Survival trends in young patients with Waldenström macroglobulinemia: Over five decades of experience.

Waldenström macroglobulinemia (WM) is a rare, indolent lymphoma, that predominately affects the elderly. We report the outcomes of young WM patients, evaluated over five decades, compared to their older counterparts, matched for the time of diagnosis. Between January 1, 1960 and October 31, 2013, 140 (11.8%) WM patients were ≤50 years of age at diagnosis in our database, and their estimated 10-year overall survival (OS) was 74%, with death attributable to WM in a higher proportion of patients compared to their older (≥65 years) counterparts (91% vs. 58%, p = .0001). Young patients were grouped into three cohorts based on the timing of the initiation of therapy: Group 1 (1960-1977, n = 12), Group 2 (1978-1995, n = 48), and Group 3 (1996-2013, n = 74). Among young patients, there was no disease-specific survival (DSS) difference across the three periods, [median DSS at 13 years (95% CI 5-23), 16 years (95% CI 14-22), and 15 years (95% CI 10-NR; p = .41), respectively]. However, DSS for the older cohort incrementally improved (Group 1, median 5.2 years, Group 2: 9.6 years, Group 3: 12 years; p = .05) over these periods. The estimated average years-of-life lost for the young cohort was 11.2 years from diagnosis, based on the expected survival for a normal age- and sex-matched population. Despite a protracted disease course, nearly all young patients succumb to their disease. In contrast to the improved survival of the elderly patient population, the evolving treatment strategies in WM have not impacted the outcome of young patients; however, the impact of Bruton tyrosine kinase inhibitors on this unique patient population remains to be determined.

Effect of Home Enteral Nutrition on Diabetes and Its Management.

BACKGROUND: Diabetes mellitus (DM) is estimated to affect 9% of Americans and is associated with significant morbidity, mortality, and increased healthcare costs. METHODS: A retrospective review of a home enteral nutrition (HEN) database of patients seen between March 1, 2004, and April 31, 2014, at our institution was conducted to identify HEN patients who had a diagnosis of DM or were diagnosed within the acute period (4 months) of starting HEN therapy. RESULTS: 174 (3.7%) of 4682 patients in the HEN program had DM. HEN was provided through a gastrostomy tube in 82 patients and through a jejunostomy tube in 92 patients. At 3 months, data were available for 42 gastrostomy patients; 44% had a change in DM management, with 60% undergoing a change to insulin. Similarly, 34 patients with jejunostomy had data available, with 41% undergoing change in medication and 93% being changed to insulin therapy. For patients with available glycated hemogloblin values, at 3 months the gastrostomy patients noted a decrease of 0.5% (7.3% ± 1.1% to 6.8% ± 0.7%, not significant) and the jejunostomy patients noted a decrease of 0.4% (6.9% ± 0.9% to 6.5% ± 1.1%, P = .06). CONCLUSIONS: Overall, our results suggest that closer follow-up and laboratory assessment are necessary for management of HEN patients with DM. In those with data available, glycemic control can be maintained in patients receiving HEN with appropriate adjustment of DM management and focus on ensuring that patients are not overfed.

A prospective double blind randomized controlled study on the use of ethanol locks in HPN patients.

BACKGROUND & AIMS: Ethanol lock therapy (ELT) has been shown to reduce the rate of catheter-related bloodstream infection (CRBSI) in high-risk home parenteral nutrition (HPN) patients. The aim of this study was to determine whether ELT therapy for all patients newly started on HPN would reduce the incidence of CRBSI. METHODS: This study was a prospective, double-blind, randomized controlled trial that was carried out from July 2014 to April 2016. The study participants were patients newly started on HPN, and they were randomly assigned to either treatment with ELT or our current standard of care with saline heparin locks. The primary outcome was occurrence of CRBSI. RESULTS: Thirty eight patients that were newly started on HPN were randomized to either treatment with ELT (n = 18) or to our current standard of care with heparin locks (n = 20). Four patients in the ELT group and one patient in the control arm had a CRBSI (p = 0.17). No significant adverse side effects were noted during the study. CONCLUSIONS: This study did not show improvement in the rate of CRBSI with ELT in all patients started on HPN. ELT therapy may be most helpful to reduce in CRBSI in high-risk HPN patients, but further studies with a randomized control trial design of high-risk patients are needed to further clarify this important issue in HPN patients. The study was registered at clinicaltrials.gov prior to patient enrollment (NCT02227329).

Pilot Study Comparing 2 Oral Rehydration Solutions in Patients With Short Bowel Syndrome Receiving Home Parenteral Nutrition: A Prospective Double-Blind Randomized Controlled Trial.

BACKGROUND: Short bowel syndrome (SBS) is a common indication for home parenteral nutrition (HPN). Oral rehydration solutions (ORSs) have the ability to supplement or reduce HPN dependence. However, ORSs have suffered from poor taste profiles, making long-term consumption and compliance unlikely. The goal of the current study was to assess the taste and compliance of 2 ORSs among patients with SBS requiring HPN. METHODS: All participants with SBS receiving HPN with anticipated duration >3 months were offered enrollment: 31 participants met inclusion criteria; 3 declined enrollment; and 28 were randomized to receive a modified World Health Organization ORS (group A) or a commercially available ORS (DripDrop; group B). RESULTS: Six participants dropped out shortly after randomization (3 in each group) due to poor taste or intolerance. An additional 3 (1 in group A and 2 in group B) discontinued the ORS before the end of the study at 6 months. At the end of the study, 19 remained. The mean taste rating given by the participants was, on a scale of 1-10, 7.3 ± 1.9 for group A and 7.6 ± 1.6 for group B ( P = .61). The mean number of days that ORSs were consumed each week was 6.0 ± 1.3 for group A and 6.6 ± 1 days for group B ( P = .06). CONCLUSION: Taste rating was not different for both ORSs; however, a significant number of participants did not complete the study.

Use of Home Parenteral Nutrition in Post-Bariatric Surgery-Related Malnutrition.

BACKGROUND: Bariatric surgery is one of the most effective techniques for achieving sustained weight loss but can be associated with surgical complications or malabsorption so significant that it leads to malnutrition. Parenteral nutrition (PN) may be necessary to help treat surgical complications or malnutrition from these procedures. There are limited data describing this patient population and role for home PN (HPN). METHODS: A retrospective review of our HPN database was conducted to identify patients who were initiated on HPN between January 1, 2003, and August 31, 2015, and had a history of bariatric surgery. RESULTS: A total of 54 HPN patients (6.3%) had a history of bariatric surgery. Average age was 52.1 ± 12.8 years, and 80% were female. The most common surgical procedure was Roux-en-Y gastric bypass (72%), with malnutrition or failure to thrive being the most common HPN indication (57%). Weight at the time of HPN initiation was 71.9 ± 20.4 kg and significantly increased to 78.9 ± 24.4 kg by the end of treatment ( P = .0001). Serum albumin levels rose from 2.8 ± 0.77 g/dL to 3.7 ± 0.58 g/dL by the end of HPN ( P < .0001). Forty-five of 54 patients (83.3%) went on to revision surgery. CONCLUSION: The results of this retrospective review support initiation of HPN in the malnourished post-bariatric surgery patient both nutritionally and as a bridge to revision surgery.

Notch Pathway Is Activated via Genetic and Epigenetic Alterations and Is a Therapeutic Target in Clear Cell Renal Cancer.

Clear cell renal cell carcinoma (CCRCC) is an incurable malignancy in advanced stages and needs newer therapeutic targets. Transcriptomic analysis of CCRCCs and matched microdissected renal tubular controls revealed overexpression of NOTCH ligands and receptors in tumor tissues. Examination of the TCGA RNA-seq data set also revealed widespread activation of NOTCH pathway in a large cohort of CCRCC samples. Samples with NOTCH pathway activation were also clinically distinct and were associated with better overall survival. Parallel DNA methylation and copy number analysis demonstrated that both genetic and epigenetic alterations led to NOTCH pathway activation in CCRCC. NOTCH ligand JAGGED1 was overexpressed and associated with loss of CpG methylation of H3K4me1-associated enhancer regions. JAGGED2 was also overexpressed and associated with gene amplification in distinct CCRCC samples. Transgenic expression of intracellular NOTCH1 in mice with tubule-specific deletion of VHL led to dysplastic hyperproliferation of tubular epithelial cells, confirming the procarcinogenic role of NOTCH in vivo Alteration of cell cycle pathways was seen in murine renal tubular cells with NOTCH overexpression, and molecular similarity to human tumors was observed, demonstrating that human CCRCC recapitulates features and gene expression changes observed in mice with transgenic overexpression of the Notch intracellular domain. Treatment with the γ-secretase inhibitor LY3039478 led to inhibition of CCRCC cells in vitro and in vivo In summary, these data reveal the mechanistic basis of NOTCH pathway activation in CCRCC and demonstrate this pathway to a potential therapeutic target.

Use of Blenderized Tube Feeding in Adult and Pediatric Home Enteral Nutrition Patients.

BACKGROUND: Long-term use of enteral nutrition (EN) continues to increase due to significant noted benefits. Patients also continue to express significant desire to pursue holistic and organic diets. Despite this, many nutrition providers are not well versed in assisting patients with blenderized tube feeding (BTF), and prevalence of its use is unknown. METHODS: A validated survey was administered to Oley Foundation members or individuals with access to the Oley website to assess the prevalence of BTF. RESULTS: A total of 216 participants took the survey, of whom 125 (57.8%) were pediatric patients with a mean age of 5.4 ± 3.5 years and 91 (42.2%) were adults with a mean age of 51.7 ± 19.5 years. Of pediatric patients, 112 (89.6%) used BTF for an average of 71% of their total daily nutrition intake; 93 (83%) reported that BTF comprised >50% of their daily EN, 12 (10.7%) reported it comprised 25%-50% of their daily enteral intake, and 7 (6.3%) reported BTF comprised < 25% of their daily intake. In the adult population, 60 (65.9%) used BTF for an average of 56% of total daily nutrition intake; 41 (68.4%) reported BTF comprised >50% of their daily nutrition intake, 11 (18.3%) reported it compromised 25%-50%, and 8 (13.3%) reported BTF comprised <25% of their daily intake. CONCLUSIONS: Most of the pediatric and adult patients surveyed use BTF as some portion of their enteral intake, making it essential that clinicians expand their knowledge related to BTF to appropriately care for this patient population.

Accuracy of Intravenous Electrocardiography Confirmation of Peripherally Inserted Central Catheter for Parenteral Nutrition.

BACKGROUND: Parenteral nutrition (PN) is a life-saving therapy for patients with intestinal failure. Safe delivery of hyperosmotic solution requires a central venous catheter (CVC) with tip in the lower superior vena cava (SVC) or at the SVC-right atrium (RA) junction. To reduce cost and delay in use of CVC, new techniques such as intravascular electrocardiogram (ECG) are being used for tip confirmation in place of chest x-ray (CXR). The present study assessed for accuracy of ECG confirmation in home PN (HPN). METHODS: Records for all patients consulted for HPN from December 17, 2014, to June 16, 2015, were reviewed for patient demographics, diagnosis leading to HPN initiation, and ECG and CXR confirmation. CXRs were subsequently reviewed by a radiologist to reassess location of the CVC tip and identify those that should be adjusted. RESULTS: Seventy-three patients were eligible, and after assessment for research authorization and postplacement CXR, 17 patients (30% male) with an age of 54 ± 14 years were reviewed. In all patients, postplacement intravascular ECG reading stated tip in the SVC. However, based on CXR, the location of the catheter tip was satisfactory (low SVC or SVC-RA junction) in 10 of 17 patients (59%). CONCLUSION: Due to the high osmolality of PN, CVC tip location is of paramount importance. After radiology review of CXR, we noted that 7 of 17 (41%) peripherally inserted central catheter lines were in an unsatisfactory position despite ECG confirmation. With current data available, intravenous ECG confirmation should not be used as the sole source of tip confirmation in patients receiving HPN.

Bortezomib in mantle cell lymphoma: comparative therapeutic outcomes.

Mantle cell lymphoma (MCL) is an incurable, typically aggressive subtype of non-Hodgkin lymphoma, accounting for 4%-7% of newly diagnosed non-Hodgkin lymphoma cases. Chemoresistance commonly ensues in MCL, and patients with this heterogeneous disease invariably relapse, underscoring the unmet need for better therapies. Over the past few years, several novel agents with promising activity and unique mechanisms of action have been deemed effective in MCL. Bortezomib is a reversible proteasome inhibitor, approved as a single agent for patients with relapsed/refractory MCL who have received at least one prior line of therapy. Addition of bortezomib to chemoimmunotherapies has demonstrated good tolerability and superior efficacy, both in the upfront and salvage settings, and recently one such combination of bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone was approved as a frontline regimen in untreated patients with MCL. This review examines the role of bortezomib in a multitude of clinical settings and ongoing clinical trials designed to optimize its integration in the current treatment paradigms of MCL.

Role of DNA methylation in renal cell carcinoma.

Alterations in DNA methylation are seen in cancers and have also been examined in clear cell renal cell carcinoma (ccRCC). Numerous tumor suppressor genes have been reported to be partially or completely silenced due to hypermethylation of their promoters in single-locus studies, and the use of hypomethylating agents has been shown to restore the expression of many of these genes in vitro. In particular, members of the Wnt and TGF-beta pathways, pro-apoptotic genes such as APAF-1 and negative cell-cycle regulators such as KILLIN have been shown to be epigenetically silenced in numerous studies in ccRCC. Recently, TCGA analysis of a large cohort of ccRCC samples demonstrated that aberrant hypermethylation correlated with the stage and grade in kidney cancer. Our genome-wide studies also revealed aberrant widespread hypermethylation that affected regulatory regions of the kidney genome in ccRCC. We also observed that aberrant enhancer hypermethylation was predictive of adverse prognosis in ccRCC. Recent discovery of mutations affecting epigenetic regulators reinforces the importance of these changes in the pathophysiology of ccRCC and points to the potential of epigenetic modulators in the treatment of this malignancy.

Waldenström macroglobulinemia: What a hematologist needs to know.

Waldenström macroglobulinemia (WM) is a distinct hematologic malignancy characterized by a lymphoplasmacytic bone marrow infiltration and the presence of immunoglobulin (Ig)M monoclonal protein. Patients typically present at an advanced age, and a substantial proportion are asymptomatic at diagnosis. A unifying diagnosis of WM may be missed by an unsuspecting hematologist, as symptomatic patients present with a multitude of non-specific manifestations. Although constitutional and neuropathy-related symptoms predominate, concomitant IgM-induced hyperviscosity-associated features can provide useful diagnostic clues. There are specific indications for initiation of therapy. This review focuses on the most up-to-date management strategies of WM, in addition to highlighting the recent discoveries of MYD88 and CXCR4 mutations that have shed unprecedented light on the complex signaling pathways, and opened avenues for novel therapeutic targeting. Although WM remains incurable, with the rapid emergence and integration of effective novel therapies, its clinical course appears poised to improve in the foreseeable future.

Kidney cancer is characterized by aberrant methylation of tissue-specific enhancers that are prognostic for overall survival.

PURPOSE: Even though recent studies have shown that genetic changes at enhancers can influence carcinogenesis, most methylomic studies have focused on changes at promoters. We used renal cell carcinoma (RCC), an incurable malignancy associated with mutations in epigenetic regulators, as a model to study genome-wide patterns of DNA methylation at a high resolution. EXPERIMENTAL DESIGN: Analysis of cytosine methylation status of 1.3 million CpGs was determined by the HELP assay in RCC and healthy microdissected renal tubular controls. RESULTS: We observed that the RCC samples were characterized by widespread hypermethylation that preferentially affected gene bodies. Aberrant methylation was particularly enriched in kidney-specific enhancer regions associated with H3K4Me1 marks. Various important underexpressed genes, such as SMAD6, were associated with aberrantly methylated, intronic enhancers, and these changes were validated in an independent cohort. MOTIF analysis of aberrantly hypermethylated regions revealed enrichment for binding sites of AP2a, AHR, HAIRY, ARNT, and HIF1 transcription factors, reflecting contributions of dysregulated hypoxia signaling pathways in RCC. The functional importance of this aberrant hypermethylation was demonstrated by selective sensitivity of RCC cells to low levels of decitabine. Most importantly, methylation of enhancers was predictive of adverse prognosis in 405 cases of RCC in multivariate analysis. In addition, parallel copy-number analysis from MspI representations demonstrated novel copy-number variations that were validated in an independent cohort of patients. CONCLUSIONS: Our study is the first high-resolution methylome analysis of RCC, demonstrates that many kidney-specific enhancers are targeted by aberrant hypermethylation, and reveals the prognostic importance of these epigenetic changes in an independent cohort.

Impact of iron overload and potential benefit from iron chelation in low-risk myelodysplastic syndrome.

Myelodysplastic syndromes (MDSs) are a group of heterogeneous clonal bone marrow disorders characterized by ineffective hematopoiesis, peripheral blood cytopenias, and potential for malignant transformation. Lower/intermediate-risk MDSs are associated with longer survival and high red blood cell (RBC) transfusion requirements resulting in secondary iron overload. Recent data suggest that markers of iron overload portend a relatively poor prognosis, and retrospective analysis demonstrates that iron chelation therapy is associated with prolonged survival in transfusion-dependent MDS patients. New data provide concrete evidence of iron's adverse effects on erythroid precursors in vitro and in vivo. Renewed interest in the iron field was heralded by the discovery of hepcidin, the main serum peptide hormone negative regulator of body iron. Evidence from ß-thalassemia suggests that regulation of hepcidin by erythropoiesis dominates regulation by iron. Because iron overload develops in some MDS patients who do not require RBC transfusions, the suppressive effect of ineffective erythropoiesis on hepcidin may also play a role in iron overload. We anticipate that additional novel tools for measuring iron overload and a molecular-mechanism-driven description of MDS subtypes will provide a deeper understanding of how iron metabolism and erythropoiesis intersect in MDSs and improve clinical management of this patient population.