A ghrelin-growth hormone axis drives stress-induced vulnerability to enhanced fear.

Hormones in the hypothalamus-pituitary-adrenal (HPA) axis mediate many of the bodily responses to stressors, yet there is no clear relationship between the levels of these hormones and stress-associated mental illnesses such as posttraumatic stress disorder (PTSD). Therefore, other hormones are likely to be involved in this effect of stress. Here we used a rodent model of PTSD in which rats repeatedly exposed to a stressor display heightened fear learning following auditory Pavlovian fear conditioning. Our results show that stress-related increases in circulating ghrelin, a peptide hormone, are necessary and sufficient for stress-associated vulnerability to exacerbated fear learning and these actions of ghrelin occur in the amygdala. Importantly, these actions are also independent of the classic HPA stress axis. Repeated systemic administration of a ghrelin receptor agonist enhanced fear memory but did not increase either corticotropin-releasing factor (CRF) or corticosterone. Repeated intraamygdala infusion of a ghrelin receptor agonist produced a similar enhancement of fear memory. Ghrelin receptor antagonism during repeated stress abolished stress-related enhancement of fear memory without blunting stress-induced corticosterone release. We also examined links between ghrelin and growth hormone (GH), a major downstream effector of the ghrelin receptor. GH protein was upregulated in the amygdala following chronic stress, and its release from amygdala neurons was enhanced by ghrelin receptor stimulation. Virus-mediated overexpression of GH in the amygdala was also sufficient to increase fear. Finally, virus-mediated overexpression of a GH receptor antagonist was sufficient to block the fear-enhancing effects of repeated ghrelin receptor stimulation. Thus, ghrelin requires GH in the amygdala to exert fear-enhancing effects. These results suggest that ghrelin mediates a novel branch of the stress response and highlight a previously unrecognized role for ghrelin and growth hormone in maladaptive changes following prolonged stress.

An individual patient-data comparison of combined modality therapy and ABVD alone for patients with limited-stage Hodgkin lymphoma.

BACKGROUND: Treatment options for patients with nonbulky stage IA-IIA Hodgkin lymphoma include combined modality therapy (CMT) using doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) plus involved-field radiation therapy (IFRT), and chemotherapy with ABVD alone. There are no mature randomized data comparing ABVD with CMT using modern radiation techniques. PATIENTS AND METHODS: Using German Hodgkin Study Group HD10/HD11 and NCIC Clinical Trials Group HD.6 databases, we identified 588 patients who met mutually inclusive eligibility criteria from the preferred arms of HD10 or 11 (n = 406) and HD.6 (n = 182). We evaluated time to progression (TTP), progression-free (PFS) and overall survival, including in three predefined exploratory subset analyses. RESULTS: With median follow-up of 91 (HD10/11) and 134 (HD.6) months, respective 8-year outcomes were for TTP, 93% versus 87% [hazard ratio (HR) 0.44, 95% confidence interval (CI) 0.24-0.78]; for PFS, 89% versus 86% (HR 0.71, 95% CI 0.42-1.18) and for overall survival, 95% versus 95% (HR 1.09, 95% CI 0.49-2.40). In the exploratory subset analysis including HD10 eligible patients who achieved complete response (CR) or unconfirmed complete response (CRu) after two cycles of ABVD, 8-year PFS was 87% (HD10) versus 95% (HD.6) (HR 2.8; 95% CI 0.64-12.5) and overall survival 96% versus 100%. In contrast, among those without CR/CRu after two cycles of ABVD, 8-year PFS was 88% versus 74% (HR 0.35; 95% CI 0.16-0.79) and overall survival 95% versus 91%, respectively (HR 0.42; 95% CI 0.12-1.44). CONCLUSIONS: In patients with nonbulky stage IA-IIA Hodgkin lymphoma, CMT provides better disease control than ABVD alone, especially among those not achieving complete response after two cycles of ABVD. Within the follow-up duration evaluated, overall survivals were similar. Longer follow-up is required to understand the implications of radiation and chemotherapy-related late effects. CLINICAL TRIALS: The trials included in this analysis were registered at ClinicalTrials.gov: HD10 - NCT00265018, HD11 - NCT00264953, HD.6 - NCT00002561.

Alignment of practice guidelines with targeted-therapy drug funding policies in Ontario.

BACKGROUND: We evaluated clinical practice guideline (cpg) recommendations from Cancer Care Ontario's Program in Evidence-Based Care (pebc) for molecularly targeted systemic treatments (tts) and subsequent funding decisions from the Ontario Ministry of Health and Long-Term Care. METHODS: We identified pebc cpgs on tt published before June 1, 2010, and extracted information regarding the key evidence cited in support of cpg recommendations and the effect size associated with each tt. Those variables were compared with mohltc funding decisions as of June 2011. RESULTS: From 23 guidelines related to 17 tts, we identified 43 recommendations, among which 38 (88%) endorsed tt use. Among all the recommendations, 38 (88%) were based on published key evidence, with 82% (31 of 38) being supported by meta-analyses or phase iii trials. For the 38 recommendations endorsing tts, funding was approved in 28 (74%; odds ratio related to cpg recommendation: 29.9; p = 0.003). We were unable to demonstrate that recommendations associated with statistically significant improvements in overall survival [os: 14 of 16 (88%) vs. 8 of 14 (57%); p = 0.10] or disease- (dfs) or progression-free survival [pfs: 16 of 21 (76%) vs. 3 of 5 (60%); p = 0.59] were more likely to be funded than those with no significant difference. Moreover, we did not observe significant associations between funding approvals and absolute improvements of 3 months or more in os [6 of 6 (100%) vs. 3 of 6 (50%), p = 0.18] or pfs [6 of 8 (75%) vs. 10 of 12 (83%), p = 1.00]. CONCLUSIONS: For use of tts, most recommendations in pebc cpgs are based on meta-analyses or phase iii data, and funding decisions were strongly associated with those recommendations. Our data suggest a trend toward increased rates of funding for therapies with statistically significant improvements in os.

Randomized controlled trials in the era of molecular oncology: methodology, biomarkers, and end points.

BACKGROUND: We previously reported metrics of systemic therapy randomized controlled trials (RCTs) in breast cancer, colorectal cancer (CRC), and non-small-cell lung cancer (NSCLC) published 1975-2004. To evaluate trends in the era of targeted therapies (TT), we have repeated a similar analysis of RCTs published 2005-2009. METHODS: A search for phase III RCTs of systemic agents published in five major journals 2005-2009 was carried out. Trials were classified as TT if they involved any non-hormonal targeted agent. We extracted data regarding biomarker use. Integral biomarkers were defined as tests used to determine eligibility, stratification, or allocation. Descriptive statistics were used to analyze trends over time. RESULTS: One hundred and thirty-seven eligible RCTs were evaluated. Compared with 1995-2004, the number (17-27 RCTs/year) and size (median sample size 446-722, P < 0.001) of RCTs increased. The proportion of RCTs evaluating TT increased from 4% (7/167) to 29% (40/137) (P < 0.001). There was an increase in the proportion of trials with financial support from industry [57% (95/167) to 78% (107/137), P = 0.001]. Biomarkers were included in 58% (80/137) of RCTs; integral biomarkers were included in 36% (49/137) of trials. Among the 49 RCTs using integral biomarkers, 40 (82%) used HER2 and/or ER/PR status in studies of breast cancer. CONCLUSIONS: RCTs published in 2005-2009 are larger, more likely to evaluate TT, and be supported by industry. Biomarkers may be increasingly used, but the most common use relates to traditional use of ER/PR and evolving use of HER2 in breast cancer RCTs.

I-Tositumomab in lymphoma.

Radioimmunoconjugates are radioisotope-bound monoclonal antibodies that target radiation specifically to sites of lymphoma involvement. Initial studies of (131)I-tositumomab in non-Hodgkin lymphoma (NHL) have suggested benefit in patients with relapsed or refractory indolent disease. However, the routine adoption of this agent is tempered by concerns about associated toxicities and unclear long-term benefit. Based on a comprehensive search for studies on (131)I-tositumomab use in lymphoma, this systematic review summarizes and evaluates the evidence on the benefits and risks of this novel therapy,the predictors for response and toxicity, and the role of dosimetry and imaging studies before treatment.We identified 18 trials investigating the use of (131)I-tositumomab for the treatment of adult patients with nhl. In trials of patients with relapsed or refractory indolent nhl, overall response rates ranged from 67% to 83%. In patients with follicular nhl refractory to the monoclonal antibody rituximab, response rates remained high (65%-72%). However, in rituximab-naïve patients with relapsed or refractory indolent or transformed nhl, improvements in time to progression or survival have not been clearly established. (131)I-Tositumomab is an active agent in relapsed and refractory non-Hodgkin lymphoma that should be considered in selected patients.

The Colon Health and Life-Long Exercise Change trial: a randomized trial of the National Cancer Institute of Canada Clinical Trials Group.

BACKGROUND: Observational studies indicate that physical activity (PA) is strongly associated with improved disease outcomes in colon cancer survivors, but a randomized controlled trial is needed to determine whether the association is causal and whether new policies to promote exercise are justified. PURPOSE: The co.21 Colon Health and Life-Long Exercise Change (challenge) trial undertaken by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) is designed to determine the effects of a structured pa intervention on outcomes for survivors of high-risk stage II or III colon cancer who have completed adjuvant therapy within the previous 2-6 months. METHODS: Trial participants (n = 962) will be stratified by centre, disease stage, body mass index, and performance status, and will be randomly assigned to a structured pa intervention or to general health education materials. The pa intervention will consist of a behavioural support program and supervised pa sessions delivered over a 3-year period, beginning with regular face-to-face sessions and tapering to less frequent face-to-face or telephone sessions. The primary endpoint is disease-free survival. Important secondary endpoints include multiple patient-reported outcomes, objective physical functioning, biologic correlative markers, and an economic analysis. SUMMARY: Cancer survivors and cancer care professionals are interested in the potential role of PA to improve multiple disease-related outcomes, but a randomized controlled trial is needed to provide compelling evidence to justify changes in health care policies and practice.

Patterns of disease progression and outcomes in a randomized trial testing ABVD alone for patients with limited-stage Hodgkin lymphoma.

BACKGROUND: In the National Cancer Institute of Canada Clinical Trials Group/Eastern Cooperative Oncology Group HD.6 trial, progression-free survival was better in patients randomized to therapy that included radiation, compared to doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD) alone. We now evaluate patterns of progression and subsequent outcomes of patients with progression. PATIENTS AND METHODS: After a median of 4.2 years, 33 patients have progressed. Two radiation oncologists determined whether sites of progression were confined within radiation fields. Freedom from second progression (FF2P) and freedom from second progression or death (FF2P/D) were compared. RESULTS: Reviewers agreed for the extended (kappa = 0.87) and involved field (kappa = 1.0) analyses. Progression after ABVD alone was more frequently confined within both the extended (20/23 vs. 3/10; P = 0.002) and involved fields (16/23 vs. 2/10; P = 0.02). There was no difference in FF2P between groups [5-year estimate 99% (radiation) versus 96% (ABVD alone)] [hazard ratio (HR) = 3.14, 95% confidence interval (CI) 0.63-15.6; P = 0.14]; the 5-year estimates of FF2P/D were 94% in each group (HR = 1.04, 95% CI 0.41-2.63; P = 0.93). CONCLUSION: Treatment that includes radiation reduces the risk of progressive Hodgkin lymphoma in sites that receive this therapy, but we are unable to detect differences in FF2P or FF2P/D.

Phase II testing of sunitinib: the National Cancer Institute of Canada Clinical Trials Group IND Program Trials IND.182-185.

Sunitinib (SU11248) is an orally bioavailable inhibitor that affects the receptor tyrosine kinases involved in tumour proliferation and angiogenesis, including vascular endothelial growth factor (VEGF) receptors 1, 2, 3, and platelet-derived growth factor receptors alpha (PDGFRA) and beta (PDGFRB). Because angiogenesis is necessary for the growth and metastasis of solid tumours, and VEGF is believed to have a pivotal role in that process, SUNITINIB treatment may have broad-spectrum clinical utility. In the present article, we discuss the biologic and clinical rationales that have recently led the Investigational New Drug Program of the National Cancer Institute of Canada Clinical Trials Group to initiate four phase ii trials testing this agent in the following four different tumour types: relapsed diffuse large cell lymphoma, malignant pleural mesothelioma, locally advanced or metastatic cervical cancer and recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma.

Addition of lenalidomide to melphalan in the treatment of newly diagnosed multiple myeloma: the National Cancer Institute of Canada Clinical Trials Group MY.11 trial.

Oral melphalan and prednisone remain an effective and tolerable treatment for patients with multiple myeloma. For approximately 40 years, this combination has been the standard of care for patients not proceeding to stem cell transplant. Within the last 10 years, new agents have been found to be efficacious in the relapsed/refractory setting. Within the last year, two trials of added thalidomide in the newly diagnosed setting have demonstrated outcomes superior to those achieved with melphalan and prednisone alone. This improved outcome comes at the cost of increased toxicity.The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) has recently developed a randomized phase ii trial (MY.11) that uses a combination of lenalidomide with melphalan for patients with newly diagnosed multiple myeloma. Lenalidomide is a thalidomide analogue and, like thalidomide, is thought to work through immunomodulatory effects. It was shown to have activity in patients with relapsed or refractory disease and, in combination with dexamethasone, is superior to dexamethasone alone. Lenalidomide holds promise as a more effective and potentially less toxic derivative of thalidomide. Experience with lenalidomide in combination with chemotherapy is very limited, and the purpose of MY.11 is to establish tolerability and to gain knowledge about efficacy. The information gained from MY.11 is expected to help inform dosing levels and schedules for a large phase iii trial being developed by the Eastern Cooperative Oncology Group that will include participation by the NCIC CTG.

A comparison of elderly patients with aggressive histology lymphoma who were entered or not entered on to a randomized phase II trial.

The purpose of this study was to compare the baseline patient characteristics, treatments and outcomes of elderly patients with aggressive histology lymphoma who were entered or not entered onto a randomized phase II trial. We previously conducted a randomized phase II trial in patients > or = 65 years of age who had advanced stage intermediate grade lymphoma. A registry of all patients meeting the inclusion criteria for that trial was maintained. Many patients were not entered on to the randomized trial because of the presence of at least one exclusion criterion, or because of patient or physician choice. We have compared the baseline characteristics, treatment, and survival of the randomized and non-randomized patients. Results show that 68 consecutive patients met inclusion criteria for the randomized trial. Thirty-eight patients satisfied all eligibility criteria, consented, and were randomized; 30 patients (44%) were not entered. In comparison with randomized patients, non-randomized patients were older (mean 75.9 vs. 72.4 years; P=0.013), had a poorer performance status (P=0.0006), were less likely to be given treatment with curative intent (60% vs. 100%; P<0.001), and were less likely to complete 6 cycles of such treatment (27% vs. 89%; P<0.001). With a median follow-up of > 7 years, actuarial 5-year survival is superior in randomized patients (44.3% vs. 10%; P<0.00001). In conclusion, a substantial number of patients did not enter our randomized trial phase II trial and had different characteristics, received different therapy and had inferior outcomes in comparison with randomized patients. Randomized trials of therapy for elderly lymphoma patients may include special selection criteria and results may not be generalizable to a substantial proportion of other older patients.

Using adult learning concepts to assist patients in completing advance directives.

BACKGROUND: Despite the fact that advance directives are legal documents that allow people to direct their future health care, few Americans have enacted them. Because lack of knowledge about what they are, and confusion regarding the process needed to complete one are the primary barriers for completion, patient education can be the key element in promoting the use of advance directives. CONCLUSION: This article offers some teaching strategies nurses may use to address patients' ignorance and confusion and help patients understand that, although advance directives do not help people make end-of-life decisions, they serve as a mechanism by which a person's wishes may be carried out.

Utilization-focused evaluation: evaluating the effectiveness of a hospital nursing orientation program.

Providing comprehensive orientation programs that prepare nurses for their role as staff nurses is an integral aspect of retention. Therefore, it is vital that staff development educators assess the effectiveness of their nursing orientation programs. In this article, the authors employ a utilization-focused evaluation format to assess a nursing orientation program and, based on the results, offer recommendations for strengthening such programs.

A phase I trial of standard and cyclophosphamide dose-escalated CHOP with granulocyte colony stimulating factor in elderly patients with non-Hodgkin's lymphoma.

The purpose of this study was to assess the safety and feasibility of using standard and escalated doses of cyclophosphamide with doxorubicin, vincristine and prednisone (CHOP) plus granulocyte colony stimulating factor (G-CSF) to treat elderly patients who have advanced stage intermediate grade lymphoma. Consenting patients age > or = 65 years who had an acceptable performance status and adequate cardiac, renal and liver function were eligible for this Phase I study. G-CSF, 5 ug per kg, was given daily with each cycle from day 2 until neutrophil recovery of > or = 10 x 10(9)/L. Ten patients received standard CHOP; sequential cohorts of 5 patients were then to be given CHOP with cyclophosphamide doses of 900, 1050, 1200, and 1350 mg/m2. If 2 patients had dose limiting toxicity, cohorts were expanded to 10 patients; if 3 patients within a cohort had dose limiting toxicity, the previous dose level was considered the maximum tolerated dose of cyclophosphamide. Secondary outcomes were average relative received dose intensity, response, progression-free and overall survival, toxicity, hospitalizations and transfusions. Eight patients (80%) completed 6 cycles of standard CHOP plus G-CSF. Therapy was stopped prematurely in 2 patients due to pneumonia (1) and disease progression (1). Six of 11 patients (55%) given CHOP with cyclophosphamide 900 mg/m2 (CHOP-900) completed treatment. Therapy was stopped in 5 patients due to a toxic death from infection (1), cumulative fatigue (3), and pneumonitis (1). Further dose escalations were not attempted due to the inability to complete 6 treatment cycles in 45% of CHOP-900 cases. The received dose intensities of cyclophosphamide relative to standard CHOP measured over the actual time on therapy were 96% with standard CHOP and 115% with CHOP-900. At 3 years, progression free survival is 40% with standard CHOP and 82% with CHOP-900; overall survivals are 40% and 91% respectively. Neutropenia of < 1.0 x 10(9)/L occurred in 47% of treatment cycles with standard CHOP and in 77% with CHOP-900. In both groups, the mean duration of neutropenia was < 2 days. From these studies we conclude that, standard CHOP with G-CSF can be safely given to elderly patients. Escalating the dose of cyclophos

Treatment of advanced Hodgkin's disease with chemotherapy--comparison of MOPP/ABV hybrid regimen with alternating courses of MOPP and ABVD: a report from the National Cancer Institute of Canada clinical trials group.

PURPOSE: This randomized, prospective trial compares outcomes for patients with advanced Hodgkin's disease treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/doxorubicin, bleomycin, and vinblastine (ABV) hybrid regimen or alternating MOPP/doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). METHODS: Three hundred one patients with advanced Hodgkin's disease were randomized to receive MOPP/ ABV hybrid regimen or alternating MOPP/ABVD after stratification for prior treatment, B symptoms, and treatment center. Eligible patients were either previously untreated and found to have stage IIIB, IVA, or IVB disease or previously treated with wide-field irradiation. Responding patients received a minimum of eight cycles of chemotherapy. Those with residual disease in a localized region received irradiation between the sixth and seventh cycle of treatment. RESULTS: Response rates to the two regimens were similar. Five-year overall survival rates were 81% and 83% for MOPP/ABV hybrid and alternating MOPP/ ABVD, respectively (P = .74; 95% confidence interval [CI] for the difference, -11% to 7%). Five-year failure-free survivals were 71% and 67% for MOPP/ABV hybrid and alternating MOPP/ABVD, respectively (P = .87; 95% CI for the difference, -9% to 17%). Significantly more episodes of febrile neutropenia and stomatitis were observed with the MOPP/ABV hybrid regimen; there was no significant difference in fatal toxicity. Patients with predefined, high-quality partial responses (PR-1s) had results similar to those with complete responses (CRs). Planned subset analysis showed no significant difference in outcome between the two arms of the trial for patients with newly diagnosed disease (5-year failure-free survival rates were 70% for MOPP/ABV hybrid and 59% for alternating MOPP/ABVD; P = .180), but superiority of alternating MOPP/ABVD for patients with prior irradiation (5-year failure-free survival 94% v 73%; P = .017). CONCLUSION: MOPP/ABV hybrid and alternating MOPP/ABVD regimens are equally effective for patients with advanced Hodgkin's disease.

CD2+, CD3-, CD56/NCAM+ malignant lymphoma with TCR beta gene rearrangement: a case report.

A case of CD56/NCAM+ malignant lymphoma is reported. Only a rare malignant lymphoma cell showed azurophilic granules in the cytoplasm of Giesma-stained preparations, while electron microscopic examination revealed occasional cytoplasmic granules with paracrystalline inclusions. The most common phenotype seen in NK lymphomas, CD2+, CD3-, CD56+, CD16-, CD57-, was present in the case. Cases with this phenotype have been interpreted to represent either true NK lymphoma or T-cell lymphoma with NK expression. Genotyping, where performed, has shown TCR germline configuration. Our case showed TCR beta rearrangement indicating that the above phenotype can be associated with a peripheral T-cell lymphoma.

Randomized phase II comparison of standard CHOP with weekly CHOP in elderly patients with non-Hodgkin's lymphoma.

PURPOSE: To determine whether modifying the standard regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) from full doses given every 3 weeks to one-third doses given weekly (chop) increases the received chemotherapy dose-intensity in elderly patients with advanced-stage intermediate-grade lymphoma. PATIENTS AND METHODS: Consenting patients, age > or = 65 years who had acceptable cardiac, renal, and liver function and an Eastern Cooperative Oncology Group (ECOG) performance status less than 4, were stratified by bone marrow and performance status and randomized to receive standard CHOP or weekly chop. Drug doses were attenuated or escalated according to a defined dose-modification schedule. The primary outcome was average relative received dose-intensity. Secondary outcomes included response, progression-free and overall survival, toxicity, and performance status. RESULTS: Nineteen patients were allocated to each group. No difference in received dose-intensity was seen. When dose-intensity was calculated for the first six cycles of therapy, average relative received dose-intensity was .92 with CHOP versus .89 with weekly chop (P = .5); when calculated for the first 18 weeks of therapy, values were .88 with CHOP versus .89 with weekly chop (P = .8). The complete response rate was 68% with CHOP versus 74% with weekly chop (P = .9). At 2 years, the progression-free survival rate was 57% with CHOP versus 46% with weekly chop (P = .16) and the survival rate was 74% with CHOP versus 51% with weekly chop (p = .05). More myelotoxicity was seen with CHOP. CONCLUSION: We conclude that CHOP can be given in sufficient doses to elderly patients and that weekly chop does not increase received dose-intensity. Progression-free and overall survival are unlikely to be superior with weekly chop, and may be worse. CHOP should remain the standard against which new therapies for elderly patients with intermediate-grade lymphoma are compared.

Implications of using a prognostic index to select therapy for patients with aggressive histology lymphoma.

The International Non-Hodgkin's Lymphoma Prognostic Factor Index (INHLPF-Index) is a validated method of determining prognosis for patients with aggressive histology lymphoma and is now being used to identify those who might benefit most from new investigative therapies. This review assesses its usefulness and potential clinical utility in this context, and shows that several factors will determine the clinical utility of using this index, including the inherent accuracy of the index, the effect of mislabelling and the efficacy and toxicity of experimental treatment.