Toxicities of high-dose chemotherapy and autologous hematopoietic cell transplantation in older patients with lymphoma.

High-dose chemotherapy and autologous hematopoietic cell transplantation is an effective consolidation therapy in lymphoma; however, its use in elderly patients has been limited because of concerns for greater toxicity in this group. We investigated the toxicities of carmustine, etoposide, cytarabine, and melphalan (BEAM) and autologous hematopoietic cell transplantation (AHCT) in 346 patients in 2 age groups: 279 patients aged 60 to 69 years and 67 patients aged ≥70 years. The majority developed severe toxicities; the most common were febrile neutropenia, gastrointestinal, infections, and cardiovascular. Older patients were at higher risk for grade ≥3 cardiovascular toxicities (hazard ratio [HR], 3.36; 95% confidence interval [CI], 2.25-5.00; P < .001) and skin toxicities (HR, 2.45; 95% CI, 1.08-5.54, P = .032). In the older group, nonrelapse mortality at 100 days and at 2 years was 2.99% (95% CI, 0.55-9.32) and 6.2% (95% CI, 1.97-13.95), respectively, vs 1.79% (95% CI, 0.68-3.92) and 2.91% (95% CI, 1.37-5.42), respectively, in the younger group. When adjusting for the number of grade ≥3 toxicities within the first 100 days, older patients had a 1.71-fold (95% CI, 1.08-2.71) increased risk for progression or death relative to younger patients. Although BEAM followed by AHCT is effective, it is associated with significant organ toxicities, especially in patients aged ≥70 years. Interventions to mitigate toxicities while maintaining efficacy are much needed.

Fecal microbiota diversity disruption and clinical outcomes after auto-HCT: a multicenter observational study.

We previously described clinically relevant reductions in fecal microbiota diversity in patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Recipients of high-dose chemotherapy and autologous HCT (auto-HCT) incur similar antibiotic exposures and nutritional alterations. To characterize the fecal microbiota in the auto-HCT population, we analyzed 1161 fecal samples collected from 534 adult recipients of auto-HCT for lymphoma, myeloma, and amyloidosis in an observational study conducted at 2 transplantation centers in the United States. By using 16S ribosomal gene sequencing, we assessed fecal microbiota composition and diversity, as measured by the inverse Simpson index. At both centers, the diversity of early pretransplant fecal microbiota was lower in patients than in healthy controls and decreased further during the course of transplantation. Loss of diversity and domination by specific bacterial taxa occurred during auto-HCT in patterns similar to those with allo-HCT. Above-median fecal intestinal diversity in the periengraftment period was associated with decreased risk of death or progression (progression-free survival hazard ratio, 0.46; 95% confidence interval, 0.26-0.82; P = .008), adjusting for disease and disease status. This suggests that further investigation into the health of the intestinal microbiota in auto-HCT patients and posttransplant outcomes should be undertaken.

Early Fluid Overload Is Associated with an Increased Risk of Nonrelapse Mortality after Ex Vivo CD34-Selected Allogeneic Hematopoietic Cell Transplantation.

In a recently published and validated definition of fluid overload (FO), grade ≥ 2 FO was significantly associated with an increased risk of nonrelapse mortality (NRM) after unmodified and haploidentical allogeneic hematopoietic cell transplantation (allo-HCT) using calcineurin inhibitor (CNI)-based graft-versus-host disease (GVHD) prophylaxis. We evaluated the effect of FO on outcomes in 169 patients undergoing myeloablative-conditioned ex vivo CD34+ selected allo-HCT using the same grading scale. Thirty patients (17.8%) had grade ≥ 2 FO within the 30 days after ex vivo CD34+ selected allo-HCT with a median onset at day 11 (range, -8 to 28). Age ≥ 55 years (odds ratio, 3.43; P = .005) and chemotherapy-based conditioning (odds ratio, 3.89; P = .007) were associated with an increased risk of grade ≥ 2 FO. Patients with early grade ≥ 2 FO had a significantly higher NRM when compared with patients with grade < 2 FO (24.1% versus 3.6% at day 100, P = .01). The HCT-specific comorbidity index (HCT-CI) ≥ 3, FEV1 < 80, adjusted DLco < 80, and HLA mismatch were associated with an increased risk of NRM, whereas total body irradiation-based conditioning was associated with a reduced risk of NRM. In a multivariate analysis grade ≥ 2 FO was associated with increased NRM after adjusting for HCT-CI and HLA match (hazard ratio, 2.3; P = .014). There was a trend toward inferior relapse-free survival in patients with grade ≥ 2 FO compared with patients with grade < 2 FO, 62% versus 72% at 1 year (P = .07), and a trend toward inferior overall survival, 69% versus 79% at 1 year (P = 0.06), respectively. Our findings show that FO should be routinely assessed to identify patients at risk for NRM. Despite a CNI-free allo-HCT platform, regimen-related tissue and endothelial injury leads to FO in susceptible patients. FO is a highly relevant post-HCT toxicity that requires further inquiry.

International collaborative study on EUS-guided gallbladder drainage: Are we ready for prime time?

BACKGROUND: Cholecystectomy remains the gold standard treatment of cholecystitis. Endoscopic treatment of cholecystitis includes transpapillary gallbladder drainage. Recently, endoscopic ultrasound-guided transmural drainage of the gallbladder (EUS-GBD) has been reported. This study reports the cumulative experience of an international group performing EUS-GBD. METHODS: Cases of EUS-GBD from January 2012 to November 2013 from 3 tertiary-care institutions were captured in a registry. Patient demographics, disease characteristics, procedural and clinical outcomes were recorded. RESULTS: 35 patients (15 malignant, 20 benign) were included. Median age was 81 years (SD=13.76 years), sixteen (46%) were males. Median follow-up was 91.5 days (SD=157 days). Transmural access was obtained from the stomach (n=17) or duodenum (n=18). Stents placed included plastic (n=6), metal (n=20), or combination (n=7). Technical success was achieved in 91.4% (n=32). Immediate adverse events (14%) included: bleeding, stent migration, cholecystitis and hemoperitoneum. Delayed adverse events (11%) included abscess formation and recurrence of cholecystitis. Long-term clinical success rate was 89%. Stent type and puncture site were not associated with immediate (p=0.88, p=0.62), or long-term (p=0.47, p=0.27) success. CONCLUSIONS: EUS-GBD appears to be feasible, safe, and effective. Prospective studies are needed to confirm these findings and identify the best technique to use. CLINICAL TRIAL REGISTRATION: NCT01522573.

Evidence for human lung stem cells.

BACKGROUND: Although progenitor cells have been described in distinct anatomical regions of the lung, description of resident stem cells has remained elusive. METHODS: Surgical lung-tissue specimens were studied in situ to identify and characterize human lung stem cells. We defined their phenotype and functional properties in vitro and in vivo. RESULTS: Human lungs contain undifferentiated human lung stem cells nested in niches in the distal airways. These cells are self-renewing, clonogenic, and multipotent in vitro. After injection into damaged mouse lung in vivo, human lung stem cells form human bronchioles, alveoli, and pulmonary vessels integrated structurally and functionally with the damaged organ. The formation of a chimeric lung was confirmed by detection of human transcripts for epithelial and vascular genes. In addition, the self-renewal and long-term proliferation of human lung stem cells was shown in serial-transplantation assays. CONCLUSIONS: Human lungs contain identifiable stem cells. In animal models, these cells participate in tissue homeostasis and regeneration. They have the undemonstrated potential to promote tissue restoration in patients with lung disease. (Funded by the National Institutes of Health.).

Combination therapy with statin and fibrate in patients with dyslipidemia associated with insulin resistance, metabolic syndrome and type 2 diabetes mellitus.

INTRODUCTION: People with insulin resistance/metabolic syndrome (IR/MS) and/or type 2 diabetes mellitus (T2DM) have increased rates of cardiovascular disease (CVD) even when low-density lipoprotein cholesterol levels are at or near target levels. Contributors to this problem are the high triglyceride (TG) levels and low levels of high-density lipoprotein cholesterol (HDLC) that are commonly present in this population, even with statin therapy. AREAS COVERED: This review focuses on the use of a combination of statins with fibrates, which lower TG and raise HDLC concentrations and, therefore, have the potential to further lower rates of CVD more in people with IR/MS and/or T2DM. Treatment with this combination is uncommon because doctors and patients are fearful of muscle, liver and renal complications and because the evidence that the combination will actually reduce risk has been lacking. In this review, the authors examine the efficacy and safety of the statin-fibrate combination, particularly fenofibrate and simvastatin, the combination used in the ACCORD trial. EXPERT OPINION: The authors' opinion is that this combination of fenofibrate and statin is as safe as either drug alone and, in patients with significant dyslipidemia, is likely to reduce CVD. Concerns remain concerning fenofibrate-associated increases in serum creatinine levels and the significant heterogeneity in the reduction in CVD by the combination in women. A trial of statin + fenofibrate in people with IR/MS and/or T2DM who also have significant dyslipidemia is needed.

Cardiomyogenesis in the adult human heart.

RATIONALE: The ability of the human heart to regenerate large quantities of myocytes remains controversial, and the extent of myocyte renewal claimed by different laboratories varies from none to nearly 20% per year. OBJECTIVE: To address this issue, we examined the percentage of myocytes, endothelial cells, and fibroblasts labeled by iododeoxyuridine in postmortem samples obtained from cancer patients who received the thymidine analog for therapeutic purposes. Additionally, the potential contribution of DNA repair, polyploidy, and cell fusion to the measurement of myocyte regeneration was determined. METHODS AND RESULTS: The fraction of myocytes labeled by iododeoxyuridine ranged from 2.5% to 46%, and similar values were found in fibroblasts and endothelial cells. An average 22%, 20%, and 13% new myocytes, fibroblasts, and endothelial cells were generated per year, suggesting that the lifespan of these cells was approximately 4.5, 5, and 8 years, respectively. The newly formed cardiac cells showed a fully differentiated adult phenotype and did not express the senescence-associated protein p16(INK4a). Moreover, measurements by confocal microscopy and flow cytometry documented that the human heart is composed predominantly of myocytes with 2n diploid DNA content and that tetraploid and octaploid nuclei constitute only a small fraction of the parenchymal cell pool. Importantly, DNA repair, ploidy formation, and cell fusion were not implicated in the assessment of myocyte regeneration. CONCLUSIONS: Our findings indicate that the human heart has a significant growth reserve and replaces its myocyte and nonmyocyte compartment several times during the course of life.

Spontaneous calcium oscillations regulate human cardiac progenitor cell growth.

RATIONALE: The adult heart possesses a pool of progenitor cells stored in myocardial niches, but the mechanisms involved in the activation of this cell compartment are currently unknown. OBJECTIVE: Ca2+ promotes cell growth raising the possibility that changes in intracellular Ca2+ initiate division of c-kit-positive human cardiac progenitor cells (hCPCs) and determine their fate. METHODS AND RESULTS: Ca2+ oscillations were identified in hCPCs and these events occurred independently from coupling with cardiomyocytes or the presence of extracellular Ca2+. These findings were confirmed in the heart of transgenic mice in which enhanced green fluorescent protein was under the control of the c-kit promoter. Ca2+ oscillations in hCPCs were regulated by the release of Ca2+ from the endoplasmic reticulum through activation of inositol 1,4,5-triphosphate receptors (IP3Rs) and the reuptake of Ca2+ by the sarco-/endoplasmic reticulum Ca2+ pump (SERCA). IP3Rs and SERCA were highly expressed in hCPCs, whereas ryanodine receptors were not detected. Although Na+-Ca2+ exchanger, store-operated Ca2+ channels and plasma membrane Ca2+ pump were present and functional in hCPCs, they had no direct effects on Ca2+ oscillations. Conversely, Ca2+ oscillations and their frequency markedly increased with ATP and histamine which activated purinoceptors and histamine-1 receptors highly expressed in hCPCs. Importantly, Ca2+ oscillations in hCPCs were coupled with the entry of cells into the cell cycle and 5-bromodeoxyuridine incorporation. Induction of Ca2+ oscillations in hCPCs before their intramyocardial delivery to infarcted hearts was associated with enhanced engraftment and expansion of these cells promoting the generation of a large myocyte progeny. CONCLUSION: IP3R-mediated Ca2+ mobilization control hCPC growth and their regenerative potential.