Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL.

In the phase 3 RESONATE study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%) and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized to ibrutinib alive and progression-free at 24 months. The improved efficacy of ibrutinib vs ofatumumab continues in all prognostic subgroups including del17p and del11q. No significant difference within the ibrutinib arm was observed for PFS across most genomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared with patients with neither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for ibrutinib-treated patients in second-line vs later lines of therapy. The robust clinical activity of ibrutinib continues to show ongoing efficacy and acceptable safety consistent with prior reports, independent of various known high-risk mutations.

Early-stage mantle cell lymphoma: a retrospective analysis from the International Lymphoma Radiation Oncology Group (ILROG).

BACKGROUND: Mantle cell lymphoma (MCL) rarely presents as early-stage disease, but clinical observations suggest that patients who present with early-stage disease may have better outcomes than those with advanced-stage disease. PATIENTS AND METHODS: In this 13-institution study, we examined outcomes among 179 patients with early-stage (stage I or II) MCL in an attempt to identify prognostic factors that influence treatment selection and outcome. Variables examined included clinical characteristics, treatment modality, response to therapy, sites of failure, and survival. RESULTS: Patients were predominantly male (78%) with head and neck being the most common presenting sites (75%). Most failures occurred outside the original disease site (79%). Although the administration of radiation therapy, either alone or with chemotherapy, reduced the risk of local failure, it did not translate into an improved freedom from progression or overall survival (OS). The treatment outcomes were independent of treatment modality. The 10-year OS for patients treated with chemotherapy alone, chemo-radiation therapy and radiation therapy alone were 69%, 62%, and 74% (P = 0.79), and the 10-year freedom from progression were 46%, 43%, and 31% (P = 0.64), respectively. CONCLUSION: Given the excellent OS rates regardless of initial therapy in patients with early-stage MCL, de-intensified therapy to limit treatment-related toxicity is a reasonable approach.

Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients.

Background: Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence. Patients and methods: We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS). Results: A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3-6.3, P = 0.01], relapsed-refractory (HR 2.8, CI 1.9-4.1, P < 0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, P = 0.06). Conclusions: In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.

Fluoroscopy-assisted epidural catheter placement: an exploratory analysis of 303 pre-operative epidurograms.

BACKGROUND: Epidural catheters that are placed for post-operative analgesia have a significant failure rate in the first 24 hours. Beginning in 2011, we have used fluoroscopic guidance to place all non-obstetrical epidural catheters. In this retrospective analysis, we hypothesized that the characteristics of dye distribution on an epidurogram obtained immediately after catheter placement would predict clinical catheter function after surgery. METHODS: The epidurograms and medical records of 303 consecutive patients who had epidural catheters placed for post-operative analgesia were reviewed. We extracted data on epidural dye distribution on the epidurograms and compared these results to the clinical function of the epidural catheters assessed on post-operative day 1 (POD1). RESULTS: The three-dimensional pattern of epidural dye distribution (cephalad-caudad, right-left, anterior-posterior) had significant correlations with clinical function of an epidural catheter after surgery. Increased cephalad-caudad and anterior dye spread both correlated with decreased epidural solution infusion rates on POD1, whereas right- or left-sided dye distribution correlated with unilateral sensory deficits. A higher catheter placement on the neuraxis correlated with lower pain scores after thoracic surgery. CONCLUSIONS: An epidurogram obtained immediately after epidural catheter placement may have clinical utility for predicting clinical function of the catheter after surgery.

Variation in Arterial Access for Invasive Coronary Procedures in New Zealand: A National Analysis (ANZACS-QI 5).

BACKGROUND: Radial arterial access (RA) and femoral arterial access (FA) rates for invasive coronary angiography (ICA) vary widely internationally. The European Society of Cardiology (ESC) suggests default RA is feasible. We aim to investigate the variation in RA rates across all New Zealand public hospitals. METHODS AND RESULTS: Patient characteristics, procedural details, and inpatient outcome data were collected in the All New Zealand Acute Coronary Syndrome - Quality Improvement (ANZACS-QI) registry on consecutive patients undergoing ICA over five months. Of the 5894 ICAs 81% were via RA. Hospitals averaged 25 - 176 procedures/month (46.5% - 96.4% via RA). Operators averaged 17 procedures/month. Those performing more than 20 ICAs/month had RA rates between 61% - 99%. Of the 75 operators, 69% met the ESC recommendation. After multivariable adjustment higher operator (RR 1.12, CI 1.09 - 1.30) and hospital (RR 1.21, CI 1.15 - 1.28) volume were independent predictors of RA. Those with prior CABG (RR 0.51, CI 0.45 - 0.57), STEMI <12h (RR 0.91, CI 0.87 - 0.96), and female sex (RR 0.96, CI 0.94 - 0.99) were less likely to receive RA. CONCLUSIONS: New Zealand has a high RA rate for ICAs. Rates vary substantially between both operators and centres. Radial arterial was highest amongst the highest volume operators and centres.

A multicenter phase II study incorporating high-dose rituximab and liposomal doxorubicin into the CODOX-M/IVAC regimen for untreated Burkitt's lymphoma.

BACKGROUND: Despite improvement with intensive multi-agent chemotherapy, 2-year progression-free survival (PFS) rates for adults with high-risk Burkitt's lymphoma (BL) remains <55%. PATIENTS AND METHODS: We conducted a phase II trial for newly diagnosed classic BL utilizing liposomal doxorubicin (Adriamycin) in lieu of doxorubicin and incorporating intravenous rituximab (at 500 mg/m(2) twice/cycle) into the CODOX-M/IVAC regimen. Correlative analyses included paired serum and cerebrospinal fluid (CSF) rituximab levels and close examination of cardiac function. RESULTS: Among 25 BL patients, the median age was 44 years (23-70) and 4 patients were HIV positive. There were 20 high-risk and 5 low-risk patients. At baseline, 40% of high-risk patients had bone marrow involvement, 35% had bulky disease and 15% had central nervous system involvement. The overall response rate was 100% (complete remission 92%). At 34-month median follow-up, the 2-year PFS and overall survival (OS) rates for all patients were 80% and 84%, respectively (low-risk: both 100%; high-risk: 76% and 81%, respectively). Furthermore, the 2-year PFS, OS, and disease-specific survival (DSS) rates for high-risk, HIV-negative patients were 84%, 89% and 100%, respectively. Adverse events (AEs) appeared to be consistent with prior CODOX-M/IVAC data, although there were several grade 3 cardiac events noted (all declined ejection fraction without clinical symptoms). The mean serum rituximab levels at 24 h after cycles 1 and 3 for patients without relapse were 258 and 306 µg/ml, respectively, versus 131 and 193 µg/ml, respectively, for patients with early progression (P = 0.002 and 0.002, respectively). The mean CSF rituximab levels for all patients were 0.11 and 0.24 µg/ml, respectively, at cycle 1 (24/72 h), which equated to serum:CSF ratios of 0.05% and 0.20%, respectively. CONCLUSIONS: The integration of rituximab into CODOX-M/IVAC for adult BL was feasible and tolerable, while changes in cardiac function warrant continued examination. This regimen was associated with excellent survival rates for HIV-negative BL. Further investigation of the predictive value of serum rituximab is needed. Clinicaltrials.gov NCT00392990.

Prospective study of one- vs two-unit umbilical cord blood transplantation following reduced intensity conditioning in adults with hematological malignancies.

As the threshold nucleated cell dose for one-unit umbilical cord blood (UCB) in adults has not to date been firmly established, we prospectively compared one- vs two-unit UCB transplantation after reduced intensity conditioning (RIC) in adult patients with hematological malignancies. Study design specified one-UCB unit if the cryopreserved total nucleated cell (TNC) dose was 2.5 × 10(7)/kg recipient weight, otherwise two units matched at minima of 4/6 HLA loci to the patient and 3/6 to each other were infused. A total of 27 patients received one unit; 23 patients received two units. Median time to ANC >500/µL was 24 days (95% confidence interval 22-28 days), 25 days for one unit and 23 days for two units (P=0.99). At day 100, ANC >500/µL was 88.4 and 91.3% in the one- and two-unit groups (P=0.99), respectively. Three-year EFS was 28.6% and 39.1% in the one- and two-unit groups (P=0.71), respectively. Infusion of two units was associated with a significantly lower relapse risk, 30.4% vs 59.3% (P=0.045). Infused cell doses (TNC, CD3(+), CD34(+) and CD56(+)CD3(neg)) did not impact on engraftment, OS or EFS. Taken together, one-unit UCB transplantation with a threshold cell dose 2.5 × 10(7)/kg recipient weight after RIC is a viable option for adults, although infusion of two units confers a lower relapse incidence.

The epidemiology of red cell transfusion.

BACKGROUND AND OBJECTIVES: Understanding of the clinical usage of red cells is limited despite its importance in transfusion practice improvement and planning for blood supply requirements. Previous studies have described red cell use based upon ICD and hospital discharge codes; however, such approaches are open to misclassification. This study addresses this limitation by undertaking an epidemiological analysis of red cell use using case note review. MATERIALS AND METHODS: Patient, disease and contextual factors were extracted from the medical records of a randomly selected sample of hospital patients in Northern Ireland who received a red cell transfusion during 2005 (n=1474). RESULTS: Transfused patients received a total of 3804 units (median of two units per transfusion episode). Most transfusions occurred in a medical setting (71%). Patients undergoing treatment for gastrointestinal conditions were responsible for the majority of the demand (29% of transfusion episodes; 34% of red cell units). The presence of bleeding and abnormal tests of coagulation were associated with receiving larger transfusions (≥ 3 units), while patients undergoing orthopaedic surgery and those with a haemoglobin level over 7 g/dl had the lowest risk of receiving ≥ 3 units in any one transfusion episode. CONCLUSION: The majority of red cells are now prescribed in a medical setting. With an ageing population and increasing therapeutic interventions, the demand for blood is likely to increase despite efforts to reduce usage by eliminating inappropriate transfusions through education and behaviour change. The post-transfusion target (and therefore the number of units to transfuse) for any given clinical situation as well as guidance on a 'safe' transfusion threshold should be considered in future guidelines.

Inhibition of Lck enhances glucocorticoid sensitivity and apoptosis in lymphoid cell lines and in chronic lymphocytic leukemia.

Glucocorticoids are used as part of front-line therapy to treat lymphoid malignancy because of their remarkable ability to induce apoptosis. Yet, in T cells, glucocorticoid-induced apoptosis is readily inhibited by lymphocyte activation and signaling. We have previously shown that the Src family kinase, Lck (lymphocyte cell-specific tyrosine kinase), which is predominantly expressed in T cells, interacts with IP3 receptors to facilitate calcium signaling. Here, we discovered that dexamethasone downregulates Lck, which, in turn, suppresses lymphocyte activation by inhibiting pro-survival calcium oscillations. Moreover, stable expression of shRNAs that selectively targeted Lck or treatment with the Src inhibitor dasatinib (BMS-354825) enhanced apoptosis induction by dexamethasone. To investigate the effect of Lck inhibition in a primary leukemia model, we employed chronic lymphocytic leukemia (CLL) cells that aberrantly expressed Lck and were relatively insensitive to dexamethasone. Lck expression was correlated with resistance to dexamethasone in CLL cells, and its inhibition by dasatinib or other inhibitors markedly enhanced glucocorticoid sensitivity. Collectively, these data indicate that Lck protects cells from glucocorticoid-induced apoptosis and its inhibition enhances sensitivity to dexamethasone. Small-molecule inhibitors of Lck, such as dasatinib, may function to reverse glucocorticoid resistance in some lymphoid malignancies.

Neosporosis in a young dog presenting with dermatitis and neuromuscular signs.

A 16-week-old, male boxer dog developed multifocal nodular dermatitis followed by rapidly progressive and fatal neuromuscular disease. Protozoal tachyzoites were demonstrated by aspiration and biopsy of dermal lesions. Necropsy and histology revealed necrotising inflammation associated with intralesional protozoal organisms in various organs including the brain, heart, skeletal muscle and skin. Serology suggested active infection with Neospora caninum. Immunohistochemistry provided a definitive diagnosis. Dermatitis is a finding rarely associated with juvenile neosporosis. The possible role of immunosuppression is discussed.

Differences in olfactory and visual memory in patients with pathologically confirmed Alzheimer's disease and the Lewy body variant of Alzheimer's disease.

Recognition and remote memory for odors, faces, and symbols were assessed in patients with pathologically confirmed Lewy body variant of Alzheimer's disease (LBV), patients with pathologically confirmed Alzheimer's disease (AD), and healthy elderly controls. On recognition memory tasks, LBV and AD patients showed significantly lower discriminability (d') than controls, particularly for olfactory stimuli. However no significant differences were found in the bias measure (c). When participants rated familiarity (a proposed measure of remote memory) of olfactory stimuli LBV and AD patients reported significantly lower familiarity than controls. Familiarity ratings were significantly lower in LBV patients than in AD patients for olfactory, but not for visual stimuli. Consistent with prior reports, the LBV patients showed significantly poorer odor thresholds than AD patients. The results suggest that recognition memory for olfactory stimuli is impaired in LBV and AD. However, patients with LBV are more impaired than patients with AD on tasks requiring remote memory for olfactory but not visual stimuli. The findings suggest that odor memory tasks may be useful in the assessment of LBV and AD.

Gastroschisis: determinants of neonatal outcome.

This retrospective study elicits information regarding the dependence of neonatal outcome in gastroschisis upon: (1) the mode of delivery, (2) place of birth, (3) time for birth to surgery, (4) method of closure, (5) time from operation to commencement of first enteral feeds. The neonatal intensive care database from five major tertiary centres was used to identify 181 neonates with gastroschisis from 1990 to 2000. There were 8 deaths. There were no significant differences in outcome for infants delivered vaginally (102) versus Caesarean section (79), those born near the tertiary centre (133) as compared to infants born away (48), ones operated within 7 hours (125) compared with those operated after 7 hours (56), with delayed closure (30) versus primary closure (151). Neonates fed within 10 days of operation (85) had significantly lower incidence of sepsis, duration of TPN and hospital stay when compared to those fed after 10 days (96). Early commencement of feeds decreases the incidence of sepsis, duration of total parenteral nutrition (TPN) and hospital stay. Place of delivery, mode of delivery, time to surgery and type of closure do not influence neonatal outcome.

Informed consent for population-based research involving genetics.

Bridging the gap between gene discovery and our ability to use genetic information to benefit health requires population-based knowledge about the contribution of common gene variants and gene-environment interactions to the risk of disease. The risks and benefits associated with population-based research involving genetics, especially lower-penetrance gene variants, can differ in nature from those associated with family-based research. In response to the urgent need for appropriate guidelines, the Centers for Disease Control and Prevention formed a multidisciplinary group to develop an informed consent approach for integrating genetic variation into population-based research. The group used expert opinion and federal regulations, the National Bioethics Advisory Commission's report on research involving human biological materials, existing consent forms, and literature on informed consent to create suggested language for informed consent documents and a supplemental brochure. This language reflects the premise that the probability and magnitude of harm, as well as possible personal benefits, are directly related to the meaning of the results for the health of the participant and that appropriate disclosures and processes for obtaining consent should be based on an assessment at the outset of the likelihood that the results will generate information that could lead directly to an evidence-based intervention. This informed consent approach is proposed to promote discussion about how best to enable potential participants to make informed decisions about population-based research involving genetics and to suggest issues for consideration by research sponsors, institutional review boards, and investigators.

Errors in the certification of neonatal death.

OBJECTIVE: To examine the precision of the perinatal death certificate (PDC) and ascertain the possible sources of error in the certification of neonatal deaths. METHODS: The 'Main' and 'Other' causes of death recorded on the PDC were obtained from the Registry of Births, Deaths and Marriages and compared with those from a clinicopathological summary (CPS) completed after all pending laboratory results and/or autopsy information were available. RESULTS: There were 179 neonatal deaths during the 7 year period under review. The PDC and CPS main causes of death were concordant in 103 of 179 infants (58%) and discordant in the remaining 76 infants (42%). The PDC main cause of death was incorrectly classified in 61 of 76 infants (80%) with discordant findings and was incompletely classified in the remaining 15 infants (20%). The following discordancies were recorded for the 61 infants with an incorrect classification: (i) transposition of the 'Main' and 'Other' causes of death, resulting in a sequencing discordancy in 14 infants (23%); (ii) recording a non-pathological condition as the main cause of death in 40 infants (66%); and (iii) recording an incorrect pathological condition as the main cause of death in seven infants (11%). Eight of the 61 (13%) incorrect classifications and four of the 15 (27%) incomplete classifications were associated with laboratory and/or autopsy data being unavailable when the PDC was completed. CONCLUSIONS: The concordancy between the PDC and CPS would have increased from 58 to 91% if the 'Main' and 'Other' causes of death had been sequenced correctly, if the main cause of death had been ascribed to a pathological disease rather than a non-pathological condition and if corrective information from pending laboratory tests and/or autopsy examination had been made available to the Registry of Births, Deaths and Marriages.

Assessing the cultural relevance of an education program for urban African Americans with diabetes.

PURPOSE: This study was conducted to assess the cultural relevance of an education program for urban African Americans with diabetes. METHODS: A set of 12 videotape vignettes were developed for use in diabetes education for urban African Americans with diabetes. Focus groups and questionnaires were used to determine if patients and diabetes educators would find the materials stimulating, culturally appropriate, and useful. RESULTS: The videotape and discussion guide were perceived as valuable by both healthcare professionals and patients. CONCLUSIONS: This education program could be a valuable resource for diabetes educators who want to provide culturally sensitive and relevant diabetes education for urban African Americans with diabetes.

Nasal versus oral intubation for mechanical ventilation of newborn infants.

BACKGROUND: This section is under preparation and will be included in the next issue. OBJECTIVES: The purpose of the review was to compare the complications associated with intubation by the nasal route with those associated with intubation by the oral route for mechanical ventilation in newborn infants. SEARCH STRATEGY: The standard search strategy of the Neonatal Review Group as outlined in the Cochrane Library was used. This included searches of the Oxford Database of Perinatal Trials, Cochrane Register of Controlled Trials, MEDLINE and CINAHL. A call was placed on the list servers, NICU-NET and Neonatal Talk for unpublished trials, conference presentations and current trials. SELECTION CRITERIA: All trials using random or quasi-random allocation of patients to either the nasal or oral route of intubation were included. Study quality and eligibility were assessed independently by each author. DATA COLLECTION AND ANALYSIS: The standard method of the Cochrane Collaboration and the Neonatal Review Group was used to assess the methodological quality of the included studies. The methodological quality of each study was reviewed by the second author blinded to study authors and institutions. Each reviewer extracted data separately before comparison and resolution of differences. The standard method of the Neonatal Review Group was used to measure the effect of the different routes of intubation, using Relative Risk (RR) and 95% Confidence Intervals (CI). MAIN RESULTS: Only two eligible randomized trials were found. Data from these two trials failed to show significant differences between the oral and nasal route of intubation for mechanically ventilated neonates. The rate of failure to intubate using the nasal route was higher in one study. One study found post extubation atelectasis occurred more frequently in nasally intubated infants who weighed less than 1500 grams. The rates of malposition of the tube at the initial intubation, accidental extubation, tube blockage, re-intubation after extubation, septicaemia, clinical infection and local trauma (nasal erosion or palatal groove) were not significantly different for the two groups. REVIEWER'S CONCLUSIONS: Post extubation atelectasis may be more frequent after nasal intubation, particularly in very low birth weight infants. One route of intubation does not seem to be preferable to the other. There is a need for further randomized controlled trials containing larger numbers of infants.

An evaluation of the autopsy following death in a level IV neonatal intensive care unit.

OBJECTIVE: To ascertain the determinants of neonatal autopsy, define clinical errors in the causes of death, and elucidate the possible audit and genetic value of the autopsy following death in a Level IV neonatal intensive care unit (NICU). METHODS: A review and correlation of clinical and autopsy information in a case series of infants who died during the period 1991-97. RESULTS: Two hundred and twenty-nine of 4057 infants admitted to the NICU died and 91 (39.7%) underwent an autopsy. The underlying cause of death was significantly different in infants who had an autopsy compared with infants who did not (P = 0.02). The autopsy rate was higher for deaths from miscellaneous causes (52.9%), lethal malformation (46.8%) and infection (45.4%) than deaths from prematurity (25.9%) and asphyxia (19%). Clinical errors in the causes of death were found in 22% of the infants, and in 4.4% a change in management may have been curative or prolonged life. The autopsy had audit value in 26% of infants and genetic value for a single gene (Mendelian) disorder in 4.4%. CONCLUSIONS: Although the autopsy following death in a Level IV NICU yields potentially useful information in more than one-third of cases, this does not seem sufficient to ensure a high neonatal autopsy rate.