Failure Of Therapy Research Articles

Treatment outcomes in patients with large B-cell lymphoma after progression to chimeric antigen receptor T-cell therapy.

Over 60% of relapsed/refractory (R/R) large B-cell lymphoma (LBCL) patients who receive chimeric antigen receptor (CAR) T cells will experience disease progression. There is no standard next line of therapy and information in this setting is scarce and heterogeneous. We analyzed 387 R/R LBCL patients who progressed after CAR T cells from July 2018 until March 2022 in Spain and the United Kingdom. Median overall survival (OS) was 5.3 months, with significant differences according to the interval between infusion and progression (<2 months [1.9 months], 2-6 months [5.2 months], and >6 months [not reached]). After progression, 237 (61%) patients received treatment. Focusing on the first subsequent therapy, overall (complete) response rates were 67% (38%) for polatuzumab-bendamustine-rituximab (POLA), 51% (36%) for bispecific antibodies (BsAb), 45% (35%) for radiotherapy (RT), 33% (26%) for immune checkpoint inhibitors (ICIs), 25% (0%) for lenalidomide (LENA), and 25% (14%) for chemotherapy (CT). In terms of survival, 12-month progression-free survival and OS was 36.2% and 51.0% for POLA, 32.0% and 50.1% for BsAb, 30.8% and 37.5% for RT, 29.9% and 27.8% for ICI, 7.3% and 20.8% for LENA, and 6.1% and 18.3% for CT. Thirty-two (14%) patients received an allogeneic hematopoietic cell transplant with median OS not reached after a median follow-up of 15.1 months. In conclusion, patients with R/R LBCL who progress within the first 2 months after CAR T-cell therapy have dismal outcomes. Novel targeted agents, such as polatuzumab and BsAbs, can achieve prolonged survival after CAR T-cell therapy failure.

Predictors of leech therapy failure in revascularized and replanted digits

IntroductionVenous congestion is a common phenomenon following digital revascularization and replantation. Leech therapy allows for venous outflow while angiogenesis and neovascularization take place. The aim of this study is to evaluate the efficacy of leech therapy in the revascularized and replanted digits and determine risk factors for unsuccessful salvage. Materials and methodsA retrospective review was performed to identify all patients with complete or incomplete digital amputations at an academic Level 1 Trauma Center who underwent digital replantation or revascularization from January 2005 to December 2020. Amputations proximal to the palmar arch as well as revascularizations that showed any degree of perfusion on preoperative assessment were excluded. Leech therapy was initiated as soon as any signs of venous congestion appeared and was titrated to clinical effect. Patient demographics, medical history, injury mechanism, extent and level, operative details, leech therapy details, number of blood transfusions, hospitalization length, as well as the digit's ultimate survival data were collected. ResultsOf the 159 patients who underwent 213 digital revascularizations (n ​= ​135) and replantations (n ​= ​78), venous congestion requiring leech therapy developed in 27 digits in the revascularization group and in 26 in the replantation group. Of the digits that were leeched, 15 failed in the revascularization group (56 ​% failure rate) and 17 failed in the replantation group (65 ​% failure rate). Avulsion mechanism of injury and presence of a circumferential laceration were significantly associated with rate of failure in the revascularization cohort (p ​< ​0.01). Proximal level of injury was significantly associated with rate of failure in the replantation group (p ​< ​0.01). ConclusionLeech therapy has limited efficacy in avulsed or more proximally injured digits. These data can aid in determining the prognosis of a digit with venous congestion after revascularization and replantation.

A contemporary systematic review of penile lengthening procedures with penile prosthesis.

Penile prosthetic devices are the standard treatment for erectile dysfunction (ED) after failure of maximum medical therapy and conservative options. Several penile lengthening procedures (PLPs) can be performed concurrently with penile prosthesis (PP) insertion in patients with severe ED, penile shortening, and/or Peyronie's disease to help combat negative emotional and psychological concerns from penile length loss with penile prosthetic device placement. An extensive, systematic literature review of the various pre-, intra-, and post-operative techniques that can be applied to preserve, restore or enhance penile length at the time of penile prosthetic implantation. Numerous pre-operative and post-operative inflation protocols exists with vacuum erection devices and penile traction therapy. Intraoperative surgical techniques include cavernosal sparing and channeling without dilatation, subcoronal incision with circumferential penile degloving and grafting, the sliding technique, the modified sliding technique, the multiple-slit technique, the tunical expansion procedure (TEP), modified TEP, and the auxetic expansion procedure. These approaches can be meaningful to restore and/or preserve length for patients undergoing PP insertion. PLPs can be performed by surgeons who have extensive penile reconstruction experience and have been trained to do these procedures, as there is significant risk to the patient and limitations to what can be expected. Each patient must be counseled in detail about the risks and benefits of these procedures and have their expectations managed as the average postoperative penile length recovery is around 3 cm and can range from 0-4.0 cm. Future research is needed to identify the appropriate candidate for each approach, and how much length gain the patient can expect.

Higher objective responses by hepatic arterial infusion chemotherapy following atezolizumab and bevacizumab failure than when used as initial therapy in hepatocellular carcinoma: a retrospective study.

Atezolizumab/bevacizumab (atezo-bev) is the first-line chemotherapy for patients with unresectable hepatocellular carcinoma (HCC). However, hepatic artery infusion chemotherapy (HAIC) can be used as an alternative. Our aim was to compare the prognosis of HAIC treatment between newly diagnosed patients and patients treated after failure of atezo-bev. We retrospectively assessed 73 patients with HCC treated with HAIC between January 2022 and September 2023. Fifty-seven patients were treated with HAIC at initial diagnosis, while 16 were treated with HAIC after first-line atezo-bev combination chemotherapy. We evaluated tumor responses, such as overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). No significant difference was observed in either OS or PFS between patients with HCC treated with HAIC at the initial diagnosis and those treated after atezo-bev treatment failure. However, the ORR of the initial HAIC group was 19.6% and that of the HAIC group after atezo-bev therapy failure was 43.6%, which was a statistically significantly difference. Although no significant difference was observed for OS and PFS, the ORR of patients in the HAIC group after the failure of atezo-bev therapy was superior to that of newly diagnosed patients. HAIC may prolong survival in patients with HCC after atezo-bev treatment failure.

Prevalence of Helicobacter pylori infection and effectiveness of first-line triple eradication therapy among dyspeptic patients at hospitals in Hawassa City, Ethiopia: a cross-sectional follow-up study

BackgroundDyspepsia is a common gastrointestinal illness sometimes associated with Helicobacter pylori (H. pylori) infection. Screening and eradicating the bacterium reduces the risk of infection-related complications. The aim of this study was to determine the magnitude of H. pylori infection among dyspeptic patients and the effectiveness of triple eradication therapy at hospitals in Hawassa city, Ethiopia.ResultsThe prevalence of H. pylori infection was 48.5%. The H. pylori eradication rate using first-line triple therapy was 83.8%. Eradication therapy failure is associated with previous exposure compared to no exposure (AOR: 4.8, 95% CI: 1.37–10.97), a regimen for 10-days compared to 14-days (AOR: 4.05, 95% CI: 1.42–11.55), and self-reported side effects compared to no report (AOR: 2.5, 95% CI: 1.12–5.97). Based on Morisky-eight scale 230 (79.0%) patients were adherent to their triple therapy. Participants with no reports of adverse effects showed increased odds of adherence to triple therapy compared to those who had reports (AOR = 2.45, 95% CI: 1.29–4.62).ConclusionsThis study demonstrated that about half of adult dyspeptic patients were infected with H. pylori, and moderate eradication was observed. Factors such as previous history of eradication therapy, duration of the eradication regimen, and perception of potential adverse effects are associated with eradication rate and should be considered during the initiation of eradication therapy.

Efficacy and Safety of Amenamevir, a Helicase-Primase Inhibitor for the Treatment of Acyclovir-Resistant Herpes Simplex Virus 1 Keratitis.

The purpose of this study was to describe the efficacy and tolerance of amenamevir (AMNV), an inhibitor of the viral helicase-primase, for the treatment of recalcitrant herpes simplex keratitis (HSK) caused by acyclovir-resistant (ACVR) herpes simplex virus 1 strains. In this retrospective case series, 6 consecutive patients with HSK caused by an ACVR herpes simplex virus 1 strain with a failure of conventional antiviral therapy were included after having been treated with AMNV (there was no control group of comparable patients for whom previous treatment would have been continued despite its inefficacy). Medical files were assessed for clinical data including reason(s) for AMNV introduction (frequent recurrences despite appropriate preventive antiviral treatment and/or clinical resistance to suppressive antiviral treatment of an ongoing clinical relapse), genotypical resistance to herpes simplex virus 1 documentation, immune status, clinical types and number of HSK episodes before and during AMNV treatment, adverse effects observed during AMNV treatment, and best corrected visual acuity. Of 6 patients, 4 (66%) did not experience a single recurrence during AMNV therapy while 2 others had recurrences (1 over 24 months of treatment and 2 over 23 months, ie two-fold less frequently than with conventional preventive treatment). On the overall history of these 6 patients, AMNV appeared to be associated with a reduction in HSK recurrences, with a mean of only 0.02 ± 0.04 episodes/month during follow-up under AMNV as compared to 0.14 ± 0.04 episodes/month in the year preceding AMNV introduction (P = 0.03). Improvement in vision acuity was also observed (mean best corrected visual acuity 0.17 ± 0.12 logarithm of the minimum angle of resolution at the end of follow-up vs. 0.30 ± 0.35 before AMNV onset), albeit nonsignificant probably due to the limited number of patients (P = 0.38). Neither clinical nor biological adverse effects were observed while under AMNV during the follow-up (16.5 ± 5.8 months). Although there was no control group, AMNV may be a valuable option to reduce ACVR HSK recurrences.

Clinical features, cerebrospinal fluid changes, and prognosis in Chinese patients with autoimmune encephalitis.

Autoimmune encephalitis (AE) is a rare, treatable disease of the central nervous system (CNS) caused by an antibody-related immune response. This study is to investigate the correlation of clinical features, cerebrospinal fluid (CSF) characteristics, and prognosis in patients with AE. A total of 71 patients diagnosed with antibody-positive AE were retrospectively analyzed. The patients were divided into three groups: anti-NMDAR group, anti-LGI1 group, and other types. Clinical data were collected to analyze clinical features and CSF results, and prognosis was determined by modified Rankin Scale (mRS). There was statistical difference in the incidences of decreased consciousness level (P < 0.001), memory loss (P = 0.017), speech disorders (P = 0.035), and dyskinesia (P = 0.001) in different antibodies groups. Younger age (P = 0.018), elevated CSF chloride content (P = 0.006), and white blood cells > 50/mm3 (P = 0.026) were highly correlated with ICU admission. Anti-LGI1 encephalitis had a relatively small risk for ICU admission (P = 0.034), and a lower risk of poor functional recovery (P = 0.048) and recurrence (P = 0.041). Patients with first-line treatment failure (P = 0.021) had an increased risk of poor functional recovery. Delayed treatment (P = 0.011) would increase the risk of recurrence. There are differences in age, gender, clinical characteristics, and CSF results in different subtypes of AE. First-line therapy failure would have poor functional recovery, and delayed therapy would increase the risk of relapse. Chloride ion content and white blood cell count in cerebrospinal fluid are positively correlated with the patient's exacerbation and admission to ICU. These indicators have certain clinical value for the prognosis of AE patients.

Intestinal ultrasound scan predicts corticosteroid failure and colectomy risk in patients with ulcerative colitis.

Intestinal ultrasound (IUS) is an emerging modality for assessing disease activity, extent, and treatment response in ulcerative colitis. This study aimed to evaluate the potential of IUS in predicting severe flares, the need for rescue therapy (corticosteroid failure), and colectomy in patients with ulcerative colitis. We conducted a retrospective review of medical records, collecting clinical and IUS data. The Milan Ultrasound Criteria (MUC) score was used to assess ulcerative colitis severity. Group comparisons were performed to identify differences in MUC scores between mild-to-moderate and severe ulcerative colitis, between steroid responders and nonresponders, and between patients who underwent colectomy and those who did not. Receiver operating characteristic (ROC) analysis was used to predict outcomes in patients with ulcerative colitis. This analysis included 102 patients with ulcerative colitis categorized as mild/moderate (60) or severe (42). MUC scores were significantly higher in the severe ulcerative colitis group compared with the mild/moderate group ( P < 0.001). Analysis (using ROC) identified a cutoff MUC score of >8.54 to indicate severe ulcerative colitis with good sensitivity (64.29%) and excellent specificity (93.33%). Similarly, a cutoff of MUC > 10.54 showed promise in predicting corticosteroid failure, with acceptable sensitivity (50%) and high specificity (90.91%). Finally, a cutoff MUC score >12.5 demonstrated potential for predicting colectomy, exhibiting moderate sensitivity (55.56%) but excellent specificity (96.97%). IUS may be useful for differentiating severe ulcerative colitis from mild-to-moderate disease, identifying early stage failure of corticosteroid therapy, and predicting the potential need for colectomy.

FGFR4-driven plasticity in breast cancer progression and resistance to therapy.

Breast cancer (BCa) is a complex and heterogeneous disease, with different intrinsic molecular subtypes that have distinct clinical outcomes and responses to therapy. Although intrinsic subtyping provides guidance for treatment decisions, it is now widely recognised that, in some cases, the switch of the BCa intrinsic subtype (which embodies cellular plasticity), may be responsible for therapy failure and disease progression. Aberrant FGFR4 signalling has been implicated in various cancers, including BCa, where it had been shown to be associated with aggressive subtypes, such as HER2-enriched BCa, and poor prognosis. More importantly, FGFR4 is also emerging as a potential driver of BCa intrinsic subtype switching, and an essential promoter of brain metastases, particularly in the HER2-positive BCa. Although the available data are still limited, the findings may have far-reaching clinical implications. Here, we provide an updated summary of the existing both pre- and clinical studies of the role of FGFR4 in BCa, with a special focus on its contribution to subtype switching during metastatic spread and/or induced by therapy. We also discuss a potential clinical benefit of targeting FGFR4 in the development of new treatment strategies.

Molecular characterization of the nonstructural 5A (NS5A) region of hepatitis C virus in Thai blood donors.

Direct acting antivirals (DAAs) have been developed for hepatitis C virus (HCV) therapy, and they are usually effective, however resistance to DAA regimens has also been reported to have a significant impact. Resistance associated substitutions (RASs) in the NS5A region are known to be correlated with failure of DAA therapy. HCV genotypes 3a and 1 are the most prevalent genotypes in Thailand. This study analyzed the type and frequency of RASs associated with DAA failure, focusing on the NS5A region. Serum samples of HCV genotype 3a, 1a, and 1b infection from Thai blood donors were selected. The NS5A region was amplified using reverse transcription-polymerase chain reaction (RT-PCR). A phylogenetic tree was constructed to identify the genotypes of HCV. Nucleotide sequencing and amino acid sequencing were conducted to determine the prevalence of RASs. Construction of the phylogenetic tree indicated that 29 samples were genotype 3a, 11 samples were genotype 1a, and 9 were genotype 1b. Both HCV genotypes 1a and 3a can be categorized into two subclades. Results showed that the NS5A substitutions A30V/K, A62T/V/I/M/P/S/L, and S98G were present in HCV genotype 3a. In HCV genotype 1a, only NS5A RASs H54Y was detected. NS5A amino acid substitutions Q54H and P58L were found in HCV genotype 1b. In conclusion, NS5A RASs at amino acid positions 30, 62, 54, 58, and 98 are present within HCV genotypes 3a and 1. While keeping in mind that additional information was not available on the anonymous blood donors tested in this study, these findings can contribute to understand the NS5A mutation. Further study with known patients under drug treatment is recommended.

Validation of Questionnaires and the Effect of Educational Videos on the Knowledge of Hyperlipidemia Patients at Banjarbaru Utara Primary Health Care

Hyperlipidemia patients have a high risk of cardiovascular disease and stroke. Low patient knowledge causes therapy failure. Education can be provided to overcome this problem. No questionnaire instrument can measure the level of knowledge of hyperlipidemia patients. The level of knowledge of hyperlipidemia patients at Banjarbaru Utara Primary Health Care has never been studied. The research aimed to validate the questionnaire and determine the effect of educational videos on patient knowledge at the Banjarbaru Utara Primary Health Care, Banjarbaru City, South Kalimantan. The research method used to validate the questionnaire was cross-sectional, while to determine the effect of educational videos on the patient's level of knowledge using a quasi-experimental method using One Group Pre – Post Design. The research was conducted in January – March 2024 at Banjarbaru Utara Primary Health Care. The study involved eight experts, 40 patients in questionnaire validation, and 100 patients to determine the effect of educational videos. The results of questionnaire content validation show that the Content Validity Ratio (CVR) value is in the range of 0.750 – 1.000, while the Content Validity Index (CVI) value is in the range of 0.875 – 1.000. The validity test with Person Correlation shows that ten out of 20 statements on the questionnaire are considered valid (&gt;0.312). The Cronbach's Alpha value is 0.655, indicating the questionnaire is reliable. The patient's knowledge before being given the educational video had a score of 5.96 (scale 1 – 10), while after it, it had a score of 8.73. There was an increase in the level of knowledge, reaching 46.47%. The conclusion is that the Hyperlipidemia Knowledge Questionnaire (HKQ), which consists of 10 statements, is declared valid and reliable. Educational videos significantly influence (p-value 0.000) in increasing knowledge of hyperlipidemia patients.

Emerging threats of high biofilm formation and antibiotic resistance in clinical methicillin-resistant Staphylococcus aureus (MRSA) isolates from Pakistan

ObjectivesThis multicenter study, conducted from a One Health perspective, aimed to comprehensively examine the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) infections and their biofilm-forming capabilities in Pakistan. Phylogenetic analysis of the study isolates was also performed. MethodsA total of 150 MRSA isolates were screened from various clinical samples using Cefoxitin antibiotic discs. Genotypic confirmation was conducted through mecA, S. aureus-specific nuc, and 16S rRNA genes. Biofilm formation was assessed using Congo red agar (CRA) and slime layer quantification methods. The intercellular adhesion (ica) operon genes, specifically icaA and icaD, were detected. Phylogenetic analysis utilized the 16S rRNA sequences. Statistical associations between various parameters were determined using chi-square analysis. ResultsThe presence of the mecA gene was observed in 131 out of 150 isolates (87.3%). CRA identified 28% and 40% of isolates as strong and moderate biofilm producers, respectively, while 9.3% were classified as non-biofilm producers. The slime layer assay exhibited higher sensitivity, classifying only 4.7% of isolates as non-biofilm producers. Biofilm-forming genes icaA and icaD were detected in 85.3% and 86.7% of the isolates, respectively. Antibiotic resistance was more prevalent among biofilm-forming isolates, particularly against ciprofloxacin, levofloxacin, erythromycin, trimethoprim-sulfamethoxazole, and fosfomycin. Ceftaroline demonstrated efficacy irrespective of biofilm-forming abilities. Conversely, non-biofilm producers exhibited complete susceptibility to clarithromycin and tigecycline. ConclusionsClinical MRSA strains exhibit a substantial potential for biofilm formation, contributing to a resistant phenotype. Routine antibiotic testing in clinical settings that overlook the biofilm aspect may lead to the failure of empiric antibiotic therapy.

Predictive and Prognostic Factors Related to Chemoradioresistance in Neoadjuvant Treatment of Locally Advanced Rectal Cancer at Panama

&amp;lt;i&amp;gt;Background:&amp;lt;/i&amp;gt; In Panama, and the rest of Latin America, there are few publications on chemoradioresistance, it leads to poor prognosis and represents the main reason for failure of therapy, ultimately it can lead to tumor recurrence and metastasis. &amp;lt;i&amp;gt;Objective:&amp;lt;/i&amp;gt; Identify factors associated with chemoradioresistance in the neoadjuvant treatment of locally advanced rectal cancer at the Instituto Oncológico Nacional de Panamá, period 2016-2020. Methodology: This retrospective study included 71 patients with LARC who received neoadjuvant chemoradiotherapy and surgery. Chemoradioresistant patients were those who did not reach a higher pathological stage of ypT2NO and the results were compared. &amp;lt;i&amp;gt;Results:&amp;lt;/i&amp;gt; Of the 71 patients, pathological complete response (pCR) was achieved in 34 patients (48%). 49% of patients met chemoradioresistance criteria. In this group, the median CEA was 136 ng/ml, the median hemoglobin was 12 g/dl, and the median BMI was 26 kg/m2. The median radiation dose was 5000Gy. The time between completion of chemoradiotherapy and surgery was 110 days (16 weeks). Depending on the type of surgery, 65% who underwent low anterior resection were chemoradioresistant. The variables with statistical significance were the CEA value &amp;gt;5 ng/mL (OR=1.81, p=0.026) prior to the start of neoadjuvant treatment, with a lower pCR rate. Likewise, the ECOG scale (OR=2.51, p=0.015) was a risk factor related to chemoradioresistance, the lower the ECOG, the lower the risk of chemoradioresistance. The median overall survival and median recurrence-free survival was not reached in both groups and there was no statistically significant difference. &amp;lt;i&amp;gt;Conclusions:&amp;lt;/i&amp;gt; Significant interactions were identified between CEA levels prior to the start of neoadjuvant treatment with the pathological complete response rate and the ECOG score with chemoradioresistance. Therefore, these factors can be used to predict patient outcomes, will help optimize personalized treatment strategies and improve patient outcomes.

Independent risk factors predicting eradication failure of standard bismuth quadruple therapy for the first‐line treatment of Helicobacter pylori infection in Taiwan

AbstractBismuth quadruple therapy is recommended as the choice treatment for Helicobacter pylori (H. pylori) infection in areas of either low or high clarithromycin resistance in the Maastricht VI/Florence Consensus Report. However, the optimal treatment duration and drug dosages of bismuth quadruple therapy remain unclear. The study aimed to search the independent risk factors predicting eradication failure of standard bismuth quadruple therapy in the first‐line treatment of H. pylori infection. From July 2014 to June 2022, 274 H. pylori‐infected patients who received 10‐day or 14‐day bismuth quadruple therapy containing a proton pump inhibitor, bismuth, tetracycline and metronidazole were included for the study. Post‐treatment H. pylori status was assessed at least 4 weeks after completion of treatment. The relationships between eradication rate and 13 clinical parameters were analyzed by univariate and multivariate analyses. The eradication rates of standard bismuth quadruple therapy were 93.8% and 94.2% by intention‐to‐treat and per‐protocol analyses, respectively. Univariate analysis revealed that patients harboring metronidazole‐resistant strains had a lower eradication rate than those harboring metronidazole‐susceptible strains (88.7% [55/62] vs. 96.7% [148/153]). The other factors including smoking, treatment duration and drug adherence were not significantly associated with cure rate. Multivariate analysis revealed that metronidazole resistance of H. pylori was the only independent risk factors related to eradication failure of standard bismuth quadruple therapy with an odds ratio of 3.8 (95% CI: 1.2–12.4). In conclusion, metronidazole resistance is an independent risk factor predicting eradication failure of standard bismuth quadruple therapy in the first‐line treatment of H. pylori infection. There is no difference in eradication efficacy between 10‐day and 14‐day bismuth quadruple therapies in Taiwan.

Traitement des fistules anales réfractaires à l’Infliximab au cours de la maladie de Crohn : Mise au point

Treatment of complex perianal fistulas in Crohn's disease remains a challenge especially after the failure of Infliximab. Update on the different therapeutic alternatives for anal fistula in Crohn's disease after failure of Infliximab. A research in the medical literature on PubMed and Google Scholar was carried out. We included cohort studies, reviews and randomized double-blinded therapeutic trials. Case reports and fundamental research studies have been excluded. Anti-TNF therapy, notably Infliximab remain the therapeutic option of choice. Since Infliximab efficacy has been estimated at 60%, with a significant loss-of response rate, new therapeutic strategies have been evaluated and may offer new opportunities for the management of anal fistulas: for example, Ustekinumab could be effective after failure of anti-TNF therapy, although further studies are required. Recent guidelines suggest that injection of mesenchymal stem cells is an effective and safe treatment for complex fistulas. Other surgical options have been proposed, such as endorectal advancement flap, fibrin glue injection, anal fistula plug and ligation of the intersphincteric fistula tract, but all with limited and debatable efficacy. Given the failure rate of all these options, new strategies are currently being evaluated. Anal fistulas in Crohn's disease are a real therapeutic challenge. New medical and surgical therapies are currently being evaluated, with promising results.

Endoscopic balloon dilatation for pediatric subglottic stenosis: a meta-analysis of successful outcomes.

The primary goal of this study was to systematically identify all relevant published articles on the use of primary endoscopic balloon dilation for the management of pediatric patients with subglottic stenosis, critically assess the technique's success, and determine which patients are the best candidates for the procedure. This was a systematic review and meta-analysis that aimed to investigate the use and success rate of EBD for treating pediatric SGS. An electronic systematic literature search of three major databases, PubMed, EBSCO, and Web of Science&MEDLINE through Clarivate, was conducted to include the eligible articles. A total of 14 unique studies were included in the final analysis, with 473 cases of pediatric SGS. The pooled success rate of EBD in treatment of pediatric SGS was 76% (k = 14 studies, 95% confidence interval [CI] = 0.65-0.86, P < 0.001, Q test for heterogeneity = 0.03, P < .001, I2 = 91%). We reported a high success rate of EBD in treating pediatric SGS. The reported complications were uncommon, although they can be serious and life threatening. The intensity of SGS may be related to the likelihood of therapy failure.

Approaches for identifying and measuring heteroresistance in azole-susceptible Candida isolates.

Heteroresistance to antifungal agents poses a significant challenge in the treatment of fungal infections. Currently, the absence of established methods for detecting and measuring heteroresistance impedes progress in understanding this phenomenon in fungal pathogens. In response to this gap, we present a comprehensive set of new and optimized methods designed to detect and quantify azole heteroresistance in Candida albicans. Here, we define two primary assays for measuring heteroresistance: population analysis profiling, based on growth on solid medium, and single-cell assays, based on growth in liquid culture. We observe good correlations between the measurements obtained with liquid and solid assays, validating their utility for studying azole heteroresistance. We also highlight that disk diffusion assays could serve as an additional tool for the rapid detection of heteroresistance. These methods collectively provide a versatile toolkit for researchers seeking to assess heteroresistance in C. albicans. They also serve as a critical step forward in the characterization of antifungal heteroresistance, providing a framework for investigating this phenomenon in diverse fungal species and in the context of other antifungal agents. Ultimately, these advancements will enhance our ability to effectively measure antifungal drug responses and combat fungal infections.IMPORTANCEHeteroresistance involves varying antimicrobial susceptibility within a clonal population. This phenomenon allows the survival of rare resistant subpopulations during drug treatment, significantly complicating the effective management of infections. However, the absence of established detection methods hampers progress in understanding this phenomenon in human fungal pathogens. We propose a comprehensive toolkit to address this gap in the yeast Candida albicans, encompassing population analysis profiling, single-cell assays, and disk diffusion assays. By providing robust and correlated measurements through both solid and liquid assays, this work will provide a framework for broader applications across clinically relevant Candida species. These methods will enhance our ability to understand this phenomenon and the failure of antifungal therapy.

Cancer stem cell, chromosomal instability, and cancer immunity

Cancer stem cells (CSCs) are a unique population of tumor cells with stem cell-like properties. They are believed to be involved in drug resistance, potential therapy failure, tumor relapse after treatment, and ultimately reduced overall survival of cancer patients. One of the causal factors that may lead to CSC formation is chromosomal instability (CIN), a dynamic event leading to numerical and structural changes in the chromosomes. The CIN is also proposed to aid the maintenance of CSCs, contribute towards their heterogeneity, and facilitate their immune escape. However, the role of CIN in the modulation of the immune system in tumors remains contradictory. Studies have revealed that it can lead to both activation and suppression of the immune system. Previous literature suggests that the CIN, CSCs, and cancer immunity (3Cs), interact with and complement each other to create a pro-tumor environment. However, the mechanisms underlying such an interaction are poorly understood. So, in this review article, an attempt has been made to understand the nature of the interaction between the triad of CIN, CSC, and the immune response in tumors and some of the pathways governing the same. Understanding the above may be a positive step towards the complete cure for malignant diseases.

266 Combination Drug Therapy in H3 K27-Altered Diffuse Midline Glioma Enhances Tumor Retention and Treatment Efficacy

INTRODUCTION: Diffuse midline gliomas (DMG) with H3 K27 alterations are uniformly lethal tumors for which no therapy has been found to be effective. One reason for our therapy failure is the blood-brain barrier (BBB), which severely restricts uptake and accumulation of systemically administered drugs in the brain. Convection-enhanced delivery (CED) has emerged as a technique that circumvents the BBB by directly infusing therapeutics into the tumor parenchyma through generation of a mechanical pressure gradient, allowing for homogenous drug distribution at high local concentrations with minimal systemic toxicity. However, efflux transport proteins expressed by the BBB and the tumor, including P-gp and BCRP, rapidly clear the majority of drugs given by CED, severely limiting its therapeutic potential. METHODS: A panel of FDA-approved drugs (ponatinib, topotecan, tretinoin) were evaluated alone and in combination with the known efflux transporter inhibitor everolimus. RESULTS: A high degree of formal synergy was observed in multiple DMG cell lines in vitro, which was attributed to everolimus’ ability to inhibit mTOR signaling and P-gp/BCRP. In vivo, drugs that were expected to penetrate the BBB and be less likely to undergo active efflux persisted at the site of infusion the longest following CED. Concurrent dosing with everolimus further enhanced this effect, which was particularly apparent with the dual P-gp/BCRP substrate ponatinib. CONCLUSIONS: The proclivity of many drugs to be rapidly cleared from the brain by efflux transporters generates a vulnerability that can be exploited for the development of novel therapeutic regimens in DMG, such as with concomitant dosing of P-gp/BCRP-inhibiting drugs when using CED.

Comparative Evaluation of the Apical Sealability of AH Plus and RealSeal SE Using 5.25% Sodium Hypochlorite with 17% EDTA and 10% Citric Acid as Irrigants-An In Vitro Study.

Apical microleakage is considered to be a common reason for the clinical failure of endodontic therapy. Three dimensional sealing of the root canal is one of the main goals of endodontic treatment and is essential for preventing reinfection of the canal and for preserving the health of the periapical tissues, Recently Epoxy resin sealers have been used because of their reduced solubility apical seal and micro-retention to root dentine. This in vitro study was done to evaluate and compare the apical sealability of AH Plus and RealSeal SE using 5.25% sodium hypochlorite with 17% EDTA and 10% citric acid as irrigants. Materials and methods: 44 single-rooted premolars were selected and the teeth are randomly divided into 4 groups (n=10) and 2 control groups (n=2). The extent of dye penetration, from the apical to the coronal part of the root canal, was assessed using a stereomicroscope at 10x magnification for all groups.One-way ANOVA and Kruskal-Wallis tests were performed to compare statistically significant differences among the groups, using SPSS software version 10.0. Group IV (Citric acid + RealSeal SE) showed a statistically lower mean microleakage when compared to all other groups. From, the present study, it was concluded that, RealSeal SE sealer with 10% citric acid as irrigant (group IV) showed better apical sealability followed by RealSeal SE sealer with 17% EDTA as irrigant (group III), when compared to AH Plus groups which showed least sealability.