Early lymphocyte collection for anti-CD19 CART production improves T-cell fitness in patients with relapsed/refractory diffuse large B-cell lymphoma.

BACKGROUND: Chimeric antigen receptor (CAR) T cells targeted to the CD19 B-cell antigen form an approved treatment for patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). However, since this therapy is administered after multiple lines of treatment and exposure to lymphotoxic agents, there is an urgent need to optimize this modality of treatment. METHODS: To circumvent the difficulties of harvesting adequate and optimal T cells from DLBCL patients and improve CART therapy, we suggest an earlier lymphopheresis (i.e. at first relapse, before salvage treatment). We conducted a prospective study and evaluated the potential benefit of an earlier lymphopheresis (early group, n = 22) on the clinical outcome of CD19-CART infused DLBCL patients, in comparison with standard lymphopheresis (i.e. at second relapse and beyond; standard group, n = 23). RESULTS: An increased percentage of naïve T cells and increased in vitro T-cell functionality were observed in the early group. Additionally, these cells exhibit a lower exhaustion profile than T cells collected in the standard group. CONCLUSION: While improved T-cell phenotype and function in the lymphopheresis product did not translate into significantly improved clinical outcomes, a trend towards better overall survival (OS) and progression-free survival (PFS) was observed. Early lymphopheresis maximizes the potential of salvage therapies, without compromising CAR T-cell quality.

Is psychiatric residential facility discharge possible and predictable? A multivariate analytical approach applied to a prospective study in Italy.

BACKGROUND: A growing number of severely ill patients require long-term care in non-hospital residential facilities (RFs). Despite the magnitude of this development, longitudinal studies surveying fairly large resident samples and yielding important information on this population have been very few. AIMS: The aims of the study were (1) to describe the socio-demographic, clinical, and treatment-related characteristics of RF patients during an index period in 2010; (2) to identify predictors and characteristics associated with discharge at the 1-year follow-up; (3) to evaluate clinicians' predictions about each patient's likelihood of home discharge (HD). METHODS: A prospective observational cohort study was conducted involving all patients staying in 23 medium-long-term RFs of the St John of God Order with a primary psychiatric diagnosis. A comprehensive set of socio-demographic, clinical, and treatment-related information was gathered and standardized assessments (BPRS, HONOS, PSP, PHI, SLOF, RBANS) were administered to each participant. Logistic regression analyses were run to identify independent discharge predictors. RESULTS: The study involved 403 patients (66.7% male), with a mean age of 49 years (SD = 10). The participants' average illness duration was 23 years; median value for length of stay in the RF was 2.2 years. The most frequent diagnosis was schizophrenia (67.5%). 104 (25.8%) were discharged: 13.6% to home, 8.2% to other RFs, 2.2% to supported housing, and 1.5% to prison. Clinicians' predictions about HD were generally erroneous. CONCLUSIONS: Very few patients were discharged to independent accommodations after 1 year. The main variables associated with a higher HD likelihood were: illness duration of <15 years and effective social support during the previous year. Lower severity of psychopathology and higher working skill levels were also associated with a significantly greater HD likelihood.

Colistin is relatively safe in hematological malignancies and hematopoietic stem cell transplantation patients.

PURPOSE: Colistin is increasingly used as the last-resort treatment option against infections caused by multidrug-resistant (MDR) Gram-negative pathogens, but its nephrotoxicity is of concern, especially in severely ill patients. The aim of this study was to analyze the toxicity of colistin therapy in adults and children with hematological malignancies (HM) and hematopoietic stem cell transplantation (HSCT) recipients. METHODS: Data on HSCT recipients and HM patients, treated with intravenous colistin (2.5-5 mg/kg/day in children and 3-6 million international units (IU) in adults, adjusted to renal function) during the period 2008-2011 in our center, were retrospectively collected and analyzed. Nephrotoxicity was defined according to the RIFLE criteria (Risk, Injury, Failure, Loss, and End-stage kidney disease). RESULTS: Twenty-nine children and adults received 38 courses of intravenous colistin (2.5-5 mg/kg/day in children and 3-6 × 10(6) IU in adults, adjusted to renal function) [allogeneic HSCT (22 courses) and HM (16 courses)] for 3-28 days (median 10 days) for empirical therapy for nosocomial clinical sepsis (28) or local infection (6), and bacteremia with MDR Gram-negative rods (4). Nephrotoxicity was observed at the end of 4 (10.5%) courses. In 32 (84%) courses, nephrotoxic medications were concomitantly administered. Two patients had convulsions, probably unrelated to colistin. Seven patients (18%) died while on colistin therapy. No death was attributed to an adverse effect of colistin. CONCLUSIONS: Treatment with intravenous colistin, with dosage adjusted to renal function, was relatively safe for HM/HSCT patients, even with concomitantly administered nephrotoxic medications. Concern about nephrotoxicity should not justify a delay in initiating empirical colistin treatment in situations where infection with MDR Gram-negative rods is likely.

Stromal gene signatures in large-B-cell lymphomas.

BACKGROUND: The addition of rituximab to combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), or R-CHOP, has significantly improved the survival of patients with diffuse large-B-cell lymphoma. Whether gene-expression signatures correlate with survival after treatment of diffuse large-B-cell lymphoma is unclear. METHODS: We profiled gene expression in pretreatment biopsy specimens from 181 patients with diffuse large-B-cell lymphoma who received CHOP and 233 patients with this disease who received R-CHOP. A multivariate gene-expression-based survival-predictor model derived from a training group was tested in a validation group. RESULTS: A multivariate model created from three gene-expression signatures--termed "germinal-center B-cell," "stromal-1," and "stromal-2"--predicted survival both in patients who received CHOP and patients who received R-CHOP. The prognostically favorable stromal-1 signature reflected extracellular-matrix deposition and histiocytic infiltration. By contrast, the prognostically unfavorable stromal-2 signature reflected tumor blood-vessel density. CONCLUSIONS: Survival after treatment of diffuse large-B-cell lymphoma is influenced by differences in immune cells, fibrosis, and angiogenesis in the tumor microenvironment.

Therapy-related leukemia: clinical characteristics and analysis of new molecular risk factors in 96 adult patients.

Therapy-related leukemia or myelodysplasia (t-leuk/MDS) is a serious problem that is increasing in frequency. We studied the clinical characteristics of 96 patients (pts) with a mean age of 48 years, and analyzed the molecular parameters that could predispose to t-leuk/MDS. Hematological malignancies were the most common primary (53%), followed by breast and ovarian cancer (30% combined). The mean latency until the development of t-AML was 45.5 months. Median survival was 10 months. Cytogenetics was abnormal in 89% of pts. FLT3 internal tandem duplications were found in six of 41 (14.6%) pts, of whom four had an abnormal karyotype. Analysis of drug metabolism and disposition genes showed a protective effect of the CYP3A4 1*B genotype against the development of t-leuk/MDS, whereas the CC genotype of MDR1 C3435T and the NAD(P)H:quinone oxidoreductase1 codon 187 polymorphism were both noncontributory. Microsatellite instability (MSI) analysis using fluoresceinated PCR with ABI sequence analyzer demonstrated that 41% of pts had high levels of MSI in four or more of 10 microsatellite loci. Immunohistochemistry demonstrated reduced expression of MSH2 and MLH1 in 6/10 pts with MSI as compared to 0/5 of pts without MSI. In conclusion, genetic predisposition as well as epigenetic events contribute to the etiology of t-AML/MDS.

Clinical utility of computed tomography-guided core needle biopsy in the diagnostic re-evaluation of patients with lymphoproliferative disorders and suspected disease progression.

BACKGROUND: Histological transformation is a common clinical event in patients with lymphoproliferative diseases, often requiring a modification in therapy. Minimally invasive biopsy techniques have been used for initial diagnosis of these disorders but their role has not been systematically evaluated in disease progression. The purpose of this study was to evaluate the yield of computed tomography (CT)-guided core needle biopsy in patients with lymphoproliferative disorders and suspected disease progression. PATIENTS AND METHODS: We performed a retrospective analysis of the records of patients with known lymphoproliferative disorders who underwent CT-guided core needle biopsy during the course of their disease, between 1990 and 2002. RESULTS: A total of 130 patients with lymphoproliferative disorders (91 patients with non-Hodgkin's lymphoma, 21 with Hodgkin's disease, 10 with chronic lymphocytic leukemia, six with combined malignancies and two with Castleman's disease) underwent CT-guided core needle biopsy 4.7 +/- 5.1 (standard deviation) (range 0-40) years after initial diagnosis. The procedure was diagnostic in 98 cases (75.4%). In 22 patients (17%) a subsequent open biopsy was performed, and in 10 (7.6%) the final diagnosis remained unconfirmed. Histological transformation was found in 20 cases (15.4%), of which 19 were suspected clinically. A new diagnosis (malignant and non-malignant) was apparent in 18 cases (13.9%) and relapsed or ongoing evidence of the original disease was found in 82 (63%). CONCLUSIONS: CT-guided core needle biopsy is a reliable procedure in patients with suspected histological transformation of lymphoproliferative disorders, and should be used as the initial tool for pathological re-evaluation.

The common mutations C677T and A1298C in the human methylenetetrahydrofolate reductase gene are associated with hyperhomocysteinemia and cardiovascular disease in hemodialysis patients.

BACKGROUND: Plasma total homocysteine (tHcy) level might be an important risk factor for the development of cardiovascular disease (CVD) in dialysis patients. While both renal failure and mutations of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene may result in hyperhomocysteinemia and CVD, the distinct roles of the thermolabile MTHFR mutation at nucleotide C677T and the more recently described mutation at nucleotide A1298C have not been evaluated concurrently in patients on hemodialysis. METHODS: A cross-sectional study was performed in 120 maintenance HD patients to determine the prevalence of MTHFR C677T and A1298C mutations and their relative association to hyperhomocysteinemia and CVD. RESULTS: Both mutations, the C677T and the A1298C, were highly prevalent in HD patients with allele frequencies of 0.41 and 0.27, respectively. The prevalence of CVD in HD patients was 55% and its significant risk factors included, in descending order, hyperhomocysteinemia, MTHFR C677T mutation, low serum folate levels, diabetes mellitus, hypertension, and double heterozygote state for both MTHFR mutations (677CT/1298AC). MTHFR A1298C mutation alone and gender were not associated with either hyperhomocysteinemia or increased CVD risk, but the HD patients with homozygotes 1298CC and wild alleles 677CC (677CC/1298CC) have significant increase of tHcy (37.7 +/- 12) and high prevalence of CVD. CONCLUSIONS: Hyperhomocysteinemia, serum folate levels and both C677T and A1298C MTHFR mutations are associated with CVD in HD patients.

Compound cardiac toxicity of oral erythromycin and verapamil.

OBJECTIVE: To report a case of complete atrioventricular (AV) block and QTc prolongation following coadministration of high-dose verapamil and erythromycin. CASE SUMMARY: A 79-year-old white woman was admitted to the hospital due to extreme fatigue and dizziness. On admission, heart rate was 40 beats/min and blood pressure was 80/40 mm Hg. An electrocardiogram showed complete atrioventricular (AV) block, escape rhythm of 50 beats/min, and QTc prolongation 583 msec. This event was attributed to concomitant treatment with verapamil 480 mg/d and erythromycin 2,000 mg/d, which was prescribed one week before admission. DISCUSSION: This is the first case published describing complete AV block and prolongation of QTc following coadministration of erythromycin and verapamil. CYP3A4 is the main isoenzyme responsible for metabolism of erythromycin and verapamil. Both drugs are potent inhibitors of CYP3A4 and of P-glycoprotein; this may be the basis for the pharmacokinetic interaction between erythromycin and verapamil. In addition to being a woman, our patient had other risk factors for QT prolongation: slow baseline heart rate (probably induced by verapamil), left-ventricular hypertrophy, and possibly ischemic heart disease. CONCLUSIONS: This life-threatening arrhythmia was probably the result of a pharmacokinetic and/or pharmacodynamic interaction of high-dose verapamil and erythromycin.

The association between two common mutations C677T and A1298C in human methylenetetrahydrofolate reductase gene and the risk for diabetic nephropathy in type II diabetic patients.

Mutations of the methylenetetrahydrofolate reductase (MTHFR) gene have been shown to be associated with a predisposition to developing diabetic nephropathy (DN) in specific populations. The frequency of two MTHFR mutations, a recently described mutation in the human MTHFR gene A1298C and C677T, whose association with DN is already known, was determined in an Israeli Jewish population with type 2 diabetes mellitus (DM). Both A1298C and C677T are highly prevalent in the diabetic population with allele frequencies of 0.35 and 0.36, respectively. The genotype frequency and allele frequency for these two polymorphisms in patients who are normoalbuminuric (n = 55) were compared with those of patients who had either micro- or macroalbuminuria (n = 43). For both polymorphisms, there were no significant differences in either the genotype distribution or allele frequency in patients with or without DN. However, in patients with serum folate <15.4 nmol/L, there was a greater incidence of DN in those patients who were homozygous or heterozygous for the C677T mutation. For the A1298C mutation, there is evidence suggesting that the homozygous state may be protective in patients with low-normal serum folate. Folate supplementation in diabetic patients with the C677T mutation and low-normal serum folate may prevent the onset or retard the progression of DN.

A common mutation A1298C in human methylenetetrahydrofolate reductase gene: association with plasma total homocysteine and folate concentrations.

Methylenetetrahydrofolate reductase (MTHFR) is one of the main regulatory enzymes of homocysteine metabolism. Previous studies revealed that a common mutation in MTHFR gene C677T is related to hyperhomocysteinemia and occlusive vascular pathology. In the current study, we determined the prevalence of a newly described mutation in the human MTHFR gene A1298C, and the already known C677T mutation, and related them to plasma total homocysteine and folate concentrations. We studied 377 Jewish subjects, including 190 men and 186 women aged 56.8 +/- 13 y (range 32-95 y). The frequency of the homozygotes for the A1298C and the C677T MTHFR mutations was common in the Jewish Israeli population (0.34 and 0.37, respectively). Subjects homozygous (TT) for the C677T mutation had significantly greater plasma total homocysteine concentrations (P < 0.01) than subjects without the mutation (CC). Homozygotes (CC) for the A1298C mutation did not have elevated plasma total homocysteine concentrations. Our study indicated that subjects with the 677CC/1298CC genotype had significantly lower concentrations (P < 0. 05) than those with a 677CC/1298AA genotype. Neither mutation (the A1298C and the C677T) was associated with established cardiovascular risk factors such as hypertension, elevated total cholesterol or body mass index.

Pituitary apoplexy manifested by sterile meningitis.

Pituitary apoplexy is rare and underdiagnosed. It results from either infarction or hemorrhage into an adenoma of the pituitary gland. The clinical presentation comprises a rapid development of impaired consciousness, severe headache, and amblyopia or diplopia. Meningeal irritation signs are considered rare and have not been reported as presenting signs. We report a 64-year-old patient whose presentation with necrosis of a pituitary adenoma was clinically indistinguishable from infectious meningitis.

Interleukin-6 secretion in mice is associated with reduced glucose-6-phosphatase and liver glycogen levels.

Mice bearing interleukin-6 (IL-6)-secreting tumor were used to study the chronic effect of IL-6 on carbohydrate metabolism. Mice were injected with allogeneic tumor cells transduced with the murine IL-6 gene. Serum IL-6 levels were correlated exponentially with tumor weight. Secretion of IL-6 from the developed tumors was associated with decreased food consumption, reduced body weight, and reduced blood glucose levels. Insulin levels did not change, and 2-deoxyglucose uptake was not affected in most tissues examined. A significant increase of 2-deoxyglucose uptake was measured in the liver. Glycogen content in the liver determined 0, 6, 12, and 18 days after tumor inoculation was 42, 23, 12, and 3 mg/g, respectively. The activity of phosphoenolpyruvate carboxykinase was not affected. The activity of glucose-6-phosphatase (G-6-Phase) determined 6, 12, and 18 days after tumor injection was 84, 70, and 50% of G-6-Pase activity in pair-fed mice bearing nonsecreting tumors, respectively. G-6-Pase mRNA levels were markedly reduced due to inhibition of G-6-Pase gene transcriptional rate.

DRG clinical surveillance: an approach to internal control.

In the present healthcare environment, internal control of hospital resources is becoming increasingly important. One hospital's approach to instituting internal control is the development of a DRG clinical surveillance program. This program uses utilization review in conjunction with quality assurance to provide the hospital with a working framework for determining whether hospital admission is appropriate or whether an alternative method of healthcare delivery should be used.