Citations

Gemcitabine plus docetaxel is an effective treatment regimen for advanced soft tissue sarcomas (STSs). However, the prognosis for patients remains poor, and thus there is an urgent medical need for novel and effective therapies to improve long-term outcomes. The aim of the ANNOUNCE 2 trial was to explore the addition of olaratumab (O) to gemcitabine (G) and docetaxel (D) for advanced STS. Adults with unresectable locally advanced/metastatic STS, ≤2 prior lines of systemic therapy, and ECOG PS 0–1 were eligible. In Phase 2, patients were randomized 1:1 from two cohorts (O-naïve and O-pretreated) to 21-day cycles of olaratumab (20 mg/kg Cycle 1 and 15 mg/kg other cycles, Days 1 and 8), gemcitabine (900 mg/m2, Days 1 and 8), and docetaxel (75 mg/m2, Day 8). The primary objective was overall survival (OS) in the O-naïve population (α level = 0.20). Secondary endpoints included OS (O-pretreated), other efficacy parameters, patient-reported outcomes, safety, pharmacokinetics, and immunogenicity. A total of 167 and 89 patients were enrolled in the O-naïve and O-pretreated cohorts, respectively. Baseline patient characteristics were well balanced. No statistically significant difference in OS was observed between the investigational vs. control arm for either cohort (O-naïve cohort: HR = 0.95 (95% CI: 0.64−1.40), p = 0.78, median OS, 16.8 vs. 18.0 months; O-pretreated cohort: HR = 0.67 (95% CI: 0.39−1.16), p = 0.15, median OS 19.8 vs. 17.3 months). Safety was manageable across treatment arms. There was no statistically significant difference in the primary endpoint of OS between the two arms in the O-naïve population, and therefore based on hierarchical evaluation no other outcomes in this study can be considered statistically significant. No new safety signals were observed.

AbstractBackgroundTobacco use is associated with adverse outcomes among patients diagnosed with cancer. Socioeconomic determinants influence access and utilization of tobacco treatment; little is known about the relationship between neighborhood socioeconomic disadvantage (NSD) and tobacco assessment, assistance, and cessation among patients diagnosed with cancer.MethodsA modified Cancer Patient Tobacco Use Questionnaire (C‐TUQ) was administered to patients enrolled in nine ECOG‐ACRIN clinical trials. We examined associations of NSD with (1) smoking status, (2) receiving tobacco cessation assessment and support, and (3) cessation behaviors. NSD was classified by tertiles of the Area Deprivation Index. Associations between NSD and tobacco variables were evaluated using logistic regression.ResultsA total of 740 patients completing the C‐TUQ were 70% male, 94% White, 3% Hispanic, mean age 58.8 years. Cancer diagnoses included leukemia 263 (36%), lymphoma 141 (19%), prostate 131 (18%), breast 79 (11%), melanoma 69 (9%), myeloma 53 (7%), and head and neck 4 (0.5%). A total of 402 (54%) never smoked, 257 (35%) had formerly smoked, and 81 (11%) were currently smoking. Patients in high disadvantaged neighborhoods were approximately four times more likely to report current smoking (odds ratio [OR], 3.57; 95% CI, 1.69–7.54; p = .0009), and more likely to report being asked about smoking (OR, 4.24; 95% CI, 1.64–10.98; p = .0029), but less likely to report receiving counseling (OR, 0.11; 95% CI, 0.02–0.58; p = .0086) versus those in the least disadvantaged neighborhoods.ConclusionsGreater neighborhood socioeconomic disadvantage was associated with smoking but less cessation support. Increased cessation support in cancer care is needed, particularly for patients from disadvantaged neighborhoods.

Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy. Small observational studies reported allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We report an analysis of patients with BPDCN who received an allo-HCT, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We identified 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007 and 2018. The 5-year overall survival (OS), disease-free survival (DFS), relapse, and nonrelapse mortality (NRM) rates were 51.2% (95% confidence interval [CI], 42.5-59.8), 44.4% (95% CI, 36.2-52.8), 32.2% (95% CI, 24.7-40.3), and 23.3% (95% CI, 16.9-30.4), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age of ≥60 years was predictive for inferior OS (hazard ratio [HR], 2.16; 95% CI, 1.35-3.46; P = .001), and higher NRM (HR, 2.19; 95% CI, 1.13-4.22; P = .02). Remission status at time of allo-HCT (CR2/primary induction failure/relapse vs CR1) was predictive of inferior OS (HR, 1.87; 95% CI, 1.14-3.06; P = .01) and DFS (HR, 1.75; 95% CI, 1.11-2.76; P = .02). Use of myeloablative conditioning with total body irradiation (MAC-TBI) was predictive of improved DFS and reduced relapse risk. Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, whereas MAC-TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes.

Abstract Purpose: Pharmacologic ascorbate (P-AscH−) is hypothesized to be an iron (Fe)-dependent tumor-specific adjuvant to chemoradiation in treating glioblastoma (GBM). This study determined the efficacy of combining P-AscH− with radiation and temozolomide in a phase II clinical trial while simultaneously investigating a mechanism-based, noninvasive biomarker in T2* mapping to predict GBM response to P-AscH− in humans. Patients and Methods: The single-arm phase II clinical trial (NCT02344355) enrolled 55 subjects, with analysis performed 12 months following the completion of treatment. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan–Meier method and compared across patient subgroups with log-rank tests. Forty-nine of 55 subjects were evaluated using T2*-based MRI to assess its utility as an Fe-dependent biomarker. Results: Median OS was estimated to be 19.6 months [90% confidence interval (CI), 15.7–26.5 months], a statistically significant increase compared with historic control patients (14.6 months). Subjects with initial T2* relaxation < 50 ms were associated with a significant increase in PFS compared with T2*-high subjects (11.2 months vs. 5.7 months, P < 0.05) and a trend toward increased OS (26.5 months vs. 17.5 months). These results were validated in preclinical in vitro and in vivo model systems. Conclusions: P-AscH− combined with temozolomide and radiotherapy has the potential to significantly enhance GBM survival. T2*-based MRI assessment of tumor iron content is a prognostic biomarker for GBM clinical outcomes. See related commentary by Nabavizadeh and Bagley, p. 255

Abstract In the pre–novel agent era, the median postprogression overall survival (PPS) of patients with classic Hodgkin lymphoma (cHL) who progress after autologous stem cell transplant (ASCT) was 2 to 3 years. Recently, checkpoint inhibitors (CPI) and brentuximab vedotin (BV) have improved the depth and durability of response in this population. Here, we report the estimate of PPS in patients with relapsed cHL after ASCT in the era of CPI and BV. In this multicenter retrospective study of 15 participating institutions, adult patients with relapsed cHL after ASCT were included. Study objective was postprogression overall survival (PPS), defined as the time from posttransplant progression to death or last follow-up. Of 1158 patients who underwent ASCT, 367 had progressive disease. Median age was 34 years (range, 27-46) and 192 were male. Median PPS was 114.57 months (95% confidence interval [CI], 91-not achieved) or 9.5 years. In multivariate analysis, increasing age, progression within 6 months, and pre-ASCT positive positron emission tomography scan were associated with inferior PPS. When adjusted for these features, patients who received CPI, but not BV, as first treatment for post-ASCT progression had significantly higher PPS than the no CPI/no BV group (hazard ratio, 3.5; 95% CI, 1.6-7.8; P = .001). Receipt of allogeneic SCT (Allo-SCT) did not improve PPS. In the era of novel agents, progressive cHL after ASCT had long survival that compares favorably with previous reports. Patients who receive CPI as first treatment for progression had higher PPS. Receipt to Allo-SCT was not associated with PPS in this population.

Introduction. Mental health and psychiatry have been terms of intense and complex use for almost a century, and they may have reached a critical level of ambiguous and imprecise synonymy that makes their definition and validation difficult. Objective. To examine these concepts in depth, establishing precise distinctions, ontological connections, and instrumental scope reinforced by well-defined ideas in ethics and bioethics. Method. Narrative review of pertinent literature, consultation with diverse scientific, medical, historical, philosophical, and literary sources, with appropriate analysis of ethical and bioethical practices. Results. A broad, comprehensive definition is elaborated of mental health as a field with sociocultural, political, and demographic implications, and of psychiatry as a medical specialty. In addition to making clear distinctions and describing the specific impact of both fields on diverse populations, various levels of conceptual linkages, sociopolitical action, and ethical content are highlighted, as well as in processes of administration, education, and research. Discussion and conclusion. There are factors that reinforce or weaken the scope of mental health and psychiatry, including their ethical and bioethical dimensions. Their effectiveness requires a reaffirmation of objectives and the reinforcement of individual and institutional initiatives, as well as the search for authentic connections and a social projection that is objective, comprehensive, and just.

Background: The transorbital approaches (TOAs) have acquired growing notoriety, thanks to their ability to offer alternative corridors to the skull base. However, the limited access and the unfamiliarity with this surgical perspective make recognition of key landmarks difficult, especially for less experienced surgeons. The study wants to offer a detailed description of the anatomy to comprehend the potential and limitations of TOAs. Methods: Measurements of the orbit region and the surrounding areas were performed on two hundred high-resolution CT scans and thirty-nine dry skulls. Five specimens were dissected to illustrate the TOA, and one was used to perform the extradural clinoidectomy. Three clinical cases highlighted the surgical applications. Results: A step-by-step description of the key steps of the TOA was proposed and a comparison with the transcranial anterior clinoidectomy was discussed. The mean work distance was 6.1 ± 0.4 cm, and the lateral working angle increased 20 ± 5.4° after removing the lateral orbital rim. Conclusions: TOAs are indicated in selected cases when tumor involves the lateral portion of the cavernous sinus or the middle skull base, obtaining a direct decompression of the optic nerve and avoiding excessive manipulation of the neurovascular structures. Comprehension of surgical anatomy of the orbit and its surrounding structures is essential to safely perform these approaches.

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

Importance Radiologically isolated syndrome (RIS) represents the earliest detectable preclinical phase of multiple sclerosis (MS) punctuated by incidental magnetic resonance imaging (MRI) white matter anomalies within the central nervous system. Objective To determine the time to onset of symptoms consistent with MS. Design, Setting, and Participants From September 2017 to October 2022, this multicenter, double-blind, phase 3, randomized clinical trial investigated the efficacy of teriflunomide in delaying MS in individuals with RIS, with a 3-year follow-up. The setting included referral centers in France, Switzerland, and Turkey. Participants older than 18 years meeting 2009 RIS criteria were randomly assigned (1:1) to oral teriflunomide, 14 mg daily, or placebo up to week 96 or, optionally, to week 144. Interventions Clinical, MRI, and patient-reported outcomes (PROs) were collected at baseline and yearly until week 96, with an optional third year in the allocated arm if no symptoms have occurred. Main outcomes Primary analysis was performed in the intention-to-treat population, and safety was assessed accordingly. Secondary end points included MRI outcomes and PROs. Results Among 124 individuals assessed for eligibility, 35 were excluded for declining to participate, not meeting inclusion criteria, or loss of follow-up. Eighty-nine participants (mean [SD] age, 37.8 [12.1] years; 63 female [70.8%]) were enrolled (placebo, 45 [50.6%]; teriflunomide, 44 [49.4%]). Eighteen participants (placebo, 9 [50.0%]; teriflunomide, 9 [50.0%]) discontinued the study, resulting in a dropout rate of 20% for adverse events (3 [16.7%]), consent withdrawal (4 [22.2%]), loss to follow-up (5 [27.8%]), voluntary withdrawal (4 [22.2%]), pregnancy (1 [5.6%]), and study termination (1 [5.6%]). The time to the first clinical event was significantly extended in the teriflunomide arm compared with placebo, in both the unadjusted (hazard ratio [HR], 0.37; 95% CI, 0.16-0.84; P = .02) and adjusted (HR, 0.28; 95% CI, 0.11-0.71; P = .007) analysis. Secondary imaging end point outcomes including the comparison of the cumulative number of new or newly enlarging T2 lesions (rate ratio [RR], 0.57; 95% CI, 0.27-1.20; P = .14), new gadolinium-enhancing lesions (RR, 0.33; 95% CI, 0.09-1.17; P = .09), and the proportion of participants with new lesions (odds ratio, 0.72; 95% CI, 0.25-2.06; P = .54) were not significant. Conclusion and Relevance Treatment with teriflunomide resulted in an unadjusted risk reduction of 63% and an adjusted risk reduction of 72%, relative to placebo, in preventing a first clinical demyelinating event. These data suggest a benefit to early treatment in the MS disease spectrum. Trial Registration ClinicalTrials.gov Identifier: NCT03122652

Background: Meniscal allograft transplantation (MAT) has been shown to provide clinical benefits in patients with symptomatic meniscal deficiency in the short term and midterm. There is, however, a paucity of data regarding long-term outcomes after MAT using fresh-frozen allografts and the bridge-in-slot technique. Purpose: To report clinical outcomes and revision rates after primary MAT with fresh-frozen allografts and the bridge-in-slot technique in a large case series of patients at a 10-year minimum follow-up. Study Design: Case series; Level of evidence, 4. Methods: A retrospective review of prospectively collected data was performed on patients undergoing primary MAT between 2001 and 2012. Lysholm, International Knee Documentation Committee subjective form, and Knee injury and Osteoarthritis Outcome Score subscales were collected preoperatively and at 1-, 2-, 5-, and minimum 10-year follow-ups. Cox proportional hazards modeling was used to identify variables associated with reoperation and failure, defined as revision MAT or conversion to arthroplasty. Reoperation was defined as a subsequent surgical intervention on the transplanted meniscus, including partial or total meniscectomy, meniscal repair, or failure as defined in the previous sentence. Results: A total of 174 patients undergoing MAT met the inclusion criteria and were followed for a mean of 12.7 ± 2.7 years (range, 10.0-21.0 years). The mean age at surgery was 28.3 ± 10.1 years. The patients were predominantly female (n = 92; 53%), and medial MAT was the most commonly performed procedure (n = 91; 52%). Concomitant procedures were performed in 115 patients (66%), with the most common procedure being osteochondral allograft transplantation (n = 59; 34%). Patients demonstrated statistically significant postoperative improvements at all time points for all patient-reported outcome measures ( P ≤ .0001). A total of 65 patients (37%) underwent a meniscal reoperation at a mean time of 6.6 ± 5.5 years (range, 0.3-16.7 years) postoperatively. A total of 40 patients (23%) met the criteria for failure at a mean time of 7.3 ± 5.0 years (range, 1.0-17.4 years) after MAT, with 22 of these patients having undergone a previous meniscal reoperation. At the final follow-up, 13 patients (7%) had undergone revision MAT and 27 (15%) had converted to arthroplasty. The MAT survival rates free of meniscal reoperation and failure were 73% and 85% at 10 years and 60% and 72% at 15 years, respectively. At the time of the final follow-up, 86% of patients reported that they were satisfied with their overall postoperative condition. Conclusion: Primary MAT demonstrates efficacy and durability with high rates of patient satisfaction at a minimum 10-year follow-up. Patients should be counseled that although reoperation rates may approach 40% at 15 years, rates of overall revision MAT and conversion to arthroplasty remain low at long-term follow-up.