Citations

AbstractHairy cell leukemia is an uncommon hematologic malignancy characterized by pancytopenia and marked susceptibility to infection. Tremendous progress in the management of patients with this disease has resulted in high response rates and improved survival, yet relapse and an appropriate approach to re-treatment present continuing areas for research. The disease and its effective treatment are associated with immunosuppression. Because more patients are being treated with alternative programs, comparison of results will require general agreement on definitions of response, relapse, and methods of determining minimal residual disease. The development of internationally accepted, reproducible criteria is of paramount importance in evaluating and comparing clinical trials to provide optimal care. Despite the success achieved in managing these patients, continued participation in available clinical trials in the first-line and particularly in the relapse setting is highly recommended. The Hairy Cell Leukemia Foundation convened an international conference to provide common definitions and structure to guide current management. There is substantial opportunity for continued research in this disease. In addition to the importance of optimizing the prevention and management of the serious risk of infection, organized evaluations of minimal residual disease and treatment at relapse offer ample opportunities for clinical research. Finally, a scholarly evaluation of quality of life in the increasing number of survivors of this now manageable chronic illness merits further study. The development of consensus guidelines for this disease offers a framework for continued enhancement of the outcome for patients.

Background: Treatment with nab-paclitaxel with gemcitabine demonstrates a survival advantage when compared with single-agent gemcitabine. However, the combination is associated with significant toxicities, leading to a high rate of drug discontinuation. We implemented a modified regimen of gemcitabine and nab-paclitaxel (mGNabP) in an attempt to minimize toxicities while maintaining efficacy. Methods: A total of 79 evaluable patients with metastatic pancreatic adenocarcinoma (mPC) treated with a modified regimen of gemcitabine (1000 mg/m 2 ) and nab-paclitaxel (125 mg/m 2 ) on days 1, 15 of every 28-day cycle were identified from our prospective database. A total of 57 patients received this regimen as first-line treatment and were evaluated for toxicities, progression-free survival (PFS), and overall survival (OS). Overall, 22 patients with advanced or metastatic PC treated with the modified regimen outside the first-line setting were only evaluated for toxicities. Results: The median OS and PFS were 10 months [95% confidence interval (CI) 5.9–13 months] and 5.4 months (95% CI 4.1–7.4 months) for patients that received the modified regimen as first-line therapy. Neurotoxicity occurred in 27% with only 1.6% of patients experiencing grade ⩾3 toxicity. The incidence of grade ⩾3 neutropenia was 19%, resulting in growth factor support in 12% of patients. This rate was similar in patients who received the modified regimen for first-line treatment of mPC versus the overall group. Conclusions: A modified regimen of biweekly nab-paclitaxel with gemcitabine is associated with a lower cost, acceptable toxicity profile and appears to be relatively effective in pancreatic cancer. Prospective randomized studies confirming its potential benefits compared with standard weekly mGNabP are warranted.

Objective Limited efficacy of immune checkpoint inhibitors in pancreatic ductal adenocarcinoma (PDAC) has prompted investigation into combination therapy. We hypothesised that interleukin 6 (IL-6) blockade would modulate immunological features of PDAC and enhance the efficacy of anti-programmed death-1-ligand 1 (PD-L1) checkpoint inhibitor therapy. Design Transcription profiles and IL-6 secretion from primary patient-derived pancreatic stellate cells (PSCs) were analyzed via Nanostring and immunohistochemistry, respectively. In vivo efficacy and mechanistic studies were conducted with antibodies (Abs) targeting IL-6, PD-L1, CD4 or CD8 in subcutaneous or orthotopic models using Panc02, MT5 or KPC-luc cell lines; and the aggressive, genetically engineered PDAC model (Kras LSL−G12D , Trp53 LSL−R270H , Pdx1-cre, Brca2 F/F (KPC-Brca2 mice)). Systemic and local changes in immunophenotype were measured by flow cytometry or immunohistochemical analysis. Results PSCs (n=12) demonstrated prominent IL-6 expression, which was localised to stroma of tumours. Combined IL-6 and PD-L1 blockade elicited efficacy in mice bearing subcutaneous MT5 (p<0.02) and Panc02 tumours (p=0.046), which was accompanied by increased intratumoural effector T lymphocytes (CD62L − CD44 − ). CD8-depleting but not CD4-depleting Abs abrogated the efficacy of combined IL-6 and PD-L1 blockade in mice bearing Panc02 tumours (p=0.0016). This treatment combination also elicited significant antitumour activity in mice bearing orthotopic KPC-luc tumours and limited tumour progression in KPC-Brca2 mice (p<0.001). Histological analysis revealed increased T-cell infiltration and reduced α-smooth muscle actin cells in tumours from multiple models. Finally, IL-6 and PD-L1 blockade increased overall survival in KPC-Brca2 mice compared with isotype controls (p=0.0012). Conclusions These preclinical results indicate that targeted inhibition of IL-6 may enhance the efficacy of anti-PD-L1 in PDAC.

This study describes trends in mean standing functional turnout angles measured on a floor protractor (FP) and the Functional Footprint® rotational instrument (RI) during routine clinical screens. Twenty-three professional ballet dancers, 26 collegiate modern students, and 46 ballet academy dancers participated in the study. All dancers demonstrated greater total turnout on the FP compared to the RI (p < 0.001), and the collegiate dancers had significantly smaller total turnout angles compared to both of the other groups (p < 0.001). A significant interaction between measurement method and training group (p = 0.047) on lower extremity asymmetry indicated that only in professionals left turnout angle was greater than right turnout angle on the RI (4.30° ± 6.64°) but not on the FP (0.17° ± 4.57°). It is concluded that turnout can be measured using either the FP or the RI measurement method, with recognition that FP measurements will be an average of 10° greater than those on the RI. Lower extremity asymmetries in turnout angles may be better detected on the RI than the FP.

AbstractBackgroundLittle is known about the optimal use of shared decision making (SDM) to guide palliative and end‐of‐life decisions in the emergency department (ED).ObjectiveThe objective was to convene a working group to develop a set of research questions that, when answered, will substantially advance the ability of clinicians to use SDM to guide palliative and end‐of‐life care decisions in the ED.MethodsParticipants were identified based on expertise in emergency, palliative, or geriatrics care; policy or patient‐advocacy; and spanned physician, nursing, social work, legal, and patient perspectives. Input from the group was elicited using a time‐staggered Delphi process including three teleconferences, an open platform for asynchronous input, and an in‐person meeting to obtain a final round of input from all members and to identify and resolve or describe areas of disagreement.ConclusionKey research questions identified by the group related to which ED patients are likely to benefit from palliative care (PC), what interventions can most effectively promote PC in the ED, what outcomes are most appropriate to assess the impact of these interventions, what is the potential for initiating advance care planning in the ED to help patients define long‐term goals of care, and what policies influence palliative and end‐of‐life care decision making in the ED. Answers to these questions have the potential to substantially improve the quality of care for ED patients with advanced illness.

Background: Anterior cruciate ligament reconstruction (ACLR) using a hamstring tendon autograft often results in hamstring muscle strength asymmetry. However, the effect of hamstring muscle strength asymmetry on knee mechanics has not been reported. Hypothesis: Participants with hamstring strength asymmetry would demonstrate altered involved limb knee mechanics during walking and jogging compared with those with more symmetric hamstring strength at least 2 years after ACLR with a hamstring tendon autograft. Study Design: Controlled laboratory study. Methods: There were a total of 45 participants at least 2 years after ACLR (22 male, 23 female; mean time after ACLR, 34.6 months). A limb symmetry index (LSI) was calculated for isometric hamstring strength to subdivide the sample into symmetric hamstring (SH) (LSI ≥90%; n = 18) and asymmetric hamstring (AH) (LSI <85%; n = 18) groups. Involved knee kinematic and kinetic data were collected using 3-dimensional motion analysis during gait and jogging. Peak sagittal-, frontal-, and transverse-plane knee angles and sagittal-plane knee moments and knee powers were calculated. Independent-samples t tests and analyses of covariance were used to compare involved knee kinematic and kinetic variables between the groups. Results: There were no differences in sagittal- and frontal-plane knee angles between the groups ( P > .05 for all). The AH group demonstrated decreased tibial internal rotation during weight acceptance during gait ( P = .01) and increased tibial external rotation during jogging at initial contact ( P = .03) and during weight acceptance ( P = .02) compared with the SH group. In addition, the AH group demonstrated decreased peak negative knee power during midstance ( P = .01) during gait compared with the SH group, after controlling for gait speed, which differed between groups. Conclusion: Participants with hamstring strength asymmetry showed altered involved knee mechanics in the sagittal plane during gait and in the transverse plane during gait and jogging compared with those with more symmetric hamstring strength. Clinical Relevance: Hamstring strength asymmetry is common at 3 years after ACLR with a hamstring tendon autograft and affects involved knee mechanics during gait and jogging. Additional research is warranted to further investigate the longitudinal effect of these alterations on knee function and joint health after ACLR.

Abstract BACKGROUND: The potential for simulation-based learning in neurosurgical training has led the Congress of Neurosurgical Surgeons to develop a series of simulation modules. The Northwestern Objective Microanastomosis Assessment Tool (NOMAT) was created as the corresponding assessment tool for the Congress of Neurosurgical Surgeons Microanastomosis Module. The face and construct validity of the NOMAT have been previously established. OBJECTIVE: To further validate the NOMAT by determining its interrater reliability (IRR) between raters of varying levels of microsurgical expertise. METHODS: The NOMAT was used to assess residents’ performance in a microanastomosis simulation module in 2 settings: Northwestern University and the Society of Neurological Surgeons 2014 Boot Camp at the University of Indiana. At Northwestern University, participants were scored by 2 experienced microsurgeons. At the University of Indiana, participants were scored by 2 postdoctoral fellows and an experienced microsurgeon. The IRR of NOMAT was estimated by computing the intraclass correlation coefficient using SPSS v22.0 (IBM, Armonk, New York). RESULTS: A total of 75 residents were assessed. At Northwestern University, 21 residents each performed microanastomosis on 2 model vessels of different sizes, one 3 mm and one 1 mm. At the University of Indiana, 54 residents performed a single microanastomosis procedure on 3-mm vessels. The intraclass correlation coefficient of the total NOMAT scores was 0.88 at Northwestern University and 0.78 at the University of Indiana. CONCLUSION: This study indicates high IRR for the NOMAT. These results suggest that the use of raters with varying levels of expertise does not compromise the precision or validity of the scale. This allows for a wider adoption of the scale and, hence, a greater potential educational impact.