Correction: Pomalidomide, bortezomib, and low-dose dexamethasone in lenalidomide-refractory and proteasome inhibitor-exposed myeloma.

Following the publication of this article, the authors noted that the pomalidomide dose for the additional SC cohort in Fig. 1 was incorrectly listed. The correct dose for pomalidomide in the additional SC cohort should be the maximum tolerated dose of 4 mg/day, not 2 mg/day as listed in the original Fig. 1. The authors apologize for any inconvenience caused.

Pomalidomide, bortezomib and low-dose dexamethasone in lenalidomide-refractory and proteasome inhibitor-exposed myeloma.

This phase 1 dose-escalation study evaluated pomalidomide, bortezomib (subcutaneous (SC) or intravenous (IV)) and low-dose dexamethasone (LoDEX) in lenalidomide-refractory and proteasome inhibitor-exposed relapsed or relapsed and refractory multiple myeloma (RRMM). In 21-day cycles, patients received pomalidomide (1-4 mg days 1-14), bortezomib (1-1.3 mg/m2 days 1, 4, 8 and 11 for cycles 1-8; days 1 and 8 for cycle ⩾9) and LoDEX. Primary endpoint was to determine the maximum tolerated dose (MTD). Thirty-four patients enrolled: 12 during escalation, 10 in the MTD IV bortezomib cohort and 12 in the MTD SC bortezomib cohort. Patients received a median of 2 prior lines of therapy; 97% bortezomib exposed. With no dose-limiting toxicities, MTD was defined as the maximum planned dose: pomalidomide 4 mg, bortezomib 1.3 mg/m2 and LoDEX. All patients discontinued treatment by data cutoff (2 April 2015). The most common grade 3/4 treatment-emergent adverse events were neutropenia (44%) and thrombocytopenia (26%), which occurred more frequently with IV than SC bortezomib. No grade 3/4 peripheral neuropathy or deep vein thrombosis was reported. Overall response rate was 65%. Median duration of response was 7.4 months. Pomalidomide, bortezomib and LoDEX was well tolerated and effective in lenalidomide-refractory and bortezomib-exposed patients with RRMM.

Associations of High-Dose Melphalan Pharmacokinetics and Outcomes in the Setting of a Randomized Cryotherapy Trial.

High-dose melphalan followed by autologous stem cell transplantation remains the standard of care for eligible patients with multiple myeloma, but disease response and toxicity, including severe mucositis, varies among patients. Our randomized trial investigated duration of cryotherapy (2 and 6 h) for reduction of mucositis prevalence and severity and explored factors associated with variability in pharmacokinetics and outcomes from melphalan therapy. The results demonstrate that 2-h is at least as effective as 6-h cryotherapy in decreasing severe mucositis. From a population pharmacokinetic model, we identified that fat-free mass, hematocrit, and creatinine clearance were significant covariates, as reported previously. Furthermore, we observed the rs4240803 SLC7A5 polymorphism was significantly associated with pharmacokinetic variability, and pharmacokinetics was associated with both mucositis and neutropenia. However, melphalan exposure was not associated with progression-free or overall survival in our dataset. These findings contribute to ongoing efforts to personalize melphalan dosing in transplant patients.

[Regional Deprivation in Germany: Nation-wide Analysis of its Association with Mortality Using the German Index of Multiple Deprivation (GIMD)]. / Regionale Deprivation in Deutschland: Bundesweite Analyse des Zusammenhangs mit Mortalität unter Verwendung des 'German Index of Multiple Deprivation (GIMD)'.

BACKGROUND: Deprivation indices are increasingly being used to assess the effects of contextual factors on health. In Germany, the recently developed 'German Index of Multiple Deprivation (GIMD)' integrates various dimensions of regional deprivation. We aim to assess the validity of the GIMD through a recalculation using more recent rural and urban district level data and by analysing its association with mortality at the national level. METHODS: We calculated a new version of the GIMD based on data from 2007 to 2010 for all 412 rural and urban districts in Germany. Mortality was quantified using indirectly standardised mortality ratios (SMRs). Correlation analyses and Poisson regression analyses were used to assess the association between the GIMD scores and total mortality, as well as premature mortality (< 65 years). RESULTS: Correlation analyses showed a positive association between the GIMD and both total mortality (p<0.001) and premature mortality (p<0.001). In the Poisson regression analyses, rural and urban districts in the quintile with the highest deprivation showed a significantly elevated risk of total mortality (RR: 1.29; 95% CI: 1.28-1.30) as well as premature mortality (RR: 1.50; 95% CI: 1.47-1.53), compared to the districts in the lowest quintile. CONCLUSION: The association between regional deprivation and mortality has already been shown for the federal state of Bavaria. Using more recent data, this relationship could be confirmed here for Germany as a whole. The GIMD has been shown to be able to effectively assess regional deprivation. Concerning public health policy, the significant, positive and stable association between regional deprivation and mortality indicates an increased need for health care provision particularly in the most deprived districts. Further studies should examine, for example, whether and how the allocation of districts to quintiles of regional deprivation changes over time, and how this affects mortality.

The hematopoietic stem cell transplant comorbidity index can predict for 30-day readmission following autologous stem cell transplant for lymphoma and multiple myeloma.

Patients who undergo autologous stem cell transplant (ASCT) for hematologic malignancies frequently have multiple comorbidities. The hematopoietic cell transplantation comorbidity index (HCT-CI), a transplant-specific modification of the Charlson comorbidity index, can predict risk of readmission following allogeneic stem cell transplant. Its utility in the autologous setting is unknown. We evaluated 620 patients who underwent ASCT at the Ohio State University from 2007 to 2012 for lymphoma or multiple myeloma (MM) to identify factors associated with readmission. Univariable and multivariable logistic regression were used to estimate the odds of readmission within 30 days of discharge following ASCT. A Cox proportional hazards model was used to evaluate OS. Sixty-four patients were readmitted within 30 days; the most common indications were fever and prolonged gastrointestinal toxicity. MM compared with lymphoma (odds ratio (OR) 1.89, 95% confidence interval (95% CI): 1.06-3.38, P=0.03), HCT-CI⩾3 (OR 1.74, 95% CI: 1.03-2.96, P=0.04) and length of hospitalization ⩾28 days (OR 3.14, 95% CI: 1.26-7.83, P=0.01) remained significantly associated with 30-day readmission in a multivariable model. While the model had excellent fit (P>0.75), its ability to predict individual patients who would be readmitted was less than acceptable (receiver-operator curve=0.64, 95% CI: 0.57-0.71). In a multivariable proportional hazards model, 30-day readmission (hazards ratio (HR) 1.81, 95% CI: 1.04-3.18, P=0.04), length of hospitalization ⩾28 days (HR 4.93, 95% CI: 2.65-9.18, P<0.001) and chemorefractory disease (HR 3.08, 95% CI: 1.74-5.43, P<0.001) were independently associated with inferior OS, but HCT-CI was not. Evaluation of other assessment tools may allow better prediction of outcomes following ASCT.

Phase I ficlatuzumab monotherapy or with erlotinib for refractory advanced solid tumours and multiple myeloma.

BACKGROUND: Ficlatuzumab, a humanised hepatocyte growth factor (HGF) IgG1κ inhibitory monoclonal antibody, was evaluated for recommended phase II dose (RP2D), safety, pharmacokinetics (PKs), antidrug antibody (ADA), pharmacodynamics (PDs) and antitumour activity as monotherapy or combined with erlotinib. METHODS: Patients with solid tumours received ficlatuzumab 2, 5, 10 or 20 mg kg(-1) intravenously every 2 weeks (q2w). Additional patients were treated at the RP2D erlotinib. RESULTS: Forty-one patients enrolled at doses ⩽20 mg kg(-1). Common adverse events (AEs) included peripheral oedema, fatigue and nausea. Three patients experienced grade ⩾3 treatment-related hyperkalaemia/hypokalaemia, diarrhoea or fatigue. Best overall response (44%) was stable disease (SD); median duration was 5.5 months (0.4-18.7 months). One patient has been on therapy with SD for >4 years. Pharmacokinetics of ficlatuzumab showed low clearance (0.17-0.26 ml h(-1) kg(-1)), a half-life of 6.8-9.4 days and dose-proportional exposure. Ficlatuzumab/erlotinib had no impact on the PK of either agent. No ADAs were detected. Ficlatuzumab increased serum HGF levels. CONCLUSIONS: Recommended phase II dose is 20 mg kg(-1) q2w for ficlatuzumab monotherapy or with erlotinib. Preliminary antitumour activity and manageable AEs were observed. Pharmacokinetics were dose-proportional and consistent with other IgG therapeutics. Ficlatuzumab was not immunogenic, and serum HGF was a potential PD marker.

CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma.

Multiple myeloma (MM) is an incurable hematological malignancy. Chimeric antigen receptor (CAR)-expressing T cells have been demonstrated successfully in the clinic to treat B-lymphoid malignancies. However, the potential utility of antigen-specific CAR-engineered natural-killer (NK) cells to treat MM has not been explored. In this study, we determined whether CS1, a surface protein that is highly expressed on MM cells, can be targeted by CAR NK cells to treat MM. We successfully generated a viral construct of a CS1-specific CAR and expressed it in human NK cells. In vitro, CS1-CAR NK cells displayed enhanced MM cytolysis and interferon-γ (IFN-γ) production, and showed a specific CS1-dependent recognition of MM cells. Ex vivo, CS1-CAR NK cells also showed similarly enhanced activities when responding to primary MM tumor cells. More importantly, in an aggressive orthotopic MM xenograft mouse model, adoptive transfer of NK-92 cells expressing CS1-CAR efficiently suppressed the growth of human IM9 MM cells and also significantly prolonged mouse survival. Thus, CS1 represents a viable target for CAR-expressing immune cells, and autologous or allogeneic transplantation of CS1-specific CAR NK cells may be a promising strategy to treat MM.

Phase II clinical trial of arsenic trioxide with liposomal doxorubicin, vincristine, and dexamethasone in newly diagnosed multiple myeloma.

In patients with multiple myeloma, there is preclinical justification to combine arsenic trioxide (ATO and As(2)O(3)) with DVd (Doxiltrade mark, vincristine, and dexamethasone) for newly diagnosed patients. Eleven patients on this phase II trial received 0.15 mg/kg of ATO for five consecutive days followed by four cycles of DVd plus ATO with the ATO at 0.25mg/kg IV twice per week. The most common grade 3 toxicities were hyperglycemia, hyponatremia, and hypocalcemia. There were four partial and no complete responses. We could not demonstrate that the addition of ATO with this schedule improved the response rate of MM to DVd.

Ex vivo expansion of umbilical cord blood stem cells for transplantation: growing knowledge from the hematopoietic niche.

Umbilical cord blood transplantation (UCBT) in adults is limited by the small number of primitive hematopoietic stem cells (HSC) in each graft, resulting in delayed engraftment post transplant, and both short- and long-term infectious complications. Initial efforts to expand UCB progenitors ex vivo have resulted in expansion of mature rather than immature HSC, confounded by the inability to accurately and reliably measure long-term reconstituting cells. Ex vivo expansion of UCB HSC has failed to improve engraftment because of resulting defects that promote apoptosis, disrupt marrow homing and initiate cell cycling. Here we discuss the future of ex vivo expansion, which we suggest will include the isolation of immature hematopoietic progenitors on the basis of function rather than surface phenotype and will employ both cytokines and stroma to maintain and expand the stem cell niche. We suggest that ex vivo expansion could be enhanced by manipulating newly discovered signaling pathways (Notch, Wnt, bone morphogenetic protein 4 and Tie2/angiopoietin-1) and intracellular mediators (phosphatase and tensin homolog and glycogen synthase kinase-3) in a manner that promotes HSC expansion with less differentiation. Improved methods for ex vivo expansion will make UCBT available to more patients, decrease engraftment times and allow more rapid immune reconstitution post transplant.

Retrospective utility of bronchoscopy after hematopoietic stem cell transplant.

Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) is thought to be the procedure of choice to evaluate pulmonary infiltrates in hematopoietic stem cell transplant (HSCT) recipients. We retrospectively reviewed 91 bronchoscopies performed on 190 in-patient HSCT recipients admitted or treated for pneumonia from January 1994 to December 2004. These yielded a diagnosis 49% of the time with an overall survival of 35 days post-bronchoscopy. We were unable to detect any survival benefit from an addition to the treatment regimen after a positive result from analysis of the BAL fluid or transbronchial biopsy. The most common bacteria isolated was Pseudomonas that was often resistant to the patient's current antibiotics, suggesting that in lieu of this diagnostic procedure, changes to better cover resistant Gram-negative bacteria are reasonable. Although transbronchial biopsies provided an additional diagnosis in one out of 21 biopsies performed, six of the seven complications in our series were directly related to the transbronchial biopsy. With approximately a 50% yield from a bronchoscopy, additional treatment given after only 20% of all bronchoscopies, and no detectable survival benefit with a bronchoscopy that yielded a diagnosis, the utility of a bronchoscopy in this patient population is questioned by these data.

Size-based speciation of natural colloidal particles by flow field flow fractionation, inductively coupled plasma-mass spectroscopy, and transmission electron microscopy/X-ray energy dispersive spectroscopy: colloids-trace element interaction.

Flow field flow fractionation (FIFFF), inductively coupled plasma-mass spectroscopy (ICP-MS), and transmission electron microscopy (TEM) coupled to X-ray energy dispersive spectrometry (X-EDS) are used in series for the first time to characterize colloids. Results demonstrate the utility of FIFFF-ICP-MS-TEM/X-EDS to relate physical properties (size) of colloids to their chemical properties (chemical composition, surface chemical composition, and colloids-trace elements association). Results suggest that the major part of natural organic matter (NOM) is concentrated in the fraction < 0.01 microm (C2). Aluminum, iron, and manganese are the main colloidal components in the fraction 0.01-0.45 microm (C1). Aluminum occurs as aluminum oxides or aluminosilicates in the whole size range, while iron and manganese occur as individual oxyhydroxides in the size range < 0.20 microm. Within the C2 fraction, Al, Mn, Cu, and Ni elements are complexed to NOM (e.g., humic substances). Iron is complexed to NOM in some samples and probably free in other samples. Lead is totally free in all samples. Within the C1 fraction, Cu and Pb are mostly associated to Fe and Mn oxyhydroxides. Consequently, NOM with Fe and Mn oxyhydroxides are the main colloidal carriers of trace elements in the Loire watershed system.

Effect of age on clinical and morphological characteristics in patients with brain arteriovenous malformation.

BACKGROUND AND PURPOSE: The goal of this work was to determine the effect of age at initial presentation on clinical and morphological characteristics in patients with brain arteriovenous malformation (AVM). METHODS: The 542 consecutive patients from the prospective Columbia AVM database (mean+/-SD age, 34+/-15 years) were analyzed. Univariate statistical models were used to test the effect of age at initial presentation on clinical (AVM hemorrhage, seizures, headaches, neurological deficit, other/asymptomatic) and morphological (AVM size, venous drainage pattern, AVM brain location, concurrent arterial aneurysms) characteristics. RESULTS: Hemorrhage was the presenting symptom in 46% (n=247); 29% (n=155) presented with seizures, 13% (n=71) with headaches, 7% (n=36) with a neurological deficit, and 6% (n=33) without AVM-related symptoms. Increasing age correlated positively with intracranial hemorrhage (P=0.001), focal neurological deficits (P=0.007), infratentorial AVMs (P<0.001), and concurrent arterial aneurysms (P<0.001); an inverse correlation was found with seizures (P<0.001), AVM size (P=0.001), and lobar (P<0.001), deep (P=0.008), and borderzone (P=0.014) location. No age differences were found for sex, headache, asymptomatic presentation, and venous drainage pattern. CONCLUSIONS: Our data suggest a significant interaction of patient age and clinical and morphological AVM features and argue against uniform AVM characteristics across different age classes at initial presentation. In particular, AVM patients diagnosed at a higher age show a higher fraction of AVM hemorrhage and are more likely to harbor additional risk factors such as concurrent arterial aneurysms and small AVM diameter. Longitudinal population-based AVM data are necessary to confirm these findings.

Phase II evaluation of paclitaxel in combination with carboplatin in advanced head and neck carcinoma.

BACKGROUND: Two-thirds of patients with squamous cell carcinomas of the head and neck (SCCHN) at diagnosis have advanced disease with projected 5-year survival rates of 30%. In those patients with distant metastatic or previously treated recurrent disease, response rate to the standard regimen of cisplatin and 5-fluorouracil is approximately 30%. The authors investigated the use of paclitaxel and carboplatin in a limited Phase II study in recurrent or metastatic SCCHN to evaluate tumor response, time to progression, survival, and toxicities of this regimen. METHODS: Patients with recurrent or metastatic SCCHN not amenable to further surgical or radiation therapy were treated with 200 mg/m(2) by 3-hour infusion of paclitaxel followed by carboplatin at an area under the concentration time curve of 6 mg/mL/minute via a 20-30-minute infusion every 3 weeks. RESULTS: Thirty-seven patients were enrolled. Ninety-five percent of patients had received prior surgery and postoperative radiotherapy. The overall response rate was 27% (95% confidence interval, 13-41%) with 1 complete and 9 PRs. Median survival of all patients was 4.9 months, and 1-year survival rate was 16%. There was a 43% response rate and 15.7-month median survival rate in patients with only distant metastatic disease and 38% response rate and a 4.5-month median survival in patients with locoregional and metastatic disease. The response rate for patients with only locoregional recurrence was 7% with a median survival of 4.8 months. Grade 3-4 myelotoxicity occurred in 24% of cycles administered. There were two treatment-related deaths due to neutropenic fever and one additional death on study may have been caused by treatment-induced thrombocytopenia. CONCLUSIONS: The combination of paclitaxel and carboplatin is significantly myelotoxic and ineffective in patients with previously treated locoregionally recurrent SCCHN, whereas it deserves further evaluation in those patients with distant metastatic disease alone. In those patients with locoregional disease, other more innovative treatments are needed.

Scattered brain infarct pattern on diffusion-weighted magnetic resonance imaging in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: Infarct patterns on brain imaging contribute to the etiologic classification of ischemic stroke. However, the association of specific subtypes of infarcts and etiologic mechanisms is often weak, and acute lesions are frequently missed on initial computed tomography (CT). Diffusion-weighted imaging (DWI) is superior in visualizing acute ischemic lesions as compared to CT and conventional magnetic resonance imaging (MRI). In our prospective study, we addressed the question whether a distinct pattern of infarction on DWI is associated with infarct etiology and clinical outcome. METHODS: Sixty-two patients with clinical signs of acute ischemic stroke and negative acute CT upon admission underwent DWI within 10 days after the ictus. Neurological status was documented using the NIH stroke scale. A scattered lesion pattern was defined by at least 2 separate hyperintense DWI lesions within the territory of one of the major cerebral arteries. Ischemic lesions were defined as acute if the region was demarcated strongly hyperintense in all DW images, and if the apparent diffusion coefficient was below normal. RESULTS: In 32 patients, DWI revealed a scattered lesion pattern, while in 30 patients a single acute lesion was detected. In patients with scattered lesions, potential arterial or cardiac embolic sources were detected in 26 patients (81.3%), as compared to 5 patients (16.6%) in the group with single lesions (chi(2) test, p < 0.0001). The neurological status of patients with scattered lesions improved significantly more than among patients with single lesions (Mann-Whitney test, p < 0.0003). CONCLUSION: A scattered lesion pattern on DWI in patients with acute brain infarction and negative initial CT scan is associated with an embolic etiology and may indicate a favorable clinical outcome.

Determinants of neurological outcome after surgery for brain arteriovenous malformation.

BACKGROUND AND PURPOSE: We sought to define determinants of neurological deficit after surgery for brain arteriovenous malformation (AVM). METHODS: One hundred twenty-four prospective patients (48% women, mean age 33 years) underwent microsurgical brain AVM resection. Patients were examined by 3 study neurologists immediately before surgery, postoperatively in-hospital, by in-person long-term follow-up, and with a structured telephone follow-up. They were classified according to the 5-point Spetzler-Martin grading system, with its 3 elements: size, venous drainage pattern, and location. The functional neurological status was classified with the modified Rankin scale. Multivariate logistic regression models were applied to test the effect of patient age, gender, and the 3 Spetzler-Martin elements on early and long-term postoperative neurological complications. RESULTS: Twelve patients (10%) were classified as Spetzler-Martin grade 1; 36 (29%) as grade 2; 47 (38%) as grade 3; 26 (21%) as grade 4; and 3 (2%) as grade 5. Postoperatively, in-hospital, 51 patients (41%) showed new neurological deficits (15% disabling [ie, Rankin scale score >2] and 26% nondisabling [ie, Rankin 1 or 2]). At long-term follow-up (mean follow-up time 12 months), 47 patients (38%) revealed surgery-related neurological deficits (6% disabling; 32% nondisabling). The rate of neurological complications increased by Spetzler-Martin grade. Female gender, AVM size, and deep venous drainage were significantly associated with neurological deficits at in-hospital and long-term evaluation. For patient age and AVM location, no significant association was found. CONCLUSIONS: The findings suggest that female gender, AVM size, and AVM drainage into the deep venous system may be determinants of neurological deficit after microsurgical AVM resection.

Demographic, morphological, and clinical characteristics of 1289 patients with brain arteriovenous malformation.

BACKGROUND AND PURPOSE: The purpose of this study was to assess demographic, clinical, and morphological characteristics of patients with brain arteriovenous malformations (AVMs). METHODS: Prospectively collected data of 1289 consecutive AVM patients from 3 independent databases (1 multicenter [Berlin/Paris/Middle and Far East, n=662] and 2 single centers [New York, n=337, and Toronto, n=290]) were analyzed. The variables assessed were age at diagnosis, sex, AVM size, AVM drainage pattern, AVM location in functionally important brain areas ("eloquence"), and type of presentation (hemorrhage, seizure, chronic headache, or focal neurologic deficit). Comparisons were made by ANOVA, contingency tables, and log-linear models. RESULTS: Overall, mean age at diagnosis was 31.2 years (95% CI 30.2 to 32.2 years), and 45% of the patients were female (95% CI 42% to 47%). AVM maximum diameter was <3 cm in 38% (95% CI 35% to 41%). Deep venous drainage was present in 55% (95% CI 52% to 59%). An eloquent AVM location was described in 71% (95% CI 69% to 74%). AVM hemorrhage occurred in 53% (95% CI 51% to 56%). Generalized or focal seizures were described in 30% (95% CI 27% to 33%) and 10% (95% CI 8% to 12%), respectively. Chronic headache was recorded in 14% (95% CI 12% to 16%). Persistent neurological deficits were found in 7% (95% CI 6% to 9%), and progressive neurological deficits in 5% (95% CI 4% to 6%). Significant differences between centers were found for age (P<0.001), sex (P=0.04), eloquence (P=0.04), size (P<0.001), hemorrhage (P=0.006), persistent neurological deficit (P<0.001), and reversible neurological deficit (P=0.013). The intercenter difference found for hemorrhage frequency did not remain after adjustment for AVM size. CONCLUSIONS: Baseline characteristics differed considerably between centers. The differences found in patient age and AVM size may be explained by center-specific referral patterns and the influence of access to treatment resources, whereas those found for other characteristics may be attributable to center-specific definitions. Analysis of natural history data from tertiary referral center databases may be improved by consistent definitions applicable to the entire population of AVM patients.