Role of Kindness in Cancer Care.

The wonders of high-tech cancer care are best complemented by the humanity of high-touch care. Simple kindnesses can help to diffuse negative emotions that are associated with cancer diagnosis and treatment-and may even help to improve patients' outcomes. On the basis of our experience in cancer care and research, we propose six types of kindness in cancer care: deep listening , whereby clinicians take the time to truly understand the needs and concerns of patients and their families; empathy for the patient with cancer, expressed by both individual clinicians and the care culture, that seeks to prevent avoidable suffering; generous acts of discretionary effort that go beyond what patients and families expect from a care team; timely care that is delivered by using a variety of tools and systems that reduce stress and anxiety; gentle honesty, whereby the truth is conveyed directly in well-chosen, guiding words; and support for family caregivers, whose physical and mental well-being are vital components of the care their loved ones receive. These mutually reinforcing manifestations of kindness-exhibited by self-aware clinicians who understand that how care is delivered matters-constitute a powerful and practical way to temper the emotional turmoil of cancer for patients, their families, and clinicians themselves.

Discussing prognosis and treatment goals with patients with advanced cancer: A qualitative analysis of oncologists' language.

BACKGROUND: The National Academy of Medicine recommends that cancer patients be knowledgeable of their prognosis to enable them to make informed treatment decisions, but research suggests few patients receive this information. OBJECTIVE: This qualitative study describes oncologists' language during discussions of prognosis and treatment goals in clinical interactions with African American patients diagnosed with cancer. DESIGN: We analysed transcripts from video recordings of clinical interactions between patients with Stage III or IV cancer (n=26) and their oncologists (n=9). In-depth discourse analysis was conducted to describe and interpret oncologists' communication behaviours and common linguistic features in the interactions. SETTING AND PARTICIPANTS: Data were from a larger study of patient-provider communication between African Americans and oncologists at two cancer hospitals in Detroit. RESULTS: Prognosis was discussed in 73.1% (n=19) of the interactions; treatment goals were discussed in 92.3% (n=24). However, analysis revealed that oncologists' description of prognosis was vague (e.g. "prognosis is a bit worse in your case") and rarely included a survival estimate. Oncologists often used ambiguous terminology, including euphemisms and jargon, and emphasized uncertainty (e.g. "lesions are suspicious for the disease"). Conversation about prognosis was frequently brief, moving quickly to the urgency and details of treatment. DISCUSSION: This study demonstrates how oncologists' language may obscure discussion of prognosis and treatment goals. The identified behaviours may lead to missed opportunities in eliciting and discussing patients' knowledge about and preferences for their care. Patient-, provider- and system-oriented interventions are needed to improve clinical communication, especially among minority patients with advanced cancer.

Clues to the Blues: Predictors of Self-Reported Mental and Emotional Health Among Older African American Men.

The mental health needs of aging African American men have been overlooked and few studies have distinguished between more severe clinically diagnosable mental health challenges and less severe emotional states for this population. African American men may not identify with or internalize the terminology of "depression" despite exhibiting the symptom criteria. This exploratory cross-sectional study examined correlates of "downheartedness" as an alternative indicator of emotional health. The authors examined the self-reported responses of 1,666 older African American men on a baseline questionnaire from a larger longitudinal study. Demographic, physical, mental and emotional health, and health system factors were examined as possible correlates of downheartedness. The mean age of participants was 73.6 years and 74.8% of men described themselves as "downhearted and blue" most or all of the time while only 18.5% of them reported feeling moderate to severe anxiety or depression. When other factors were controlled, mobility problems (odds ratio [ OR] = 2.36), problems getting health care ( OR = 2.69), having a doctor who never listens ( OR = 2.18), physical or mental problems that interfere with social activities ( OR = 1.34), accomplishing less due to physical health ( OR = 1.35), and accomplishing less due to mental/emotional health ( OR = 1.57) were all associated with greater odds of being downhearted. The current findings indicate that this sample more closely identified with language accurately describing their emotional health state (i.e., downhearted) and not with clinical mental health terminology (i.e., depression) that may be culturally stigmatized.

An Analysis of Race-related Attitudes and Beliefs in Black Cancer Patients: Implications for Health Care Disparities.

This research concerned relationships among Black cancer patients' health care attitudes and behaviors (e.g., adherence, decisional control preferences,) and their race-related attitudes and beliefs shaped by (a) general life experiences (i.e., perceived discrimination, racial identity) and (b) experiences interacting with health care systems (i.e., physician mistrust, suspicion about medical care). Perceived discrimination, racial identity, and medical suspicion correlated weakly with one another; mistrust and suspicion correlated only moderately. Race-related attitudes and beliefs were associated with health care attitudes and behavior, but patterns of association varied. Physician mistrust and medical suspicion each independently correlated with adherence and decisional control preferences, but discrimination only correlated with control preferences. Associations among patients' different racial attitudes/beliefs are more complex than previously assumed. Interventions that target patient attitudes/beliefs and health care disparities might be more productive if they focus on mistrust or suspicion specific to health care providers/systems and their correlates identified in this study.

Risk of Lung Cancer Associated with COPD Phenotype Based on Quantitative Image Analysis.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer. This study evaluates alternative measures of COPD based on spirometry and quantitative image analysis to better define a phenotype that predicts lung cancer risk. METHODS: A total of 341 lung cancer cases and 752 volunteer controls, ages 21 to 89 years, participated in a structured interview, standardized CT scan, and spirometry. Logistic regression, adjusted for age, race, gender, pack-years, and inspiratory and expiratory total lung volume, was used to estimate the odds of lung cancer associated with FEV1/FVC, percent voxels less than -950 Hounsfield units on the inspiratory scan (HUI) and percent voxels less than -856 HU on expiratory scan (HUE). RESULTS: The odds of lung cancer were increased 1.4- to 3.1-fold among those with COPD compared with those without, regardless of assessment method; however, in multivariable modeling, only percent voxels <-856 HUE as a continuous measure of air trapping [OR = 1.04; 95% confidence interval (CI), 1.03-1.06] and FEV1/FVC < 0.70 (OR = 1.71; 95% CI, 1.21-2.41) were independent predictors of lung cancer risk. Nearly 10% of lung cancer cases were negative on all objective measures of COPD. CONCLUSION: Measures of air trapping using quantitative imaging, in addition to FEV1/FVC, can identify individuals at high risk of lung cancer and should be considered as supplementary measures at the time of screening for lung cancer. IMPACT: Quantitative measures of air trapping based on imaging provide additional information for the identification of high-risk groups who might benefit the most from lung cancer screening. Cancer Epidemiol Biomarkers Prev; 25(9); 1341-7. ©2016 AACR.

Fatalistic Beliefs About Cancer Prevention Among Older African American Men.

OBJECTIVES: Evidence suggests that minority groups are more likely to exhibit fatalistic beliefs about cancer prevention (FBCP), which are defined as confusion, pessimism, and helplessness about one's ability to prevent cancer. This study examines the socioeconomic and psychosocial predictors of FBCP among older African American men (AAM). METHODS: AAM (N = 1,666) enrolled in Medicare and participating in a longitudinal study on patient navigation were surveyed. Measures included three FBCP constructs, namely demographic items and physical and mental health variables. Binary logistic regression was performed. RESULTS: The average participant was 73.6 years old; 76.5% felt helpless, 44.2% were confused, and 40.7% were pessimistic about the ability to prevent cancer. As education increased, so did all three FBCP. Being downhearted was predictive of confused and helpless beliefs. DISCUSSION: It is critical for health practitioners to understand how psychosocial and economic challenges influence beliefs that may impede cancer prevention efforts for older AAM.

Unexpected findings in the exploration of African American underrepresentation in biospecimen collection and biobanks.

Racial/ethnic minorities are underrepresented in current biobanking programs. The current study utilized community-based participatory research to identify motivating factors and barriers that affect older African Americans' willingness to donate biospecimens. The standardized phone survey was administered to 78 African Americans who are 55 years old or older and live in the metropolitan Detroit area to assess their overall willingness to donate biospecimens and what factors were associated with it. The majority of the participants were willing to donate biospecimens, along with their personal information, for medical research and indicated that they did donate biospecimens when they were asked. However, African Americans were rarely asked to participate in biobanking programs. Furthermore, African Americans were not as concerned with research exploitation or as mistrusting of medical researchers as previously thought by the medical researchers. Even if African Americans were concerned over potential research exploitation or mistrust of medical researchers, these concerns or mistrust did not translate into an actual unwillingness to participate in biobanking programs. Rather, transparency in medical research and biobanking programs was more important when predicting African Americans' willingness to donate biospecimens for medical research. The findings suggest that underrepresentation of African Americans in current biobanking programs may not be due to their willingness/unwillingness to participate in such programs but rather due to a failure of medical researchers to approach them. Additionally, researchers and clinicians should focus on increasing the transparency of medical research and biobanking programs rather than changing African Americans' potential negative attitudes toward them.

Phase II trial of romidepsin (NSC-630176) in previously treated colorectal cancer patients with advanced disease: a Southwest Oncology Group study (S0336).

INTRODUCTION: Patients with metastatic colorectal cancer who progress on standard chemotherapy have limited treatment options. New and effective drugs are needed for these patients. Romidepsin is a histone deacetylase inhibitor that can alter chromatin structure and gene transcription leading to multiple changes in cellular protein production. This may result in cell cycle arrest and tumor growth inhibition. Romidepsin has shown anti-proliferative activity in vitro against multiple mouse and human tumor cell lines and in vivo in human tumor xenograft models. PATIENTS AND METHODS: Patients were required to have pathologically verified, measurable, metastatic or locally advanced colorectal cancer that was surgically unresectable. They must have failed either one or two prior chemotherapy regimens, had performance status of 0-1, adequate bone marrow, renal and hepatic function, and no significant cardiac disease. Patients were treated with romidepsin at a dose of 13 mg/m(2) as a 4-h iv infusion on days 1, 8, and 15 of a 28-day cycle. The study had a two stage design. The primary objective of the study was to determine the confirmed response probability in this group of patients treated with romidepsin. RESULTS: Twenty-eight patients were registered to the study, two of whom were ineligible. One eligible patient refused all treatment and was not analyzed. For the 25 remaining patients, performance status was 0 in 16 patients and 1 in nine patients. Ten patients had received one prior chemotherapy regimen and fifteen 2 prior regimens. Out of the 25 eligible and analyzable patients accrued in the first stage of the protocol, no objective responses were observed and the study was permanently closed. Four patients had stable disease as the best response. Twenty-five patients were assessed for toxicity. No grade 4 or greater toxicities were seen. Fourteen of the 25 patients experienced grade 3 toxicities the most common of which were fatigue or anorexia. CONCLUSION: Romidepsin at this dose and schedule is ineffective in the treatment of patients with metastatic colorectal cancer after prior chemotherapy. Future trials might evaluate combinations of romidepsin with chemotherapeutic or other agents.

Antiandrogen withdrawal in castrate-refractory prostate cancer: a Southwest Oncology Group trial (SWOG 9426).

BACKGROUND: Antiandrogen withdrawal is a potential therapeutic maneuver for patients with progressive prostate cancer. This study was designed to examine antiandrogen withdrawal effects within the context of a large multi-institutional prospective trial. METHODS: Eligibility criteria included progressive prostate adenocarcinoma despite combined androgen blockade. Eligible patients received prior initial treatment with an antiandrogen plus orchiectomy or luteinizing hormone-releasing hormone (LHRH) agonist. Patients were stratified according to type of antiandrogen, type of progression (prostate-specific antigen [PSA] or radiographic), presence or absence of metastatic disease, and prior LHRH agonist versus surgical castration. RESULTS: A total of 210 eligible and evaluable patients had a median follow-up of 5.0 years; 64% of patients previously received flutamide, 32% bicalutamide, and 3% nilutamide. Of the 210 patients, 21% of patients had confirmed PSA decreases of >or=50% (95% CI, 16% to 27%). No radiographic responses were recorded. Median progression-free survival (PFS) was 3 months (95% CI, 2 months to 4 months); however, 19% had 12-month or greater progression-free intervals. Median overall survival (OS) after antiandrogen withdrawal was 22 months (20 and 40 months for those with and without radiographic evidence of metastatic disease, respectively). Multivariate analyses indicated that longer duration of antiandrogen use, lower PSA at baseline, and PSA-only progression at study entry were associated with both longer PFS and OS. Longer antiandrogen use was the only significant predictor of PSA response. CONCLUSIONS: These data indicate a relatively modest rate of PSA response in patients who were undergoing antiandrogen withdrawal; however, PFS can be relatively prolonged (>or=1 year) in approximately 19% of patients.

Chemotherapy in patients > or = 80 with advanced non-small cell lung cancer: combined results from SWOG 0027 and LUN 6.

INTRODUCTION: We report outcomes for the combined cohort of patients ages 80 or older from two chemotherapy trials in advanced non-small cell lung cancer (NSCLC) conducted by the Southwest Oncology Group (S0027) and an investigator-initiated trial (LUN 6). METHODS: Patients with chemotherapy-naïve, stage IIIB/IV NSCLC, ages 70 years or older with a performance status (PS) of 0 or 1, or patients of any age with PS 2, were eligible. Treatment in the S0027 study was 25 mg/m2 of vinorelbine on days 1 and 8, every 21 days for three cycles, and then 35 mg/m2 of docetaxel on days 1, 8, and 15, every 28 days for three cycles. Treatment in the LUN 6 study was 30 mg/m2 of docetaxel on days 1, 8, and 15, every 28 days, or 75 mg/m2 every 21 days. Of the 228 patients treated, 49 (21.5%; 26 in LUN 6 and 23 in S0027) were ages 80 years or older. Analysis of outcome was conducted in the 80-and-older group and was compared with the under-80 cohort from S0027. RESULTS: Among patients with measurable disease, disease-control rates (partial response + stable disease) were 54% (n = 48) and 46% (n = 89) in the 80-and-older and under-80 groups, respectively. Median survival was 7 and 11 months in PS 0/1 patients in the 80-and-older and under-80 groups, respectively. Median survival was 4 and 5 months in PS 2 patients in the 80-and-older and under-80 groups, respectively. Treatment was well tolerated. Five treatment-related deaths were noted: two (4%) and three (3.4%) in the 80-or-younger and the under-80 groups, respectively. CONCLUSIONS: These chemotherapy regimens were associated with an encouraging disease-control rate (54%) in patients 80 years or older with advanced NSCLC, with good tolerance. Selected octogenarians with advanced NSCLC may benefit from single-agent chemotherapy.

Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321.

PURPOSE: Results of a prospective randomized trial conducted by the Intergroupe Francais du Myélome (IFM 90) indicated that autologous hematopoietic cell-supported high-dose therapy (HDT) effected higher complete response rates and extended progression-free survival (PFS) and overall survival (OS) compared with standard-dose therapies (SDT) for patients with multiple myeloma (MM). PATIENTS AND METHODS: In 1993, three North American cooperative groups launched a prospective randomized trial (S9321) comparing HDT (melphalan [MEL] 140 mg/m2 plus total-body irradiation 12 Gy) with SDT using the vincristine, carmustine, MEL, cyclophosphamide, and prednisone regimen. Responders on both arms (> or = 75%) were randomly assigned to interferon (IFN) or no maintenance treatment. RESULTS: With a median follow-up time of 76 months, no differences were observed in response rates between the two study arms (HDT, n = 261 patients; SDT, n = 255 patients). Similarly, PFS and OS durations did not differ between the HDT and SDT arms, with 7-year estimates of PFS of 17% and 16%, respectively, and OS of 37% and 42%, respectively. Of 242 patients achieving at least 75% tumor reduction, no difference was observed in PFS or OS among the 121 patients randomly assigned to IFN and the 121 patients randomly assigned to no maintenance therapy. Among 157 patients relapsing on SDT, 87 received a salvage autotransplantation; their median survival time of 30 months was only slightly better than the survival time of the remaining patients who were managed with further SDT (23 months; P = .13). CONCLUSION: The HDT and SDT regimens used in S9321 yielded comparable response rates and PFS and OS durations. IFN maintenance therapy did not benefit patients who achieved > or = 75% tumor reduction on either arm.

Sequential vinorelbine and docetaxel in advanced non-small cell lung cancer patients age 70 and older and/or with a performance status of 2: a phase II trial of the Southwest Oncology Group (S0027).

BACKGROUND: This phase II study (S0027) evaluated the efficacy and tolerability of planned sequential single-agent chemotherapy with vinorelbine followed by docetaxel in patients with advanced non-small cell lung cancer (NSCLC) age 70 and older and/or a performance status (PS) of 2. METHODS: Patients with stage IIIB (pleural effusion) or stage IV NSCLC, age 70 and older with a PS of 0-1 or 2, any age, received three cycles of vinorelbine 25 mg/m days 1 and 8 every 21 days followed by three cycles of docetaxel 35 mg/m days 1, 8, and 15 every 28 days. RESULTS: A total of 125 patients entered the study; 117 patients were assessable for response, survival, and toxicity. Seventy-five patients were in stratum1 (age 70 and older, PS 0-1) and 42 patients in stratum 2 (PS 2, any age). Objective response was 19% (95% confidence interval [CI]: 11%-30%) and 11% (95% CI: 3%-25%) in strata 1 and 2, respectively. Median survival was 9.1 months (95% CI: 7.1-12.7) and 5.5 months (95% CI: 3.1-6.5) in strata 1 and 2, respectively. Survival at 12 months was 41% and 13% in strata 1 and 2, respectively. Grade 3/4 neutropenia was seen in 32% and 31% of patients in strata 1 and 2, respectively. Three deaths probably related to treatment were noted: one in stratum 1 and two in stratum 2. CONCLUSION: Sequential vinorelbine and docetaxel is a well-tolerated and effective regimen in comparison with reports of other treatments tested in patients with advanced NSCLC age 70 and older and/or with a PS of 2.

Curcumin sensitizes prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand/Apo2L by inhibiting nuclear factor-kappaB through suppression of IkappaBalpha phosphorylation.

Epidemiologic studies suggest that diet rich in plant-derived foods plays an important role in the prevention of prostate cancer. Curcumin, the yellow pigment in the spice turmeric, has been shown to exhibit chemopreventive and growth inhibitory activities against multiple tumor cell lines. We have shown previously that curcumin and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo2L interact to induce cytotoxicity in the LNCaP prostate cancer cell line. In this study, we investigated the mechanism by which curcumin augments TRAIL-induced cytotoxicity in LNCaP cells. Subtoxic concentrations of the curcumin-TRAIL combination induced strong apoptotic response in LNCaP cells as demonstrated by the binding of Annexin V-FITC and cleavage of procaspase-3. Furthermore, LNCaP cells express constitutively active nuclear factor-kappaB (NF-kappaB), which is inhibited by curcumin. Because NF-kappaB has been shown to mediate resistance to TRAIL-induced apoptosis in tumor cells, we investigated whether there is a relationship between NF-kappaB activation and resistance to TRAIL in LNCaP prostate cancer cells. Pretreatment with curcumin inhibited the activation of NF-kappaB and sensitized LNCaP cells to TRAIL. A similar increase in the sensitivity of LNCaP cells to TRAIL-induced apoptosis was observed following inhibition of NF-kappaB by dominant negative mutant IkappaBalpha, an inhibitor of NF-kappaB. Finally, curcumin was found to inhibit NF-kappaB by blocking phosphorylation of IkappaBalpha. We conclude that NF-kappaB mediates resistance of LNCaP cells to TRAIL and that curcumin enhances the sensitivity of these tumor cells to TRAIL by inhibiting NF-kappaB activation by blocking phosphorylation of IkappaBalpha and its degradation.

Immunomodulatory activity of curcumin: suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production in vitro.

Curcumin (diferuloylmethane), a major curcumanoid found in the spice turmeric, exhibits anti-inflammatory, anti-oxidant, and chemopreventive activities. However, the effect of curcumin on the development of T cell-mediated immunological responses largely remains unknown. In this study we have investigated the effect of curcumin on mitogen/antigen induced proliferation of splenic lymphocytes, induction of cytotoxic T lymphocytes (CTLs), lymphokine activated killer (LAK) cells, and the production of cytokines by T lymphocytes and macrophages. We found that mitogen, interleukin-2 (IL-2) or alloantigen induced proliferation of splenic lymphocytes, and development of cytotoxic T lymphocytes is significantly suppressed at 12.5-30 micromol/L curcumin. The generation of LAK cells at similar concentrations was less sensitive to the suppressive effect of curcumin compared to the generation of antigen specific CTLs. Curcumin irreversibly impaired the production of these immune functions, since lymphoid cells failed to respond to the activation signals following 8h pretreatment with curcumin. Curcumin also inhibited the expression/production of IL-2 and interferon-gamma (IFN-gamma) by splenic T lymphocytes and IL-12 and tumor necrosis factor-alpha (TNF-alpha) by peritoneal macrophages irreversibly. Curcumin inhibited the activation of the transcription factor nuclear factor kappaB (NF-kappaB) without affecting the levels of constitutively expressed NF-kappaB. The latter result suggests that curcumin most likely inhibits cell proliferation, cell-mediated cytotoxicity (CMC), and cytokine production by inhibiting NF-kappaB target genes involved in induction of these immune responses.

Immunomodulatory activity of resveratrol: discrepant in vitro and in vivo immunological effects.

trans-Resveratrol is a dietary polyphenolic compound present in grapes, which has been shown to exhibit strong anti-inflammatory, antioxidant, and chemopreventive activities. In this study we have compared the in vitro and in vivo effects of resveratrol on the development of various cell-mediated immune responses, including mitogen/antigen-induced T cell proliferation, induction of cytotoxic T lymphocytes (CTLs), interleukin-2 (IL-2) induced lymphokine activated killer cells, and cytokine production. We found significant suppression (>90%) of the mitogen/antigen-induced T cell proliferation and development of allo-antigen specific CTLs in vitro with resveratrol at a concentration of 25 microM. Intragastric administration of resveratrol (2 mg daily) to mice for 4 weeks showed no effect on age-related gain in body weight, peripheral blood cell counts (WBC, RBC, or platelets), or the cellularity of bone marrow or spleen. The CD4(+) and CD8(+) T cells in spleen or colony-forming units-total in the marrow also remained unaffected by treatment with resveratrol. Spleen cells, which were stimulated in vitro after being removed from mice which had been administered resveratrol for 2 or 4 weeks, showed no significant change in IL-2 or concanavalin A induced proliferation of T cells or production of IL-2 induced lymphokine activated killer cells. Further, the production of in interferon-gamma and IL-12 was not affected by administration of resveratrol, but production of tumor necrosis factor-alpha was reduced. Even when conducted entirely in vivo, treatment with resveratrol was found to only marginally reduce allo-antigen induced T cell proliferation and the generation of CTLs in the draining lymph nodes. Thus, even though resveratrol strongly inhibits T cell proliferation and production of cytolytic cells in vitro, oral administration of resveratrol for 4 weeks does not induce hematologic or hematopoietic toxicity, and only marginally reduces the T cell-mediated immune responses.

High-dose ifosfamide with mesna and granulocyte-colony-stimulating factor (recombinant human G-CSF) in patients with unresectable malignant mesothelioma.

BACKGROUND: The current study was conducted to assess the activity and toxicity of high-dose ifosfamide and mesna with recombinant human granulocyte-colony-stimulating factor (rhG-CSF), given in an outpatient setting, in the treatment of patients with unresectable malignant mesothelioma. METHODS: Between September 1994 and September 1996, 41 patients with histologically verified, unresectable malignant mesothelioma were registered, 38 of whom were analyzable (2 were ineligible and 1 was nonanalyzable). Patients received intravenous ifosfamide at a dose of 2.8 g/m2 over 3 hours (total dose of 14 g/m2), plus mesna at a dose of 0.56 g/m2 prior to and at 4 hours and 8 hours after ifosfamide infusion daily for 5 days every 21 days. rhG-CSF at a dose of 5 microg/kg/day was administered subcutaneously on days 6-15. RESULTS: Response assessment could be determined adequately in 21 patients. Two patients obtained responses; 1 was a confirmed partial response (3%; 95% confidence interval [95% CI], 0-14%) and 1 was an unconfirmed response (3%; 95% CI, 5-14%). Eleven patients had stable disease (29%), 7 patients developed disease progression (18%), 1 patient had an early death (3%), and 17 patients had inadequate assessment (45%). At the time of last follow-up, 36 of the 38 eligible patients had developed disease progression, with a median progression-free survival of 5 months (95% CI, 3-7 months) and 34 patients had died with a median survival of 7 months (95% CI, 6-9 months). Twenty-four patients (63%) and 7 patients (18%), respectively, had Grade (according to Southwestern Oncology Group Toxicity Criteria) 4 hematologic toxicities and Grade 4 nonhematological toxicities. There was one treatment-related death, the result of infection, pulmonary edema, and renal failure. CONCLUSIONS: This regimen demonstrated a low overall objective response rate with substantial toxicity, and in the opinion of the authors does not warrant further investigation in the treatment of patients with unresectable malignant mesothelioma.

In vitro analysis of the antileukemic effect of tumor necrosis factor-alpha gene therapy with myeloid progenitor cells: the role of dendritic cells.

We have previously demonstrated that tumor necrosis factor-alpha (TNF-alpha) gene therapy with transgene-expressing myeloid progenitor cells (32DTNF-alpha) is effective in inhibiting the progression of leukemia with a lethal dose of murine 32Dp210 myeloid leukemia cells. Because TNF-alpha has been shown to induce the activation and maturation of dendritic cells (DCs), we investigated the effect of TNF-alpha secreted by transduced cells (32DTNF-alpha cells) on the activation of DCs and their role in the production of antileukemic cytotoxic T lymphocytes (CTLs). We demonstrate that administration of 32DTNF-alpha cells to the mice enhances the allo-stimulatory capacity of the splenic (CD11c+) and bone marrow-derived DCs in both mixed leukocyte response and CTL development. The enhanced allo-stimulatory capacity of splenic DCs from mice injected with 32DTNF-alpha cells correlated with increase in the cell-surface expression of the costimulatory molecules CD40, CD80, CD86, and major histocompatibility complex (MHC) class II molecules (I-Ak), and production of interleukin-12 (IL-12). Furthermore, administration of 32DTNF-alpha cells during immunization with irradiated 32Dp210 leukemia cells augmented the capacity of splenic DCs to stimulate antileukemic CTL response in spleen cells. Collectively, these data suggest that in vivo production of TNF-alpha by transduced cells enhances the phenotypic and functional activation of DCs, resulting in induction of a stronger antileukemic cytotoxic T-cell immune response.

Dose-intense chemotherapy every 2 weeks with dose-intense cyclophosphamide, doxorubicin, vincristine, and prednisone may improve survival in intermediate- and high-grade lymphoma: a phase II study of the Southwest Oncology Group (SWOG 9349).

PURPOSE: To test the hypothesis that therapy of intermediate- and high-grade (excluding Burkitt lymphoblastic) lymphoma with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) could be safely dose-intensified with routine filgrastim support. PATIENTS AND METHODS: Eligible patients were those who were previously untreated and who had either bulky stage II, or stage III or IV lymphoma with working formulation histology D, E, F, G, H, or J; performance status < or = 2; and acceptable end organ function. No upper age limit was specified. Therapy was dose-intensified CHOP (CHOP-DI) with filgrastim support. Each course was repeated every 14 days for six planned courses. RESULTS: Eighty-eight eligible patients were treated with CHOP-DI and had a median follow-up of 5.1 years on this phase II study, designated Southwest Oncology Group (SWOG) 9349. The progression-free survival was 51% at 2 years and 41% at 5 years. The overall survival was 60% at 5 years. Three fatal treatment-related events occurred. One patient with myelodysplastic syndrome was reported. CONCLUSION: Treatment with CHOP-DI can be safely administered in the cooperative group setting and results in improved survival. Estimated overall survival at 5 years was 14% better than that of patients treated with standard-dose CHOP in an earlier SWOG study, although progression-free survival of 60% at 2 years-the prespecified end point-was not achieved. CHOP-DI, given every 2 weeks at escalated doses, is a strategy that should be tested in a future randomized clinical trial in lymphoma.

Combination of fludarabine and mitoxantrone in untreated stages III and IV low-grade lymphoma: S9501.

PURPOSE: To determine the efficacy of combination fludarabine and mitoxantrone (FN) in untreated stages III and IV low-grade lymphoma. The major end point was to estimate progression-free survival (PFS) in all eligible patients. PATIENTS AND METHODS: Seventy-eight eligible patients were registered. Chemotherapy courses were administered every 4 weeks with mitoxantrone 10 mg/m2 on day 1 and fludarabine 25 mg/m2 on days 1, 2, and 3 for a total of six to eight cycles. Pneumocystis carinii prophylaxis was required. RESULTS: Seventy-three patients (94%) attained an objective response. Complete remission was demonstrated in 34 patients (44%) and partial remission was demonstrated in 39 patients (50%). With a median follow-up time of 5.5 years, the median PFS was 32 months, with a 4-year PFS rate of 38%. Median survival has not been reached and 88% of all patients are alive at 4 years. The application of the International Prognostic Index and serologic staging showed significant differences in PFS in all risk groups, whereas overall survival was markedly worse for the highest-risk group in either prognostic model. Three prior Southwest Oncology Group trials using a regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone or a combination of prednisone, vincristine, methotrexate, cytarabine, cyclophosphamide, etoposide, nitrogen mustard, vincristine, procarbazine, and prednisone in similar patient populations demonstrated comparable clinical outcome, although the 4-year survival for FN was better. FN was well tolerated, but mild to severe reversible myelosuppression was noted. Other complications were rare. CONCLUSION: FN is an effective, safe chemotherapy combination for patients with advanced-stage, low-grade lymphoma. Clinical outcomes were comparable to prior published data using anthracycline-based regimens.

Curcumin (diferuloyl-methane) enhances tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in LNCaP prostate cancer cells.

The role of natural food products in prevention of prostate cancer has been confirmed in recent epidemiological studies; however, the mechanism of chemoprevention by the dietary constituents largely remains unknown. Curcumin, the yellow pigment and active component of turmeric (Curcuma longa), exhibits chemopreventive and growth inhibitory activity against several tumor cell lines. The androgen-sensitive human prostate cancer cell line LNCaP is only slightly susceptible to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor family of cell death-inducing ligands. In this study, we investigated whether curcumin and TRAIL cooperatively interact to promote death of LNCaP cells. At low concentrations (10 micro M curcumin and 20 ng/ml TRAIL), neither of the two agents alone produced significant cytotoxicity (curcumin, <10%; TRAIL, approximately 15%) in LNCaP cells, as measured by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfonyl)-2H-tetrazolium dye reduction assay. On the other hand, cell death was markedly enhanced (2-3-fold) if tumor cells were treated with curcumin and TRAIL together. The combined curcumin and TRAIL treatment increased the number of hypodiploid cells and induced DNA fragmentation in LNCaP cells. The combined treatment induced cleavage of procaspase-3, procaspase-8, and procaspase-9, truncation of Bid, and release of cytochrome c from the mitochondria, indicating that both the extrinsic (receptor-mediated) and intrinsic (chemical-induced) pathways of apoptosis are triggered in prostate cancer cells treated with a combination of curcumin and TRAIL. These results define a potential use of curcumin to sensitize prostate cancer cells for TRAIL-mediated immunotherapy.