High Treatment Failure Research Articles

Efficacy and Safety of Intraoperative Radiotherapy for High-Grade Gliomas: A Systematic Review and Meta-Analysis.

High-grade gliomas (HGGs) are aggressive tumors of the central nervous system that cause significant morbidity and mortality. Despite advances in surgery and radiation therapy (RT), HGG still has a high incidence of recurrence and treatment failure. Intraoperative radiotherapy (IORT) has emerged as a promising therapeutic approach to achieve local tumor control while sparing normal brain tissue from radiation-induced damage. A systematic review and meta-analysis were conducted following PRISMA guidelines to evaluate the use of IORT for HGG. Eligible studies were included based on specific criteria, and data were independently extracted. Outcomes of interest included complications, IORT failure, survival rates at 12 and 24months, and mortality. Sixteen studies comprising 436 patients were included. The overall complication rate after IORT was 17%, with significant heterogeneity observed. The IORT failure rate was 77%, while the survival rates at 12 and 24months were 74% and 24%, respectively. The mortality rate was 62%. This meta-analysis suggests that IORT may be a promising adjuvant treatment for selected patients with HGG. Despite the high rate of complications and treatment failures, the survival outcomes were comparable or even superior to conventional methods. However, the limitations of the study, such as the lack of a control group and small sample sizes, warrant further investigation through prospective randomized controlled trials to better understand the specific patient populations that may benefit most from IORT. However, the limitations of the study, such as the lack of a control group and small sample sizes, warrant further investigation. Notably, the ongoingRP3 trial (NCT02685605) is currently underway, with the aim of providing a more comprehensive understanding of IORT. Moreover, future research should focus on managing complications associated with IORT to improve its safety and efficacy in treating HGG.

Debridement, Antibiotics, and Implant Retention (DAIR) Plus Offers Similar Periprosthetic Joint Infection Treatment Success Rates to Two-Stage Revision in Oncologic Megaprosthesis

BackgroundProsthetic joint infections (PJIs) after megaprosthesis implantation are associated with high rates of treatment failure and amputation. Our study analyzed PJI treatment success rates by surgical strategy and assessed risks of reinfection and amputation. MethodsWe retrospectively analyzed the outcomes of patients diagnosed with PJI after undergoing megaprosthesis implantation for oncologic indications. The 2011 Musculoskeletal Infection Society criteria were used to define PJI. Reinfection, reoperation, and amputation for PJI recurrence were assessed. A total of 67 patients with megaprosthesis PJIs were included. There were fourteen patients who were treated with debridement, antibiotics, and implant retention (DAIR), 31 with DAIR plus (DAIR with modular component exchange and stem retention), and 21 with two-stage revisions. Kaplan-Meier estimates were used for survival analyses and Cox proportional hazards for risk factor analyses. ResultsThe two-year reinfection-free survival was 25% for DAIR and 60% for DAIR plus or two-stage revision (P = .049). The five-year amputation-free survival was 84% for DAIR plus or two-stage revision, and 48% for DAIR (P = .13). Reinfection-free, reoperation-free, and amputation-free survival were similar between DAIR plus and two-stage revision at the 2- and 5-year marks. Body mass index ≥30 (hazard ratio [HR] = 2.65) and chronic kidney disease (HR = 11.53) were risk factors for reinfection. Treatment with DAIR plus or two-stage revision (HR = 0.44) was a protective factor against reinfection. ConclusionsA DAIR was associated with high rates of treatment failure and higher amputation rates than DAIR plus or 2-stage surgery. A DAIR plus was not inferior to 2-stage revision clearing a PJI and might be performed in patients who cannot withstand two-stage revision surgery.

Revolutionizing the treatment for nasopharyngeal cancer: the impact, challenges and strategies of stem cell and genetically engineered cell therapies.

Nasopharyngeal carcinoma (NPC) is a distinct malignancy of the nasopharynx and is consistently associated with the Epstein-Barr virus (EBV) infection. Its unique anatomical location and complex aetiology often result in advanced-stage disease at first diagnosis. While radiotherapy (RT) and chemotherapy have been the mainstays of treatment, they often fail to prevent tumour recurrence and metastasis, leading to high rates of treatment failure and mortality. Recent advancement in cell-based therapies, such as chimeric antigen receptor (CAR)-T cell therapy, have shown great promise in hematological malignancies and are now being investigated for NPC. However, challenges such as targeting specific tumour antigens, limited T cell persistence and proliferation, and managing treatment-related toxicities must be addressed. Extensive research is needed to enhance the effectiveness and safety of these therapies, paving the way for their integration into standard clinical practice for better management of NPC and a better quality of life for human health.

In vitro efficacy of different concentrations of lupeol on old world Leishmania donovani.

Leishmaniosis is a tropical neglected parasitic disease that is endemic in many countries, including Middle East, with no existing effective vaccines. The bite of female sand-fly transmits the causative agent, Leishmania spp., to humans. High toxicity, resistance and treatment failure of the available chemotherapy against visceral leishmaniosis demands the investigation of new anti-leishmanial compounds. Lupeol is a form of triterpene isolated from several medicinal plants and possesses an antimicrobial property. In this study, cytotoxic effect of lupeol was screened against the mammalian amastigotes form and insect promastigote form of Leishmania donovani, following three cycles of incubation at different concentrations by MTT assay. Results revealed the in vitro anti-leishmanial effect of lupeol on both forms of the parasite where significant decline in promastigotes and amastigotes growth was observed. This was conducted along three times of follow up (24, 48, 72) hours, in comparison to the classical sodium stibogluconate treatment. Cell viability was calculated and the minimum IC50 was detected after 48 hours for amastigotes and 24 hours for promastigotes, 12.125 μM, 102.78 μM, respectively. Given the severity of visceral leishmaniosis and the toxicity of conventional chemotherapies, the anti-leishmanial activity of lupeol suggested a promising compound for additional clinical trials.

Screening Candida auris through a multiplex stepwise PCR algorithm directly from clinical samples of patients suspected of otomycosis in south of Iran; Detection of five cases.

Otomycosis is an infection of the external auditory canal caused by molds and yeasts with descending frequency. Laboratory diagnosis is usually confirmed by microscopy and culture. However, they are not specific enough to reliably differentiate the causative agents, especially for rare pathogens such as Candida auris. The purpose of the current study was to the molecular screening of C. auris species from direct clinical samples of patients with suspected otomycosis in Southern of Iran. A total of 221 ear aspirates collected from 221 patients with suspected otomycosis over a four-year period. All the ear aspirations were examined with pan-fungal primers, then those with a positive result was included in two separate reaction mixtures simultaneously to identify the most clinically relevant Aspergillus and Candida species. The validity of positive samples for C. auris was assessed by sequencing. Of the 189 pan-fungal positive PCRs, 78 and 39 specimens contained Aspergillus spp. and Candida spp., respectively. Furthermore, 65 specimens showed simultaneous positive bands in both Candida and Aspergillus species-specific multiplex PCR including five samples/patients with positive result for C. auris (5/189; 2.6%). Four out of five cases with C. auris species-specific PCR were reconfirmed by sequencing, while none were positive for C. auris in culture. Unfortunately, due to high treatment failure rates of antifungal classes against C. auris species, rapid and accurate identification of patients colonised with C. auris is critical to overcome the challenge of preventing transmission. This PCR assay can be successfully applied for rapid and accurate detection of C. auris directly in patient samples and is able to differentiate C. auris from closely related Candida species.

Surgery for Vertebral Osteomyelitis Lowers 1-Year Mortality and Failure Rates Compared with Nonsurgical Treatment: A Propensity-Matched Analysis.

The aim of this study was to determine differences between patients who underwent surgical treatment and those who underwent nonsurgical treatment of vertebral osteomyelitis (VO) and to identify potential factors influencing treatment failure (death and/or recurrence within 1 year). We performed a retrospective analysis of clinical data prospectively collected from patients treated for VO between 2008 and 2020. The decision between surgical and nonsurgical treatment was made for each patient based on defined criteria. A 1:1 propensity score matching was performed to exclude confounders between the 2 treatments. Univariate and multivariable analyses were performed to identify potential risk factors for death and/or recurrence within the first year after VO diagnosis. Forty-two patients (11.8%) were treated nonsurgically and 313 patients (88.2%) underwent surgery. A higher percentage of the surgically treated patients than the nonsurgically treated patients had an American Society of Anesthesiologists score of >2 (69.0% versus 47.5%; p = 0.007), and the thoracic spine was affected more often in the surgical group (30.4% versus 11.9%; p = 0.013). Endocarditis was detected significantly more often in the nonsurgically treated patients (14.3% versus 4.2%; p = 0.018). The recurrence rate was 3 times higher in the nonsurgically treated patients (16.7% versus 5.4%; p = 0.017), but this difference was no longer detectable after propensity matching. After matching, the nonsurgically treated patients showed an almost 7-fold higher 1-year mortality rate (25.0% versus 3.7%; p = 0.018) and an almost 3-fold higher rate of treatment failure (42.9% versus 14.8%; p = 0.022). Multivariable analysis revealed nonsurgical treatment and bacteremia to be independent risk factors for treatment failure. In our matched cohort of patients with VO, surgical intervention resulted in a significantly lower rate of treatment failure (death and/or recurrence within 1 year) compared with nonsurgical intervention. Furthermore, nonsurgical treatment was an independent risk factor for treatment failure. Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Promoter swapping of truncated PDGFRB drives Ph-like acute lymphoblastic leukemia

Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) is a subset of ALL that demonstrated a high treatment failure rate. One of the hallmarks of Ph-like ALL is PDGFRB gene fusion, with fusion partner proteins often harboring dimerization domains and enhancing the kinase activity of PDGFRB. We determined a novel oncogenic PDGFRB fusion gene, NRIP1::PDGFRB, from a pediatric patient with ALL, encoding a protein with the carboxy-terminal kinase domain of PDGFRB, without the partner peptide. We confirmed the oncogenic potential of NRIP1::PDGFRB in vitro and the efficacy of all ABL1-specific inhibitor generations, including imatinib, dasatinib, nilotinib, and ponatinib, in suppressing this potential. PDGFRB activation mechanism may include juxtamembrane domain truncation in the predicted peptide. In conclusion, we determined a novel fusion gene pattern in Ph-like ALL.

Characterizing utilization patterns and reoperation risk factors of interspinous process devices: analysis of a national claims database.

Interspinous process devices (IPDs) were developed as minimally invasive alternatives to open decompression surgery for spinal stenosis. However, given high treatment failure and reoperation rates, there has been minimal adoption by spine surgeons. This study leveraged a national claims database to characterize national IPD usage patterns and postoperative outcomes after IPD implantation. Using the PearlDiver database, we identified all patients who underwent 1- or 2-level IPD implantation between 2010 and 2018. Univariate and multivariable logistic regression was performed to identify predictors of the number of IPD levels implanted and reoperation up to 3 years after the index surgery. Right-censored Kaplan-Meier curves were plotted for duration of reoperation-free survival and compared with log-rank tests. Patients (n = 4865) received 1-level (n = 3246) or 2-level (n = 1619) IPDs. Patients who were older (adjusted odds ratio [aOR] 1.02, 95% confidence interval [CI] 1.01-1.03, P < .001), male (aOR 1.31, 95% CI 116-1.50, P < .001), and obese (aOR 1.19, 95% CI 1.05-1.36, P < .01) were significantly more likely to receive a 2-level IPD than to receive a 1-level IPD. The 3-year reoperation rate was 9.3% of patients when mortality was accounted for during the follow-up period. Older age decreased (aOR 0.97, 95% CI 0.97-0.99, P = .0039) likelihood of reoperation, whereas 1-level IPD (aOR 1.37, 95% CI 1.01-1.89, P = .048), Charlson Comorbidity Index (aOR 1.07, 95% CI 1.01-1.14, P = .018), and performing concomitant open decompression increased the likelihood of reoperation (aOR 1.68, 95% CI 1.35-2.09, P = .0014). Compared with 1-level IPDs, 2-level IPDs were implanted more frequently in older, male, and obese patients. The 3-year reoperation rate was 9.3%. Concomitant open decompression with IPD placement was identified as a significant risk factor for subsequent reoperation and warrants future investigation.

Candida auris in a tertiary healthcare setting in south India: A case series.

Candida species can produce a variety of clinical manifestations, and several non-albicans species of Candida, including Candida auris, have been linked to the rise of invasive fungal infections with high rates of treatment failure. Nosocomial outbreaks and high mortality rates in healthcare institutions across the globe have been associated with C. auris, an emerging infectious yeast that was initially discovered in the ear canal of an elderly Japanese patient in 2009. The fact that C. auris has been found on six continents after it was initially isolated has raised serious concerns among scientists and healthcare practitioners. At present, healthcare facilities lack defined protocols for the effective prevention and control of C. auris infections, as well as appropriate treatment alternatives. This leads to frequent therapeutic failures and complicates the eradication of C. auris infection in healthcare facilities. Studies on C. auris in South India are often limited, and healthcare workers urgently need to be made aware of infections caused by it in order to assess its impact and possible implications for the healthcare system. This study aimed to report seven patients hospitalized in our center who developed C. auris infections with varying clinical manifestations.

High treatment failure rate in haematogenous compared to non-haematogenous periprosthetic joint infection.

A higher failure rate has been reported in haematogenous periprosthetic joint infection (PJI) compared to non-haematogenous PJI. The reason for this difference is unknown. We investigated the outcome of haematogenous and non-haematogenous PJI to analyze the risk factors for failure in both groups of patients. Episodes of knee or hip PJI (defined by the European Bone and Joint Infection Society criteria) treated at our institution between January 2015 and October 2020 were included in a retrospective PJI cohort. Episodes with a follow-up of > one year were stratified by route of infection into haematogenous and non-haematogenous PJI. Probability of failure-free survival was estimated using the Kaplan-Meier method, and compared between groups using log-rank test. Univariate and multivariate analysis was applied to assess risk factors for failure. A total of 305 PJI episodes (174 hips, 131 knees) were allocated to the haematogenous (n = 146) or the non-haematogenous group (n = 159). Among monomicrobial infections, Staphylococcus aureus was the dominant pathogen in haematogenous PJI (76/140, 54%) and coagulase-negative staphylococci in non-haematogenous PJI (57/133, 43%). In both groups, multi-stage exchange (n = 55 (38%) in haematogenous and n = 73 (46%) in non-haematogenous PJI) and prosthesis retention (n = 70 (48%) in haematogenous and n = 48 (30%) in non-haematogenous PJI) were the most common surgical strategies. Median duration of antimicrobial treatment was 13.5 weeks (range, 0.5 to 218 weeks) and similar in both groups. After six years of follow-up, the probability of failure-free survival was significantly lower in haematogenous compared to non-haematogenous PJI (55% vs 74%; p = 0.021). Infection-related mortality was significantly higher in haematogenous than non-haematogenous PJI (7% vs 0% episodes; p = 0.001). Pathogenesis of failure was similar in both groups. Retention of the prosthesis was the only independent risk factor for failure in multivariate analysis in both groups. Treatment failure was significantly higher in haematogenous compared to non-haematogenous PJI. Retention of the prosthesis was the only independent risk factor for failure in both groups.

Human genetics and molecular genomics of Chiari malformation type 1.

Chiari malformation type 1 (CM1) is the most common structural brain disorder involving the pboard1 junction, characterized by caudal displacement of the cerebellar tonsils below the foramen magnum into the spinal canal. Despite the heterogeneity of CM1, its poorly understood patho-etiology has led to a 'one-size-fits-all' surgical approach, with predictably high rates of morbidity and treatment failure. In this review we present multiplex CM1 families, associated Mendelian syndromes, and candidate genes from recent whole exome sequencing (WES) and other genetic studies that suggest a significant genetic contribution from inherited and de novo germline variants impacting transcription regulation, craniovertebral osteogenesis, and embryonic developmental signaling. We suggest that more extensive WES may identify clinically relevant, genetically defined CM1 subtypes distinguished by unique neuroradiographic and neurophysiological endophenotypes.

Utilizing Chemotherapy to Enhance the Anti-Tumor Properties of Ex Vivo Expanded Gamma Delta (γδ) T Cells Against Acute Myeloid Leukemia

Background: Acute myeloid leukemia (AML) is the second most common type of blood cancer in children with a high rate of treatment failure and aggressive relapse. While allogeneic HSCT offers a cure, limitations arise in achieving remission prior to transplant. Immunotherapy-based approaches can induce remission, gaining interest in AML. Here, we explore the use of gamma delta (γδ) T cells as a promising tool to fulfill this unmet need. Unlike predominant alpha beta (αβ) T cells, γδ T cells do not require antigen presentation and identify their targets in a major histocompatibility complex (MHC) independent manner. Allogeneic γδ T cells thus have minimal risk of causing graft-versus-host disease (GvHD), creating ‘off-the-shelf’ cellular therapeutics. This would be ideal to target AML, especially given the aggressive nature of relapsed disease. Cytotoxic mechanisms used by γδ T cells include recognition of cellular stress molecules such as NKG2D and DNAM-1 receptor ligands on target cells, activation of death receptor pathway through Fas-FasL and TRAIL-R interactions, as well as γδ ΤCR mediated killing through recognition of butyrophilins (BTNs) on target cells. These stress molecules are expressed on AML cells and can be further upregulated through chemotherapeutic agents such as azacitidine (a hypomethylating agent) and venetoclax (BCL-2 antagonist), drugs currently in use to treat relapsed AML. Here, we tested these drugs in combination with γδ T cells to target AML. Methods Our studies explored four different AML cell lines (Kasumi-1, Nomo-1, MV4-11 and MOLM13). Each one was respectively treated at their corresponding inhibitory concentration 25 (IC 25) and 50 (IC 50) of azacitidine and/or venetoclax for 24 hours. After treatment, AML cells were assessed by flow cytometry for expression of NKG2D and DNAM-1 ligands, death receptor pathway molecules (CD95, TRAIL-R1/R2) as well as the butyrophillins (BTN2A and BTN3A1) to elucidate which pathways are over-expressed, aiding in γδ T cell targeting and cytotoxicity. Next, we co-cultured AML cells pre-treated with azacitidine and/or venetoclax with γδ T cells and measured cytotoxicity using a flow cytometry-based assay and a bioluminescence assay. Results: Each cell line expressed a unique pattern of markers at baseline. Cell lines treated with azacitidine had a robust expression of the NKG2D ligands ULBP1, ULBP2/5/6 and ULBP3. Azacitidine also increased CD155 and TRAIL-R2 in Nomo-1 while CD112 increased in MOLM13. Most venetoclax-treated AML cells over-expressed BTN2A and BTN3A1 along with CD95 in MOLM13. Cell lines were then treated with a combination of both drugs. Dual treatment of cells resulted in a significant increase in expression of most NKG2D markers as well the death receptor Fas (CD95). Additionally, increase in CD155 as well as BTNs was seen in several cell lines. Importantly, azacitidine and venetoclax had minimal effects on the viability of γδ Τ cells when treated for 24 hours. In vitro cytotoxicity studies indicate increased cell death across multiple AML cell lines when γδ T cells were co-cultured with cells pretreated with azacitidine and venetoclax. Conclusions: Azacitidine and venetoclax treatment resulted in upregulation of several markers involved in γδ Τ cell-mediated cytotoxicity. Ex vivo expanded γδ Τ cells combined with chemotherapy-treated AML cells resulted in increased overall cytotoxicity, which is likely both additive and synergistic. Our next steps include preclinical validation of this combinatorial approach in an in-vivo mouse study.

Asciminib Is Effective Against ABL1 Gene Fusions in Acute Lymphoblastic Leukemia but Only When the ABL1 SH3 Domain Is Present

Background Ph-like acute lymphoblastic leukemia (ALL) is high risk and comprised of many kinase activating gene fusions including those involving the ABL1 gene ( ABL1-rearranged, ABL1r). ABL1r ALL is associated with poor relapse-free and overall survival and incidence increases with age. Tyrosine kinase inhibitors (TKIs) such as dasatinib effectively target BCR::ABL1+ ALL and are in clinical trials for ABL1r ALL. However, resistance to TKIs is often observed, and novel treatments are required. The allosteric inhibitor asciminib binds the myristate pocket of Bcr-Abl kinase and is currently in Phase III trials for treatment of BCR::ABL1+leukemias. We assessed asciminib efficacy in ABL1r ALL. Methods Ba/F3 cells were transduced with four ABL1 fusions observed in ALL and asciminib efficacy evaluated in AnnexinV/7-AAD cell death assays (LD 50). Specific regions of the ABL1 fusion partner were deleted by site-directed mutagenesis (SDM). STAT5/CRKL phosphorylation and hCD45 levels were investigated by flow cytometry. Cells from three NUP214::ABL1 ALL patients were injected into NSG mice to establish patient-derived xenograft (PDX) models. Once mice reached 5% hCD45+ cells in peripheral blood (PB), treatment was commenced: vehicle control, dasatinib, asciminib. At experimental endpoint (&amp;gt;50% hCD45+ cells in PB) mice were humanely killed and organs harvested for analysis. Results Transduced Ba/F3 cells demonstrated varying sensitivity to asciminib (Table 1). While asciminib was not efficacious against Ba/F3 RCSD1::ABL1 and SNX2::ABL1 cells, Ba/F3 RANBP2::ABL1 (Heatley et al 2021)and NUP214::ABL1 cells demonstrated LD 50 concentrations within the clinically achievable range (3 µM, p&amp;lt;0.0001; 0.8 µM, p=0.0238 compared with control, respectively). Following asciminib treatment, Ba/F3 NUP214::ABL1 cells demonstrated reduced phosphorylation of STAT5 (mean fluorescence intensity [MFI]=1820 to 790, 57% reduction) and CRKL (MFI=2069 to 951, 54% reduction), confirming asciminib inhibits kinase signalling. No phosphorylation of STAT5 or CRKL was observed in control cells (MFI=290 and 406, STAT5 and CRKL, respectively). Additionally, ex vivo assessment of ETV6::ABL1 patient blasts demonstrated reduced phosphorylation of STAT5 (MFI=3395 to 1788, 47% reduction) and CRKL (MFI=5039 to 3000, 40% reduction) following asciminib treatment. Interrogation of the different ABL1 fusion breakpoints (Figure 1) revealed fusions demonstrating asciminib sensitivity retained exons 2 or 3 of ABL1 (corresponding to complete/partial SH3 and complete SH2 domains). Conversely, gene fusions lacking exons 1-3 (truncating the SH3 domain and retaining a partial SH2 domain) were resistant to asciminib suggesting a critical region in the SH3 and/or SH2 domain/s required for asciminib efficacy. To further investigate this we systematically deleted regions of ABL1 exon 3 using the NUP214::ABL1 construct as the model system and generated transduced Ba/F3 cells expressing different SDM regions. Cell death assays indicated the SH3 domain is critical for asciminib efficacy (Table 1). Asciminib also demonstrated efficacy in pre-clinical mouse modelsof NUP214::ABL1 ALL (where ABL1 exon 3 and partial SH3 domain is retained). Asciminib treatment significantly increased survival outcomes compared with control mice (84 vs 46d, p=0.01) by a time comparable to that of dasatinib treatment (93 vs 46d, p=0.0046). Results were confirmed in two additional NUP214::ABL1 PDX models demonstrating asciminib's potential to treat NUP214::ABL1 patients. Asciminib treatment reduced spleen and liver weights to that of healthy mice and resolved the leukemic immunophenotype of PB and bone marrow cells. Conclusion ABL1r ALL is associated with high rates of treatment failure and relapse. For the first time, we demonstrate the efficacy of asciminib in this high risk disease. Our data support addition of asciminib to treatment regimens of patients with NUP214::ABL1 ALL, the most common ABL class gene fusion affecting up to 6% of B-ALL patients and up to 10% of T-ALL patients. We also identify a critical region of ABL1 required for asciminib efficacy in ABL1r ALL. We propose interrogation of ABL1r patient breakpoints to determine inclusion/exclusion of the ABL1 SH3 domain as a surrogate test to be used in conjunction with in vitro kinase sensitivity assays for predicting whether a patient is likely to respond to asciminib treatment.

Feasibility of a Dose-Intensive Regimen for Pediatric Burkitt Lymphoma in Malawi

Introduction: Burkitt lymphoma (BL) is the commonest childhood cancer diagnosed in Sub-Saharan Africa (SSA). It is highly curable with survival rates &amp;gt;90% in resource-rich settings with dose-intensive regimens that contain the anti-CD20 monoclonal antibody, rituximab, high-dose methotrexate (HDMTX; ≥ 3000 mg/m 2) and high-dose cytarabine. In contrast, outcomes in SSA where patients typically receive less intense chemotherapy with lower-dose methotrexate (≤1000 mg/m 2) and without rituximab, remain poor. Major drawbacks to implementing HDMTX regimens in SSA include lack of adequate supportive care and inability to monitor drug levels. Improving long-term outcomes for BL in SSA requires graduated, stepwise, and cautious escalation of treatment tailored to available supportive care infrastructure. Based on the available evidence, we adopted a resource-adapted HDMTX-containing regimen as our standard of care for pediatric BL in Lilongwe, Malawi. We report preliminary data on patients treated with this regimen. Methods: This is a prospective study of children (&amp;lt;18 years) with newly diagnosed BL, treated with our locally adapted regimen at Kamuzu Central Hospital in Malawi. This risk-stratified regimen incorporates HDMTX at doses of 1000-3000 mg/m 2 per cycle (Table 1) and is based on the Group B arm of the FAB/LMB backbone (standard of care in high-resource settings) with a 60% dose reduction of anthracycline-based on previously published data. Rituximab and two maintenance cycles were incorporated into the therapy for very high-risk patients (Table 1). Treatments were administered in 14-day cycles. Patients not in complete remission (CR) at the end of the first consolidation cycle received 4 cycles of DHAP (Dexamethasone, Cisplatin, HD-Cytarabine, Prednisone). To mitigate toxicity, we established locally appropriate best practices for supportive care and extended bicarbonate-containing fluid hydration for days with rate adjustments based on changes in daily creatinine levels in lieu of MTX levels-which were unavailable (Table 2). Adverse events (AE) were defined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria. Using descriptive statistics, we report on the frequency of severe AEs in this cohort. Results: Between June 2022 and July 2023, 40 consecutive patients with biopsy-proven BL were treated with this approach. They were mostly male (n=26, 65%) with a median age of 9 years (interquartile range, 6-12). The majority (n=22, 55%) had Murphy stage III disease, and 15 (38%) were stage IV at diagnosis. Five patients (13%) had central nervous system (CNS) disease, and 12 (31%) with bone marrow (BM) disease. All patients were stratified as high-risk or very high-risk. Nineteen (48%) have completed their planned first-line therapy, 7 (17%) are currently in therapy, 8 (20%) died before treatment completion, and 6 (15%) abandoned therapy. Treatment delays occurred in 12/107 (11%) HDMTX-containing cycles. For the non-rituximab HDMTX cycles (n=90), there have been 14 episodes (16%) of grade ≥3 febrile neutropenia, 1 episode (1%) of grade ≥3 mucositis, and 5 episodes (6%) of grade ≥3 anemia. One patient developed grade 3 acute kidney injury, which resolved with hydration. In patients who received rituximab (n=17) there have been 3 episodes (18%) of grade ≥3 febrile neutropenia, and 1 episode (6%) of grade ≥3 mucositis or anemia. In total, there were 12 (30%) deaths: 5 disease-related deaths, 4 early deaths from sepsis, or tumor lysis before pre-HDMTX, 1 unknown cause, and 2 (6%) treatment-related deaths associated with HDMTX. Twenty-three patients had interim assessment at the end of the first consolidation and 18 (78%) were in CR. Of the patients with relapse or progressive disease (n=8), 4 (50%) had either CNS or BM disease. Conclusion: We demonstrate feasibility of administering dose-intensive intermediate dose MTX-containing treatment for pediatric BL in a very resource-limited setting with rigorous surveillance and supportive care. We will build on this by incorporating rituximab into all risk-groups, while evaluating its impact on efficacy and the immune reconstitution in a population with high prevalence of malnutrition, malaria, and tropical infections. Furthermore, given higher treatment-failure rates in patients with CNS or BM disease, strategies to intensify treatment in this cohort in the context of available support care resources will be needed.

2764. Experience with dalbavancin in a pediatric hospital

Abstract Background Due to its long half-life allowing for once-weekly dosing, dalbavancin has become an appealing option for the treatment of infections that require prolonged antibiotic courses. While studies have shown non-inferiority of dalbavancin compared to conventional antibiotic regimens, there is limited information regarding its use in the pediatric population. We describe the experience with dalbavancin use in a large pediatric hospital. Methods Children and young adults who were seen at Cincinnati Children’s Hospital between the period of July 1st, 2019 and December 31st, 2022 and received antibiotic therapy with Dalbavancin were included in this study. We reviewed the patient’s demographic data, laboratory findings including microbiologic data, clinical course, response to treatment and outcomes. Treatment failure was defined as no response or worsening after initial improvement. Clinical response was also evaluated at day 90 after end of therapy. Results We identified 26 children and young adults who received dalbavancin between July 1st 2019 and December 31st 2022 (Table 1). Ages ranged between 6 months and 22 years. Most common indication was osteomyelitis. Side effects were rare and included flushing and transient vision loss, which was later diagnosed as ocular migraine. Seven patients (26.9%) had treatment failure at 90 days, including 33.3% and 18.2% of patients with and without comorbidities, respectively. Ages of patients with treatment failure ranged from 6 months to 20 years. Five of them showed initial improvement during the first week after therapy but required an antibiotic switch due to worsening. Time to failure from first dose of dalbavancin ranged from 10 to 35 days. Of all 7 patients who failed therapy, four had no recovered organisms, two had MRSA and one had MSSA. One patient with no initial recovered organism grew Pseudomonas aeruginosa on a repeat culture. Characteristics of patients who received dalbavancin between July 1st, 2019 and December 31st,2022 Conclusion While our population was small, a high treatment failure rate was seen when using dalbavancin, particularly in patients with comorbidities. More data is needed to evaluate its performance in the pediatric population and clinicians should be thoughtful about deciding who is a good candidate for dalbavancin therapy. Disclosures All Authors: No reported disclosures

High Rates of Treatment Failure and Amputation in Modular Endoprosthesis Prosthetic Joint Infections Caused by Fungal Infections With Candida.

Fungal prosthetic joint infections (PJIs) are rare yet severe events associated with high rates of recurrent infection. Although bacterial PJIs associated with megaprostheses are known to be associated with higher rates of recurrence and amputation, little is known about fungal PJIs near megaprostheses. In patients with fungal megaprosthesis PJIs from one institutional registry, we asked: (1) What were the most common microorganisms isolated? (2) What were the reoperation-, revision-, and amputation-free survival rates 1 and 2 years after surgery? We conducted a retrospective analysis of megaprostheses in our institutional database. Between 2000 and 2022, 86 patients with a diagnosis of PJI after megaprosthesis implantation were surgically treated at our institution. We considered patients with microbiological cultures that were positive for fungal organisms and who had a minimum follow-up of 2 years from the initial treatment for PJI. Ten patients with fungal megaprosthesis PJIs were included. Although four patients had a follow-up shorter than 2 years, all reached one of the study endpoints at that earlier interval, and therefore were included. All included patients were treated between 2016 and 2022, and the diagnosis of PJI was made in accordance with the 2011 Musculoskeletal Infection Society criteria. Patients were treated with either debridement, antibiotics, and implant retention (DAIR), DAIR-plus (debridement, antibiotics, modular implant component exchange, and stem retention), or one-stage or two-stage revision. In general, DAIR was used for acute PJIs, while DAIR-plus was performed in patients with chronic PJIs who were deemed medically unfit to endure the high morbidity associated with removal of the stems. In cases of prior unsuccessful DAIR-plus or patients with fewer comorbidities, one-stage or two-stage revision was the main treatment approach. The median age at diagnosis was 67 years (range 32 to 84 years), 5 of 10 patients were female, and the median BMI was 31 kg/m 2 (range 20 to 43 kg/m 2 ). The median follow-up was 26 months (range 1 to 54 months). A Kaplan-Meier survival analysis was performed to calculate reoperation-, revision-, and amputation-free survival at 1 and 2 years from the index surgery for PJI. The two most common organisms were Candida albicans (5 of 10 patients) and C.parapsilosis (3 of 10). Six of 10 patients had coinfection with a bacterial organism. One-year reoperation-free and revision-free survival were 35% (95% CI 9% to 64%) and 42% (95% CI 11% to 71%), respectively. Two-year reoperation-free and revision-free survival were 12% (95% CI 1% to 40%) and 14% (95% CI 1% to 46%), respectively. Amputation-free survival was 74% (95% CI 30% to 93%) at the 1-year interval and 40% at the 2-year interval (95% CI 7% to 73%). At the final follow-up interval, four patients had undergone amputations and four were being administered chronic antifungal suppression. Megaprosthesis fungal PJIs are rare but devastating. Arthroplasty surgeons should consider treatment efficacy, which appears to be low across surgical strategies, and the patient's capacity to withstand it. A lower decision threshold for performing amputation may be considered in patients who require rapid infection control to initiate immunosuppressive treatments. Future studies should aim to compare the surgical and clinical outcomes of fungal PJIs with those of other etiologies while controlling for potential variables. Efforts should be made to establish multi-institutional collaborations to achieve larger study samples. Level IV, therapeutic study.

Cytogenetic and Molecular Remission in Chronic Myeloid Leukemia in Togo

The availability of tyrosine kinase inhibitors (TKIs) in Togo through the GIPAP program has revolutionized the management of chronic myeloid leukemia and increased patient life expectancy. However, diagnosis and molecular monitoring of therapeutic efficacy remain a real challenge due to the inaccessibility of cytogenetic and molecular biology tools. We’ve conducted, a cross-sectional, descriptive study that ran from December 21, 2022, to January 20, 2023, with the aim to evaluate the cytogenetic and molecular remission in CML patients followed at the CHU Campus de Lomé in Togo. Patients diagnosed with chronic-phase CML who had been treated for at least three months with imatinib or dasatinib and had achieved complete hematological remission were included. Dosage of BCR-ABL transcript levels was performed by RQ-PCR in Seattle, USA, using Dried Blood Spot. The transcript detection limit was 0.003% i.e., MR4. A total of 38 patients were included, 68.4% of them were treated with imatinib and 31.6% with dasatinib. In terms of remission, 28.9% had not achieve a partial cytogenetic remission while 15.8% of patients had achieved a MR4 remission and 7.9% a major molecular remission. Major molecular remission was achieved at a mean follow-up time of 95 months for patients taking imatinib and 22 months for those taking dasatinib. Patients in MR4 were on imatinib after a mean of 68 months. All in one, our study showed a high rate of treatment failure. Better access to cytogenetic and molecular biology tools is needed to improve management.

Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in Secondary Central Nervous System Large B-Cell Lymphoma (SCNSL): A Multicenter Retrospective Analysis

Introduction Secondary central nervous system (CNS) involvement develops in 2-10% of large B-cell lymphoma (LBCL) cases. Current treatment approaches for relapsed or refractory CNS disease generally do not provide durable responses. Limited data suggest efficacy and feasibility of CAR-T therapy in SCNSL. We report here the largest multicenter retrospective analysis of the safety and efficacy of CD19-directed CAR-T therapy in SCNSL patients. Methods This study included SCNSL patients who received commercial CD19-directed CAR-T therapy at 9 academic institutions in the United States between 2016 and 2022. SCNSL was defined as history of parenchymal and/or leptomeningeal/cerebrospinal fluid (CSF) involvement by lymphoma at any time prior to receiving CAR-T therapy. Systemic response was assessed using the Lugano criteria while CNS response was assessed as per International PCNSL Collaborative Group criteria. Kaplan-Meier curves were generated for progression-free survival (PFS) and overall survival (OS) for entire cohort, as well as subsets of patients with and without active CNS disease at the time of CAR-T infusion. Results Ninety patients were included in the analysis, with baseline characteristics shown in Table 1. CAR-T products utilized include axicabtagene ciloleucel (n= 38, 42%), tisagenlecleucel (n=37, 41%) and lisocabtagene maraleucel (n= 15, 14%). Fludarabine/cyclophosphamide was used as lymphodepletion in 84 patients (93%). 28 patients received CNS directed radiation therapy (RT) prior to CAR-T infusion (31%) within a median time of 28.5 days (range 5 - 906) from last day of RT. Amongst all patients at the time of CAR-T infusion 82 (91.1%) had active CNS and/or systemic involvement while 8 (8.9%) had no evidence of disease; 68 (75.5%) had active CNS involvement while 22 (24.5%) had a prior history of CNS involvement but no active at the time of CAR-T infusion. ( Table 1) Median follow up all patients was 0.5 year (range 0.01 - 4.7). 71 patients (79%) developed cytokine release syndrome (CRS; median time to onset 3 days) with 3.3% patients developing Grade 3-4. Immune effector cell-associated neurotoxicity syndrome (ICANS; median time to onset 5 days) was reported in 55 patients (61%), with 28.8% developing Grade 3-4. No patients died due to CRS or ICANS. At 1-month post CAR-T, 80 patients were evaluable for CNS response and 71 patients in the entire cohort were evaluable for systemic response. Similarly, at 3-months these numbers were 66 and 60, respectively. Objective response rates (ORR) were 75% and 80% at 1-month for CNS and systemic disease respectively, while corresponding ORRs at 3-months were 68% and 76.7%. At 1- and 3-months timepoint 36 (45%) and 33 (50%) patients, respectively achieved CNS complete remission (CR), while 44 (62%) and 42 (70%) patients respectively achieved systemic CR. 1- and 2-year PFS for entire cohort were 25% (95%Cl 15% - 34%) and 16% (95%Cl 8.5% - 28%) respectively, while 1- and 2-year OS were 46% (95%Cl 36% - 59%) and 31% (95%Cl 22% - 46%). Non-relapse mortality (NRM) were 4.6% (95%CI, 1.8% -12%) and 7.2% (95%CI 2.9% - 18%) at 1- and 2-year. Cumulative incidence of relapse at 1- and 2-year were 73% (95%Cl 63% - 83%) and 77% (95%Cl 68% - 88%), respectively. ORRs for CNS response in patients with active CNS disease at 1-month and 3-month interval were 71% (n=45) and 60% (n=31). Similarly, ORR for systemic response with active CNS disease at 1-month and 3-month interval were 85% (n=43) and 74.3% (n=32).The 2-year PFS for patients with and without active CNS disease at CAR-T infusion were 12% (95%Cl 5.4% - 27%) and 28% (95%Cl 12% - 65%) respectively, with a corresponding OS of 25% (95%Cl 15% - 41%) and 58% (95%Cl 37% - 91%). ( Figure 1) The 2-year NRM rates for patients with and without active CNS disease at CAR-T infusion were 4.6% (95%Cl 1.5% - 14%) and 14% (95%Cl 3.6% - 53%) respectively, while the cumulative incidence of relapse in similar order were 83% (95%Cl 73% - 95%) and 58% (95%Cl 39% - 88%). Conclusion In this largest known case series to date, CAR-T therapy appeared safe and feasible in patients with SCNSL, but is associated with high rates of treatment failure, particularly in patients with active CNS disease at CAR-T infusion. This warrants further study of optimal CNS-directed treatment strategies prior to CAR-T, development of novel cellular therapy platforms or consideration of post CAR-T maintenance therapy in these high-risk patients.

Sero-Prevalence, Epidemiology, and Public Health Significance of Small Ruminant Brucellosis

Brucellosis is a widespread zoonosis mainly transmitted from cattle, sheep, goats, pigs, and camels through direct contact with blood, placenta fetuses, or uterine secretion or through consumption of the contaminated raw animal product (especially unpasteurized milk and soft cheeses) in endemic areas. Therefore, the objective of this paper are to explain the Current Epidemiological Aspects of Brucellosis and the Importance of Small ruminant Brucellosis for Public Health and briefly illustrate the Economic Importance of Small ruminant Brucellosis. Sources of infection include aborted fetuses, fetal membranes, vaginal discharges and milk from infected sheep and goat. Brucellosis is caused by facultative, intracellular and Gram- negative bacteria called Brucella. Small ruminant brucellosis is caused by B. ovis (for sheep) and B. melitensis (mainly for goats), the latter one is the most virulent species of the Brucella genus. The disease in naturally infected sheep and goats is characterized by abortion in the last trimester of pregnancy, stillbirth and birth of weak offspring in females, and acute orchitis and epididymitis in males. Brucellosis occurs worldwide in domestic animals such as cattle, sheep, goats, camels and pigs and creates a high economic problem for both the intensive and extensive livestock production system in the tropics and a threat to public health. Diagnostic tests fall into two categories: those that demonstrate the presence of the organisms and those that detect an immune response to its antigens. As a general rule, treatment of infected livestock is not attempted because of the high treatment failure rate, cost, and potential problems related to maintaining infected animals in the face of ongoing eradication programs. To control the disease in human, prevention of the disease in reservoir host is important, so test and slaughter followed by proper disposal of seropositive animals to decrease the incidence of infection and effective vaccination and hygienic practices would reduce the disease spreading in/from endemic regions and to lessen the economic and zoonotic effects of brucellosis, the government, public health officials, and veterinarians must collaborate.

The Association Between Human Immunodeficiency Virus and Bacterial Vaginosis and Metronidazole Treatment Failure for Trichomonas vaginalis.

Trichomonas vaginalis (TV) is a common sexually transmitted infection. High rates of repeated infections have been observed, particularly among women living with human immunodeficiency virus (HIV). Trichomonas vaginalis frequently cooccurs with bacterial vaginosis (BV). The purpose of this study was to determine if coinfections with TV, BV, and HIV could lead to differential treatment failure outcomes. Data were pooled from 2 prior randomized control trials comparing 2 g oral single-dose versus 500-mg twice daily oral 7-day dose metronidazole for the treatment of TV in HIV infected and HIV uninfected women. Trichomonas vaginalis rates 1-month postcompletion of treatment were compared by arm, HIV and BV status after removing those who had sexual reexposure, and/or did not complete their treatment. Data for 795 subjects were included in the study, of which 76 (9.6%) experienced treatment failure. In the final multivariable model, which included treatment dose, HIV status, and BV status, odds of treatment failure infection in the 7-day dose group were lower than the odds in the single dose group (odds ratio, 040; 95% confidence interval, 0.23-0.68). Treatment failure was lower in the multidose arm compared with single dose for both HIV-infected (4.0% vs 10.3%; P = 0.0568) and HIV-uninfected (7.3% vs 15.4%; P = 0.0037). Neither HIV nor BV was associated with higher treatment failure. Human immunodeficiency virus infection and BV status did not significantly alter the rate of repeat infection for either single dose or 7-day dose metronidazole. Among all women, 7-day metronidazole lowered the odds of treatment failure.