Complete Induction Research Articles

Prolonged Arsenic Trioxide (ATO) and All- Trans Retinoic Acid (ATRA) Therapy for Relapsed Acute Promyelocytic Leukemia

▪Background.The recommended salvage treatment for patients with acute promyelocytic leukemia (APL) who relapse after front-line all-trans retinoic acid (ATRA) and chemotherapy is arsenic trioxide (ATO) combined to ATRA. However, the best consolidation strategy to be adopted after the achievement of a second remission is still a matter of debate. Currently, hematopoietic stem cell transplantation (HSCT, autologous or allogeneic) represents one of the preferred strategies but non-transplant based approaches may be taken into account in selected cases considering patient and disease-related factors. Prolonged therapy with ATRA-ATO without conventional chemotherapy was recently shown to be highly effective in front-line therapy of APL. However, only limited data is available on the efficacy of this protocol in the relapse setting. We report here on 22 APL patients treated with prolonged ATRA-ATO at the time of disease relapse.Patients and methods. Twenty-two adult patients with APL undergoing disease relapse and treated between 2006-2017 in 2 hematology units located in Rome (Policlinico Tor Vergata and Policlinico Umberto I) were included in this study. All patients received for induction and consolidation ATO-ATRA as reported elsewhere (Lo-Coco et al, NEJM 2013) followed in 2 cases by transplant procedures. For 9 patients who were included in a previous report (Breccia et al, Haematologica 2011) we provide here an updated follow-up. All 22 patients signed an informed consent prior to treatment and the study was approved from the local IRBs. Molecular and haematologic relapse was in all cases confirmed by quantitative reverse-transcript PCR (RQ-PCR) according to standardized procedures. The RQ-PCR analysis for PML/RARA monitoring was repeated after the second ATRA-ATO cycle and at the end of therapy in all cases and at 3 months intervals during follow-up.Results. The main patient characteristics, treatment response and outcome are summarized in Table 1. Median age at the time of relapse was 45.5 years (range: 20-81 years). Eighteen patients were treated in 1st relapse, 3 in 2nd relapse and 1 in 4th relapse after allogeneic HSCT. All patients received first line therapy according to AIDA protocols. Details of successive treatments for patients receiving ATRA-ATO in ≥2 relapse are reported in Table 1. Of the 22 patients receiving ATRA-ATO, 7 were treated for hematologic recurrence, 14 for molecular relapse (with concomitant extramedullary disease in 3 cases) and 1 for isolated extramedullary relapse in the form of a paravertebral mass. The median length of the CR preceding ATRA-ATO therapy was 29 months (range: 1-120); 16 patients had a CR1 ≥ 12 months. Twenty-two patients completed induction and proceeded to consolidation for a median of 5 ATRA-ATO cycles (range:2-5, see Table 1 for details). Twenty of 22 patients (91%) obtained a new molecular remission (CRm) after the 2nd ATO-ATRA cycle, while 2 patients showed molecular persistence of disease and discontinued therapy after the third consolidation course due to disease progression. One patient underwent allogeneic HSCT from an HLA-identical sibling donor and one received autologous HSCT after 3 ATRA-ATO cycles in both cases. The remaining 18 patients were treated with repeated ATRA-ATO due to physician choice (prolonged previous remission, 8 patients; age and/or unfitness for intensive chemotherapy, 5 patients), refusal of HSCT (3 patients) or lack of a suitable donor (2 patients). With a median follow-up of 58 months from the time of relapse (range: 21-128 months), 14 patients (63.6%) are alive in prolonged CRm, 2 showed progressive disease and 5 relapsed at a median of 19 months (range: 6-27). Of the relapsed/refractory patients, 4 (18%) died due to disease progression, while 3 patients (14%) were rescued with allogeneic HSCT (2 patients) or with other agents + donor lymphocytes infusion (1 patient) and are currently alive and in CRm. Overall, 17 patients are alive (77%) and 5 died of disease progression (4 patients) or unrelated causes while still in CRm (1 patient).Conclusions. Although based on a retrospective series, this study suggests a potentially curative effect of the prolonged ATRA-ATO regimen used as salvage therapy for APL patients relapsed after long CR1. Prospective studies are warranted to confirm these observations. [Display omitted] DisclosuresCicconi:TEVA: Speakers Bureau. Breccia:TEVA: Speakers Bureau. Foa:AbbVie: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Sandoz: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau. Lo Coco:TEVA: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Lundbeck: Honoraria, Speakers Bureau.

Randomized Phase II Study of R-CHOP-14 Versus R-CHOP-14 Followed By Chaser As Induction Therapy for High-Dose Chemotherapy (HDT), LEED, and Autologous Stem-Cell Transplantation (ASCT) in Poor-Risk Diffuse Large B-Cell Lymphoma (DLBCL): Japan Clinical Oncology Group (JCOG) Study (JCOG0908)

Randomized Phase II Study of R-CHOP-14 Versus R-CHOP-14 Followed By Chaser As Induction Therapy for High-Dose Chemotherapy (HDT), LEED, and Autologous Stem-Cell Transplantation (ASCT) in Poor-Risk Diffuse Large B-Cell Lymphoma (DLBCL): Japan Clinical Oncology Group (JCOG) Study (JCOG0908)

Blinatumomab Treatment in Korean Adult Patients with Relapse/Refractory Acute Lymphoblastic Leukemia

Blinatumomab is a bispecific T- cell engaging antibody construct targeting CD19 on B-cell lymphoblast and has demonstrated the efficacy for relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). In this study, we evaluated the efficacy and toxicity of blinatumomab monotherapy in Korean patients with relapse/refractory ALL. A total of 40 patients received blinatumomab monotherapy between July 2016 and July 2017 in Korea. Median time to blinatumomab treatment from initial diagnosis was 13.6 months (range 1.3 - 104.7). Twenty-four patients completed induction therapy (2 cycles of blinatumomab), 15 ended in cycle 1 due to disease progression or toxicity, and 1 died in 1 cycle due to infection. Among 39 evaluable patients, 17 patients (42.5%) achieved complete response (CR) or CR with incomplete blood count recovery, and 10 responders underwent subsequent allogenic stem cell transplantation. Nine patients had extramedullary disease at relapse and 3 (33.3%) achieved CR. Median progression free survival (PFS) and overall survival (OS) were 2.8 months and 5.7 months, respectively. Patients responded to blinatumomab had significantly better PFS and OS compare to those who did not. In multivariate analysis, patients with 50% or more of bone marrow blast at relapse and relapse within 12 months after initial diagnosis were significantly associated with poor response to blinatumomab. The most common non-hematologic toxicity was neurologic toxicity. Thirteen patients (32.5%) had neurologic events and severe neurologic events (grade 3-4) occurred in two patients in 2nd cycle of blinatumomab. Severe cytokine release syndrome (grade 3) occurred in 2 patients (5.0%) despite pretreatment with dexamethasone. In conclusion, blinatumomab monotherapy was effective and tolerable in Korean adult patients with relapse/refractory ALL. DisclosuresNo relevant conflicts of interest to declare.

Enolase 2-Mediated Glucose Metabolism Promotes Cell Proliferation and Survival in Acute Lymphoblastic Leukemia

Background: The metabolic profiles of cancer cells have long been acknowledged to be altered and to provide new therapeutic opportunities. Expression of glycolytic enzyme enolase 2(ENO2) was found to be closely related with clinical features of acute lymphoblastic leukemia (ALL) patients, but its functions are still unclear in ALL.Methods: We evaluated the association between ENO2 mRNA expression of bone marrow mononuclear cells(BM-MCs) and efficacy of chemotherapy, and further explored the function of ENO2 in ALL.Results: The results showed that ENO2 mRNA expression in BM-MCs was significantly decreased when patients completed induction chemotherapy and reached complete remission(CR). ENO2 mRNA expression was increased when patients suffered relapse. Functional study demonstrated that ENO2 promoted cell growth, glycolysis, and glucocorticoid-resistance, all of which were effectively inhibited when ENO2 was silenced with shRNAs. Further study found that ENO2 upregulated various glycolysis-related genes, and ENO2 enhanced Akt activity with subsequent Glycogen synthase kinase3β(GSK-3β) phosphorylation, inducing cell proliferation and glycolysis. The combination of silencing ENO2 and 2-deoxyglucose (2-DG) synergistically inhibited leukemia cell survival.Conclusion: These results indicate that ENO2 may be a biological marker for monitoring chemotherapeutic efficacy and relapse in ALL. ENO2 may provide a potential therapeutic strategy for ALL. DisclosuresNo relevant conflicts of interest to declare.

Long-Term Follow-up of a Prospective Clinical Trial of Carfilzomib, Rituximab and Dexamethasone (CaRD) in Waldenstrom's Macroglobulinemia

The proteasome-inhibitor bortezomib is active in Waldenstrom's macroglobulinemia (WM) though is associated with considerable peripheral neuropathy (PN) that results in frequent dose reduction and treatment discontinuation. We therefore examined the efficacy and safety of carfilzomib, a neuropathy-sparing proteasome-inhibitor, along with rituximab, and dexamethasone (CaRD) in 31 proteasome inhibitor-naive and rituximab-naive symptomatic WM patients. The preliminary findings of this study were previously published (Treon et al, Blood 2014), and herein we provide a long-term update of this study. The median baseline characteristics for patients enrolled on this prospective clinical trial were as follows: Age 61 (range 47-75 years), prior therapies 0 (range 0-1), hematocrit 32.3%, serum IgM 3,375 mg/dL, serum B2M 3.6 mg/L, and bone marrow disease involvement 60%. Therapy consisted of IV carfilzomib 20mg/m2 (cycle 1) and 36mg/m2 (cycles 2 and beyond) along with IV dexamethasone 20 mg on days 1, 2, 8, 9. Rituximab 375 mg/m2 was administered on days 2, 9 of each 21-day cycle. Treatment consisted of six 21-day induction cycles, followed by maintenance therapy that was given every 8 weeks for eight cycles and consisted of carfilzomib 36 mg/m2 and IV dexamethasone 20 mg on days 1, 2. Rituximab was given at 375 mg/m2 on day 2 of each maintenance cycle. Following protocol therapy, the median serum IgM levels declined to 561 mg/dL at best response (p<0.00001). Median hematocrit rose to 41.9% (p<0.00001). Thirty patients completed induction therapy, with reduction in bone marrow tumor burden from a median of 60% to 7.5% at end of induction (p<0.0001). Twenty patients completed maintenance therapy and had a bone marrow tumor burden reduction to 2.5% at end of maintenance treatment (p<0.0001 versus pre-treatment baseline; p=0.0088 versus end of induction). The best overall response was 80.64% (1 CR, 11 VGPR, 10 PR, 3 MR), and major response rate was 71%. Median time to response (MR or better) was 2.1 months. As shown in Figure 1A, the median progression-free survival (PFS) for all patients was reached at 46 months (range 2-63 months). PFS was associated with depth of response. Patients who achieved at least a VGPR have not reached median PFS, whereas the median PFS was 52 months for those who attained a PR, and 4 months for those with less than a PR (Figure 1B; Chi-square 35.5, p<0.0001). All patients are alive, and 14 patients remain in follow-up without a progression event.Grade >2 treatment-related toxicities included elevated lipase (12.9%), steroid-related hyperglycemia (6.45%), neutropenia (9.67%), and reversible cardiomyopathy in a patient with multiple risk factors (3.22%). Only one grade 2 PN (3.2%), and no grade 3/4 PN events occurred. At baseline, the median serum IgA level was 47 mg/dL, versus 46 mg/dL at last follow-up (p=0.11). Conversely, median serum IgG levels declined from 715 mg/dL at baseline to 372 mg/dL at last follow-up (p=0.0004). Treatment related IgG hypogammaglobulinemia was associated with recurring sino-bronchial infections, and necessitated IVIG treatment in 6 (19.4%) patients. Discontinuation of protocol therapy occurred for non-response (n=8), hypogammaglobulinemia associated with infections (n=2), grade 2 PN (n=1), cardiomyopathy (n=1), progressive disease (n=1), and prolonged hold of protocol therapy for an unrelated procedure (n=1). The long-term results of this study show that CaRD is an active, PN-sparing regimen that is associated with durable responses in symptomatic patients with WM. PFS is impacted by depth of response, and IgG hypogammaglobulinemia is commonly encountered with this regimen. [Display omitted] DisclosuresCastillo:Pharmacyclics: Consultancy, Research Funding; Millennium: Research Funding; Abbvie: Research Funding; Janssen: Consultancy, Research Funding. Treon:Pharmacyclics: Consultancy, Research Funding.

Efficacy of anti-vascular endothelial growth factor agents for treating neovascular age-related macular degeneration in vitrectomized eyes.

To evaluate the efficacy of intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents for treatment of neovascular age-related macular degeneration (nAMD) in vitrectomized eyes. The medical records were reviewed of nAMD patients treated with anti-VEGF agents who previously underwent pars plana vitrectomy (PPV). PPV was performed with complete posterior vitreous detachment induction. A total of 44 eyes from 44 patients were included. The mean central foveal thickness (CFT) was 478.50 ± 156.93 μm at baseline, 414.25 ± 143.55 μm (86.6% of baseline) at 1 month after first injection (P < 0.001), and 386.75 ± 141.45 μm (80.8% of baseline) after monthly multiple injections (2.30 ± 1.07; range, 1-5) (P < 0.001). The mean logarithm of the minimum angle of resolution best-corrected visual acuity visual acuity (BCVA) was 0.85 ± 0.57 at baseline, 0.86 ± 0.63 after the first injection, and 0.84 ± 0.64 after monthly multiple injections. BCVA improved in 39.5% at 1 month after first injection and 45.2% at 1 month after monthly multiple injections. In the subgroup analysis, CFT of eyes with the posterior capsule decreased significantly to 85.8% and 79.8% of baseline values at 1 month after the first injection and after monthly multiple injections, respectively. CFT of eyes without the posterior capsule decreased to 91.6% and 87.4% of baseline values at 1 month after the first injection and after monthly multiple injections, respectively, without statistical significance. Monthly injections of Intravitreal anti-VEGF agents induced favorable anatomical improvement and vision maintenance in vitrectomized eyes with nAMD.

Rifampicin Induces Gene, Protein, and Activity of P-Glycoprotein (ABCB1) in Human Precision-Cut Intestinal Slices.

P-glycoprotein (ABCB1), an ATP-binding cassette efflux transporter, limits intestinal absorption of its substrates and is a common site of drug–drug interactions. Drug-mediated induction of intestinal ABCB1 is a clinically relevant phenomenon associated with significantly decreased drug bioavailability. Currently, there are no well-established human models for evaluating its induction, so drug regulatory authorities provide no recommendations for in vitro/ex vivo testing drugs’ ABCB1-inducing activity. Human precision-cut intestinal slices (hPCISs) contain cells in their natural environment and express physiological levels of nuclear factors required for ABCB1 induction. We found that hPCISs incubated in William’s Medium E for 48 h maintained intact morphology, ATP content, and ABCB1 efflux activity. Here, we asked whether rifampicin (a model ligand of pregnane X receptor, PXR), at 30 μM, induces functional expression of ABCB1 in hPCISs over 24- and 48-h incubation (the time to allow complete induction to occur). Rifampicin significantly increased gene expression, protein levels, and efflux activity of ABCB1. Moreover, we described dynamic changes in ABCB1 transcript levels in hPCISs over 48 h incubation. We also observed that peaks of induction are achieved among donors at different times, and the extent of ABCB1 gene induction is proportional to PXR mRNA levels in the intestine. In conclusion, we showed that hPCISs incubated in conditions comparable to those used for inhibition studies can be used to evaluate drugs’ ABCB1-inducing potency in the human intestine. Thus, hPCISs may be valuable experimental tools that can be prospectively used in complex experimental evaluation of drug–drug interactions.

Flush Intensity of Mango (Mangifera indica L. c.v. Carabao mango) Leaves as Affected by Different Flush Induction Protocol

The study was carried out to validate the effect of different flush induction protocol on carabao mango which was conducted in Alion, Mariveles, Bataan, Philippines with the following treatments: no intervention (T1), pruning only (T2), pruning with urea applied in soil (T3), pruning with urea spray (T4), pruning with irrigation (T5), and complete flush induction protocol (T6). Results revealed that providing water hasten the flush induction of mango. The complete flush induction protocol (T6) significantly had the highest flushing percentage and the longest flushing duration. In terms of leaf produced per flush, pruning alone (T2) and pruning with urea spray (T4) equally produced the highest number of leaves per flush having 16 leaves. On the other hand, different flush induction protocols have no direct effect on flush and stem length, stem diameter, flush dry weight, and in the amount of nutrients in the flushes except for total amount of iron.

Retrospective cohort of total neoadjuvant therapy (TNT) in high-risk locally advanced rectal cancer (HR-LARC): Additional sintilimab (PD-1) in tri-modality approach.

e15604 Background: TNT is an emerging practice adapted to ensure all patients (pts) receive of systemic therapy, particularly for pts with high risk recurrence. Our previous phase II trial of TNT in MRI stratified HR-LARC demonstrated high down-staging rate and improved complete response with acceptable toxicity (manuscript under review). The aim of this retrospective cohort study was to evaluate the feasibility of sintilimab in combination with chemotherapy in TNT tri-modality treatment of pts with HR-LARC. Methods: HR-LARC pts who were given 3 cycles of sintilimab (200mg, iv, q3w) in combination with CapeOx followed by sequential long-course radiotherapy (IMRT GTV50.6 Gy/CTV 41.8 Gy/22f), 2 cycles CapeOx and surgery were enrolled from Beijing Cancer Hospital, CHN. The high risk was defined as middle to low RC (≤8cm to ARJ or 12 cm per sigmoidoscopy) with ≥1 factor from MRI features: clinical stage T3c/d-T4a/b, or N2 or MRF (+) or EMVI (+). The clinical outcomes included pathological response, major response rate (cCR+MPR), R0 resection rate, and toxicity. Results: From Feb 2019 to Oct 2020, 19 cases were identified with median distal location 4 cm (3-7), T2/T3/T4 1/15/3, N1/N2a/N2b 7/4/8, MRF+ 8/11, EMVI+ 8/11. Other characteristics were pMMR/MSS 100%, age 67y (47-78), male 57.9%, PS 1 100%, c-stage III 100% (18), median diameter of primary lesion 5.1 cm (2.1-7.5). As of 30th Dec 2020, 84.2% (16/19) received neoadjuvant therapy and completed surgical resection, with R0 resection rate 100%. One pts denied surgery and two chose watch &amp; wait since achieving cCR 10.5% (2/19). Of 16 resection pts, 13 had sphincter-sparing surgery (LAR or TaTME). One had Hartmann procedure, and two had abdominal perineal resection. The sphincter preservation rate was 84.2% (16/19). The pCR was 26.3% (5/19), and MPR was 47.3% (9/13). The major response rate was 57.9% (11/19), 4/2/13 of which completed intact TNT schema, induction and RT, and induction phase only, respectively. Treatment related adverse events (TRAE) occurred in 6 pts (31.6%) in grade (gr) 1-2 (CTCAE 5.0) without any gr 3-5 events occurred. Immune-related AEs were found in 2 pts with hypothyroidism (gr 1,2). Postoperative complications included two gr2 (Clavien-Dindo) events of anastomtic bleeding and infection. Of note, 3 pts with anastomotic stenosis got stoma reversion after dilation. Conclusions: Given the impressive response rate (57.9%), this retrospective analysis suggested a potential enhanced anti-cancer activity and good tolerability in pMMR/MSS HR-LARC from sintilimab in combination with TNT. The encouraging results warrant further evaluation of this approach in prospective trial.

Wilms Tumor 1 Mutations Are Independent Poor Prognostic Factors in Pediatric Acute Myeloid Leukemia.

The prognostic impact of Wilms tumor 1 (WT1) mutations remains controversial for patients with acute myeloid leukemia (AML). Here, we aimed to determine the clinical implication of WT1 mutations in a large cohort of pediatric AML. The clinical data of 870 pediatric patients with AML were downloaded from the therapeutically applicable research to generate effective treatment (TARGET) dataset. We analyzed the prevalence, clinical profile, and prognosis of AML patients with WT1 mutations in this cohort. Our results showed that 6.7% of total patients harbored WT1 mutations. These WT1 mutations were closely associated with normal cytogenetics (P<0.001), FMS-like tyrosine kinase 3/internal tandem duplication (FLT3/ITD) mutations (P<0.001), and low complete remission induction rates (P<0.01). Compared to the patients without WT1 mutations, patients with WT1 mutations had a worse 5-year event-free survival (21.7 ± 5.5% vs 48.9 ± 1.8%, P<0.001) and a worse overall survival (41.4 ± 6.6% vs 64.3 ± 1.7%, P<0.001). Moreover, patients with both WT1 and FLT3/ITD mutations had a dismal prognosis. Compared to chemotherapy alone, hematopoietic stem cell transplantation tended to improve the prognoses of WT1-mutated patients. Multivariate analysis demonstrated that WT1 mutations conferred an independent adverse impact on event-free survival (hazard ratio 1.910, P = 0.001) and overall survival (hazard ratio 1.709, P = 0.020). In conclusion, our findings have demonstrated that WT1 mutations are independent poor prognostic factors in pediatric AML.

Protective role of intravesical BCG in COVID-19 severity

ObjectivesTo establish the role of BCG instillations in the incidence and mortality of COVID-19.Patients and methodsNMIBC patients in instillations with BCG (induction or maintenance) during 2019/2020 were included, establishing a COVID-19 group (with a diagnosis according to the national registry) and a control group (NO-COVID). The cumulative incidence (cases/total patients) and the case fatality rate (deaths/cases) were established, and compared with the national statistics for the same age group. T-test was used for continuous variables and Fisher's exact test for categorical variables.Results175 patients were included. Eleven patients presented CIS (11/175, 6.3%), 84/175 (48.0%) Ta and 68/175 (38.9%) T1. Average number of instillations = 13.25 ± 7.4. One hundred sixty-seven patients (95.4%) had complete induction. Forty-three patients (cumulative incidence 24.6%) were diagnosed with COVID-19. There is no difference between COVID-19 and NO-COVID group in age, gender or proportion of maintenance completed. COVID-19 group fatality rate = 1/43 (2.3%). Accumulated Chilean incidence 70–79 years = 6.3%. Chilean fatality rate 70–79 years = 14%.ConclusionsAccording to our results, patients with NMIBC submitted to instillations with BCG have a lower case-fatality rate than the national registry of patients between 70 and 79 years (2.3% vs. 14%, respectively). Intravesical BCG could decrease the mortality due to COVID-19, so instillation schemes should not be suspended in a pandemic.

Children's Pain During IV Induction: A Randomized-Controlled Trial With the MEDi® Robot.

This study examined the impact of a humanoid robot (MEDi®) programmed to teach deep breathing as a coping strategy, on children's pain and fear as primary and secondary outcomes, respectively, during intravenous (IV) line placement. The completion of IV induction was also examined as an exploratory outcome. In this randomized controlled, two-armed trial, 137 children (4-12 years) were recruited in Short Stay Surgery at a tertiary pediatric hospital. Patients were randomly assigned to standard care (SC) with Ametop© only (N = 60) or SC and robot-facilitated intervention (N = 59) before induction. Pain and fear before, during, and after IV insertion were rated by patients and observers. No significant differences were found between groups and there were no changes over time for pain or fear (ps > .05). Exploratory analyses show that patients in the MEDi® group were 5.04 times more likely to complete IV induction, compared to SC, Fisher's exact test: X2 (1) = 4.85, p = .04, φc = 0.22, odds ratio = 5.04, 95% CI [1.06, 24.00]. This study was the first to examine children's IV induction experience when provided MEDi® support. Reasons for nonsignificance, limitations, and research suggestions were made.

Nonlinear Modeling of a C-Core Connected Two-Phase Switched Reluctance Motor

The main idea of this paper is to offer a continuous C-cores unique configuration for switched reluctance motor (SRM) and to present an analytical model for its analysis. The advantages of this structure are having a short path for the main part of the magnetic flux, resulting in less core losses and as well as less negative torque. On the other hand, there is less leakage flux in the proposed structure. Another advantage of this structure is that it has a high mean torque compared to conventional structures, so that this increase in mean torque also increases a small amount of torque ripple, which is negligible. However, power density at a constant volume increases relatively much. The proposed SRM is analyzed by the finite element method (FEM) and by employing a magnetic flux density pattern and magnetic fluxes path, its magnetic equivalent circuit (MEC) is obtained. In this MEC model, the main fluxes and leakage fluxes are fully modeled. After its complete analysis, electromagnetics torque, inductance, flux-linkage, mean torque, and peak torque are evaluated. Static and dynamic performances are then determined. Finally, the proposed SRM was prototyped and tested. The experimental results consisting of static torque, flux-linkage, voltage, and current waveforms and input power are compared with the corresponding results in the MEC model and FEM. The comparisons verify the accuracy and validity of the introduced analytical model. Besides, static torque, flux-linkage characteristics, and dynamic performance at a nominal speed of 1000 rpm and the current chopping control mode with chopping 5A under the load of the proposed SRM are compared with the conventional SRM and its merits are observed.

Partial Versus Complete Bacillus Calmette-Guérin Intravesical Therapy and Bladder Cancer Outcomes in High-risk Non–muscle-invasive Bladder Cancer: Is NIMBUS the Full Story?

BackgroundIt is important to understand the implications of reduced bacillus Calmette-Guérin (BCG) treatment intensity, given global shortages and early termination of the NIMBUS trial. ObjectiveTo assess the association of partial versus complete BCG induction with outcomes. Design, setting, and participantsThis is a retrospective cohort study of veterans diagnosed with high-risk non–muscle-invasive bladder cancer (NMIBC; high grade [HG] Ta, T1, or carcinoma in situ) between 2005 and 2011 with follow-up through 2014. InterventionPatients were categorized into partial versus complete BCG induction (one to five vs five or more instillations). Partial BCG induction subgroups were defined for comparison with the NIMBUS trial. Outcome measurements and statistical analysisPropensity score–adjusted regression models were used to assess the association of partial BCG induction with risk of recurrence and bladder cancer death. Results and limitationsAmong 540 patients, 114 (21.1%) underwent partial BCG induction. Partial versus complete BCG induction was not significantly associated with the risk of recurrence in HG Ta (cumulative incidence [CIn] 46.6% vs 53.9% at 5 yr, p = 0.38) or T1 (CIn 47.1% vs 56.7 at 5 yr, p = 0.19) disease. Similarly, we found no increased risk of bladder cancer death (HG Ta: CIn 4.7%7vs 5.4% at 5 yr, p = 0.87; T1: CIn 10.0% vs 11.4% at 5 yr, p = 0.77). NIMBUS-like induction was associated with an increased risk of recurrence in patients with HG Ta disease, although not statistically significant. Unmeasured confounding is a limitation. ConclusionsCancer outcomes were similar among high-risk NMIBC patients who underwent partial versus complete BCG induction, suggesting that future research is needed to determine how to optimize BCG delivery for the greatest number of patients, especially during global shortages. Patient summaryOutcomes were similar between patients receiving partial and complete courses of bacillus Calmette-Guérin (BCG) therapy. Future research is needed to determine how to best deliver BCG to the greatest number of patients, particularly during medication shortages.

Implications of uncertainty for optimal policies

We study the implications of ambiguity for optimal fiscal policy in macro public finance environments with heterogeneous agents and private idiosyncratic shocks. We describe conditions under which ambiguity implies that it is optimal to periodically reform policies. Periodic reforms lead to simplified optimal policies that are not fully contingent on future shocks; at times they also lose dependence on the full history of past shocks. These simplified policies can be characterized without complete backward induction when the time horizon is finite. However, linear policies can be far from optimal. We also show that equilibria in decentralized versions of these economies are not generally efficient, implying a meaningful role for government provision of insurance, unlike in conventional environments with a narrower view of uncertainty.

Pénurie en souche de BCG entre 2012 et 2014 : évaluation de son impact sur la prise en charge des patients présentant une TVNIM de haut risque

BCG instillations are the gold-standard treatment for high-risk non-muscle-invasive bladder cancer (NMIBC) with a decreased risk of tumor recurrence and muscle infiltration. From 2012 to 2014, a stock shortage of the Connaught strain has led to the cessation of supply for immucyst in France. The objective of this study was to evaluate the potential impact of BCG shortage on the management of patients with NMIBC. We conducted a retrospective single-center study including patients followed from May 2005 to May 2015 with a high-risk NMIBC (primo-diagnosis). Patients were separated into two groups: not impacted by the shortage (NISG: 56 patients) and impacted by the shortage (ISG: 53 patients). Data on tumour recurrence (RFS), muscle progression (PFS) and overall and specific survival (OS and SS) were also analysed. The BCG induction schedule could not be carried out in 20.8% of cases in the ISG compared to only 5.3% of cases in NISG (P=0.02). Similarly, the maintenance treatment was incomplete for 56.6% of cases versus 37.5% in NISG (P=0.047). Nevertheless, it should be underlined that very high-risk NMIBC received a complete induction BCG schedule. The ISG seems to have benefited with the evolution of the guidelines with the use of diagnosis bladder fluorescence but without significant difference on the rate of second look bladder trans-uretral resection. The cystectomy rate was higher in ISG. No significant difference in RFS, PFS, OS, and SS between the two groups. In our experience, RFS, PFS, OS or SS were not impacted by the BCG shortage. These data may be explained by a better selection of very high-risk patients including the recommended BCG schedule and more frequently the use of diagnosis bladder fluorescence. 3.

The association of salvage intravesical therapy following BCG with pathologic outcomes and survival after radical cystectomy for patients with high-grade non-muscle invasive bladder cancer: A multi-institution analysis

IntroductionWhile numerous current clinical trials are testing novel salvage therapies (ST) for patients with recurrent nonmuscle invasive bladder cancer (NMIBC) after bacillus Calmette-Guérin (BCG), the natural history of this disease state has been poorly defined to date. Herein, we evaluated oncologic outcomes in patients previously treated with BCG and ST who subsequently underwent radical cystectomy (RC). MethodsWe identified 378 patients with high-grade NMIBC who received at least one complete induction course of BCG (n = 378) with (n = 62) or without (n = 316) additional ST and who then underwent RC between 2000 and 2018. Oncologic outcomes were compared using the Kaplan-Meier method and Cox proportional hazards models. Sensitivity analyses were conducted stratifying by presenting tumor stage, matched 1:3 for receipt vs. no receipt of ST. ResultsPatients receiving ST were more likely to initially present with CIS (26% vs. 17%) and less likely with T1 disease (34% vs. 50%, P = 0.06) compared to patients not treated with ST. Receipt of ST was not associated with increased risk of adverse pathology (≥pT2 or pN+) at RC (31% vs. 41%, P = 0.14). Likewise, 5-year cancer-specific survival did not significantly differ between groups on univariable Kaplan-Meier analysis (73% for ST and 74% for no ST, P = 0.7). Moreover, on multivariable analysis, receipt of ST was not significantly associated the risk of death from bladder cancer (HR 1.12; 95% CI 0.60–2.09, P = 0.7). Results were unchanged on sensitivity analysis. ConclusionsThese data suggest that, in carefully selected patients, ST following BCG for high grade NMIBC does not compromise oncologic outcomes for patients who ultimately undergo RC.

Resection rate of locally advanced pancreatic cancer in gemcitabine plus nab-paclitaxel versus FOLFIRINOX.

381 Background: There is no established treatment for locally advanced pancreatic cancer (LAPC), but by utilizing the regimens approved for metastatic pancreatic cancer, hope remains for rendering tumors resectable with chemotherapy. In this context, we looked at the resection rate in patients receiving gemcitabine plus nab-paclitaxel (Gem-Nab) in a prospective trial of patients with LAPC. Methods: TIGeR-PaC is an ongoing phase III clinical trial, studying the role of intra-arterial Gemcitabine (IA-Gem) in LAPC. The trial is designed with an induction phase where patients receive 3 cycles of Gem-Nab and a cycle of radiation after which they are randomized to IA-Gem or continuing with 4 cycles of Gem-Nab. We studied the resection rate in patients receiving Gem-Nab during induction who had subsequently continued receiving Gem-Nab post-randomization. Results: As of July 2020, 80 patients have been enrolled in the study. From this report, 30 patients were excluded because they had not completed induction and/or active treatment or were randomized to IA-Gem at the time of analysis. From the remaining 50 patients, 5 underwent resection for an overall resection rate of 10%. The median age for the total cohort was 67 years (range 47-83). Most of the resections were performed on the younger cohort of patients under 65 years (median age 60, range 47-65) in whom the resection rate was 4 out of 22 (18.2%). Conclusions: In the younger cohort of patients, TIGeR-PaC results are in line with the 15% resection rate in the LAPACT trial of patients with median age of 65 years, as reported by Phillip et al., 2020. In the TIGeR-PaC study the resection rate for LAPC treated with Gem-Nab was 10% overall, and 18.2% for younger patient population. These resection rates are comparable to the other reports for Gem-Nab and are similar to retrospective reports for the younger patients undergoing resection after treatment with FOLFIRINOX. Clinical trial information: NCT03257033.

Post-release immune responses of Tasmanian devils vaccinated with an experimental devil facial tumour disease vaccine

Abstract Context Disease is increasingly becoming a driver of wildlife population declines and an extinction risk. Vaccines are one of the most successful health interventions in human history, but few have been tested for mitigating wildlife disease. The transmissible cancer, devil facial tumour disease (DFTD), triggered the Tasmanian devil’s (Sarcophilus harrisii) inclusion on the international endangered species list. In 2016, 33 devils from a DFTD-free insurance population were given an experimental DFTD vaccination before their wild release on the Tasmanian northern coast. Aim To determine the efficacy of the vaccination protocol and the longevity of the induced responses. Method Six trapping trips took place over the 2.5 years following release, and both vaccinated and incumbent devils had blood samples and tumour biopsies collected. Key results In all, 8 of the 33 vaccinated devils were re-trapped, and six of those developed DFTD within the monitoring period. Despite the lack of protection provided by the vaccine, we observed signs of immune activation not usually found in unvaccinated devils. First, sera collected from the eight devils showed that anti-DFTD antibodies persisted for up to 2 years post-vaccination. Second, tumour-infiltrating lymphocytes were found in three of four biopsies collected from vaccinated devils, which contrasts with the ‘immune deserts’ typical of DFTs; only 1 of the 20 incumbent devils with DFTD had a tumour biopsy exhibiting immune-cell infiltrate. Third, immunohistochemical analysis of the vaccinated devils’ tumour biopsies identified the functional immune molecules associated with antigen-presenting cells (MHC-II) and T-cells (CD3), and the immune checkpoint molecule PD-1, all being associated with anti-tumour immunity in other species. Conclusions These results correlate with our previous study on captive devils in which a prophylactic vaccine primed the devil immune system and, following DFTD challenge and tumour growth, immunotherapy induced complete tumour regressions. The field trial results presented here provide further evidence that the devil immune system can be primed to recognise DFTD cells, but additional immune manipulation could be needed for complete protection or induction of tumour regressions. Implications A protective DFTD vaccine would provide a valuable management approach for conservation of the Tasmanian devil.

Poor Outcome of Pediatric Patients with Acute Myeloid Leukemia Harbour High FLT3/ITD Allelic Ratios

Purpose: To evaluate the outcome and prognostic significance of FLT3/ITD allelic ratios (AR) among pediatric acute myeloid leukemia (AML) from TARGET dataset. Methods: A total of 1,857 pediatric patients who were diagnosed with AML were enrolled in this study by using a retrospective cohort study method from September 1996 to December 2016. Results: The prevalence of FLT3/ITD mutation in the whole cohort was 18.4%. Generalized additive models and threshold effect analysis using piece-wise linear regression were applied to identify the cut-off value of 0.5 on FLT3/ITD AR. High FLT3/ITD AR were significantly associated with higher WBC ( P <0.001), higher proportion of peripheral blood blast and bone marrow blast (both of P <0.001), high risk group ( P <0.001), more common to have FAB M1 ( P <0.001) and lower complete remission induction rates ( P =0.048). Overall, high FLT3/ITD AR patients had a significantly inferior 5-year EFS ( P =0.036) and OS ( P =0.04) compared to low AR patients. Stem cell transplantation (SCT) had no significant impact on the survival of patients with low FLT3/ITD AR patients, while SCT may improve the outcome patients with high AR. Multivariate analysis further confirmed that high FLT3/ITD AR were an independent adverse indicators of inferior outcome in terms of EFS ( P =0.017) and OS ( P =0.032). Conclusions: The current study demonstrates that high FLT3/ITD AR, but not the presence of FLT3/ITD, are independent poor prognostic factors in pediatric AML. Furthermore, the optimal cut-off value for FLT3/ITD AR is 0.5, which could serve as an useful marker for risk-stratified therapy and prognostic evaluation. Funding Statement: This work was supported by the Guangdong Basic and Applied Basic Research Foundation (NO.2021A1515011809), Guangzhou Science and Technology Program key projects (No.201803010032), and Bethune Medical Scientific Research Fund Project (No.SCE111DS). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The study protocol and informed consent were approved by the Ethics Committee of COG.