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Patients in complete cytogenetic response (CCyR) with detectable BCR-ABL1 after ≥2 years on imatinib were randomized to nilotinib (400 mg twice daily, n = 104) or continued imatinib (n = 103) in the Evaluating Nilotinib Efficacy and Safety in clinical Trials-Complete Molecular Response (ENESTcmr) trial. By 1 and 2 years, confirmed undetectable BCR-ABL1 was achieved by 12.5% vs 5.8% (P = .108) and 22.1% vs 8.7% of patients in the nilotinib and imatinib arms, respectively (P = .0087). Among patients without molecular response 4.5 (BCR-ABL1(IS) ≤0.0032%; MR(4.5)) and those without major molecular response at study start, MR(4.5) by 2 years was achieved by 42.9% vs 20.8% and 29.2% vs 3.6% of patients in the nilotinib and imatinib arms, respectively. No patient in the nilotinib arm lost CCyR, vs 3 in the imatinib arm. Adverse events were more common in the nilotinib arm, as expected with the introduction of a new drug vs remaining on a well-tolerated drug. The safety profile of nilotinib was consistent with other reported studies. In summary, switching to nilotinib enabled more patients with chronic myeloid leukemia in chronic phase (CML-CP) to sustain lower levels of disease burden vs remaining on imatinib. This trial was registered at www.clinicaltrials.gov as #NCT00760877., (© 2014 by The American Society of Hematology.)

Previous studies have suggested a link between sleep disordered breathing (SDB) and dementia risk. In the present study, we analyzed the relationship between SDB severity, cerebrospinal fluid (CSF) Alzheimer's disease-biomarkers, and the ApoE alleles. A total of 95 cognitively normal elderly participants were analyzed for SDB severity, CSF measures of phosphorylated-tau (p-tau), total-tau (t-tau), and amyloid beta 42 (Aβ-42), as well as ApoE allele status. In ApoE3+ subjects, significant differences were found between sleep groups for p-tau (F[df2] = 4.3, p = 0.017), and t-tau (F[df2] = 3.3, p = 0.043). Additionally, among ApoE3+ subjects, the apnea and/or hypopnea with 4% O2-desaturation index was positively correlated with p-tau (r = 0.30, p = 0.023), t-tau (r = 0.31, p = 0.021), and Aβ-42 (r = 0.31, p = 0.021). In ApoE2+ subjects, the apnea and/or hypopnea with 4% O2-desaturation index was correlated with lower levels of CSF Aβ-42 (r = -0.71, p = 0.004), similarly to ApoE4+ subjects where there was also a trend toward lower CSF Aβ-42 levels. Our observations suggest that there is an association between SDB and CSF Alzheimer's disease-biomarkers in cognitively normal elderly individuals. Existing therapies for SDB such as continuous positive airway pressure could delay the onset to mild cognitive impairment or dementia in normal elderly individuals., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Context: Fatigue is the most common symptom among Hodgkin's lymphoma survivors., Objectives: To evaluate the psychometric properties of the Brazilian version of the Multidimensional Fatigue Inventory (MFI)., Methods: The MFI was translated into Brazilian Portuguese using established forward-backward translation procedures, and the psychometric properties were evaluated in a sample of 200 Hodgkin's lymphoma survivors. The psychometric properties evaluated included internal consistency and construct validity. The MFI was administered along with the informed consent form., Results: The overall Cronbach's alpha coefficient for the 20 items was 0.84, ranging from 0.59 to 0.81 for each of the five scales. Correlations between items and scales ranged from 0.32 to 0.72. The factor analysis yielded a five-factor solution that explained 65% of the variance. The first factor merged the original "general fatigue" and "physical fatigue" scales, as has been previously reported. The second factor identified the original "mental fatigue" scale and the fifth factor identified the original "reduced activity" scale. Questions from the original "reduced motivation" scale were represented in both factors three and four., Conclusion: The Brazilian version of the MFI showed satisfactory psychometric properties and can be considered a valid research tool for assessing cancer-related fatigue., (Copyright © 2012 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

CD137 (also known as 4-1BB and TNFRSF9) is a member of the tumor necrosis factor receptor superfamily. Originally identified as a costimulatory molecule expressed by activated T cells and NK cells, CD137 is also expressed by follicular dendritic cells, monocytes, mast cells, granulocytes, and endothelial cells. Anti-CD137 immunotherapy has recently shown promise as a treatment for solid tumors and lymphoid malignancies in preclinical models. We defined the expression of CD137 protein in both normal and neoplastic hematolymphoid tissue. CD137 protein is expressed by follicular dendritic cells in the germinal center and scattered paracortical T cells, but not by normal germinal-center B cells, bone marrow progenitor cells, or maturing thymocytes. CD137 protein is expressed by a select group of hematolymphoid tumors, including classical Hodgkin lymphoma, T-cell and NK/T-cell lymphomas, and follicular dendritic cells neoplasms. CD137 is a novel diagnostic marker of these tumors and suggests a possible target for tumor-directed antibody therapy., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: A recent study demonstrated that an increased number of CD68+ macrophages were correlated with primary treatment failure, shortened progression-free survival (PFS) and disease-specific survival (DSS) in patients with classical Hodgkin's lymphoma (cHL)., Patients and Methods: The aim of the present study was to verify the relationship between the number of CD68+ and CD163+ macrophages with clinical outcomes in a cohort of 265 well-characterized patients with cHL treated uniformly with the standard doxorubicin, bleomycin, vinblastine and dacarbazine chemotherapy regimen. Two pairs of hematopathologists carried out independent pathological evaluations of tissue microarray slides., Results: There were no associations between clinical characteristics and the expression of CD68 or CD163. However, higher levels of CD68 and CD163 expression were correlated with the presence of Epstein-Barr virus-positive Hodgkin tumor cells (P = 0.01 and 0.037, respectively). The expression of CD68 or CD163 was not associated with either the PFS or the DSS., Conclusion: CD68 and CD163 expression require further evaluation before their use can be recommended for prognostic stratification of patients with cHL.

Currently, Hodgkin's lymphoma is one of the most curable types of cancer. Patients are often young and so the long-term morbidities of treatment have become of increasing concern. Among these, infertility is one of the most challenging consequences for patients in reproductive age. Premature ovarian failure in premenopausal women is a serious long-term sequel of the toxicity of chemotherapy. The main consequence of this syndrome is infertility, but women also present other symptoms related to estrogen deprivation. Different rates of impaired gonadal function are reported, depending on the patient's age, stage of disease, dose and intensity of chemotherapy and the use of radiation therapy. The most established strategy in female infertility is cryopreservation of embryos after in vitro fertilization. Additionally, the use of oral contraceptives or gonadotropinreleasing hormone analogs (GnRH-a) during treatment is under study. This review will provide a general overview of the main studies conducted to evaluate the infertility rate among female Hodgkin's lymphoma survivors and risk factors associated to treatment, different end-point definitions for evaluating fertility and also a brief description of the available strategies for fertility preservation.

Background: Data on patients with cancer who have a prolonged length of stay (LOS) in the ICU are scarce. The aim of the present study was to evaluate the characteristics and the outcomes of cancer patients with life-threatening complications with an ICU stay > or = 21 days., Methods: A cohort study performed at a 10-bed oncology medical-surgical ICU from May 2000 to December 2005. Prolonged ICU LOS was defined as an ICU stay > or = 21 days., Results: During the period, 1,090 patients were admitted to the ICU and 163 patients (15%) had a prolonged ICU LOS. These patients, however, accounted for 48% (5,828/12,224) of the total ICU bed-days. The hospital and 6-month mortality rates were 50% and 60%, respectively, and similar to patients with ICU LOS < 21 days (51% and 61%, respectively). ICU-acquired events and complications were common, and the most frequent were infections (90%), mechanical ventilation (99%), and need for vasopressors (88%). The number of organ failures, older age, and poor performance status were the main outcome predictors. The median long-term follow-up after hospital discharge was 537 days (range, 193 to 1,119 days), and 29 patients (18%) were alive., Conclusions: Fifteen percent of critically ill patients with cancer had a prolonged ICU LOS. Short- and long-term survival rates were reasonable, and the prognosis was better than expected a priori. In our opinion, the length of ICU admission per se should not be used in the clinical decisions regarding the continuation of treatment in these patients.

Although trastuzumab-based therapy has changed the treatment paradigm for ErbB2-positive breast cancers, most patients eventually develop progressive disease. Of particular interest is the issue of disease progression in the central nervous system, a safe haven from high molecular weight antibodies like trastuzumab, which have limited ability to cross the blood-brain barrier. This review will discuss therapeutic options for when disease progression has occurred on trastuzumab-based therapies, including central nervous system progression, continuation of trastuzumab-based therapy, addition of novel targeted therapies, and the use of small-molecule tyrosine kinase inhibitors targeting ErbB receptors.

Background: The management of patients with lung cancer has improved recently, and many of them will require admission to the ICU. The aims of this study were to determine hospital mortality and to identify risk factors for death in a large cohort of critically ill patients., Methods: Cohort study in two ICUs specialized in the management of patients with cancer, in France and Brazil., Results: Of the 143 patients (mean age, 61.6 +/- 9.9 years [+/- SD]), 25 patients (17%) had small cell lung cancer and 118 patients (83%) had non-small cell lung cancer. The main reasons for ICU admission were sepsis (44%) and acute respiratory failure (31%). Mechanical ventilation (MV) was used in 100 patients (70%), including 38 patients in whom lung cancer was considered a reason for MV. Hospital mortality was 59% overall and 69% in patients receiving MV. By multivariate logistic regression, airway infiltration or obstruction by cancer, number of organ failures, cancer recurrence or progression, and severity of comorbidities were associated with increased mortality., Conclusions: The improved survival previously reported in patients with cancer admitted to the ICU seems to extend to patients with lung cancer, including those who need MV. Mortality increased with the number of organ failures, severity of comorbidities, and presence of respiratory failure due to cancer progression. The type of the cancer per se was not associated with mortality and, therefore, should not be factored into ICU triage decisions.

Modern scientific evidence of interactions among the nervous, endocrine, and immune systems dates from the late nineteenth century, although this concept was certainly known to the ancients in Asia, Europe, Africa, and the Americans. Within the past two decades, the mechanisms of these interactions, known today as neuroimmunomodulation (NIM), have been investigated, from the subcellular to the behavioral levels, using the modern tools of receptor and membrane physiology, biochemistry, pharmacology, immunology, chronobiology, and genetics. One of the best demonstrations of neural-immune interactions was classical (Pavlovian) conditioning of immune responses, first reported by Metal'nikov et al. at the Pasteur Institute in the 1920's. Within the past 10 years, my colleagues at the University of Alabama in Birmingham and the Gerontology Research Center in Italy, and I, in experiments with mice, demonstrated (a) a 3- to 39-fold enhancement of natural killer (NK) cell activity by conditioning; (b) reversal of an otherwise fatal cancer (myelo-MOPC-104 E) by perinoculation conditioning ; and (c) that very old animals can be similarly conditioned to increase, many fold, their NK activity in the absence of an antigen. NK cells are among the body's first-line defenses against cancer and viral infections. Research on NIM and its mechanisms is growing exponentially; indeed, it may be the fastest growing field in biomedical sciences. (The International Society for NIM, founded only a few years ago, now has active members in 40 countries.) This revolution in the basic sciences will undoubtedly lead to a corresponding revolution in clinical practice and, most importantly, in the area of preventive medicine.

Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) clearly hastens myeloid recovery in patients with relapsed hematologic malignancies undergoing autologous bone marrow transplantation (ABMT). In efforts to further improve neutrophil engraftment and shorten hospital stay in ABMT patients, rhGM-CSF was administered by a potentially more potent route (continuous infusion) to non-Hodgkin's lymphoma (NHL) patients with better BM reserve (first remission). Time to myeloid engraftment was compared with that of NHL patients treated in first remission at our institution on a similar ABMT protocol but without growth factor support (controls). Median neutrophil engraftment (absolute neutrophil count, 500 cells/microL) in first remission patients treated with rhGM-CSF was 14 days, compared with 22 days in controls (P = .0001). Hospital stays were also significantly reduced for rhGM-CSF patients (P = .0003). Platelet engraftment did not differ between the two groups. Persistent fever and generalized serositis were the primary toxicities. rhGM-CSF, delivered by this route, was efficacious but more toxic than 2-hour rhGM-CSF infusions previously reported by other investigators. Future alterations in both dose and schedule may retain comparable efficacy yet diminish toxicity.

Forty patients with plasma cell dyscrasias underwent high-dose chemoradiotherapy and either anti-B-cell monoclonal antibody (MoAb)-treated autologous, anti-T-cell MoAb-treated HLA-matched sibling allogeneic or syngeneic bone marrow transplantation (BMT). The majority of patients had advanced Durie-Salmon stage myeloma at diagnosis, all were pretreated with chemotherapy, and 17 had received prior radiotherapy. At the time of BMT, all patients demonstrated good performance status with Karnofsky score of 80% or greater and had less than 10% marrow tumor cells; 34 patients had residual monoclonal marrow plasma cells and 38 patients had paraprotein. Following high-dose chemoradiotherapy, there were 18 complete responses (CR), 18 partial responses, one non-responder, and three toxic deaths. Granulocytes greater than 500/microL and untransfused platelets greater than 20,000/microL were noted at a median of 23 (range, 12 to 46) and 25 (range, 10 to 175) days posttransplant (PT), respectively, in 24 of the 26 patients who underwent autografting. In the 14 patients who received allogeneic or syngeneic grafts, granulocytes greater than 500/microL and untransfused platelets greater than 20,000/microL were noted at a median of 19 (range, 12 to 24) and 16 (range, 5 to 32) days PT, respectively. With 24 months median follow-up for survival after autologous BMT, 16 of 26 patients are alive free from progression at 2+ to 55+ months PT; of these, 5 patients remain in CR at 6+ to 55+ months PT. With 24 months median follow-up for survival after allogeneic and syngeneic BMT, 8 of 14 patients are alive free from progression at 8+ to 34+ months PT; of these, 5 patients remain in CR at 8+ to 34+ months PT. This therapy has achieved high response rates and prolonged progression-free survival in some patients and proven to have acceptable toxicity. However, relapses post-BMT, coupled with slow engraftment post-BMT in heavily pretreated patients, suggest that such treatment strategies should be used earlier in the disease course. To define the role of BMT in the treatment of myeloma, its efficacy should be compared with that of conventional chemotherapy in a randomized trial.

Although molecular biologic techniques can now detect minimal numbers of residual cancer cells in patients in complete clinical remission, the clinical significance of minimal residual disease has never been conclusively established. If the detection of minimal residual disease predicts which patients will relapse, then therapy could be altered based upon the detection of these cells. The t(14;18) can be detected by polymerase chain reaction (PCR) amplification in 50% of patients with B-cell non-Hodgkin's lymphoma and allows detection of one lymphoma cell in up to 1 million normal cells. To determine the clinical significance of the detection of minimal residual lymphoma cells in the bone marrow (BM) PCR amplification was used to detect the presence of residual lymphoma cells after autologous BM transplantation (ABMT) in serial BM samples from 134 patients with B-cell lymphoma in whom a bcl-2 translocation could be detected. PCR analysis was performed on a total of 542 BM samples obtained while these patients were in complete remission. Disease-free survival was markedly increased in patients with no PCR-detectable lymphoma cells in the marrow compared with those in whom residual lymphoma cells were detected (P < .00001), and the presence of detectable lymphoma cells was associated with a 48-fold increase in the risk of relapse. Of the 77 patients (57%) with no PCR-detectable lymphoma cells in their most recent BM sample, none have relapsed. In contrast, all 33 patients (25%) who have relapsed had PCR-detectable lymphoma cells detected in their BM before clinical relapse occurred. In 19 patients (14%), residual lymphoma cells in the BM were detected early following transplantation and subsequently were no longer detectable, although these patients received no further therapy. In these patients, residual lymphoma cells may already have been irreversibly damaged by the high-dose therapy or an endogenous immune mechanism may be capable of eliminating residual lymphoma cells in some patients. Therefore, although the detection of minimal residual disease by PCR following ABMT in patients with lymphoma identifies those patients at high risk of relapse, the presence of residual minimal disease early after transplantation may not be associated with poor prognosis in a small subset of patients. Confirmatory studies will be required to determine more definitively the role of minimal disease detection to identify which patients require additional therapy.

Anti-B4-blocked Ricin (Anti-B4-bR) is an immunotoxin comprised of the anti-B4 monoclonal antibody (MoAb) and the protein toxin "blocked ricin." The anti-B4 MoAb is directed against the B-lineage-restricted CD19 antigen expressed on more than 95% of normal and neoplastic B cells. Blocked ricin is an altered ricin derivative that has its nonspecific binding eliminated by chemically blocking the galactose binding domains of the B chain. In vitro cytotoxicity studies demonstrate that the IC37 of Anti-B4-bR is 2 x 10(-11) mol/L compared with 4 x 10(-12) mol/L for native ricin. A phase I dose escalation clinical trial was conducted in 25 patients with refractory B-cell malignancies. Anti-B4-bR was administered by daily 1-hour bolus infusion for 5 consecutive days at doses ranging from 1 microgram/kg/d to 60 micrograms/kg/d. Serum levels above 1 nmol/L were achieved transiently in the majority of patients treated at the maximum tolerated dose of 50 micrograms/kg/d for 5 days for a total dose of 250 micrograms/kg. The dose-limiting toxicity was defined by transient, reversible grade 3 elevations in hepatic transaminases, without impaired hepatic synthetic function. Minor toxicities included transient hypoalbuminemia, thrombocytopenia, and fevers. Human antimouse antibody and human anti-ricin antibody were detected in nine patients. One complete response, two partial responses, and eight mixed or transient responses were observed. These results show the in vitro and in vivo cytotoxicity of Anti-B4-bR and indicate that this immunotoxin can be administered as a daily bolus infusion for 5 days with tolerable, reversible toxicity.

The importance of restraint in determining the magnitude of alteration in the rat's core temperature (Tc) after the administration of morphine sulphate (M) and heroin hydrochloride (H) was investigated. M, in doses of 5, 15 and 30 mg/kg, or H, in doses of 0.1, 1 and 5 mg/kg was administered IP to either the restrained or free-moving rats as Tc was measured. After the administration of 5 mg/kg of H or 30 mg/kg of M to the restrained rat, a marked hypothermia was observed which reached a maximum mean depth of 3.1 and 4.5 degrees C below the baseline Tc, respectively. Conversely, a mean increase in Tc of 1.5 and 1.9 degrees C occurred following the administration of these same doses of M and H in the unrestrained animal. Furthermore, the hypothermic effect of the highest dose of M was not observed when the third of 3 consecutive injections of M, administered at 48-hr intervals, was administered to the restrained rat. On the other hand, when M was repeatedly administered to the free-moving rat, the hyperthermic response was consistently observed. Pretreatment with naloxone hydrochloride (5 mg/kg IP) effectively blocked the opiate-induced hypothermia in the restrained animal, but a total dose of 10 mg/kg was necessary to completely block the hyperthermic response in the free-moving rat. Although the factor of restraint itself did not alter the rat's Tc, it did dramatically alter the action of M and H on the body temperature of the rat.