent of YAs had severe overall FT versus 40.7% of other working-age adults and 9.6% of older adults (P < .001). CONCLUSIONS: Younger age adults with cancer bore disproportionate FT. Interventions to address unmet needs are critical components for addressing FT in this population.

Clinical Outcomes of Patients With Newly Diagnosed Acute Lymphoblastic Leukemia in a County Hospital System.

BACKGROUND: Major advances in the treatment of acute lymphoblastic leukemia (ALL) over the past decade have resulted in 5-year overall survival (OS) rates of 80% in mature B cell ALL, 50% in precursor B cell ALL, 50% to 60% in T cell ALL, and 60% to 70% in Philadelphia chromosome-positive (Ph+) ALL, as reported in studies from large, specialized centers. However, many patients treated in the community have limited access to novel therapies and stem cell transplantation (HSCT). PATIENTS AND METHODS: The purpose of this retrospective cohort analysis was to evaluate the clinical outcomes of patients ≥ 16 years with newly diagnosed ALL treated from October 2007 to June 2019 in the Harris County Health System, Houston, TX. RESULTS: One hundred forty-six patients were included, with newly diagnosed pre-B-ALL (n = 127), T-ALL (n = 18), and chronic myeloid leukemia and/or lymphoid blast crisis (n = 1). Median age was 35 years (16-82) at diagnosis, and 81(55%) were male. The majority of patients with pre-B ALL identified as Hispanic (n = 118, or 92%). Ninety-eight (67%) of patients were uninsured or indigent, receiving care under the county's financial assistance programs. Hyper-CVAD-based induction chemotherapy was administered in 134 (92%) of patients, while 9 (6%) were treated on different protocols, and 3 (2%) were not treated due to early death, or patient refusal. Imatinib was the most common TKI used in 17 of 30 or 57% of patients with Ph+ disease. Out of 137 evaluable for response patients, 117 (85%) achieved complete remission (CR + CRi), 19 (14%) had refractory disease, and 1 (1%) died within 4 weeks of diagnosis. Median follow-up time was 50 months (1.5-135). For the entire study cohort, the median duration of CR/CRi was 15.4 months. Out of 62 patients who were eligible for consolidative HSCT at first CR, 52 (89%) did not receive it, with lack of insurance being the most common reason (n = 29, or 56%). Barriers to utilization of novel therapies such as blinatumomab or CAR-T were also observed. Patient-caused delays in administration of chemotherapy and treatment interruptions of at least 30 days were seen in 31(23%) patients. At 1, 2, and 5 years, relapse rates were 37%, 56%, and 70%. Recurrent and/or refractory disease was the cause of death in most patients (n = 69 [85%]). Five-year EFS and OS rates were 22% and 38% for patients with pre-B ALL, 24% and 44% for patients with T ALL, and 13% and 27% for patients with Ph+ ALL. Median OS was significantly increased (not reached [NR] vs. 24 months; P = .00088) in patients with an indication for HSCT in first CR due to high-risk features who underwent HSCT, versus those who did not. CONCLUSION: Addressing barriers raised by socioeconomic disparities, increasing access to effective therapies, and including patients with ALL treated in the community in clinical trials may improve survival for underserved populations.

Primary Effusion Lymphoma: A Clinicopathological Study of 70 Cases.

Primary effusion lymphoma (PEL) is a rare type of large B-cell lymphoma associated with human herpesvirus 8 (HHV8) infection. Patients with PEL usually present with an effusion, but occasionally with an extracavitary mass. In this study, we reported a cohort of 70 patients with PEL: 67 men and 3 women with a median age of 46 years (range 26-91). Of these, 56 (80%) patients had human immunodeficiency virus (HIV) infection, eight were HIV-negative, and six had unknown HIV status. Nineteen (27%) patients had Kaposi sarcoma. Thirty-five (50%) patients presented with effusion only, 27 (39%) had an extracavitary mass or masses only, and eight (11%) had both effusion and extracavitary disease. The lymphoma cells showed plasmablastic, immunoblastic, or anaplastic morphology. All 70 (100%) cases were positive for HHV8. Compared with effusion-only PEL, patients with extracavitary-only PEL were younger (median age, 42 vs. 52 years, p = 0.001), more likely to be HIV-positive (88.9% vs. 68.6%, p = 0.06) and EBV-positive (76.9% vs. 51.9%, p = 0.06), and less often positive for CD45 (69.2% vs. 96.2%, p = 0.01), EMA (26.7% vs. 100%, p = 0.0005), and CD30 (60% vs. 81.5%, p = 0.09). Of 52 (50%) patients with clinical follow-up, 26 died after a median follow-up time of 40.0 months (range 0-96), and the median overall survival was 42.5 months. The median OS for patients with effusion-only and with extracavitary-only PEL were 30.0 and 37.9 months, respectively (p = 0.34), and patients with extracavitary-only PEL had a lower mortality rate at the time of last follow-up (35% vs. 61.5%, p = 0.07). The median OS for HIV-positive and HIV-negative patients were 42.5 and 6.8 months, respectively (p = 0.57), and they had a similar mortality rate of 50% at last follow-up. In conclusion, patients presenting with effusion-only versus extracavitary-only disease are associated with different clinicopathologic features. PEL is an aggressive lymphoma with a poor prognosis, regardless of extracavitary presentation or HIV status.

Cultural Adaptation of Evidence-Based Lifestyle Interventions for African American Men With Prostate Cancer: A Dyadic Approach.

Although a number of lifestyle interventions have been developed for cancer survivors, the extent to which they are effective for African American men with cancer is unclear. Given that African American men have the highest prostate cancer burden and the lack of proven interventions, this study developed a culturally-tailored lifestyle intervention for African American men with prostate cancer and their partners that aimed to improve healthy lifestyle behaviors (physical activity and healthy eating) and quality of life. The aim of the present study is to provide a detailed overview of the model-based process of intervention adaptation. Based on the IM Adapt approach (Highfield et al., 2015) and Typology of Adaptation (Davidson et al., 2013), the present study adapted existing, evidence-based interventions to address African American prostate cancer survivors' and their partners' potential unmet needs including anxiety/uncertainty about cancer progression, communication between partners, cultural sensitivity, and concordance/discordance of motivation and behaviors between partners. The intervention adaptation was a comprehensive and fluid process. To the best knowledge of the author, this is the first couple-based lifestyle intervention specifically developed for African American men with prostate cancer. The present study will be highly informative to future investigators by providing flexible and detailed information regarding lifestyle intervention adaptation for racial/ethnic minority men with prostate cancer and their partners.

Study protocol: a lifestyle intervention for African American and Hispanic prostate cancer survivors on active surveillance and their partners.

BACKGROUND: Prostate cancer is the most commonly diagnosed cancer in both African American and Hispanic men. Active surveillance is a treatment option for low- or very low-risk prostate cancer survivors, and lifestyle interventions have been found to reduce the disease progression and improve the quality of life for both survivors and their partners. To date, no lifestyle interventions that specifically target African American or Hispanic men and their partners exist. This protocol describes a study that tests the feasibility of a randomized controlled trial, a lifestyle intervention developed to enhance healthy lifestyle and quality of life among African American and Hispanic men on active surveillance and their partners. METHODS: A mixed-method study, including a two-arm randomized controlled trial (n = 30 dyads in the intervention arm and n = 10 dyads in the control arm) and in-depth interviews, will be conducted. Intervention arm participants will receive bi-weekly health coaching calls (a total of 12 calls based on Motivational Interviewing), as well as physical activity-specific (e.g., power point slides, print materials about physical activity, and activity trackers for self-monitoring) and nutrition-specific education (e.g., two nutrition counseling sessions from a registered dietitian, print materials about nutrition, and food intake recording for self-monitoring) over 6 months. All participants will be assessed at baseline, month 3, and month 6. Blood will be collected at baseline and month 6 from the prostate cancer survivors. Finally, in-depth interviews will be conducted with subsamples (up to n = 15 dyads in the intervention arm and up to n = 5 dyads in the control arm) at baseline and months 3 and 6 to conduct a process evaluation and further refine the intervention. DISCUSSION: If effective, the intervention may have a higher health impact compared with a typical lifestyle intervention targeting only survivors (or partners), as it improves both survivors' (tertiary prevention) and partners' health (primary prevention). Results from this study will provide important information regarding recruiting racial/ethnic minority cancer survivors and their partners. Lessons learned from this study will be used to apply for a large-scale grant to test the impact of the dyadic intervention in a fully powered sample. TRIAL REGISTRATION: ClinicalTrials.gov (NCT No. 03575832) registered on 3 July 2018.

A rare presentation of carcinosarcoma of the bone in a young female; response with gemcitabine and docetaxel.

BACKGROUND: Sarcomatoid carcinoma, or carcinosarcoma, is a neoplasm that contains both sarcomatous and carcinomatous elements. It is an extremely rare cancer most often arising from visceral organs. Here we report the seventh documented de novo case of carcinosarcoma of the bone, in a young female who showed initial clinical improvement with gemcitabine and docetaxel. CASE PRESENTATION: A 36-year-old Caucasian female presented with diffuse musculoskeletal pain that had progressed from her shoulder to her back, arm, and knee over 6 months. Imaging revealed diffuse sclerotic lesions of bilateral humeral heads, iliac and ischial bones, and thoracic and lumbar spine. Histopathologic examination of biopsies from the T9 vertebra and left femur showed mainly sarcomatous spindle cells with focal osteoid production. Immunostaining showed the cells to be OSCAR cytokeratin, patchy positive for pankeratin, and negative for CK7, GATA3, S100, SOX10, CD99, EMA, AE1/AE3, and HMW keratin indicative of an epithelial origin. After thorough clinical correlation, sarcomatoid carcinoma of a visceral organ was excluded and the diagnosis of primary sarcomatoid carcinoma of the bone was ultimately favored. She received chemotherapy with gemcitabine and docetaxel, and showed improvement at 6 months but ultimately passed 1 year post diagnosis. CONCLUSIONS: Primary carcinosarcoma of the bone is an extremely rare malignancy. Early diagnosis is crucial as localized disease may be curable with resection. As shown in this case, combination chemotherapy with gemcitabine and docetaxel is a potential option in patients with unresectable or metastatic disease.

Standardizing Opioid Prescribing Practices for Cancer-Related Pain Via a Novel Interactive Documentation Template at a Public Hospital.

PURPOSE: Opioid misuse during cancer pain management places patients at risk for harm and physicians for legal liability. Identifying and monitoring patients who are at risk is challenging given the lack of validated clinical tools and evidence-based guidelines. In the current study, we aimed to standardize opioid prescribing practices at a community oncology clinic to help ensure patient safety and physician compliance with Texas state regulations. METHODS: We used the Plan-Do-Study-Act methodology. In the planning phase, current practices of assessing opioid efficacy, toxicity, and misuse were determined by surveying clinic physicians and reviewing patients' charts. We developed a new standardized process that incorporated published literature, the Texas Administrative Code, and expert opinion. Two interactive documentation templates (SmartPhrases) were designed to implement the standardized process. The intervention was studied using repeat physician surveys and chart reviews, which prompted action for refinement and sustainability. RESULTS: At baseline, 9% of providers followed a systematic approach to prescribing opioids and 86% expressed an interest in process standardization. We noted high interprovider variability in the opioid risk stratification and refill process. At 2 months and 6 months postimplementation, provider satisfaction with the intervention was 83% and 75%, whereas compliance with SmartPhrase use was 70% and 54%, respectively. The frequency of state database check improved from 36% to 94% at 6 months. Improvement was also noted in assessment and documentation of baseline risk, chemical coping, and toxicity. CONCLUSION: We implemented a systematic approach for assessing opioid misuse, toxicity, and efficacy during cancer pain management at a community oncology clinic. The approach resulted in notable improvement in provider practices and documentation compliance.

Successful Implementation of a Multidisciplinary Chemotherapy Efficiency Initiative at a Community Hospital.

PURPOSE: Long wait times at chemotherapy infusion centers adversely affect patients' perception of quality of care and result in patient dissatisfaction. We conducted a quality improvement initiative at a busy community hospital to improve infusion center efficiency and reduce patient wait time, while maintaining patient safety and avoiding chemotherapy waste. METHODS: We used a coordinated and collaborative effort between providers, infusion center nurses, and pharmacists to ensure completion of orders, review of laboratory data, and prepreparation of chemotherapy 1 day ahead of each patient's scheduled infusion center appointment. Monthly Plan-Do-Study-Act cycles were conducted for 6 months beyond the pilot month to refine and sustain the intervention. RESULTS: The average patient cycle time, measured as time from patient check-in to check-out from the infusion chair, decreased from 252 minutes to 173 minutes in the last 4 months evaluated (30% decrease) after the intervention. Similarly, the average chemotherapy turnaround time, measured as time from chemotherapy request by nursing to pharmacy delivery, improved from 90 minutes to 27 minutes after the intervention (70% decrease). Infusion center capacity was unaffected by the intervention. The cost of wasted chemotherapy was minimal after the first postintervention month. Surveys revealed extremely high patient and employee satisfaction with the new system. CONCLUSION: A strategy involving prepreparation of chemotherapy on the day before the scheduled infusion is feasible to implement at a busy community hospital infusion center and is associated with significant improvement in infusion center efficiency as well as patient and employee satisfaction.

Driving Toward Precision Medicine for Acute Leukemias: Are We There Yet?

Despite recent progress in the understanding of the molecular basis of acute leukemias, treatment options for these diseases have not changed significantly over the last few decades. We present a nonexhaustive summary of the current cytogenetic and molecular changes associated with acute leukemias in disease prognostication and potential targeted therapies. An emerging paradigm is that many genetic or molecular alterations target similar signal transduction, transcriptional, and epigenetic pathways. Some of these targets may be used as predictive biomarkers for the development of novel targeted therapies that depart significantly from conventional chemotherapy, the current mainstay for the treatment of acute leukemias. Established leukemia-specific predictive biomarkers for precision medicine include those genetic lesions such as BCR-ABL1 for Philadelphia-positive acute lymphoblastic leukemia and PML-RARα for acute promyelocytic leukemia. Evidence indicates that targeted therapy for FLT-ITD gene mutations with small-molecule tyrosine kinase inhibitors can extend its use from relapsed disease to up-front induction therapy. Core-binding factor acute myeloid leukemia in adults predicts benefit with high-dose cytarabine in the absence of KIT mutation. Although risk-adapted therapy based on genetic abnormalities in acute leukemias has allowed the beginning of personalized treatment and selective use of hematopoietic stem cell transplantation, the prognostic and/or predictive value of many novel mutations of the acute leukemic genome is yet to be elucidated. Many challenges lie ahead in targeted therapies due to overlapping of chromosomal and molecular lesions as well as other limiting factors. Future work should focus on the understanding of pathogenetic changes that lead to leukemogenesis, which may guide the rational design of new targeted therapies and make the drive toward precision medicine for acute leukemias one step closer.

Predictors and outcome of patients with acute respiratory distress syndrome caused by miliary tuberculosis: a retrospective study in Chongqing, China.

BACKGROUND: Miliary tuberculosis (TB) is an uncommon cause of acute respiratory distress syndrome (ARDS) with a high mortality. The aim of the present study was to evaluate the clinical characteristics, predictors and outcome of patients with ARDS caused by miliary TB. METHODS: A retrospective study was conducted among patients with a diagnosis of ARDS with miliary TB in four hospitals from 2006 to 2010. Medical records and laboratory examinations of these patients were taken during the first 24 h of admission. RESULTS: Eighty-five patients with miliary TB developed ARDS, 45 of whom survived (52.9%). The median age was 36.6 ± 12.5 years with 38 males (44.7%). Diabetes mellitus (DM) was the most common underlying disease (18.8%).ICU mortality was 47.1%. The time from admission to anti-tuberculosis therapy was 4.5 ± 2.0 days. Mean duration of mechanical ventilation was 8.5 ± 3.0 days in all patients. Duration of time to diagnosis, time from diagnosis to mechanical ventilation, and time to anti-tuberculosis therapy were significantly shorter in survivors than those in non-survivors. Diabetes mellitus (OR 5.431, 95%CI 1.471-20.049; P = 0.005), ALT (70-100U/L, OR 10.029, 95%CI 2.764-36.389; P = 0.001), AST (>94U/L,OR 8.034, 95%CI 2.200-29.341; P = 0.002), D-dimer (>1.6mg/L, OR 3.167, 95%CI 0.896-11.187; P = 0.042), hemoglobin (<90g/L, OR 14.824, 95%CI 3.713-59.179; P = 0.001), albumin (<25g/L, OR 15.896, 95%CI 3.975-63.566; P = 0.001) were independent predictors of ARDS development in the setting of miliary TB. CONCLUSIONS: Accurate diagnosis, early initiation of anti-tuberculosis therapy and mechanical ventilation are important for the outcome of patients with ARDS caused by miliary TB. DM, ALT, AST, D-dimer, hemoglobin, and albumin are independent predictors of ARDS development in patients with miliary TB.

Regulation of alveolar fluid clearance and ENaC expression in lung by exogenous angiotensin II.

Angiotensin II (Ang II) has been demonstrated as a pro-inflammatory effect in acute lung injury, but studies of the effect of Ang II on the formation of pulmonary edema and alveolar filling remains unclear. Therefore, in this study the regulation of alveolar fluid clearance (AFC) and the expression of epithelial sodium channel (ENaC) by exogenous Ang II was verified. SD rats were anesthetized and were given Ang II with increasing doses (1, 10 and 100 µg/kg per min) via osmotic minipumps, whereas control rats received only saline vehicle. AT1 receptor antagonist ZD7155 (10 mg/kg) and inhibitor of cAMP degeneration rolipram (1 mg/kg) were injected intraperitoneally 30 min before administration of Ang II. The lungs were isolated for measurement of alveolar fluid clearance. The mRNA and protein expression of ENaC were detected by RT-PCR and Western blot. Exposure to higher doses of Ang II reduced AFC in a dose-dependent manner and resulted in a non-coordinate regulation of α-ENaC vs. the regulation of ß- and γ-ENaC, however Ang II type 1 (AT1) receptor antagonist ZD7155 prevented the Ang II-induced inhibition of fluid clearance and dysregulation of ENaC expression. In addition, exposure to inhibitor of cAMP degradation rolipram blunted the Ang II-induced inhibition of fluid clearance. These results indicate that through activation of AT(1) receptor, exogenous Ang II promotes pulmonary edema and alveolar filling by inhibition of alveolar fluid clearance via downregulation of cAMP level and dysregulation of ENaC expression.

Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells.

Despite similarities between tumor-initiating cells with stem-like properties (TICs) and normal neural stem cells, we hypothesized that there may be differences in their differentiation potentials. We now demonstrate that both bone morphogenetic protein (BMP)-mediated and ciliary neurotrophic factor (CNTF)-mediated Jak/STAT-dependent astroglial differentiation is impaired due to EZH2-dependent epigenetic silencing of BMP receptor 1B (BMPR1B) in a subset of glioblastoma TICs. Forced expression of BMPR1B either by transgene expression or demethylation of the promoter restores their differentiation capabilities and induces loss of their tumorigenicity. We propose that deregulation of the BMP developmental pathway in a subset of glioblastoma TICs contributes to their tumorigenicity both by desensitizing TICs to normal differentiation cues and by converting otherwise cytostatic signals to proproliferative signals.

A phase I trial of lenalidomide in patients with recurrent primary central nervous system tumors.

PURPOSE: Inhibition of angiogenesis represents a promising new therapeutic strategy for treating primary malignant brain tumors. Lenalidomide, a potent analogue of the antiangiogenic agent thalidomide, has shown significant activity in several hematologic malignancies, and therefore we chose to explore its tolerability and activity in patients with primary central nervous system tumors. EXPERIMENTAL DESIGN: A phase I interpatient dose escalation trial of lenalidomide in patients with recurrent primary central nervous system tumors was conducted. RESULTS: Thirty-six patients were accrued to the study, of which 28 were evaluable for toxicity, the primary end point of the trial. We show that lenalidomide can be given safely up to doses of 20 mg/m(2), with the only toxicity being a probable increased risk of thromboembolic disease. Pharmacokinetic studies reveal good bioavailability, linear kinetics, and no effects of enzyme-inducing antiepileptic drugs on the metabolism of lenalidomide. No objective radiographic responses were seen in any of the treated patients. In the group of 24 patients with recurrent glioblastoma, the median time to tumor progression was <2 months and only 12.5% of patients were progression-free at 6 months. CONCLUSION: Lenalidomide is well tolerated in patients with recurrent glioma in doses up to 20 mg/m(2). Treatment may be associated with an increased risk of thromboembolic disease. Preliminary data suggest that single agent activity may be limited in patients with recurrent glioblastoma at the doses evaluated although larger studies will be needed to confirm these observations.