Preemptive Treatment Research Articles

Titin: The Missing Link in Cardiac Physiology

Titin, an extraordinary protein known for its colossal size and multifaceted roles, is a cornerstone in the structural and functional dynamics of striated muscle tissues, including the heart and skeletal muscles. Its sheer enormity, with a molecular weight exceeding 3000 kDa, is paralleled only by the immense influence it exerts on muscle physiology. This review will delve into the remarkable structural organization of Titin and the genetics of this molecule, including the common mutations resulting in various cardiomyopathies. We will delve deeper into its role in dilated cardiomyopathy, familial restrictive cardiomyopathy, hypertrophic cardiomyopathy, and left ventricular noncompaction cardiomyopathy. This review culminates by discussing the prospects of therapeutic strategies targeting Titin. While these interventions remain primarily theoretical, the possibilities are intriguing. Patients with Titin truncation mutations present unique challenges, but innovative approaches like gene therapy or preemptive treatments with drugs such as angiotensin-converting enzyme inhibitors or beta-blockers offer hope. This multi-pronged approach highlights the significance of understanding Titin’s multifaceted role and its potential as a target for future therapeutic interventions.

Intentional intoxication with monkshood plant leading to atrioventricular dissociation and ventricular ectopy in a 17-year-old female: a case report

BackgroundMonkshood, a toxic plant containing a potent cardio- and neurotoxin called aconitine, can lead to a range of symptoms, including nausea, vomiting, dizziness, seizures, and cardiac arrhythmias. Mortality associated with this intoxication are due to ventricular tachyarrhythmias which are difficult to treat and often refractory in nature.Case presentationWe present a case of a 17-year-old female patient who presented to the emergency department after intentionally ingesting a monkshood plant and developed atrioventricular dissociation and frequent ventricular ectopy. The patient was successfully treated with activated charcoal, supportive care, and cardiac monitoring.ConclusionThis case highlights the importance of early recognition of aconitine poisoning and the need for prompt supportive care, cardiac rhythm monitoring, and preemptive antiarrhythmic treatment planning.

Evaluation of the Occurrence and Risk Factors for Spontaneous Cytomegalovirus Clearance after Low Level Reactivation Using a Pre-Emptive Treatment Threshold of 4,000 IU/Ml in Seropositive Allogeneic Hematopoietic Cell Transplant Recipients Receiving Letermovir Prophylaxis

Evaluation of the Occurrence and Risk Factors for Spontaneous Cytomegalovirus Clearance after Low Level Reactivation Using a Pre-Emptive Treatment Threshold of 4,000 IU/Ml in Seropositive Allogeneic Hematopoietic Cell Transplant Recipients Receiving Letermovir Prophylaxis

Conversion to mTOR Inhibitor to Reduce the Incidence of Cytomegalovirus Recurrence in Kidney Transplant Recipients Receiving Preemptive Treatment: A Prospective, Randomized Trial.

Conversion to mTOR Inhibitor to Reduce the Incidence of Cytomegalovirus Recurrence in Kidney Transplant Recipients Receiving Preemptive Treatment: A Prospective, Randomized Trial.

Close monitoring and early intervention: management principles for cystic fibrosis in Denmark.

Cystic fibrosis (CF) care in Denmark has been characterized by close monitoring and pre-emptive treatment of lung disease and other CF-related complications. Continuous evaluation through data collection and commitment to clinical research has incrementally improved outcomes. This approach has been in line with best practices set forth by European Standards of Care but has also gone beyond Society standards particularly pertaining to early treatment with high-dose combination antimicrobial therapy. Despite a high prevalence of severe CF variants, lung function has been among the best in Europe. In this review, the Danish approach to management of CF prior to the introduction of new CF modulator treatment is explained and benchmarked. Downsides to the Danish approach are discussed and include increased burden of treatment, risk of antimicrobial resistance, side-effects and costs.

Outcome and Prognostic Factors of Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Relapsed or Refractory ETV6/RUNX1-Positive Acute Lymphoblastic Leukemia

Introduction: The role of haploidentical allogeneic hematopoietic stem cell transplantation (haplo-HSCT) in pediatric patients with relapsed or refractory (R/R) ETV6/RUNX1-positive acute lymphoblastic leukemia (ALL) is unclear. This study aimed to identify prognostic factors and explore the role of haplo-HSCT in the treatment of ETV6/RUNX1-positive ALL. Methods: We analyzed the clinical characteristics and treatment outcomes of 20 pediatric patients who were diagnosed with ETV6/RUNX1-positive ALL and received chemotherapy/chimeric antigen receptor T-cell bridged to haplo-HSCT between 2016 and 2021 at our institution. Results: With a median follow-up time of 47 months, the 3-year cumulative incidence of relapse, disease-free survival, and overall survival were 35.9% (95% confidence interval (CI): 15.3–57.1%), 59.1% (95% CI: 37.2–81.0%), and 75.0% (95% CI: 56.0–94.0%), respectively. Multivariate analysis revealed that pre-HSCT measurable residual disease (MRD) positivity (hazard ratio, 13.275; 95% CI: 2.406–73.243; p = 0.003) had a significant negative impact on relapse. A total of 7 patients experienced positive ETV6/RUNX1 gene expression at a median of 7.2 months after haplo-HSCT, and 5 of them experienced relapse at a median time of 12.1 months after haplo-HSCT. ROC curve analysis was performed to analyze the significance of pre-HSCT and post-HSCT ETV6/RUNX1 transcripts for predicting relapse; the AUC were 0.798 (95% CI: 0.567–1.0, p = 0.035) and 0.875 (95% CI: 0.690–1.0, p = 0.008), respectively. The optimal cut-off points to predict an inevitable relapse were 0.011% and 0.0019%, respectively. Conclusion: Patients with R/R ETV6/RUNX1-positive ALL may benefit from haplo-HSCT. Deeply eliminating pre-HSCT MRD and preemptive treatment for post-HSCT MRD may be crucial to further improving the prognosis.

Pre-emptive treatment of heart failure exacerbations in patients managed with the HeartLogic™ algorithm.

Heart failure (HF) is a chronic disease affecting 64 million people worldwide and places a severe burden on society because of its mortality, numerous re-hospitalizations and associated costs. HeartLogic™ is an algorithm programmed into implanted devices incorporating several biometric parameters which aims to predict HF episodes. It provides an index which can be monitored remotely, allowing pre-emptive treatment of congestion to prevent acute decompensation. We aim to assess the impact and security of pre-emptive HF management, guided by the HeartLogic™ index. The HeartLogic™ France Cohort Study is an investigator-initiated, prospective, multi-centre, non-randomized study. Three hundred ten patients with a history of HF (left ventricular ejection fraction ≤40%; or at least one episode of clinical HF with elevated NT-proBNP ≥450ng/L) and implanted with a cardioverter defibrillator enabling HeartLogic™ index calculation will be included across 10 French centres. The HeartLogic™ index will be monitored remotely for 12months and in the event of a HeartLogic™ index ≥16, the local investigator will contact the patient for assessment and adjust HF treatment as necessary. The primary endpoint is unscheduled hospitalization for HF. Secondary endpoints are all-cause mortality, cardiovascular death, HF-related death, unscheduled hospitalizations for ventricular or atrial arrhythmia and HeartLogic™ index evolution over time. Blood samples will be collected for biobanking, and quality of life will be assessed. Finally, the safety of a HeartLogic™-triggered strategy for initiating or increasing diuretic therapy will be assessed. A blind and independent committee will adjudicate the events. The HeartLogic™ France Cohort Study will provide robust real-world data in a cohort of HF patients managed with the HeartLogic™ algorithm allowing pre-emptive treatment of heart failure exacerbations.

Modified EASIX scores predict severe CRS/ICANS in patients with acute myeloid leukemia following CLL1 CAR-T cell therapy.

Chimeric antigen receptor T (CAR-T) cell therapy targeting CLL1 has been considered a potent weapon for patients with acute myeloid leukemia (AML). This study aims to evaluate the efficacy and toxicity of CLL1 CAR-T cell therapy in a larger cohort, with particular attention to cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Among the 32 patients assessed for efficacy, complete remission occurred in 71.88% (23/32) of cases and undetectable minimal residual disease in 14 patients. The CRS developed in all patients, with 8 individuals experiencing ICANS. Severe CRS and ICANS were observed in 11 and 2 patients, respectively. Furthermore, the Endothelial Activation and Stress Index (EASIX) and its derivatives measured before and after CLL1 CAR-T cell infusion were employed for predicting the severe complications. Significant differences were observed in EASIX scores on the day before lymphodepletion (Day BL, P = 0.023), -1 (P < 0.001), +1 (P < 0.001), and +3(P = 0.014); sEASIX scores on Day BL (P = 0.007), -1 (P < 0.001), +1 (P < 0.001), and +3 (P < 0.001); and mEASIX score on Day -1 (P = 0.004) between patients with mild and severe CRS/ICANS. Additionally, there was a significant difference in mEASIX scores between responders and non-responders on Day BL (P = 0.004) and Day -1 (P = 0.044). Our findings indicate that pre- and post-infusion assessments of EASIX/mEASIX/sEASIX scores serve as reliable prognostic indicators for severe CRS/ICANS and treatment response following CLL1 CAR-T cell therapy, which can assist physicians in implementing preemptive treatment strategies for potential severe complications and screening patients who are suitable candidates for CLL1 CAR-T cell therapy. EASIX/mEASIX/sEASIX scores serve as reliable prognostic indicators for severe CRS/ICANS following CLL1 CAR-T cell therapy. The preinfusion mEASIX scores of CLL1 CAR-T cells can effectively predict treatment response.

Preemptive administration of mesenchymal stem cells-derived conditioned medium can attenuate the development of neuropathic pain in rats via downregulation of proinflammatory cytokines

Neuropathic pain (NP) is a chronic condition characterized by persistent pain following nerve injury. It is a challenging clinical problem to manage due to limited treatment options. Mesenchymal stem cells (MSCs)-derived conditioned medium (CM) is a cell-free product that contains the secretome of MSCs and has been shown to have therapeutic potential in various inflammatory and degenerative disorders. Several animal studies have examined the antinociceptive effects of MSCs-CM on established neuropathic pain, but none have investigated the early prevention of neuropathic pain using MSCs-CM. Therefore, in this study, we tested whether preemptive administration of MSCs-CM could attenuate the development of NP in rats. To this end, NP was induced in Wistar rats using a chronic constriction injury (CCI) model (day 0), and then the animals were divided into four groups: Sham, CCI, CCI-Dulbecco's Modified Eagle Medium (DMEM), and CCI-CM. The CCI-CM group received 1 ml intraperitoneal administration of MSCs-CM on days − 1, 1, and 2, while the Sham, CCI, and CCI-DMEM groups received vehicle only (normal saline or DMEM). Mechanical withdrawal threshold and thermal withdrawal latency were assessed to evaluate pain sensitivities. In addition, the expression levels of proinflammatory cytokines (TNF-α and IL-1β) in the spinal cord tissues were measured using quantitative real-time PCR (qRT-PCR). The results demonstrated that preemptive treatment with MSCs-CM can significantly attenuate the development of NP, as evidenced by improved mechanical withdrawal threshold and thermal withdrawal latency in the CCI-CM group compared to the CCI and CCI-DMEM groups. Furthermore, the relative gene expression of proinflammatory cytokines TNF-α and IL-1β were significantly decreased in the spinal cord tissues of the CCI-CM group compared to the control groups. These findings suggest that preemptive administration of MSCs-CM can attenuate the development of NP in rats, partly due to the downregulation of proinflammatory cytokines.

Early Detection of Molecular Residual Disease and Risk Stratification for Children with Acute Myeloid Leukemia via Circulating Tumor DNA.

Patient-tailored minimal residual disease (MRD) monitoring based on circulating tumor DNA (ctDNA) sequencing of leukemia-specific mutations enables early detection of relapse for pre-emptive treatment, but its utilization in pediatric acute myelogenous leukemia (AML) is scarce. Thus, we aim to examine the role of ctDNA as a prognostic biomarker in monitoring response to the treatment of pediatric AML. A prospective longitudinal study with 50 children with AML was launched, and sequential bone marrow (BM) and matched plasma samples were collected. The concordance of mutations by next-generation sequencing-based BM-DNA and ctDNA was evaluated. In addition, progression-free survival (PFS) and overall survival (OS) were estimated. In 195 sample pairs from 50 patients, the concordance of leukemia-specific mutations between ctDNA and BM-DNA was 92.8%. Patients with undetectable ctDNA were linked to improved OS and PFS versus detectable ctDNA in the last sampling (both P < 0.001). Patients who cleared their ctDNA post three cycles of treatment had similar PFS compared with persistently negative ctDNA (P = 0.728). In addition, patients with >3 log reduction but without clearance in ctDNA were associated with an improved PFS as were patients with ctDNA clearance (P = 0.564). Thus, ctDNA-based MRD monitoring appears to be a promising option to complement the overall assessment of pediatric patients with AML, wherein patients with continuous ctDNA negativity have the option for treatment de-escalation in subsequent therapy. Importantly, patients with >3 log reduction but without clearance in ctDNA may not require an aggressive treatment plan due to improved survival, but this needs further study to delineate.

Camrelizumab for Preemptive Treatment of Molecular Recurrence after Allogeneic Hematopoietic Stem Cell Transplantation in Core-Binding Factor Acute Myeloid Leukemia: Two Case Reports

Camrelizumab for Preemptive Treatment of Molecular Recurrence after Allogeneic Hematopoietic Stem Cell Transplantation in Core-Binding Factor Acute Myeloid Leukemia: Two Case Reports

Concomitant use of pre-emptive analgesia with local and general anesthesia in rat uterine pain surgical model.

Preemptive analgesia is used for postoperative pain management, providing pain relief with few adverse effects. In this study, the effect of a preemptive regime on rat behavior and c-fos expression in the spinal cord of the uterine surgical pain model was evaluated. It was a lab-based experimental study in which 60 female Sprague-Dawley rats; eight to 10 weeks old, weighing 150-300 gm were used. The rats were divided into two main groups: (i) superficial pain group (SG) (with skin incision only), (ii) deep pain group (with skin and uterine incisions). Each group was further divided into three subgroups based on the type of preemptive analgesia administered i.e., "tramadol, buprenorphine, and saline subgroups." Pain behavior was evaluated using the "Rat Grimace Scale" (RGS) at 2, 4, 6, 9 and 24 h post-surgery. Additionally, c-fos immunohistochemistry was performed on sections from spinal dorsal horn (T12-L2), and its expression was evaluated using optical density and mean cell count 2hours postoperatively. Significant reduction in the RGS was noted in both the superficial and deep pain groups within the tramadol and buprenorphine subgroups when compared to the saline subgroup (p ≤ .05). There was a significant decrease in c-fos expression both in terms of number of c-fos positive cells and the optical density across the superficial laminae and lamina X of the spinal dorsal horn in both SD and DG (p ≤ .05). In contrast, the saline group exhibited c-fos expression primarily in laminae I-II and III-IV for both superficial and deep pain groups and lamina X in the deep pain group only (p ≤ .05). Hence, a preemptive regimen results in significant suppression of both superficial and deep components of pain transmission. These findings provide compelling evidence of the analgesic efficacy of preemptive treatment in alleviating pain response associated with uterine surgery.

Invasive fungal infections in critically ill children: epidemiology, risk factors and antifungal drugs.

Invasive fungal infections (IFIs) are important infectious complications amongst critically ill children. The most common fungal infections are due to Candida species. Aspergillus, Zygomycetes and Fusarium are also emerging because of the empirical use of antifungal drugs. This updated review discusses the epidemiology of IFIs as well as antifungal drugs, dosing and potential adverse effects in critically ill children. A PubMed search was conducted with Clinical Queries using the key terms "antifungal", "children", "critical care" AND "paediatric intensive care unit" OR "PICU". The search strategy included clinical trials, randomized controlled trials, meta-analyses, observational studies and reviews and was limited to the English literature in paediatrics. Candida and Aspergillus spp. are the most prevalent fungi in paediatric IFIs, causing invasive candidiasis infections (ICIs) and invasive aspergillosis infections (IAIs), respectively. These IFIs are associated with high morbidity, mortality and healthcare costs. Candida albicans is the principal Candida spp. associated with paediatric ICIs. The risks and epidemiology for IFIs vary if considering previously healthy children treated in the paediatric intensive care unit or children with leukaemia, malignancy or a severe haematological disease. The mortality rate for IAIs in children is 2.5-3.5-fold higher than for ICIs. Four major classes of antifungals for critically ill children are azoles, polyenes, antifungal antimetabolites and echinocandins. Antifungal agents are highly efficacious. For successful treatment outcomes, it is crucial to determine the optimal dosage, monitor pharmacokinetics parameters and adverse effects, and individualized therapeutic monitoring. Despite potent antifungal medications, ICIs and IAIs continue to be serious infections with high mortality rates. Pre-emptive therapy has been used for IAIs. Most guidelines recommend voriconazole as initial therapy of invasive aspergillosis in most patients, with consideration of combination therapy with voriconazole plus an echinocandin in selected patients with severe disease. The challenge is to identify critically ill patients at high risks of ICIs for targeted prophylaxis. Intravenous/per os fluconazole is first-line pre-emptive treatment for Candida spp. whereas intravenous micafungin or intravenous liposomal amphotericin B is alternative pre-emptive treatment.This article is part of the Challenges and strategies in the management of invasive fungal infections Special Issue: https://www.drugsincontext.com/special_issues/challenges-and-strategies-in-the-management-of-invasive-fungal-infections.

Adoptive transfer of CMV-specific TCR-T cells for the treatment of CMV infection after haploidentical hematopoietic stem cell transplantation

BackgroundCytomegalovirus (CMV) reactivation after unmanipulated haploidentical stem cell transplantation (SCT) frequently occurs, causing life-threatening morbidities and transplantation failure. Pre-emptive therapy upon the detection of CMV viremia using antiviral agents is...

Pain@home: An integrated, holistic, multimodal, digital approach to the prevention of chronic pain.

Chronic pain is one of the most debilitating medical conditions and one of the greatest medical challenges globally. In Western countries, almost 25% of adults are suffering from recurrent and prolonged pain symptoms. Chronic pain has a huge negative impact on the quality of life of patients, such as sleep disturbances, limitation in daily activities, and prolonged sick leaves. &#x0D; The best treatment for chronic pain is preventing it from occurring in the first place through an aggressive and multimodal approach to acute pain conditions. Such an approach has been previously described as pre-emptive analgesia. Despite multiple previous research projects, the ideal approach to the prevention of chronic pain has still not been identified. We hereby propose an integrated, multidisciplinary approach to the prevention of long-lasting pain syndromes. &#x0D; This innovative approach was previously tested and refined in patient populations at high risk of developing chronic pain, such as adolescents undergoing pectus operations, and young adults undergoing scoliosis correction procedures. Its rationale is based on the early activation of a digital follow-up before the nociceptive insult has even occurred. At the moment a potential future pain-inducing medical act has been identified (eg surgical procedure, initiation of chemotherapy or radiotherapy, traumatic injury) inclusion in digital long-term monitoring is initiated. The first step in the follow-up consists of the identification of patient-specific risk factors through the application of a validated nociceptive risk identification survey. After an individual risk profile has been completed a daily follow-up is initiated through the application of diaries. &#x0D; After that, a personalized anti-nociceptive approach is conceptualized. One of the major risk factors for the chronification of pain is the presence of fear or catastrophizing behavior. If these are identified during the pre-operative screening process, an integrated and multidisciplinary approach will be tailored to tackle these problems at the individual level. In addition, the interval between the initiation of the follow-up and the start of the medical treatment is used to start a pre-emptive treatment (in most cases gabapentin). Furthermore, educational material is provided to the participating patients in order to educate them on crucial matters such as the pathophysiology of pain, the importance of physical activities, and training in coping strategies.&#x0D; &#x0D; At the moment of hospitalization, patients receive a personalized pain treatment regimen based on the pre-op home-based assessment. Experience has learned us that this improves the health-related quality of life of patients while reducing length of stay significantly. &#x0D; After discharge from the hospital, remote monitoring is reinitiated. Patients are kept under digital supervision during the entire postoperative period, with multidisciplinary support and a strong focus on the functional reintegration of the concerned patients. When functional outcomes are obtained and the use of analgesics is stopped then the remote follow-up is discontinued.&#x0D; The described care pathway is an innovative approach to the prevention of chronic pain. All healthcare providers are gathered around the patient, who is treated as much as possible in a trusted home environment. The application of digital technologies creates a unique opportunity for this long-term interdisciplinary approach.

Tolvaptan: a possible preemptive treatment option in children with autosomal dominant polycystic kidney disease?

Tolvaptan is a highly selective vasopressin receptor 2 antagonist that regulates cyclic adenosine monophosphate levels to inhibit both epithelial cell proliferation and chloride ion excretion, two mechanisms known to induce cyst expansion in autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan is currently the preferred treatment of rapidly progressive disease ADPKD in adult patients; however, since cyst formation in ADPKD begins early in life, (frequently in utero), and significant disease progression with cyst expansion occurs in the first decade, tolvaptan may be advantageous as a preemptive treatment in children with ADPKD. Tolvaptan has already been used to successfully treat refractory edema or hyponatremia in children; this literature review provides insight into the biochemical basis of its action to contextualize its use in the pediatric population.

Rectal culture could predict carbapenem-resistant organism bloodstream infection and reduce the mortality in haematological patients: A retrospective cohort study

The objective is to explore the correlation between rectal swab culture and the overall 30-d survival of hematologic patients diagnosed with carbapenem-resistant organism (CRO) bloodstream infection. A total of 434 haematological patients who were complicated with Gram-negative bacilli (GNB) bloodstream infections (BSIs) caused by Gram-negative bacteria between January 2020 and December 2021 were included in our retrospective study. Based on their drug susceptibility results, we classified patients into CRO BSIs and non-CRO BSIs cases. Through group comparison, to uncover the correlation between the positive screening of rectal swabs and reducing the mortality of CRO BSI in patients with haematological diseases. Among the 434 cases of Gram-negative bacteria bloodstream infection, 96 were identified as carbapenem-resistant bloodstream infection, which consisted of 57 cases of carbapenem-resistant Klebsiella pneumoniae (CR-KP), 19 cases of carbapenem-resistant Pseudomonas aeruginosa (CR-PA), 11 cases of carbapenem-resistant Escherichia coli (CR-CO), 5 cases of carbapenem-resistant Acinetobacter baumannii (CR-AB), and 4 cases of other Enterobacteriaceae. Before the onset of CRO bloodstream infection, rectal swab cultures were conducted on 36 patients, and the positive result rate was 75.0% (27/36), with 20 cases of CR-KP, 6 cases of CR-CO, and one case of carbapenem-resistant Enterobacter cloacae. It was observed that the rectal and blood cultures had matching outcomes in 75.0% of cases. The mortality rate within 30 d for CRO BSIs was 53.1% (51/96), while for carbapenem-resistant Enterobacteriaceae (CRE) BSIs it was 62.5% (45/72). Univariate analysis showed that 30-d mortality was significantly reduced when there were positive rectal culture results preceding bloodstream infection (P < 0.001), as well as preemptive anti-infection treatment (P < 0.001). Multivariate analysis demonstrated that preemptive adjustment to an effective antibiotic regimen, guided by positive rectal culture results, had a significant effect on decreasing 30-d mortality following CRO BSIs (P= 0.002). Furthermore, for the management of CRE BSIs, antibiotic treatments utilising ceftazidime/avibactam (CAV/AVI) may be more beneficial compared to those that use tigecycline (TGC) or polymyxin (PMB). CRO BSI, especially CRE BSI, can be life-threatening for those with haematological diseases. Utilising rectal culture can effectively identify CRO strains with high sensitivity and specificity. Adjusting antibiotic treatment based on the preemptive positive rectal culture results may significantly decrease 30-d mortality rates for haematological patients with CRO BSIs.

Identification and surveillance of rare relapse-initiating stem cells during complete remission after transplantation

AbstractRelapse after complete remission (CR) remains the main cause of mortality after allogeneic stem cell transplantation for hematological malignancies and, therefore, improved biomarkers for early prediction of relapse remains a critical goal toward development and assessment of preemptive relapse treatment. Because the significance of cancer stem cells as a source of relapses remains unclear, we investigated whether mutational screening for persistence of rare cancer stem cells would enhance measurable residual disease (MRD) and early relapse prediction after transplantation. In a retrospective study of patients who relapsed and patients who achieved continuous-CR with myelodysplastic syndromes and related myeloid malignancies, combined flow cytometric cell sorting and mutational screening for persistence of rare relapse-initiating stem cells was performed in the bone marrow at multiple CR time points after transplantation. In 25 CR samples from 15 patients that later relapsed, only 9 samples were MRD-positive in mononuclear cells (MNCs) whereas flowcytometric-sorted hematopoietic stem and progenitor cells (HSPCs) were MRD-positive in all samples, and always with a higher variant allele frequency than in MNCs (mean, 97-fold). MRD-positivity in HSPCs preceded MNCs in multiple sequential samples, in some cases preceding relapse by >2 years. In contrast, in 13 patients in long-term continuous-CR, HSPCs remained MRD-negative. Enhanced MRD sensitivity was also observed in total CD34+ cells, but HSPCs were always more clonally involved (mean, 8-fold). In conclusion, identification of relapse-initiating cancer stem cells and mutational MRD screening for their persistence consistently enhances MRD sensitivity and earlier prediction of relapse after allogeneic stem cell transplantation.

Approach to multidrug resistant infections in pediatric transplant recipients.

There is increasing recognition of infections due to multidrug-resistant Gram negative (MDRGN) bacterial infections among children undergoing solid organ and hematopoietic cell transplantation, which may be associated with morbidity and mortality. We present two vignettes that highlight the clinical challenges of evaluation, management, and prevention of MDRGN bacterial infections in children prior to and after transplantation. The goal of this discussion is to provide a framework to help develop an approach to evaluation and management of these infections. Source control remains the utmost priority in management of MDR infections and is paired with antibiotic selection guided by in vitro susceptibilities, adverse effect profiles, and clinical response. Identification and confirmation of resistance can be challenging and often requires additional testing for recognition of complex mechanisms. Current antimicrobial approaches to MDRGN infections include use of novel agents, prolonged infusion, and/or combination therapy. We also discuss preventative efforts including infection control, antimicrobial stewardship, targeted pre-emptive or prophylactic treatment, and decolonization. The impact of MDRGN infections on patient and graft survival highlights the need to optimize treatment and prevention strategies.

Evaluation of the additional prophylactic effect of topical steroid ointment to systemic minocycline against anti-epidermal growth factor antibody-induced skin toxicities in metastatic colorectal cancer treatment.

Anti-epidermal growth factor receptor (EGFR) antibodies often cause skin toxicities. Preemptive skin treatments using systemic antibiotics with or without topical steroid are reportedly effective although the most suitable method remains unclear. This study aimed to determine whether combination prophylaxis using systemic minocycline and topical steroid is superior to minocycline alone in a real-world metastatic colorectal cancer (mCRC) treatment. Patients with mCRC (n = 87) who received anti-EGFR monoclonal antibodies were retrospectively assessed. The primary objective was to compare the incidence of grade ≥ 2 overall skin toxicities during all treatment periods between the control group receiving prophylactic minocycline 100 mg/day, and the combination prophylaxis group receiving minocycline 100 mg/day + topical steroid. The incidence of each skin symptom was also evaluated. The incidence of grade ≥ 2 overall skin toxicities was 63.6% in the control and 56.9% in the combination groups, with no significant difference (P = 0.63). Similarly, the incidence of grade ≥ 2 dry skin, fissures, paronychia, and pruritus did not significantly differ. In addition, incidence of all-grade skin toxicities was not different. However, the incidence of grade ≥ 2 papulopustular rashes was significantly lower in the combination group (23.1% vs. 50.0%, P = 0.03). Propensity score-matched analysis supported these results. Multivariate logistic regression analysis showed no significant association between combination prophylaxis and grade ≥ 2 overall skin toxicities, but it did show a reduction in grade ≥ 2 papulopustular rashes. Adding topical steroids to systemic minocycline did not mitigate grade ≥ 2 overall skin toxicities induced by anti-EGFR antibodies; however, it significantly improved papulopustular rashes.