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Alemtuzumab is used as part of reduced-intensity and reduced-toxicity transplant conditioning regimens for nonmalignant diseases. Prior studies identified an ideal target concentration range of 0.15-0.6 mcg/mL at day 0. However, only 24% of patients fall within this window using standard intermediate dosing. We performed a pilot study of a novel target concentration intervention strategy to target day 0 alemtuzumab concentrations to 0.15-0.6 mcg/mL. Twelve patients received model-informed alemtuzumab dosing of 0.5-0.6 mcg/kg divided over days -14 to -12. Alemtuzumab concentrations were measured, and pharmacokinetic (PK) modeling was performed on day -5 to predict day 0 concentrations. If the day 0 alemtuzumab concentration was predicted to fall below 0.15 mcg/mL, simulations were performed to identify the individual "top-up" dose needed to achieve the target day 0 concentration window. Six (50%) patients achieved day 0 alemtuzumab concentrations between 0.15 and 0.6 mcg/mL (4 received a top-up dose). Five patients had day 0 concentrations above the target window (no top-up doses). One patient had a day 0 concentration below the target range in the presence of anti-alemtuzumab antibodies. A concentration intervention strategy approach to alemtuzumab treatment can successfully target a greater proportion of patients into the ideal therapeutic window. Additional dose-reduction studies are needed to further optimize the initial dosing and achieve target attainment in all patients.

Alemtuzumab is used as part of reduced-intensity and reduced-toxicity transplant conditioning regimens for nonmalignant diseases. Prior studies identified an ideal target concentration range of 0.15-0.6 mcg/mL at day 0. However, only 24% of patients fall within this window using standard intermediate dosing. We performed a pilot study of a novel target concentration intervention strategy to target day 0 alemtuzumab concentrations to 0.15-0.6 mcg/mL. Twelve patients received model-informed alemtuzumab dosing of 0.5-0.6 mcg/kg divided over days -14 to -12. Alemtuzumab concentrations were measured, and pharmacokinetic (PK) modeling was performed on day -5 to predict day 0 concentrations. If the day 0 alemtuzumab concentration was predicted to fall below 0.15 mcg/mL, simulations were performed to identify the individual "top-up" dose needed to achieve the target day 0 concentration window. Six (50%) patients achieved day 0 alemtuzumab concentrations between 0.15 and 0.6 mcg/mL (4 received a top-up dose). Five patients had day 0 concentrations above the target window (no top-up doses). One patient had a day 0 concentration below the target range in the presence of anti-alemtuzumab antibodies. A concentration intervention strategy approach to alemtuzumab treatment can successfully target a greater proportion of patients into the ideal therapeutic window. Additional dose-reduction studies are needed to further optimize the initial dosing and achieve target attainment in all patients.

Peroxynitrite [ONOO(H)] is an oxidant associated with deleterious effects in cells. Because it is an inorganic peroxide that reacts rapidly with peroxidases, we speculated that cells may respond to ONOO(H) and H2O2 challenge in a similar manner. We exposed yeast cells to SIN-1, a well-characterized ONOO(H) generator, and observed stimulation of catalase and peroxiredoxin (Prx) activities. Previously, we reported that H2O2 challenge increases these activities in wild-type cells and in cells producing the hyperactive mutant H2O2 sensor Ccp1(W191F) but not in Ccp1-knockout cells (ccp1Δ). We find here that the response of ccp1Δ and ccp1(W191F) cells to SIN-1 mirrors that to H2O2, identifying Ccp1 as a sensor of both peroxides. SIN-1 simultaneously releases (•)NO and O2(•-), which react to form ONOO(H), but exposure of the three strains separately to an (•)NO donor (spermine-NONOate) or an O2(•-) generator (paraquat) mainly depresses catalase or Prx activity, whereas co-challenge with the NONOate and paraquat stimulates these activities. Because Ccp1 appears to sense ONOO(H) in cells, we examined its reaction with ONOO(H) in vitro and found that peroxynitrous acid (ONOOH) rapidly (k210(6)M(-1)s(-1)) oxidizes purified Ccp1 to an intermediate with spectral and ferrocytochrome-oxidizing properties indistinguishable from those of its well-characterized compound I formed with H2O2. Importantly, the nitrite released from ONOOH is not oxidized to (•)NO2 by Ccp1(׳)s compound I, unlike peroxidases involved in immune defense. Overall, our results reveal that yeast cells mount a common antioxidant response to ONOO(H) and H2O2, with Ccp1 playing a pivotal role as an inorganic peroxide sensor.

The Shwachman-Diamond Syndrome Registry (SDSR) was established in December 2008 with the goal of understanding the natural history and biology of SDS to improve the lives of people with SDS. The SDSR has enrolled 220 patients with biallelic SBDS mutations or SDS-Like features. Longitudinal data has been collected for 176 patients with a median duration of follow-up of 10.7 (0.3-52.8) years. Biallelic SBDS mutations were noted in 117 patients, and biallelic DNAJC21 mutations in one patient. Sequencing of genetically undefined cases did not identify EFL1 or SRP54 mutations. Ongoing characterization of SBDS mutation-negative individuals has identified subgroups of clinically defined SDS individuals, as well as a more heterogenous subgroup with features of SDS but who do not meet classic diagnostic criteria. Clinical characteristics and outcomes of patients with biallelic SBDS mutations were examined. AML developed in 5 patients and MDS in 11 patients at a median age 37.9 years (range, 19.5-47.3) and 10.7 years (range, 1-45) respectively. No solid tumors were diagnosed. 21 individuals have undergone stem cell transplantation. Overall survival was 91% in the 10 years since registry establishment, with deaths mainly caused by myelodysplasia (MDS) (n=3) and acute myeloid leukemia (AML) (n=4). One individual with MDS died of hepatic failure unrelated to MDS. Hematologic parameters, trends over time, and clinical correlations were examined.. Cytopenias were almost universal (98.8%) and often intermittent, with neutropenia the most frequent in 98.8%, anemia in 16.5% and thrombocytopenia in 45.3%. Bone marrow evaluations were available in 98, with 88.2% demonstrating marrow hypoplasia. Notable, marrow hypoplasia was progressive, with average marrow cellularity of 74% in patients There is a paucity of evidence to guide optimal surveillance strategies for leukemia predisposition syndromes. The SDSR revealed wide variation in clinical practice amongst local hematologists including: 1) no surveillance for well-appearing patients, 2) intermittent blood counts, or 3) bone marrow exams of variable frequency with variable testing of cytogenetics and FISH. Some patients were not followed by hematology because they looked well until they presented with AML. In one illustrative case, a teenage patient with a transient iso7q clone had improving hemoglobin, platelet counts, absolute neutrophil counts, and reduction in red cell macrocytosis over the year prior to diagnosis of MDS. Additional clinical and laboratory studies are underway to provide evidence-based guidelines and to develop more sensitive tests for optimal surveillance of patients with predisposition to myeloid malignancies. Disclosures Myers: Novartis: Membership on an entity's Board of Directors or advisory committees; Bellicum Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Penetrating trauma to the brain and skull is commonly caused by gunshot wounds (GSWs), self-inflicted or otherwise, and carries a grave prognosis. After epidemic growth in the 1980s and 1990s, GSWs are currently endemic in our society. It is likely that many healthcare personnel will be confronted with victims of GSWs. Neuroscience nurses will be asked to care for patients with craniocerebral trauma caused by GSWs. To provide optimal care to these patients, neuroscience nurses will need a basic knowledge of GSW injuries. In this two-part review, the authors will focus on gunshot-related trauma to the brain and the calvarium. This first article will introduce the reader to the epidemiology, ballistics, pathophysiology and pathology of craniocerebral GSWs, as well as to the initial management and relevant diagnostics. The second article will discuss management, complications and outcomes of craniocerebral GSWs.

Increasingly, spasticity is managed with surgically implanted Intrathecal Baclofen pumps. Intrathecal Baclofen pump revision surgery unrelated to programmable pump end-of-life is not uncommon, requiring special attention during pre-, intra-, and postoperative management. We aimed to identify and describe complications of Intrathecal Baclofen pump as well as to report avoidance and management of complications. Methods and Materials. Through 2002–2006, at the department of neurosurgery, Henry Ford and Oakwood Health Systems, Intrathecal Baclofen pumps were implanted in 44 patients: 24 children versus 20 adults; 30 “primary-implant-patients”; 14 “revision-only patients”. We evaluated reasons for revision surgeries and diagnostic workup requirements. Results. Eight primary-implant-patients required 14 revisions and 7 of revision-only patients needed 13 procedures. Seven patients with slowly increasing baclofen-resistant spasticity had either (i) unsuspected pump-catheter connector defects, (ii) an X-ray-documented pump-catheter connector defect, (iii) X-ray-demonstrated fractured catheter with intrathecal fragment. Implant infections occurred in 4 cases. Scintigraphy revealed occult CSF leakage and intrinsic pump failure . Conclusion. Intrathecal Baclofen pumps, although very gratifying, have a high, technique-related complication incidence during implant life. Meticulous technique, high clinical suspicion, appropriate workup, and timely surgical management can reduce surgical complications of Intrathecal Baclofen pump implantation.