Lenalidomide and cyclophosphamide immunoregulation in patients with metastatic, castration-resistant prostate cancer.

Lenalidomide (LEN) and metronomic cyclophosphamide (CTX) regulate angiogenesis and immunosuppressive cells linked to the progression of metastatic castration-resistant prostate cancer (mCRPC). A phase-I/II, dose-escalation trial of LEN plus oral CTX was conducted in patients with previously treated mCRPC. In the phase-I study, CTX was given at 50 mg (day 1-28) and LEN at 10-25 mg (day 1-21) on a 28-day cycle using a "3+3" study design. In phase II, patients received LEN at 25 mg (day 1-21) with CTX at 50 mg PO QD (day 1-28) on a 28-day cycle. Nineteen patients in phase I were evaluable for toxicity. The maximum tolerated dose (MTD) was not observed at any of the dose levels (DLs) tested. Six patients received treatment in phase II before the trial was closed. A ≥ 50% reduction in PSA was observed in 31.7% evaluable patients. Radiographically, one patient had a partial response. Stable disease was documented in 68% of evaluable patients after two therapy cycles. Circulating tumor cells (CTCs) decreased in 22.7% and remained stable in 31.8% of patients. Baseline numbers of peripheral MDSCs (MDSC; Lin-DR(-)CD11b(+)) were significantly increased in patients versus normal donors, and were decreased by chemotherapy. At baseline, MDSCs correlated directly with CTCs, and inversely with T- and B cell frequency supporting their immunosuppressive activity. The combination of LEN and metronomic CTX can be safely administered, reversing cellular immunosuppression in this group of elderly patients with mCRPC. Further research is required to identify responsive subgroup(s) and validate the biomarkers.

Advance care planning among hematopoietic cell transplant patients and bereaved caregivers.

Younger, healthier patients contemplating high-risk (but potentially curative) hematopoietic cell transplants (HCT) may not consider advance care planning (ACP). We investigated the effect of pre transplant ACP in surviving HCT patients and bereaved caregivers using retrospective, audiotaped telephone surveys. Subjects were identified between 2001 and 2003 via databases at two high-volume HCT centers. Transcripts were coded by two investigators, with differences resolved by consensus. HCT survivors (n=18) were interviewed a median of 13 months after HCT for acute leukemia (7), lymphoma (5) or other (6); 50% had living wills, 72% had a formal proxy. Twelve (67%) had discussed mortality risk pre HCT with the medical team. Of those, 92% felt their hope and perception of the medical team's truthfulness was increased or unchanged (I/U) by the conversation, whereas all felt clinician commitment to transplant was I/U. Bereaved caregivers (n=11) were interviewed a median of 10 months post death (median 31 days post HCT, range 13-152). Nine (82%) had discussed mortality risk pre-HCT with the medical team; 7 (78%) felt hope was I/U, all felt clinician commitment to transplant and truthfulness was I/U, and most felt ACP reduced burden (67%). ACP discussions with patients and caregivers pre-HCT did not affect hope and supported confidence in medical teams.

Factors affecting the development of atrial fibrillation and atrial flutter (AF/AFL) following autologous hematopoietic SCT (auto-HSCT).

The use of autologous hematopoietic SCT (auto-HSCT) has expanded to include older patients. Increasing age is a well-appreciated risk factor for the development of atrial fibrillation and/or atrial flutter (AF/AFL) in the general population. As more elderly patients undergo auto-HSCT, the risk of developing AF/AFL post transplant may also increase. However, few data evaluating other risk factors for the development of AF/AFL following auto-HSCT exist. Therefore, we performed a retrospective study to determine the incidence of AF/AFL following auto-HSCT and to determine the risk factors associated with the development of AF/AFL. Patients who developed AF/AFL were compared with a group of patients who received auto-HSCT within the same time period (April 1999 to May 2005) and were within 5 years of age. Of the 516 patients who underwent auto-HSCT at the University of Nebraska Medical Center 44 (8.5%) developed AF/AFL at a median time of 4 days (range, days 1-9) following auto-HSCT. In multivariate analysis, risk factors for developing AF/AFL were older age, odds ratio and 95% CI of 1.14 (1.07-1.21), elevated serum creatinine level, 2.69 (1.00-7.22), history of previous arrhythmia, 9.33 (3.01-28.99), and history of previous mediastinal irradiation, 11.12 (1.33-92.96).

Long-term outcomes of adults with acute lymphoblastic leukemia after autologous or unrelated donor bone marrow transplantation: a comparative analysis by the National Marrow Donor Program and Center for International Blood and Marrow Transplant Research.

For adults with high-risk or recurrent ALL who lack a suitable sibling donor, the decision between autologous (Auto) and unrelated donor (URD) hematopoietic stem cell transplantation (HSCT) is difficult due to variable risks of relapse and treatment-related mortality (TRM). We analysed data from two transplant registries to determine outcomes between Auto and URD HSCT for 260 adult ALL patients in first (CR1) or second (CR2) CR. All patients received a myeloablative conditioning regimen. The median follow-up was 77 (range 12-170) months. TRM at 1 year post transplant was significantly higher with URD HSCT; however, there were minimal differences in TRM according to disease status. Relapse was higher with Auto HSCT and was increased in patients transplanted in CR2. Five-year leukemia-free (37 vs 39%) and overall survival (OS) rates (38 vs 39%) were similar for Auto HSCT vs URD HSCT in CR1. There were trends favoring URD HSCT in CR2. The long-term follow-up in this analysis demonstrated that either Auto or URD HSCT could result in long-term leukaemia-free survival and OS for adult ALL patients. The optimal time (CR1 vs CR2) and technique to perform HSCT remains an important clinical question for adult ALL patients.

Pre-transplantation physical and mental functioning is strongly associated with self-reported recovery from stem cell transplantation.

Previous studies of quality of life (QOL) note compromised QOL after stem cell transplantation (HCT), but do not usually consider the impact of pre-transplantation deficits in QOL on post transplantation outcomes. To examine these associations, multivariate models for six self-reported QOL outcomes at 6 and 12 months were constructed, considering pre-transplantation clinical status and QOL, and subsequent clinical events. Outcomes measured overall subjective health, social functioning and agreement with statements such as 'Life has returned to normal.' Of 320 autologous and allogeneic HCT recipients who completed pre-transplantation surveys, 197 completed 6-month surveys and 175 completed 12-month surveys. Pre-transplantation overall health and mental health were independent predictors of all QOL outcomes at 6 months. Baseline physical health was also predictive of four of six outcomes at 12 months. In contrast, disease risk was predictive only of enjoying normal activities at 6 months. Relapse and chronic graft-versus-host disease were associated with poorer QOL. In conclusion, pre-transplantation self-reported physical and mental health are more strongly associated with QOL after HCT than commonly noted baseline clinical predictors such as age and disease risk. Measurement of baseline QOL can help place the effects of the transplantation procedure in context.

Routine screening for psychosocial distress following hematopoietic stem cell transplantation.

The diagnosis and treatment of cancer is often associated with high levels of psychosocial distress, yet exploration of these issues is rarely included in routine oncologic care. We conducted a pilot study to evaluate the feasibility of screening for psychosocial distress after autologous and allogeneic stem cell transplantation. A total of 80 adults were enrolled in Boston, MA, USA. Subjects completed self-administered assessments prior to hospital admission, at their first clinic visit after hospital discharge, and at 100 days post transplant. Assessments included validated instruments assessing psychosocial distress and quality of life (QOL). Elevated levels of anxiety and/or depression were detected in 55% of those providing pre-transplant assessments and were associated with compromised QOL. Post transplant screening was successfully performed in 69% of subjects and identified that 44% had symptoms of depression, anxiety or post traumatic stress disorder. Pre-transplant distress was associated with detection of distress after transplantation (81 vs 13%, P< 0.0001). In summary, we detected high levels of distress in transplant patients using self-administered tools. Pre-transplant distress appears to be highly predictive of distress post transplant and is a feasible marker to target screening and intervention programs.

Transplant center characteristics and clinical outcomes after hematopoietic stem cell transplantation: what do we know?

Center effects are differences in outcome among treatment centers that cannot be explained by identifiable differences in patients treated or specific treatments applied and are presumed to result from differences in the ways health care is delivered. This paper will briefly review studies of association between treatment center factors and clinical outcomes in general medicine and surgery and look more closely at studies involving hematopoietic stem cell transplantation. We will also attempt to identify conceptual domains to study further the processes and mechanisms that may be associated with better outcomes.

The effect of pretransplant interferon therapy on the outcome of unrelated donor hematopoietic stem cell transplantation for patients with chronic myelogenous leukemia in first chronic phase.

Various therapeutic options are available for patients with chronic myelogenous leukemia. Allogeneic stem cell transplantation, though often curative, is associated with high nonrelapse mortality and long-term morbidity, particularly when cells from unrelated donors are used. Many physicians and patients opt for a trial of interferon-alpha (IFN)-based therapy first, reserving transplantation for patients with inadequate response or intolerance to IFN. Data were analyzed on 740 patients receiving unrelated donor transplants for chronic myelogenous leukemia in first chronic phase provided by the International Bone Marrow Transplant Registry and the National Marrow Donor Program to see whether IFN pretreatment compromised transplantation outcome. A total of 489 (66%) had received IFN prior to transplantation; 251 (34%) had not. Disease characteristics in the 2 groups were similar at diagnosis but at the time of transplantation, hematologic parameters and weight were lower in IFN patients and the interval between diagnosis and transplantation was longer. After adjustment for baseline covariates, no effect of IFN exposure was found on overall survival, leukemia-free survival, nonrelapse mortality, engraftment, relapse, or acute or chronic graft-versus-host disease. Evaluation of effects based on duration of therapy and time off IFN prior to transplantation was limited by missing data and confounding with IFN intolerance and disease responsiveness. In conclusion, no evidence was found for an independent adverse effect of IFN pretreatment on the outcome of subsequent unrelated donor transplantation.

Transplant registries: guiding clinical decisions and improving outcomes.

About 50,000 hematopoietic stem cell transplantations are performed yearly, primarily for malignancies. Use of this therapy increased dramatically over the past 30 years due to its proven and potential efficacy in diverse diseases, better understanding of appropriate timing of transplantation and patient selection, and greater availability of allogeneic donors. The International Bone Marrow Transplant Registry (IBMTR) and the Autologous Blood and Marrow Transplant Registry (ABMTR) collect data on consecutive allogeneic and autologous transplants, respectively, in more than 400 participating centers worldwide. The IBMTR/ABMTR database contains information on more than 120,000 transplant recipients. Among 11,347 patients transplanted in 101 IBMTR/ABMTR research centers in North America during 1995-1997, 66% received autologous transplants, 24% related-donor transplants, and 10% unrelated-donor transplants. More than 90% of transplantations were for malignant disease, with more than half of these done in patients with advanced disease. Of the recipients, 70% were younger than 50 years. Posttransplant survivals varied substantially by disease, transplant type, recipient age, and disease status at transplantation. IBMTR/ABMTR data provide an important tool for assessing transplant use and outcome, identifying prognostic factors for transplant outcomes, evaluating new transplant therapies, comparing transplant and nontransplant therapies, evaluating late transplant complications, and planning prospective phase II and III clinical trials.

Autotransplants for Hodgkin's disease in first relapse or second remission: a report from the autologous blood and marrow transplant registry (ABMTR).

Although patients with relapsed Hodgkin's disease have a poor prognosis with conventional therapies, high-dose chemotherapy and autologous hematopoietic stem cell transplantation (autotransplantation) may provide long-term progression-free survival. We reviewed data from the Autologous Blood and Marrow Transplant Registry (ABMTR) to determine relapse, disease-free survival, overall survival, and prognostic factors in this group of patients. Detailed records from the ABMTR on 414 patients with Hodgkin's disease in first relapse (n = 295) or second complete remission (CR) (n = 119) receiving an autotransplant from 1989 to 1995 were reviewed. Median age was 29 (range, 7-64) years. Median time from diagnosis to relapse was 18 (range, 6-219) months; median time from relapse to transplant was 5 (range, <1-215) months. Most patients received high-dose chemotherapy without total body irradiation for conditioning (n = 370). The most frequently used high-dose regimen was cyclophosphamide, BCNU, VP-16 (CBV) (n = 240). The graft consisted of bone marrow (n = 246), blood stem cells (n = 112), or both (n = 56). Median follow-up was 46 (range, 5-96) months. One hundred-day mortality (95% confidence interval) was 7 (5-9)%. One hundred and sixty-five of 295 patients (56%) transplanted in relapse achieved CR after autotransplantation. Of these, 61 (37%) recurred. Twenty-four of 119 patients (20%) transplanted in CR recurred. The probability of disease-free survival at 3 years was 46 (40-52)% for transplants in first relapse and 64 (53-72)% for those in second remission (P < 0.001). Overall survival at 3 years was 58 (52-64)% after transplantation in first relapse and 75 (66-83)% after transplantation in second CR (P < 0.001). In multivariate analysis, Karnofsky performance score <90% at transplant, abnormal serum LDH at transplant, and chemotherapy resistance were adverse prognostic factors for outcome. Progression of Hodgkin's disease accounted for 69% of all deaths. Autotransplantation should be considered for patients with Hodgkin's disease in first relapse or second remission. Future investigations should focus on strategies designed to decrease relapse after autotransplantation, particularly in patients at high risk for relapse.

Flow-induced dilation of human coronary arterioles: important role of Ca(2+)-activated K(+) channels.

BACKGROUND: Flow-induced vasodilation (FID) is a physiological mechanism for regulating coronary flow and is mediated largely by nitric oxide (NO) in animals. Because hyperpolarizing mechanisms may play a greater role than NO in the microcirculation, we hypothesized that hyperpolarization contributes importantly to FID of human coronary arterioles. METHODS AND RESULTS: Arterioles from atria or ventricles were cannulated for videomicroscopy. Membrane potential of vascular smooth muscle cells (VSMCs) was measured simultaneously. After constriction with endothelin-1, increases in flow induced an endothelium-dependent vasodilation. Nomega-Nitro-L-arginine methyl ester 10(-4) mol/L modestly impaired FID of arterioles from patients without coronary artery disease (CAD), whereas no inhibition was seen in arterioles from patients with CAD. Indomethacin 10(-5) mol/L was without effect, but 40 mmol/L KCl attenuated maximal FID. Tetraethylammonium 10(-3) mol/L but not glibenclamide 10(-6) mol/L reduced FID. Charybdotoxin 10(-8) mol/L impaired both FID (15+/-3% versus 75+/-12%, P<0.05) and hyperpolarization (-32+/-2 mV [from -28+/-2 mV after endothelin-1] versus -42+/-2 mV [-27+/-2 mV], P<0.05). Miconazole 10(-6) mol/L or 17-octadecynoic acid 10(-5) mol/L reduced FID. By multivariate analysis, age was an independent predictor for the reduced FID. Conclusions-We conclude that shear stress induces endothelium-dependent vasodilation, hyperpolarizing VSMCs through opening Ca(2+)-activated K(+) channels in human coronary arterioles. In subjects without CAD, NO contributes to FID. NO and prostaglandins play no role in patients with CAD; rather, cytochrome P450 metabolites are involved. This is consistent with a role for endothelium-derived hyperpolarizing factor in FID of the human coronary microcirculation.

Analysis of risk factors for the development of GVHD after T cell-depleted allogeneic BMT: effect of HLA disparity, ABO incompatibility, and method of T-cell depletion.

Multivariate analysis was performed to determine the independent factors affecting the risk of acute GVHD (aGVHD) grades II to IV and extensive chronic GVHD (cGVHD) and the rate of survival in 481 recipients of T cell-depleted (TCD) marrow allografts who received transplants at a single center between 1991 and 2000. All patients received grafts partially depleted of CD3+ T cells by complement-mediated lysis using 2 narrow-specificity monoclonal antibodies (MoAbs), T10B9.1A-31 (n = 400) or Muromonab-Orthoclone OKT3 (n = 81). Factors considered in the analysis included patient/donor sex, age, cytomegalovirus (CMV) status, and ABO blood group along with T-cell dose, disease, and disease status, donor relationship, HLA antigen (Ag)mismatch (MM), growth-factor use, anti-thymocyte globulin use, year of transplantation, and the MoAb used for TCD. The results showed an association of HLA with an increased relative risk (RR) of aGVHD for recipients of grafts from relateddonors that were > or =2 Ag MM (n = 73, RR = 2.09, P = .005), matched unrelated (UR) donors (n = 130, RR = 1.98, P = .004), and > or =2 Ag MM UR donors (n = 34, RR = 2.68, P = .003) compared with the baseline matched-sibling group (n = 121). No increased risk of aGVHD was seen for 0 to 1 Ag MM family donors (n = 24) or 1 Ag MM UR donors (n = 99). aGVHD risk was increased with minor, but not major or major-minor, ABO disparity (RR = 2.0, P = .003) compared with that of ABO-identical pairs. We found less effective TCD and resultant higher T-cell dose for recipients of grafts that were T cell depleted using OKT3. However, the use of OKT3 and not the T-cell dose was associated with increased aGVH-D risk (RR of 1.84, P = .001). Increased risk of extensive cGVHD was associated with patient age of >20 years (RR = 2.2, P < .0001) and with CMV status (positive patient/negative donor, RR = 1.9, P = .002). Decreased survival was associated with older age (>20 years), a > or =2 Ag MM related donor, a 1 or > or =2 Ag MM UR donor, risk group, and a CMV-positive patient/-negative donor pair. There was no difference in survival for 0 to 1 Ag MM related or matched UR donors compared with the baseline group. These data indicate that there are quantitative as well as potential qualitative differences in outcome depending on the TCD method. Expected and unexpected risk factors for GVHD and survival were associated with partial TCD. Our data support the consideration of ABO match in donor selection, the preferential selection of CMV-positive donors for CMV-positive recipients, and the acceptance of 1 but not > or =2 Ag HLA MM donors.

Blood stem cells compared with bone marrow as a source of hematopoietic cells for allogeneic transplantation. IBMTR Histocompatibility and Stem Cell Sources Working Committee and the European Group for Blood and Marrow Transplantation (EBMT).

Peripheral blood cells are increasingly used in place of bone marrow as a source of hematopoietic stem cells for allogeneic transplantation. The relative efficacy of these 2 approaches is unknown. This retrospective multivariate analysis compared results of 288 HLA-identical sibling blood stem cell transplantations with results of 536 HLA-identical sibling bone marrow transplantations. No transplants were T-cell depleted. Median follow-up was 12 months, and analyses focused on 1-year outcomes. Recipients of blood stem cell transplants had more rapid recovery of neutrophils to at least 0.5 x 10(9)/L (median time to recovery, 14 days, compared with 19 days for marrow transplants; P <.001) and of platelets to at least 20 x 10(9)/L (median time, 18 days, compared with 25 days for marrow transplants; P <.001). There was no significant difference in the incidence of grades II to IV acute graft versus host disease (GVHD). The incidence of chronic GVHD was significantly higher after blood stem cell transplantation (1-year probability [95% confidence interval], 65% [56%-72%] compared with 53% [47%-59%]; P =.02) Relapse incidence in the 2 transplant groups did not differ significantly. Treatment-related mortality rates were lower and leukemia-free survival rates were higher with blood stem cell transplants in patients with advanced leukemia (acute leukemia in second remission or chronic myelogenous leukemia in accelerated phase) but not in early leukemia (acute leukemia in first remission or chronic myelogenous leukemia in chronic phase). The median time from transplantation to hospital discharge was 23 days after blood stem cell transplantation and 28 days after bone marrow transplantation (P =.003). Further study with longer follow-up is necessary to definitively establish the role of blood stem cells for allogeneic transplantation, especially in patients with good-risk disease. (Blood. 2000;95:3702-3709)

Initial results, reliability, and validity of a mental health survey of Mount Pinatubo disaster victims.

This report presents the initial results of a mental health survey of 351 tribal and non-tribal Mount Pinatubo disaster victims 6 years after they were displaced following the volcanic eruption in the Philippines on June 12, 1991. Mental illness prevalence rates in both Filipino ethnic groups were comparable to those found in a U.S. study using the same assessment instrument. Post-traumatic stress disorder (PTSD; 27.6%) and major depression (14.0%) were the two most frequent diagnoses. Diagnostic test-retest interviewer agreement was good for probable alcohol abuse (kappa = .65, agreement = 97%) and any mood disorder (kappa = .53, agreement = 91%) but was reduced for any anxiety disorder (kappa = .15, agreement = 81%) and separately evaluated PTSD (kappa = .18, agreement = 69%). Diagnostic test-retest agreement was good among typical Filipinos (mean kappa = .66, mean agreement = 93%) but was reduced among tribal aborigines (mean = .30, mean agreement = 86%). Internal consistency of the PTSD rating scale was high within and across both ethnic groups, including total scale (alpha = .91) and DSM-IV Criteria B, C, and D sub-scales (alpha = .80, 81, and .78, respectively). With the exception of probable alcohol abuse, construct and criterion validity was demonstrated among both tribal and non-tribal Filipinos for all classes of psychiatric disorders by comparing diagnostic results with respondents' views of their physical and mental health and level of functional impairment. Overall, DSM-IV mood, anxiety, alcohol use, and PTSDs with adequate reliability and construct and criterion validity were made in this culturally diverse, non-Western, disaster victim population. However, test-retest diagnostic agreement was reduced for anxiety disorders and among aboriginal respondents, and validity was not demonstrated for probable alcohol abuse.

The effect of prostate volume on the yield of needle biopsy.

PURPOSE: Early diagnosis of prostate carcinoma has undergone significant evolution mainly due to the widespread use of serum prostate specific antigen, transrectal ultrasonography and spring loaded biopsy devices. A common dilemma faced by clinicians arises when a negative biopsy is obtained in a patient and there is a high suspicion for prostate carcinoma. The literature reveals a 20 to 40% positive repeat biopsy rate in men with elevated prostate specific antigen who had an initial negative biopsy. We determined the yield of 6 systematic sector biopsies as a function of total gland and peripheral zone volumes. MATERIALS AND METHODS: The database of transrectal ultrasound guided prostate needle biopsies performed at the Department of Urology, University of Washington Medical Center and Veterans Affairs Puget Sound Health Care System was reviewed. The yield of the 6 biopsies was determined as a function of the total gland and peripheral zone volumes. RESULTS: A total of 1,057 men who underwent transrectal ultrasound guided prostate needle biopsies were investigated in our study. Of the men 326 were diagnosed with prostate cancer for a positive biopsy rate of 30.8%. No relationship between gland size and cancer yield was seen using total gland volume compared to the first quartile until the largest quartile when a significantly lower cancer detection rate was noted (odds ratio 1.5). CONCLUSIONS: The positive yield of the systematic 6-sector biopsy decreases significantly when the total gland volume is greater than 55.6 cc or peripheral zone volume is greater than 33.61 cc. In men with smaller prostates 6 systematic sector biopsies should be adequate.

Repeat ultrasound guided prostate needle biopsy: use of free-to-total prostate specific antigen ratio in predicting prostatic carcinoma.

PURPOSE: Despite being the most useful tumor marker for the diagnosis of patients with prostate cancer, serum prostate specific antigen (PSA) is still hampered by lack of specificity. A negative prostate biopsy is associated with a 20 to 40% incidence of positive repeat biopsy in men with persistently elevated serum PSA levels. We determine whether the free-to-total PSA ratio could be predictive of prostate cancer in men undergoing repeat biopsy. MATERIALS AND METHODS: Archival sera, drawn before the first biopsy, were gathered from 51 men with a total serum PSA of 2 to 15 ng./ml. who underwent repeat prostate needle biopsy for various indications. The percent free PSA was calculated using the Hybritech Tandem-Rt free and total PSA as well as Dianon Systems freet and Hybritech total PSA assays. The free-to-total PSA ratio results between the cancer and noncancer groups were compared using Student's t test. RESULTS: The median Hybritech free-to-total PSA ratio was significantly lower in patients with positive repeat prostate needle biopsy compared to those with negative biopsy (14.9 versus 19.4%, p=0.05). Total PSA as well as the percent Dianon free-to-Hybritech total PSA ratio were not significantly different between the 2 groups of men. CONCLUSIONS: For total PSA in the range of 2 to 15 ng./ml. Hybritech free-to-total PSA ratio appeared to aid in the prediction of cancer on repeat biopsy.