Failure Of Therapy Research Articles

Predictive factors for failure of neoadjuvant docetaxel, cisplatin, and 5-fluorouracil therapy in esophageal squamous cell carcinoma.

Recently, neoadjuvant chemotherapy comprising docetaxel, cisplatin, and 5-fluorouracil showed promising efficacy for esophageal squamous cell carcinoma. However, some patients do not achieve curative resection despite neoadjuvant chemotherapy using these drugs. This study aimed to clarify the pretherapeutic characteristics of these patients. We included 113 patients who underwent neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil for potentially resectable esophageal squamous cell carcinoma and compared the clinical characteristics between patients who achieved curative resection (curative group) and those who failed to achieve curative resection after planned neoadjuvant chemotherapy (noncurative group). Moreover, we determined the factors predicting noncurative outcomes. Ninety-one (81%) and 22 patients (19%) were in the curative and noncurative groups, respectively. The noncurative group had significantly more tumors located in the upper third of the esophagus, larger-sized tumors, and borderline resectable tumors than the curative group (P = 0.003, 0.049, and <0.001, respectively). Moreover, the noncurative group had significantly higher serum squamous cell carcinoma antigen concentrations than the curative group (P = 0.008). Multivariable analysis identified tumor location in the upper third of the esophagus (odds ratio 7.31, P = 0.002), tumor size ≥50mm (odds ratio 4.71, P = 0.037), and borderline resectable tumors (odds ratio 6.65, P = 0.003) as independent predictors for noncurative outcomes. Tumor location in the upper third of the esophagus, larger-sized tumors, and borderline resectable tumors might be significant predictors for noncurative outcomes in patients who received neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil.

Application of the TIDieR checklist to improve the HFNC use in bronchiolitis management.

Our results suggest complete reporting of our TIDieR checklist in future studies may improve the quality of the research on HFNC use in children with bronchiolitis. Ourfindings encourage researchers to clarify the personalization of treatment administration andto better define the criteria for treatment failure. The adoption of universal definitions in thisfield is needed to increase the results' comparability and create standardized protocols.Researchers may use the proposed TIDieR checklist to develop, conduct and report clinicalresearch into HFNC and bronchiolitis as this may help to create a consensus for establishingan evidence-based protocol for HFNC. • High-flow nasal cannula (HFNC) is a common device used in children with bronchiolitis in the presence of respiratory distress, after the failure of standard oxygen therapy. However, no evidence-based and standardized protocol for the use of this device is globally available. • By using an adapted Template for Intervention Description and Replication (TIDieR) checklist to review previous studies on HFNC in bronchiolitis, we found a global heterogeneity in the description of interventions with some items of the checklist poorly reported. Thus, we suggest using our TIDieR checklist for developing, conducting and reporting clinical research into HFNC and bronchiolitis as this may help to create a consensus for establishing an evidence-based protocol for HFNC.

Experience of Metronidazole Triple Therapy After Clarithromycin Triple Therapy Failure for Helicobacter pylori Eradication in Korea

Background/Objectives: Bismuth quadruple therapy (BQT) is recommended as the best second-line regimen after failure of first-line clarithromycin triple therapy (CTT) for Helicobacter pylori eradication. However, there are some limitations to this approach, including the lack of an appropriate sequel regimen after failure of BQT and complicated administration. Metronidazole triple therapy (MTT) is simple to administer, but it is not widely recommended. This study was conducted to determine the efficacy of MTT as second-line regimen for H. pylori eradication after failure of CTT. Methods: We retrospectively reviewed the medical records of the Korean patients with H. pylori infection who underwent second-line treatment after failure of first-line CTT from October 2013 to October 2019. The efficacy of MTT and BQT for H. pylori eradication was compared. Results: The eradication rate in the BQT group tended to be higher than that in the MTT group; however, the difference was not statistically significant (208/233, 89.3% versus 244/284, 85.9%, p = 0.287). Among 40 patients with second-line MTT eradication failure, 21 received the third-line BQT, and 15 showed successful eradication (15/21, 71.4%). In the men 70 years or older, the eradication rate of MTT was lower than that of BQT without statistical significance (75.8% versus 94.1%, p = 0.141). Conclusions: These findings suggested that MTT could be a second-line treatment option, reserving BQT for Helicobacter pylori eradication after first line CTT failure, except in elderly men 70 years or older.

Real-World Comparison of Maribavir to Foscarnet for the Treatment of Cytomegalovirus in Solid Organ and Hematopoietic Stem Cell Transplant Recipients

Cytomegalovirus (CMV) infection in solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients may increase the risk of rejection or allograft dysfunction, other infection(s), and morbidity and mortality. Treatment can be challenging due to medication-associated toxicities. Maribavir (MBV) is a promising option for the treatment of resistant or refractory (R/R) CMV infection in lieu of foscarnet (FOS), which has long been the recommended therapy for (val)ganciclovir-resistant infection. This was a single-center retrospective study of clinical outcomes of patients who received MBV compared to a control group who received FOS for an episode of CMV infection. Each cohort consisted of 27 episodes of CMV infection. Twenty patients in the MBV cohort and from the FOS cohort cleared the infection, with five and three patients developing MBV or FOS resistance, respectively. There were no statistically significant differences in failure of therapy as evidenced by persistent DNAemia (p = 0.56) or development of antiviral resistance (p = 0.24). In conclusion, MBV was as effective as FOS for the treatment of R/R CMV infection and was better tolerated without increased risk of antiviral resistance.

Low-osmolarity oral rehydration solution for childhood diarrhoea: A systematic review and meta-analysis.

Oral rehydration solution (ORS) is crucial in the management of diarrhoea. Until the early 2000s, the standard formulation of glucose-based ORS with a total osmolarity of 311 mmol/L was being used for this purpose. However, due to concerns about sodium levels and cases of hypernatremia, a low-osmolarity ORS solution (LORS) with an osmolarity of 245mmol/L or less was developed to replace the standard ORS. With this systematic review, we aimed to assess the effectiveness of LORS compared to standard ORS for the treatment of acute and persistent diarrhoea. We comprehensively searched PubMed, CINAHL, the Cochrane Library, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform, and Scopus until 20 July 2023 for studies published after 1990 assessing the efficacy of LORS in acute and persistent diarrhoea in children under 10 years of age. Meta-analysis was conducted using the RevMan software. We performed log approximation for all the values for an outcome when studies reported arithmetic and geometric means per the Cochrane Handbook. We otherwise used the Cochrane Risk of Bias II tool to assess the risk of bias in individual studies, and assessed the quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluations approach. This review was commissioned by the WHO for revision of guidelines for childhood diarrhoea. For the comparison of LORS to standard ORS in acute diarrhoea, our findings suggest that there was a significant decrease in the duration of diarrhoea (mean difference (MD) = -0.28; 95% confidence interval (CI) = -0.41, -0.15; moderate certainty of evidence), stool output (MD = -0.25; 95% CI = -0.35, -0.16; very low certainty of evidence), and ORS intake (MD = -0.18; 95% CI = -0.28, -0.07; moderate certainty of evidence) in patients receiving LORS. There was a comparable effect on the number of patients cured within five days, treatment failure, and frequency of unscheduled intravenous therapy (risk ratio (RR) = 0.77; 95% CI = 0.72, 9.38; low certainty of evidence). For persistent diarrhoea, there was a significant decrease in duration of diarrhoea (MD = -30.60; 95% CI = -48.95, -12.25), stool output (MD = -14.00; 95% CI = -26.63, -1.37), and ORS intake (MD = -21.40; 95% CI = -41.01, -1.79), while there was a comparable effect on the number of patients cured. Our findings suggest that LORS should continue to be recommended in children under the age of 10 years with acute watery or persistent diarrhoea and upholds the current WHO recommendations. PROSPERO: CRD42023438762.

Prognostic Role of Lung-Ultrasound Score in Acute Bronchiolitis Patients Treated With High Flow Nasal Cannula: A Prospective Study.

Lung ultrasound (LUS) has emerged as a reliable, noninvasive tool for bedside assessment of acute bronchiolitis (AB) in infants. Its role in guiding therapeutic decisions is increasingly recognized. This study aimed to determine the predictive value of LUS in identifying infants with AB at risk of HFNC therapy failure. This prospective, single-center study was conducted in the pediatric department of Fattouma Bourguiba Hospital in Monastir from January 2022 to March 2024. Infants under 12 months hospitalized with moderate to severe AB and requiring HFNC therapy were enrolled. LUS was performed within 3-6 h of HFNC initiation and repeated 24 h later. Clinical and laboratory data, including the Wang score and LUS findings, were analyzed to predict HFNC failure. Among 124 enrolled infants, 98 (79%) responded successfully to HFNC therapy, while 26 (21%) failed. Baseline characteristics, including age, weight, and clinical symptomes, were comparable between groups, except for a higher Wang score in the failure group (p = 0.008). LUS scores were significantly higher in the failure group on both day 1 and day 2 (p < 0.001), with a more pronounced score progression (p < 0.001). ROC analysis identified a LUS score > 7 on day 1 and > 9 on day 2 as predictive thresholds for HFNC failure. Multivariate analysis confirmed the day 2 LUS score as an independent predictor of HFNC failure (p = 0.022). LUS is a valuable prognostic tool in infants with AB undergoing HFNC therapy. Incorporating LUS into routine clinical assessments may help predict therapy failure early, allowing timely escalation of care.

Hyaluronic acid-functionalized MOFs for combined sunitinib and siRNA therapy in renal cell carcinoma

Sunitinib is a first-line treatment for renal cell carcinoma (RCC), but suffers from drug resistance, causing therapy failure. Therefore, nano-scale delivery systems should be introduced for targeted delivery. Metal-organic frameworks (MOFs) are attractive drug carriers that not only enable multidrug combination therapies but also exert photodynamic effects by incorporating photosensitizers as components. Here, a Zr-based porphyrinic nanoscale MOF, PCN224, was prepared as the carrier for the co-delivery of sunitinib and the siRNA against vascular endothelial growth factor receptor-2 (VEGFR-2). Drug-loaded PCN-224 is coated with hyaluronic acid (HA) to prevent drug molecular leakage and to exert tumor-targeting effects (CD44 in tumor cells). Photodynamic therapy was conducted under 660 nm laser (50 mW·cm−2, 10 min) irradiation. Compared with St/siVEGFR-2@PCN-224@HA without the HA coating, St/siVEGFR-2@PCN-224@HA significantly suppressed cell viability and promoted cell apoptosis. Laser irradiation further increased the anti-cancer effect of St/siVEGFR-2@PCN-224@HA by generating cytotoxic ROS. H&E staining of major organs revealed no signs of damage, indicating the biosafety of St/siVEGFR-2@PCN-224@HA. The prepared St/siVEGFR-2@PCN-224@HA system enables triple inhibition of tumor growth via a combination of targeted therapy and genetic and photodynamic therapy to enhance the therapeutic effects on RCC.

Examining effective monotherapy hypothesis for TB therapy failure and resistance emergence.

<sec><title>BACKGROUND</title>We tested the hypothesis that because of the different metabolic states of Mycobacterium tuberculosis (Mtb) in lesions, drugs in combination therapy often act effectively as monotherapy, leading to therapy failure and resistance emergence.</sec><sec><title>METHODS</title>Bactericidal and sterilizing activity studies were performed in the hollow fiber system of TB (HFS-TB) using the human equivalent dose of isoniazid (INH) 300 mg/day, rifampin (RIF) 600 mg/day, and pyrazinamide (PZA) 1.5 g/day either as monotherapy, two-, and three-drug combination for 28 days. The Mtb population (log10 CFU/ml) for each drug, either monotherapy or combination, was compared using an analysis of variance.</sec><sec><title>RESULTS</title>In the bactericidal activity studies, the microbial kill was driven by INH, followed by RIF, and PZA monotherapy failed. During the sterilizing activity, INH and RIF displayed similar microbial kill. The INH + RIF and RIF + PZA combinations were significantly different from each other but not from the INH + RIF + PZA combination. RIF and INH-resistant subpopulations did not increase despite premixing the inoculum with isogenic-resistant strains.</sec><sec><title>CONCLUSION</title>Effective monotherapy arising from the selectivity of antibiotics against special Mtb sub-populations may not be the primary mechanism of resistance emergence. Different metabolic populations of Mtb were killed by more than one drug and were not under monotherapy when combination therapy was administered.</sec>.

Clinical Value of HACOR Score in Predicting High Flow Nasal Oxygen Therapy Failure in Hypoxemic Patients

Objective: To assess the sensitivity of the HACOR score in successfully predicting high flow nasal oxygen (HFNO) failure in acute hypoxemic patients. Methodology: A Prospective observational study was conducted at Critical care departments of Combined Military Hospital, Lahore, Okara and Rahim Yar Khan from Jan-Dec 2023. A total of 390 patients diagnosed as having acute hypoxemic respiratory failure (PaO2&lt;60 mm Hg and/or pH &lt;7.35) were selected and started on HFNO therapy. Primary variables studied were the sensitivity and specificity of the HACOR score in predicting HFNO failure after the first hour of therapy . Secondary variables studied compared the improvement in HACOR parameters after 1-hour of HFNO therapy in those patients who has success with HFNO. Results: While assessing the power of the HACOR score in predicting failure of HFNO therapy with scores obtained after one hour, the area under the curve showed a value of 0.88 showing a good predictive power of failure for the test. A cut off value &gt;6 was able to predict failure with a sensitivity of 85.9%, specificity of 93.8% with a positive and negative predictive value of 96.6% and 76.4% respectively Conclusion: We conclude the HACOR score as a useful method with a cut-off value of more than 6 predicting a failure rate to HFNO to be &gt; 86% after 1 hour of therapy. Key Words: Failure, HACOR, HFNO, Hypoxemic

Oxygenation indices and early prediction of outcome in hypoxemic patients with COVID-19 pneumonia requiring noninvasive respiratory support in pulmonary intermediate care unit

BackgroundEarly prediction of non-invasive respiratory therapy (NIRT) failure is crucial to avoid needless prolongation of respiratory support and delayed endotracheal intubation. Data comparing the predictive value of oxygenation indices (OI) in COVID-19 receiving NIRT are scant.The aim of this monocentric retrospective study of prospectively collected data was to assess the effectiveness of different OI in predicting NIRT outcome at baseline (t0), 12 h (t12) and 24 h (t24) of treatment in hypoxemic patients with COVID-19-related pneumonia, managed in a Pulmonary Intermediate Care Unit (October 2020-June 2021).MethodsWe assessed the predictive value of SpO2/FiO2, PaO2/FiO2, standardised PaO2/FiO2 ratio (s-PaO2/FiO2), respiratory index (RI), arterial–alveolar oxygen gradient (a-ADO2), age adjusted arterial–alveolar oxygen ratio (adj-a-ADO2D). Receiver operating characteristics (ROC), AUC and best sensitivity–specificity cut-off values were calculated at t0, t12, t24. NIRT failure risk was adjusted for non-oxygenation predictors.ResultsAmong 590 patients with COVID-19 infection, 368 met the eligibility criteria for inclusion in the study [mean (CI95%): PaO2/FiO2 214(206,8–221,9); PaCO2 mean 32,9 mmHg,(32,4–33,4)]. NIRT failure and hospital mortality rate were 23,4% and 19,6%, respectively. Older age, male gender, agitation/confusion, need for sedation, inability to tolerate prone positioning were independent predictors of NIRT failure. SpO2/FiO2, a-ADO2 and adj-aADO2 at t12 and t24, PaO2/FiO2 and RI at t24 were associated with NIRT failure. Prognostic predictivity of OI increased from t0 to t24. Greater ROC-AUC values were obtained with SpO2/FiO2 0,662 (0,60–0,72) (t0), PaO2/FiO2 0,697 (0,63–0,76) (t12) and s-PaO2/FiO2 0,769 (0,71–0,83) (t24). NIRT failure was independently predicted by PaO2/FiO2, s-PaO2/FiO2 and RI at any observation time and by SpO2/FiO2 and O2 gradients respectively at t0 and t24. SaO2/FiO2 ≤ 300 (t0), PaO2/FiO2 ≤ 151,7 (t12) and s-PaO2/FiO2 ≤ 160,4 (t24) turned out to be the best predictors of NIRT outcome.ConclusionsOI showed different effectiveness in predicting NIRT failure within 24 h of treatment in COVID-19 related pneumonia. This may be due to the multi-factorial pathophysiology of hypoxemia. Our study empathises furthermore the role of non-oxygenation-related parameters in contributing to the outcome. These findings may be useful to build a predictive model also in no COVID-19 related hypoxemic pneumonia.

Jack Surgery: Reconstructing Collapsed Femoral Head in Association Research Circulation Osseous Stage III Osteonecrosis: A Series of 13 Cases.

According to Association Research Circulation Osseous (ARCO) staging, patients with ARCO III osteonecrosis of femoral head (ONFH) have joint pain and dysfunction due to the collapse of femoral head. Current hip preservation surgeries are not satisfying in the treatment of ARCO III ONFH according to the long-term follow-up. In our practice, we focused on reconstructing femoral head by restoring the round shape of femoral head and subsequently preventing the development of hip arthritis. To lift the collapsed femoral head and postpone the potential total hip arthroplasty, we practiced Jack surgery, combining surgical hip dislocation, removal of necrotic bone, impaction bone grafting, and lifting the cartilage of femoral head. From February 2019 to July 2022, 13 patients (15 hips) who received Jack surgery in the research center were included in this retrospective study. Follow-up was conducted every 3 months after surgery for imaging and clinical evaluation. The differences between visual analogue scale (VAS) and Harris hip score (HSS) before and after surgery were compared to observe whether the femoral head collapsed and whether osteotomy healed after surgery. Severe collapse of the femoral head ( > 2 mm) or receiving total hip arthroplasty (THA) was defined as failure of hip preservation therapy. An Independent sample t-test was used to compare the data, and the chi-square test was used for categorical data. All the 13 patients successfully completed the surgery and were followed up. The average time of follow-up was 36.46 ± 16.87 months (ranging from 14 to 66 months). HSS was assessed 12 months after surgery: excellent in 1 patient with 1 hip; good in 9 patients with 11 hips; modest in 3 patients with 3 hips. To the last follow-up, the VAS scores decreased from 6.17 ± 1.02 to 2.08 ± 0.90 (p < 0.001), HSS increased from 46.69 ± 4.15 to 89.77 ± 2.86 (p < 0.001). No deep infection, fracture, osteotomy nonunion, nerve injury, deep vein thrombosis, pulmonary embolism, or other complications occurred. For young patients with ONFH of ACRO III, this surgical technique can effectively restore the original shape of the femoral head and achieve satisfactory hip function in the short term. The mechanism is similar to jacking the roof of a house; thus, we named it "Jack surgery".

Pigmented pathological type and depth of follicular extension as predictors of treatment failure in 5-aminolevulinic acid photodynamic therapy for actinic keratosis: A retrospective, matched nested case-control study

Background: While 5-Aminolevulinic acid photodynamic therapy (ALA-PDT) is widely used to treat actinic keratosis (AK), treatment resistance and recurrence after ALA-PDT remain significant clinical challenges. Methods: This single-site, retrospective, matched case-control study included 119 patients with histologically confirmed AK to identify clinical and pathological predictors for effectiveness of ALA-PDT. Patients received four consecutive ALA-PDT sessions at intervals of 1 or 2 weeks. Initial complete clearance (ICC) at 3 months and sustained complete clearance (SCC) at 12 months were assessed. Case patients were those with treatment-resistant or recurrent AK, matched with controls based on age, sex, and the treatment date. Baseline characteristics were collected and compared between the case and control groups. Results: ICC at 3 months was achieved in 106 out of 119 patients (89.07%), with 65 out of 82 patients (79.27%) maintaining SCC at 12 months. Pigmented AK emerged as an independent predictor of treatment resistance (OR=44.05, p=0.00). Furthermore, follicular extension to the isthmus or deeper was significantly associated with recurrence within 1 year (OR=17.26, p=0.00). Conclusion: Pigmented AK and AK with follicular extension to the isthmus or deeper may serve as independent predictors of treatment resistance and recurrence, respectively. These findings highlight the importance of these specific features when assessing prognosis and tailoring treatment strategies for individual AK patients.

Efficacy of ceftazidime-avibactam with or without polymyxin for carbapenem-resistant Klebsiella pneumoniae infections after initial treatment with polymyxin.

Although polymyxins are a suboptimal option for difficult-to-treat resistant infections, they are still preferred as the first-line treatment, especially in low- and middle-income countries. This study assesses the efficacy of ceftazidime-avibactam (CAZ-AVI) following polymyxin B failure in patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) infections. We retrospectively reviewed cases of infections caused by CRKP in adults who received CAZ-AVI as salvage therapy. Clinical features and outcomes were described, and a logistic regression model was used to assess the risk factors associated with in-hospital crude mortality. One hundred and six patients were included in this study. The median age was 56 years. The most common infectious sites were lung. The patients received CAZ-AVI as salvage therapy for a median duration of 9 days following initial treatment with polymyxin B (median, 12.5 days). Also, 91 (85.8%) patients received CAZ-AVI combination therapy, and 34 (32.1%) patients received CAZ-AVI in combination with polymyxin B. The rate of in-hospital crude mortality was 25.5% (27/106), with the highest rate observed in patients treated with regimens containing polymyxin B (41.2%; 14/34). Therapeutic response was observed in 81 (76.4%) patients, with microbiological eradication achieved in 77.1% (74/96) of cases. Multivariable analysis identified that the length of intensive care unit stays, the sequential organ failure assessment (SOFA) score at CAZ-AVI withdrawal, and regimens containing polymyxin B were independently associated with in-hospital mortality, whereas the duration of CAZ-AVI treatment was independently associated with survival. CAZ-AVI salvage therapy demonstrated improved survival outcomes in patients who experienced failure with polymyxin B therapy.IMPORTANCEFor patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) infections, published experience with salvage therapy is limited after the failure of polymyxin-based initial therapy. Here, we found that ceftazidime-avibactam salvage therapy for patients with CRKP infections offers benefit in mortality.

Therapy for Non-Diabetic Foot Infections After Orthopedic Foot and Ankle Surgery: The Duration of Post-Debridement Antibiotic Treatment Does Not Alter Failure Risk.

Despite growing numbers of scientific publications on the optimal antibiotic treatment for diabetic foot infections, the data on the adult population with non-diabetic (postsurgical) foot infections is limited. Therefore, one of the largest single-center databases at the Balgrist University Hospital in Zurich, Switzerland, was established between January 2014 and August 2022. Using a case-control study design, we retrospectively investigated failures of combined surgical and antibiotic therapy for surgical site foot infections (SSIs). Overall, 17.4% of the episodes experienced therapeutic failures, particularly in patients with infected ankle prostheses. However, age, biological sex, pathogens, the duration of post-debridement antibiotic treatment, the number of surgical debridements, or the use of negative-pressure wound care altered the failure risk. In the multivariate logistic regression analyses, the duration of postsurgical antibiotic use was completely indifferent (as a continuous variable with an odds ratio of 1.0 and a 95% confidence interval ranging from 0.96 to 1.03) when stratified into inter-tertiary groups. Our findings suggest that shorter courses of systemic antibiotics may be appropriate in non-diabetic adults, supporting better antibiotic stewardship. Ongoing randomized controlled trials are under way to investigate which patients might safely receive shorter antibiotic treatments for surgical site infections following elective foot and ankle procedures.

Toripalimab plus anlotinib in patients with recurrent or metastatic nasopharyngeal carcinoma: A multicenter, single-arm phase 2 trial (TORAL).

Treatment options for patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) after failure of platinum-based therapy are limited. In this phase 2 trial, 40 patients with RM-NPC who failed platinum-based chemotherapy receive toripalimab plus anlotinib regimen. The objective response rate is 37.5%, and the disease control rate is 85.0%. With a median follow-up of 17.4months, the median progression-free survival (PFS) is 9.5months and 1-year overall survival rate is 73.3%. The most common treatment-related grade 3-4 adverse events are hand-foot syndrome (22.5%) and oral mucositis (17.5%). Analyses of plasma circulating tumor DNA (ctDNA) demonstrate that the blood tumor mutation burden at cycle 1/2 is associated with response and PFS, and disease progression indicated by ctDNA precedes radiological progression by a median of 2.3months. In conclusion, toripalimab plus anlotinib is well tolerated and shows promising efficacy in patients with RM-NPC, and ctDNA could be a potential predictive biomarker. The trial is registered at ClinicalTrials.gov (NCT04996758).

A stochastic population model for the impact of cancer cell dormancy on therapy success

Therapy evasion – and subsequent disease progression – is a major challenge in current oncology. An important role in this context seems to be played by various forms of cancer cell dormancy. For example, therapy-induced dormancy, over short timescales, can create serious obstacles to aggressive treatment approaches such as chemotherapy, and long-term dormancy may lead to relapses and metastases even many years after an initially successful treatment.In this paper, we focus on individual cancer cells switching into and out of a dormant state both spontaneously as well as in response to treatment. We introduce an idealized mathematical model, based on stochastic agent-based interactions, for the dynamics of cancer cell populations involving individual short-term dormancy, and allow for a range of (multi-drug) therapy protocols. Our analysis – based on simulations of the many-particle limit – shows that in our model, depending on the specific underlying dormancy mechanism, even a small initial population (of explicitly quantifiable size) of dormant cells can lead to therapy failure under classical single-drug treatments that would successfully eradicate the tumour in the absence of dormancy. We further investigate and quantify the effectiveness of several multi-drug regimes (manipulating dormant cancer cells in specific ways, including increasing or decreasing resuscitation rates or targeting dormant cells directly). Relying on quantitative results for concrete simulation parameters, we provide some general basic rules for the design of (multi-)drug treatment protocols depending on the types and processes of dormancy mechanisms present in the population.

Barriers and facilitators to quality HS biologic care and outcomes for the Medicaid population across US states

Introduction: Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease characterized by painful skin lesions and dermal abscesses.1 US-based patients with HS are often covered by Medicaid (21.6–31.0%)2–5 with substantial state-by-state variations in coverage. Barriers to accessing biologics for HS may delay treatment and worsen patient outcomes. Here, we report differences in Medicaid criteria to access biologic care for HS across all 50 US states. Procedure/study: A qualitative review of the Medicaid Utilization Management (UM) policies for biologic use in HS was conducted. Data were collected from the Medicaid UM policies, Medicaid websites, and Managed Medicaid UM policies of each state in February 2024. All 50 states were analyzed; barriers to access and discrepancies across state Medicaid UM policies were identified, and opportunities to address these discrepancies in the form of an HS coalition were recognized. The analysis stratified the Medicaid UM criteria for each state for treatment with a biologic (adalimumab/secukinumab) into no or low, medium, and high barrier levels. For high barrier level states, comparison with UM criteria for psoriasis was made. Results: Overall, the UM policies varied widely, and burdensome barriers to biologic care were identified in some states. In total, 40 states had no or low barrier criteria; states with low barrier criteria required an HS diagnosis and a prescription, or inadequate responses to ≥1 therapy (steroids/antibiotics). Alabama, Kentucky, Minnesota, Missouri, Ohio, Oregon, Pennsylvania, and Washington had medium barrier criteria and generally required an HS diagnosis and failure with ≥2 therapies. Here, criteria may be reduced to align with low barrier states. Iowa and Oklahoma had high barrier criteria. Both required ≥3 abscesses or inflammatory nodules, an HS diagnosis with Hurley Stage II/III, and failure with ≥2 therapies. In Iowa, eligible requests received three months treatment, with additional authorizations conditional upon ≥50% reduction in abscess and nodule count. The approval criteria of biologics for psoriasis were less stringent than HS in Iowa and Oklahoma, including fewer criteria items and therapy failures: Iowa ≥2 vs ≥3; Oklahoma ≥1 vs ≥2. Conclusion: Substantial state-by-state variations in Medicaid criteria were observed, with ten out of 50 states having medium to high barriers to accessing biologics. Large disparities in criteria for access to biologic care between psoriasis and HS were observed in two states. These barriers and discrepancies represent opportunities for an HS coalition at the state level, to improve access to care and patient outcomes.6

Loss of Fine Motor Dexterity and Reduced Oral Hygiene 15 Years After Diagnosis of Multifocal Motor Neuropathy with Screw-Retained Implant-Supported Rehabilitation: Literature Review and Case Report.

Multifocal motor neuropathy (MMN) is a rare immune-mediated neuropathy causing progressive, asymmetric weakness without sensory loss. Long-term administration of intravenous (IVIg) or subcutaneous (SCIg) immunoglobulins is the primary therapeutic approach. Despite this, therapy failure can result in a decline in strength, particularly in the hands, impacting daily activities. This review and case report presents the current literature on this complex dental and medical topic and explores the novel use of dental implants for full-mouth rehabilitation in MMN patients undergoing long-term IVIg therapy. A patient with MMN underwent 15 years of long-term treatment with intravenous immunoglobulin (IVIg), starting with an initial dose of 0.4 g/kg for 5 days every 4 months in 2008. The maintenance dosage of 0.2 g/kg as a single dose every 3 months was established as a long-term therapy. In 2017, the patient received a maxillary and mandibular complete-arch implant-supported prosthesis. MMN showed no progression until the IVIg interval was extended to every 4 months in 2022. Significant deterioration in dental health resulted from a loss of right-hand dexterity, which affected toothbrush use and interproximal brushing, resulting in poor oral hygiene. Dental hygiene and dental health, which were not optimal anyway, were considerably worsened by the loss of dexterity in the right hand, which impaired the use of the toothbrush and the cleaning of the interdental spaces. Dental implants are a well-established treatment for edentulous patients, but their success in those with MMN requires careful consideration of oral health practices. Effective maintenance protocols and optimised prosthetic designs are crucial for long-term implant therapy success in MMN patients. Peri-implant diseases pose risks influenced by various factors. In the case of MMN and its neurological considerations, implications for dental implant provision warrant further exploration, considering clinical symptoms, therapy, and potential progression.

Abstract A029: Integrated modeling of renal cancer bone metastasis to illuminate tumor progression and therapy response

Abstract Bone metastatic clear cell renal cell carcinoma (BM ccRCC) is a persistent clinical challenge and a source of significant morbidity and lethality for up to 40% of metastatic patients. Despite the recent approval of life-prolonging agents (antiangiogenic agents, immunotherapy) patients with BM ccRCC will eventually progress, due to emerging resistance. Bidirectional communication between tumor cells and bone stroma has emerged as a key determinant of disease progression and recurrence. However, a major challenge in addressing the black box of therapy response in bone is the lack of efficient and informative systems that allow us to analyze the heterotypic stromal-epithelial interaction, further complicated by the anatomical inaccessibility of bone. For these reasons, the evolution of the metastatic niche and its implications in therapy response remain elusive. In order to improve clinical results, it is critical to establish biologically informed pre-clinical models to provide a mechanistic understanding of tumor progression in bone and treatment outcomes. To this purpose, we have established clinically relevant models of ccRCC bone metastasis that span in vivo and ex vivo multiphoton microscopy (iMPM and eMPM), tissue engineered bone window systems, and computational oncology. iMPM displays both sensitivity and time-resolution to identify dynamic interactions between ccRCC cells and bone 3D adaptive niches, which support therapy response and resistance. However, iMPM in bone is limited due to its cortical thickness, increased light scattering, and complex topology. As a novel alternative, we created a tissue-engineered bone construct (TEBC) that, after direct implantation of cancer cells, is combined with an adjacent skin window, allowing for non- destructive intravital examination of tumor growth. To flank these in vivo dynamic analyses, we established a pipeline for ex vivo extraction of topological information related to the molecular and cellular niches involved in tumor progression and response to treatment (eMPM). This method allows reconstruction of whole lesions, including zones more distant from the bone interface, paired with an extensive panel of molecular markers. To further investigate the effects of a broad multi-parameter space on tumor regression or persistence upon treatment, in silico, we developed an in vivo-inspired agent-based model (ABM) of ccRCC in bone. A computational approach combined to ad hoc biological experimentation can refine the experimental design, test clinically relevant hypotheses (including impact of treatments on disease progression) and predict scenarios that guide biological testing towards more successful outcomes. Consequently, by integrating these approaches, we are currently studying the progression of the bone metastatic niche and its response to therapy, with the ultimate goal of overcoming therapy failure. Citation Format: Sergio Barrios, Luca Marsilio, Stefan Maksimovic, Matthew Campbell, Stefano Casarin, Eleonora Dondossola. Integrated modeling of renal cancer bone metastasis to illuminate tumor progression and therapy response [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A029.

A SYSTEMATIC REVIEW ON ADHERENCE TO ORAL ANTIDIABETIC DRUGS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

Type 2 diabetes mellitus (DM) is a chronic metabolic disorder in which prevalence has been increasing steadily all over the world and one of the main reason for this is poor adherence to oral anti-diabetic drugs, which can lead to therapy failure and increase risk of complications. So we planned this systematic review with an aim to get an adherence estimation to oral anti-diabetic drugs in type 2 diabetes mellitus patients for which a literature search was performed in pubmed, Google Scholar, scopus, and central databases to find observational studies on therapeutic adherence in users of oral anti-diabetic drugs. Our analyses showed that adherence rate to oral anti-diabetic drugs therapy ranged from 23 to 90%. This review confirms that many patients for whom diabetes medication was prescribed were poor compliers with treatment of oral anti-diabetic drugs.