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JX-594 is a targeted oncolytic poxvirus designed to selectively replicate in and destroy cancer cells with cell-cycle abnormalities and epidermal growth factor receptor (EGFR)- ras pathway activation. Direct oncolysis plus granulocyte-macrophage colony-stimulating factor (GM-CSF) expression also stimulates shutdown of tumour vasculature and antitumoral immunity. We aimed to assess intratumoral injection of JX-594 in patients with refractory primary or metastatic liver cancer. Between Jan 4, 2006, and July 4, 2007, 14 patients with histologically confirmed refractory primary or metastatic liver tumours (up to 10·9 cm total diameter) that were amenable to image-guided intratumoral injections were enrolled into this non-comparative, open-label, phase I dose-escalation trial (standard 3×3 design; two to six patients for each dose with 12–18 estimated total patients). Patients received one of four doses of intratumoral JX-594 (10 8 plaque-forming units [pfu], 3×10 8 pfu, 10 9 pfu, or 3×10 9 pfu) every 3 weeks at Dong-A University Hospital (Busan, South Korea). Patients were monitored after treatment for at least 48 h in hospital and for at least 4 weeks as out-patients. Adverse event-monitoring according to the National Cancer Institute Common Toxicity Criteria (version 3) and standard laboratory toxicity grading for haematology, liver and renal function, coagulation studies, serum chemistry, and urinalysis were done. The primary aims were to ascertain the maximum-tolerated dose (MTD) and safety of JX-594 treatment. Data were also collected on pharmacokinetics, pharmacodynamics, and efficacy. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00629759. Of 22 patients with liver tumours who were assessed for eligibility, eight patients did not meet inclusion criteria. Therefore, 14 patients, including those with hepatocellular, colorectal, melanoma, and lung cancer, were enrolled. Patients were heavily pretreated (5·6 previous treatments, SD 2·8, range 2·0–12·0) and had large tumours (7·0 cm diameter, SD 2·7, range 1·8–10·9). Patients received a mean of 3·4 (SD 2·2, range 1·0–8·0) cycles of JX-594. All patients were evaluable for toxicity. All patients experienced grade I–III flu-like symptoms, and four had transient grade I–III dose-related thrombocytopenia. Grade III hyperbilirubinaemia was dose-limiting in both patients at the highest dose; the MTD was therefore 1×10 9 pfu. JX-594 replication-dependent dissemination in blood was shown, with resultant infection of non-injected tumour sites. GM-CSF expression resulted in grade I–III increases in neutrophil counts in four of six patients at the MTD. Tumour responses were shown in injected and non-injected tumours. Ten patients were radiographically evaluable for objective responses; non-evaluable patients had contraindications to contrast medium (n=2) or no post-treatment scans (n=2). According to Response Evaluation Criteria in Solid Tumors (RECIST), three patients had partial response, six had stable disease, and one had progressive disease. Intratumoral injection of JX-594 into primary or metastatic liver tumours was generally well-tolerated. Direct hyperbilirubinaemia was the dose-limiting toxicity. Safety was acceptable in the context of JX-594 replication, GM-CSF expression, systemic dissemination, and JX-594 had anti-tumoral effects against several refractory carcinomas. Phase II trials are now underway. Jennerex Biotherapeutics (San Francisco, CA, USA) and Green Cross Corporation (Giheung-Gu, Yongin, South Korea).

Abstract BACKGROUND Spine stereotactic body radiotherapy (sSBRT) is commonly limited to 1 or 2 vertebral levels given a paucity of efficacy and toxicity data when more than 2 levels are treated. OBJECTIVE To prove our hypothesis that multilevel sSBRT could provide similar rates of local control (LC) (primary endpoint) and toxicity as single-level treatment using the same clinical target, planning target, and planning organ-at-risk volumes. METHODS We analyzed consecutive cases of sSBRT treated from 2013 to 2017. Time-to-event outcomes for single-level and multilevel cases were compared using mixed effect Cox models and differences in toxicity rates were evaluated using linear mixed effect models. All models incorporate a patient-level random intercept to account for any within-patient correlation across cases. RESULTS There were 101 single-level and 84 multilevel sSBRT cases (2-7 continuous vertebral levels). One-year LC was 95% vs 85%, respectively. After adjusting for baseline covariates, dose delivered, and accounting for within-patient correlation, there was no significant difference in time to local failure (hazard ratio, HR 1.79 [0.59-5.4]; P = .30). Pain improved in 83.5% of the 139 initially symptomatic tumors. There were no significant differences in grade 2+ acute or late toxicities between single-level and multilevel sSBRT. CONCLUSION With rigorous patient immobilization, quality assurance, and image guidance, multilevel sSBRT provides high rates of LC, similar to single-level treatment, without need for larger planning volume margins. Efforts to improve prognostication and case selection for multilevel sSBRT are warranted to ensure that the benefits of improved LC over palliative radiation are justified.

BackgroundWe aimed to develop an actionable and feasible prospective clinical model to estimate toxicity risk to assist chimeric antigen receptor (CAR) T-cell therapy providers with the management of patients with relapsed and/or refractory large B-cell lymphoma.MethodsWe conducted an observational, retrospective cohort study using secondary data from 390 patients treated with the CD19 CAR T-cell therapy axicabtagene ciloleucel under two prospective clinical trials, ZUMA-1 and ZUMA-7; these clinical trials enrolled patients with relapsed/refractory large B-cell lymphoma between 2015 and 2019. Using machine learning and statistical methods, we developed a classification model for identifying patients unlikely to experience early cytokine release syndrome (CRS) and neurological events (NE) of any grade.ResultsWe found the use of prophylactic corticosteroids to be an important factor in remaining CRS-free and NE-free within the first 3 days post-treatment (p<0.001). We identified a top model for no early CRS/NE using a set of six pre-lymphodepletion clinicopathologic features: number of lines of prior systemic therapy, age, baseline tumor burden (as measured by sum of the product of the diameters), C-reactive protein, aspartate transaminase, and hemoglobin, which achieves a positive predictive value of 0.71 in the holdout validation cohort. Additionally, we find that predicted probabilities generated from the model are strongly associated with incidence of Grade 2 or higher NE.ConclusionsWe illustrated that routine clinicopathologic variables can be used to identify patients at low risk of developing early post-treatment CRS and/or NE. Such knowledge can be used to help treating centers prospectively manage patient care, including consideration of outpatient treatment.

Oncolytic viruses (OVs) are selected or designed to eliminate malignancies by direct infection and lysis of cancer cells. In contrast to this concept of direct tumor lysis by viral infection, we observed that a significant portion of the in vivo tumor killing activity of two OVs, vesicular stomatitis virus (VSV) and vaccinia virus is caused by indirect killing of uninfected tumor cells. Shortly after administering the oncolytic virus we observed limited virus infection, coincident with a loss of blood flow to the interior of the tumor that correlated with induction of apoptosis in tumor cells. Transcript profiling of tumors showed that virus infection resulted in a dramatic transcriptional activation of pro-inflammatory genes including the neutrophil chemoattractants CXCL1 and CXCL5. Immunohistochemical examination of infected tumors revealed infiltration by neutrophils correlating with chemokine induction. Depletion of neutrophils in animals prior to VSV administration eliminated uninfected tumor cell apoptosis and permitted more extensive replication and spreading of the virus throughout the tumor. Taken all together, these results indicate that targeted recruitment of neutrophils to infected tumor beds enhances the killing of malignant cells. We propose that activation of inflammatory cells can be used for enhancing the effectiveness of oncolytic virus therapeutics, and that this approach should influence the planning of therapeutic doses.

Purpose The aromatase inhibitors (AI) exemestane (EXE), letrozole (LET), and anastrozole suppress estrogen biosynthesis, and are effective treatments for estrogen receptor (ER)-positive breast cancer. Prior work suggests that anastrozole blood concentrations are associated with the magnitude of estrogen suppression. The objective of this study was to determine whether the magnitude of estrogen suppression, as determined by plasma estradiol (E2) concentrations, in EXE or LET treated patients is associated with plasma AI concentrations. Methods Five hundred post-menopausal women with ER-positive breast cancer were enrolled in the prospective Exemestane and Letrozole Pharmacogenetic (ELPh) Study conducted by the COnsortium on BReast cancer phArmacogomics (COBRA) and randomly assigned to either drug. Estrogen concentrations were measured at baseline and after 3 months of AI treatment and drug concentrations were measured after 1 or 3 months. EXE or LET concentrations were compared with 3-month E2 concentration or the change from baseline to 3 months using several complementary statistical procedures. Results Four-hundred patients with on-treatment E2 and AI concentrations were evaluable (EXE n  = 200, LET n  = 200). Thirty (7.6%) patients (EXE n  = 13, LET n  = 17) had 3-month E2 concentrations above the lower limit of quantification (LLOQ) (median: 4.75; range: 1.42–63.8 pg/mL). EXE and LET concentrations were not associated with on-treatment E2 concentrations or changes in E2 concentrations from baseline (all p  > 0.05). Conclusions Steady-state plasma AI concentrations do not explain variability in E2 suppression in post-menopausal women receiving EXE or LET therapy, in contrast with prior evidence in anastrozole treated patients.

Optimal treatment for traumatic finger amputation is unknown to date. To use statistical learning methods to estimate evidence-based treatment assignment rules to enhance long-term functional and patient-reported outcomes in patients after traumatic amputation of fingers distal to the metacarpophalangeal joint. This decision analytical model used data from a retrospective cohort study of 338 consenting adult patients who underwent revision amputation or replantation at 19 centers in the United States and Asia from August 1, 2016, to April 12, 2018. Of those, data on 185 patients were included in the primary analysis. Treatment with revision amputation or replantation. Outcome measures were hand strength, dexterity, hand-related quality of life, and pain. A tree-based statistical learning method was used to derive clinical decision rules for treatment of traumatic finger amputation. Among 185 study participants (mean [SD] age, 45 [16] years; 156 [84%] male), the median number of fingers amputated per patient was 1 (range, 1-5); 115 amputations (62%) were distal to the proximal interphalangeal joint, and 110 (60%) affected the nondominant hand. On the basis of the tree-based statistical learning estimates, to maximize hand dexterity or to minimize patient-reported pain, replantation was found to be the best strategy. To maximize hand strength, revision amputation was the best strategy for patients with a single-finger amputation but replantation was preferred for all other injury patterns. To maximize patient-reported quality of life, revision amputation was the best approach for patients with dominant hand injuries, and replantation was the best strategy for patients with nondominant hand injuries. The findings suggest that the approach to treating traumatic finger amputations varies based on the patient's injury characteristics and functional needs.

Despite appropriate treatment, many patients who sustain distal radius fractures (DRFs) report persistent wrist pain. Chronic musculoskeletal pain is among the leading health problems in the elderly population associated with significant personal and societal burden. To identify modifiable preoperative factors that are significantly associated with developing chronic pain. This is a secondary analysis of the Wrist and Radius Injury Surgical Trial (WRIST), a randomized multicenter clinical trial of 24 study sites in the United States, Canada, and Singapore that enrolled patients from April 10, 2012, to December 31, 2016. Adults older than 60 years who sustained closed extra-articular DRFs, were treated operatively, and completed 12-month Michigan Hand Outcomes Questionnaires (MHQs) were included in this study. Analysis was conducted from September to December 2019. Volar locking plate internal fixation, external fixation, or percutaneous pinning. 12-month MHQ pain domain score. Inverse probability weighted logistic regression was used to identify factors associated with of chronic pain. A total of 146 patients with DRF who were treated operatively and had 12-month MHQ scores met inclusion criteria. The mean (SD) patient age was 68.9 (7.2) years, 128 (87.6%) were women, and 93 (63.7%) were retired. Chronic pain was present in 87 patients (59.6%) and absent in 59 patients (40.4%) at 1-year follow-up. A 1-week delay in surgery was associated with more than triple the odds of developing chronic pain (odds ratio [OR], 3.65; 95% CI, 1.48-9.00), and each 10-point increase in preoperative pain was associated with a 17% increase in the odds of experiencing chronic pain (OR, 1.17; 95% CI, 1.02-1.34). Internal fixation was associated with decreased odds of developing chronic pain compared with the other 2 procedures (OR, 0.29; 95% CI, 0.10-0.90). In this study, preoperative pain, time to surgery, and procedure type were modifiable factors associated with chronic pain 1 year after DRF treated with surgery. Adequate pain control in patients with acute DRFs even before definitive surgical management and earlier fixation for patients requiring surgery may decrease the risk of developing chronic pain. Internal fixation may decrease the risk of chronic pain after DRF surgery, compared with percutaneous pinning or external fixation. ClinicalTrials.gov Identifier: NCT01589692.

Importance Stenosing tenosynovitis (trigger finger) affects approximately 2% of the population. Given the prevalence of trigger finger and rising health care costs, adherence to the cost-effective and evidence-based treatment algorithm will permit better outcomes and allocation of resources. Objectives To examine treatment patterns for trigger finger and to determine surgeon-level and patient-level factors that influence adherence to evidence-based treatment. Design, Setting, and Participants This retrospective population-based cohort study examined deidentified claims for treatment of trigger finger from a national insurance provider using the Clinformatics Data Mart database. Patients were included if they were 18 years or older and treated from January 1, 2002, through December 31, 2016 (excluding a washout period from July 1, 2008, until June 30, 2010), with a new diagnosis of single-digit trigger finger. Data were analyzed from December 21, 2018, through April 28, 2019. Exposures Cost-effective and evidence-based research published in July 2009 for the treatment of trigger finger. Main Outcomes and Measures After excluding the 1-year washout period on either side of July 1, 2009, adherence to the recommended treatment algorithm of 2 corticosteroid injections before surgical release of trigger finger was compared with practice before publication of research supporting this cost-effective and evidence-based approach. Results In this analysis of 83 667 patients with trigger finger, 52 698 (63.0%) were women, and 20 045 (24.0%) had type 1 or 2 diabetes. Mean (SD) age was 61 (13) years. From 2002 to 2016, an overall increasing trend in adherence to the cost-effective and evidence-based approach to treatment was noted, with no significant increase in adherence in the postpublication era (67.5% vs 73.3%;P = .27). Substantial variation in adherence was observed at the surgeon level (intraclass correlation, 33%). Plastic surgeons had no change in adherence over time compared with orthopedic surgeons (odds ratio [OR], 1.00; 95% CI, 0.98-1.02;P = .90), whereas general surgeons had increased adherence (OR, 1.04; 95% CI, 1.02-1.06;P < .001). Higher-volume surgeons were also more adherent to these evidence-based recommendations (OR, 1.59; 95% CI, 1.53-1.65;P < .001). Conclusions and Relevance This study found substantial surgeon-level variation in adherence to evidence-based treatment of trigger finger. Surgeon specialty and volume were associated with differences in adherence. Efforts to understand surgeon barriers to implementation, regardless of physician specialty, appear to be necessary, and better implementation strategies may permit increased uptake of evidence-based treatment of trigger finger.

A clustered adaptive intervention (cAI) is a pre-specified sequence of decision rules that guides practitioners on how best - and based on which measures - to tailor cluster-level intervention to improve outcomes at the level of individuals within the clusters. A clustered sequential multiple assignment randomized trial (cSMART) is a type of trial that is used to inform the empirical development of a cAI. The most common type of secondary aim in a cSMART focuses on assessing causal effect moderation by candidate tailoring variables. We introduce a clustered Q-learning framework with the M-out-of-N Cluster Bootstrap using data from a cSMART to evaluate whether a set of candidate tailoring variables may be useful in defining an optimal cAI. This approach could construct confidence intervals (CI) with near-nominal coverage to assess parameters indexing the causal effect moderation function. Specifically, it allows reliable inferences concerning the utility of candidate tailoring variables in constructing a cAI that maximizes a mean end-of-study outcome even when \"non-regularity\", a well-known challenge exists. Simulations demonstrate the numerical performance of the proposed method across varying non-regularity conditions and investigate the impact of varying number of clusters and intra-cluster correlation coefficient on CI coverage. Methods are applied on ADEPT dataset to inform the construction of a clinic-level cAI for improving evidence-based practice in treating mood disorders.

Cancers are an insidious set of diseases characterized by uncontrolled cell growth, many of which rapidly adapt to maintain their survival. Cancer treatments differ based on the organ of origin of the cancer, the cancer histology (cell type), tumor stage at diagnosis, whether the cancer is local or has metastasized (spread to other organs), and the patient's personal preferences and characteristics, including age and health status, among others. Depending on the above, standard therapies may include surgery, radiation therapy, chemotherapy, immunotherapy, stem-cell transplantation, and/or targeted therapy. Or, if the cancer is of minimal risk of proliferation, active surveillance may also be used.