ANGI-1 Impact of neoadjuvant bevacizumab on transcriptional factor for stemness, macrophage polarization, and oxygenation of tumor microenvironment in glioblastoma

Background: Previously we reported that bevacizumab (Bev) produces tumor oxygenation with immunosupportive tumor microenvironment (TME) and inhibition of stemness. To confirm whether those effects might contribute prolongation of clinical outcome, in the present study paired samples from same patients with newly diagnosed GBM who received Bev during its effectiveness and refractoriness were investigated by immunohistochemistry. Methods: Eighteen samples from 9 patients with newly diagnosed GBM who received preoperative neoadjuvant Bev (neoBev) followed by surgical operation and chemoradiotherapy in addition to salvage surgery after recurrence were investigated. Expressions of FOXM1, HIF-1, and CD163 were evaluated by immunohistochemistry. Overall survial (OS) were analyzed with the present cohort divided into two groups between good and poor responder (GR and PR, respectively) of Bev defined as tumor regression rate judged by T1 gadolinium enhancement (T1Gd) and fluid attenuated inversion recovery (FLAIR) images. Results: In the group of good responder of T1Gd (T1Gd-GR; defined as >38% of regression rate after neoBev), OS was prolonged compared with T1Gd-PR along with inhibition of FOXM1 expression and HIF-1a. In contrast, in the group of good responder of FLAIR (FLAIR-GR; defined as >54% of regression rate after neoBev), there were no significant differences of OS and FOXM1 expression between GR and PR. HIF-1a expression tended to be elevated in T1Gd-PR of initial tumors, T1Gd-GR of recurrent tumors, and FLAIR-PR of both initial and recurrent tumors.Conclusion: T1Gd-GR after neoBev might attribute to inhibition of FOXM1 and oxygenation. Bev might provide tumor oxygenation, leading to inhibition of stemness and M2 TAM infiltration during its effectiveness. These results suggested that Bev combined with immunotherapy for newly diagnosed GBM might provide clinical benefits including inhibition of stemness and induction of immunosupportive TME, when tumor volume assessed by T1 Gd. was significantly decreased following neoBev.

Cost per Responder Analysis for Pegcetacoplan and Eculizumab in the Treatment of Adults with Paroxysmal Nocturnal Hemoglobinuria

Background: In the absence of clinical guidelines for paroxysmal nocturnal hemoglobinuria (PNH), the European Society for Blood and Marrow Transplantation (EBMT) developed categories for classifying hematological response to complement inhibitor treatment (per Risitano AM, et al. Front Immunol. 2019;10:1157). These categories are: complete (no transfusions, normal stable Hb, and no evidence of hemolysis); major (no transfusions, normal Hb, but evidence of residual intravascular/extravascular hemolysis); good (no transfusions, but persistent chronic mild anemia); partial (persistent chronic moderate anemia and/or occasional red blood cell transfusions); minor (3-6 transfusions every 6 months); no response (>6 transfusions every 6 months). In the phase 3 PEGASUS trial (NCT03500549), 41 and 39 patients previously treated with C5 inhibitors with Hb<10.5 were randomized for treatment with pegcetacoplan or eculizumab, respectively. In a post hoc analysis of the 16-week PEGASUS data, patients were classified by EBMT category to compare hematologic responses of each treatment (per Risitano AM, et al. Blood. 2020; 136(Suppl1):44-5). Objectives: The objective of this study was to evaluate the number needed to treat (NNT) and treatment costs of pegcetacoplan and eculizumab using EBMT response criteria. Methods: The analysis used a United States payer perspective and included drug acquisition costs and associated intravenous or subcutaneous administration costs. Drug costs were calculated using dosages for each treatment as given in the PEGASUS trial, including dosage and frequency escalations. Weekly dosages were multiplied by each drug's wholesale acquisition costs from RedBook (2020 United States dollars). We calculated the following outcomes over 16 weeks and by treatment: NNT to achieve each level of response, mean cost per treated patient, total costs, mean cost per treated patient per week, cost per complete responder, cost per good responder, and cost spent on patients with partial/minor/no response. Additional analyses were conducted to calculate outcomes for treatment-naïve patients treated with pegcetacoplan using similar post hoc analyses of combined 16-week data from the phase 1b-2a PADDOCK/PALOMINO (NCT02588833 and NCT03593200) trials. Results: Results are summarized in Table 1. Based on response rates, patients with PNH treated with pegcetacoplan had a lower NNT (1.4) to achieve good-to-complete response compared with eculizumab (19.5). NNT to achieve complete response was 2.6 for pegcetacoplan; no patients treated with eculizumab achieved complete response at 16 weeks. For the PEGASUS trial, mean cost per treated patient was $182,762 (with C5 inhibitor loading dose) and $176,504 over 16 weeks for pegcetacoplan and eculizumab, respectively. Among the 41 pegcetacoplan-treated patients, the total costs were $7,493,256 over 16 weeks. Of 41 pegcetacoplan patients, 16 achieved a complete response, and their total costs were $2.9 million over the 16-week period ($468,328 per complete responder). The total 16-week costs were $2.6 million for 14 patients with good response ($535,233 per good responder). For the 39 eculizumab-treated patients, total 16-week costs were $6,883,637. Two of 39 patients achieved a good response, and their total costs were $353,007 ($3,441,818 per good responder). Of the 39 patients, 37 achieved partial, minor, or no response or discontinued treatment, for a total cost of $6.5 million. This resulted in 95% of total treatment costs being spent on inadequate or no response in the eculizumab arm compared with 27% in the pegcetacoplan arm. For treatment-naïve patients treated with pegcetacoplan, the mean cost per complete responder ($347,339) and per good responder ($496,198) over 16 weeks were both lower than the cost per responder for patients treated with either pegcetacoplan or eculizumab after previous C5 inhibitor treatment. Conclusion: Based on the treatment response observed in PEGASUS, the NNT and cost to achieve good or good-to-complete response was lower for pegcetacoplan-treated patients than eculizumab-treated patients, according to EBMT consensus-based hematological response categories. PNH treatment with pegcetacoplan allowed more patients to achieve EBMT defined good-to-complete response and better overall response and is a more efficient use of spending with lower cost per responder in all response categories. Figure 1 Figure 1. Disclosures Anderson: Apellis: Consultancy, Research Funding. Talbird: Apellis: Consultancy, Research Funding. Fishman: Apellis: Current Employment, Current equity holder in publicly-traded company.

Analysis of treatment response about low-dose (0.01%) atropine eye-drops in myopic children

Introduction: Myopia usually commences during primary school and progresses until the mean age of 16 years. Topical low-dose (0.01%) atropine eye-drop appears to be safe and efficacious for myopia control in children. However, in some cases, a higher concentration of atropine is required in some cases because low-dose atropine treatment is not effective. Methods: This is a retrospective study among young myopic children between 5 and 15 years with myopia progression > 0.50 D/year. We selected patients treated with low-dose atropine (0.01%) eye-drops for 12 months and conducted a comparative analysis of the group with good responder and poor responder. Patients were classified as good responders if spherical equivalent refractive error (SE) progression was ⩽ 0.50 D after 12 months of treatment and poor responders if SE progression > 0.50 D. The prognostic factors before and after treatment were analyzed in two groups. Results: A total of 68 eyes were included. Low-dose (0.01%) atropine eye-drops have a good treatment response in 54% of patients. In the good responder group ( n = 37), the mean rate of myopia progression after 12 months of treatment (0.36 ± 0.17 D) was significantly slower compared with the baseline progression ( p < 0.001). Good responders have smaller changes in axial length (AL) elongation and SE than poor responders ( p < 0.001). The only adverse event was temporary near vision difficulty (10%), photophobia (10%), and mild pupil dilation (30%). Discussion: The AL elongation is an important indicator for monitoring the treatment response. Children with a family history of myopia at a young age may not respond well to low-dose (0.01%) atropine eye-drops. In these cases, increasing the concentration of atropine eye-drops should be considered.

Differential response to pulmonary rehabilitation in COPD: multidimensional profiling

The aim of the present study was to profile a multidimensional response to pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD).Dyspnoea, exercise performance, health status, mood status and problematic activities of daily life were assessed before and after a 40-session pulmonary rehabilitation programme in 2068 patients with COPD (mean forced expiratory volume in 1 s of 49% predicted). Patients were ordered by their overall similarity concerning their multidimensional response profile, which comprises the overall response on MRC dyspnoea grade, 6MWD, cycle endurance time, Canadian Occupational Performance Measure performance and satisfaction scores, Hospital Anxiety and Depression Scale anxiety and depression, and St George's Respiratory Questionnaire total score, using a novel non-parametric regression technique.Patients were clustered into four groups with distinct multidimensional response profiles: n=378 (18.3%; “very good responder”), n=742 (35.9%; “good responder”), n=731 (35.4%; “moderate responder”), and n=217 (10.5%; “poor responder”). Patients in the “very good responder” cluster had higher symptoms of dyspnoea, number of hospitalisations <12 months, worse exercise performance, worse performance and satisfaction scores for problematic activities of daily life, more symptoms of anxiety and depression, worse health status, and a higher proportion of patients following an inpatient PR programme compared to the other three clusters.A multidimensional response outcome needs to be considered to study the efficacy of pulmonary rehabilitation services in patients with COPD, as responses to regular outcomes are differential within patients with COPD.

Neoadjuvant Chemotherapy With Methotrexate, Cisplatin, and Doxorubicin With or Without Ifosfamide in Nonmetastatic Osteosarcoma of the Extremity: An Italian Sarcoma Group Trial ISG/OS-1

Purpose We compared two chemotherapy regimens that included methotrexate (MTX), cisplatin (CDP), and doxorubicin (ADM) with or without ifosfamide (IFO) in patients with nonmetastatic osteosarcoma of the extremity. Patients and Methods Patients age ≤ 40 years randomly received regimens with the same cumulative doses of drugs (ADM 420 mg/m2, MTX 120 g/m2, CDP 600 mg/m2, and IFO 30 g/m2) but with different durations (arm A, 44 weeks; arm B, 34 weeks). IFO was given postoperatively when pathologic response to MTX-CDP-ADM was poor (arm A) or given in the primary phase of chemotherapy with MTX-CDP-ADM (arm B). End points of the study included pathologic response to preoperative chemotherapy, toxicity, and survival. Given the feasibility of accrual, the statistical plan only permitted detection of a 15% difference in 5-year overall survival (OS). Results From April 2001 to December 2006, 246 patients were enrolled. Two hundred thirty patients (94%) underwent limb salvage surgery (arm A, 92%; arm B, 96%; P = .5). Chemotherapy-induced necrosis was good in 45% of patients (48% in arm A, 42% in arm B; P = .3). Four patients died of treatment-related toxicity (arm A, n = 1; arm B, n = 3). A significantly higher incidence of hematologic toxicity was reported in arm B. With a median follow-up of 66 months (range, 1 to 104 months), 5-year OS and event-free survival (EFS) rates were not significantly different between arm A and arm B, with OS being 73% (95% CI, 65% to 81%) in arm A and 74% (95% CI, 66% to 82%) in arm B and EFS being 64% (95% CI, 56% to 73%) in arm A and 55% (95% CI, 46% to 64%) in arm B. Conclusion IFO added to MTX, CDP, and ADM from the preoperative phase does not improve the good responder rate and increases hematologic toxicity. IFO should only be considered in patients who have a poor histologic response to MTX, CDP, and ADM.