Short-course Treatment Research Articles

Intensive cycles of neoadjuvant camrelizumab combined with chemotherapy in locally advanced esophageal squamous cell carcinoma: a single-arm, phase II trial

BackgroundTwo cycles of neoadjuvant PD-1 blockade plus chemotherapy induced favorable pathological response and tolerant toxicity in patients with locally advanced esophageal squamous cell carcinoma (ESCC). However, approximately 25% of patients relapsed within 1 year after surgery, indicating that a short course of treatment may not be sufficient. Therefore, exploring the effects of intensive treatment is needed for optimal clinical outcomes.MethodsLocally advanced ESCC patients were administered three cycles of camrelizumab plus nab-paclitaxel and capecitabine, followed by thoracoscopic esophagectomy. The primary endpoint was pathologic response. Secondary endpoints included safety, feasibility, radiologic response, survival outcomes, and immunologic/genomic correlates of efficacy.ResultsForty-seven patients were enrolled in the study. Forty-two patients received surgery, and R0 resection was achieved in all cases. The complete and major pathological response rates were 33.3% and 64.3%, respectively, and the objective response rate was 80.0%. Three cycles of treatment significantly improved T down-staging compared to two cycles (P = 0.03). The most common treatment-related adverse events were grades 1–2, and no surgical delay was reported. With a median follow-up of 24.3 months, the 1-year disease-free survival and overall survival rates were both 97.6%, and the 2-year disease-free survival and overall survival rates were 92.3% and 97.6%, respectively. Three patients experienced disease recurrence or metastasis ranging from 12.5 to 25.8 months after surgery, and one patient died 6 months after surgery due to cardiovascular disease. Neither programmed death-ligand 1 expression nor tumor mutational burden was associated with pathological response. An increased infiltration of CD56dim natural killer cells in the pretreatment tumor was correlated with better pathological response in the primary tumor.ConclusionsIt seems probable that intensive cycles of neoadjuvant camrelizumab plus nab-paclitaxel and capecitabine increased tumor regression and improved survival outcomes. Randomized controlled trials with larger sample sizes and longer follow-up periods are needed to validate these findings.Trial registration Chinese Clinical Trial Registry, ChiCTR2000029807, Registered February 14, 2020, https://www.chictr.org.cn/showproj.aspx?proj=49459.

Current evidence for moderate and ultra-hypofractionated radiation therapy in prostate cancer: a summary of the results from phase 3 randomised trials.

A low α/β ratio for prostate cancer (PCa) compared to surrounding normal tissue theoretically implies therapeutical advantages with hypofractionated treatment. Data from large randomised control trials (RCTs) comparing moderate hypofractionated (MHRT, 2.4-3.4 Gray/fraction (Gy/fx)) and ultra-hypofractionated (UHRT, >5 Gy/fx) with conventionally fractionated radiation therapy (CFRT, 1.8-2 Gy/fx) and the possible clinical implications have been reviewed. We searched PubMed, Cochrane and Scopus for RCT comparing MHRT/UHRT with CFRT treatment of locally and/or locally advanced (N0M0) PCa. We found six RCTs, which compared different radiation therapy regimes. Tumour control and acute and late toxicities are reported. MHRT was non-inferior to CFRT for intermediate-risk PCa, non-inferior for low-risk PCa and not superior in terms of tumour control for high-risk PCa. Acute toxicity rates were increased compared to CFRT, especially an increase in acute gastrointestinal adverse effects was seen. Late toxicity related to MHRT seems to be comparable. UHRT was non-inferior in terms of tumour control in one RCT, with increased acute toxicity, but with comparable late toxicity. One trial, however, indicated increased late toxicity rates with UHRT. MHRT delivers similar therapeutic outcomes compared to CFRT in terms of tumour control and late toxicity for intermediate-risk PCa patients. Slightly more acute transient toxicity could be tolerated in favour of a shorter treatment course. UHRT should be regarded as an optional treatment for patients with low- and intermediate-risk disease applied at experienced centres in concordance with international and national guidelines.

The efficacy and safety of short-course neoadjuvant denosumab for en bloc spondylectomy in spinal giant cell tumor of bone: a preliminary report

PurposeThis study aimed to investigate whether short course of neoadjuvant denosumab treatment for spinal GCTB could (1) Induce radiological and histological response? (2) Facilitate en bloc resection? (3) Achieve satisfactory oncological and functional outcomes?MethodsThe clinical information of ten consecutive patients between 2018 and 2022 with spinal GCTB treated with short course of neoadjuvant denosumab (≤ 5 doses) and en bloc spondylectomy was retrospectively reviewed. The radiological and histological response, operative data, oncological and functional outcomes were analyzed.ResultsThe mean doses of neoadjuvant denosumab were 4.2 (range 3–5 doses). After neoadjuvant denosumab, there were 9 cases showing new ossification and 5 cases with reappearance of cortical integrity. The values of Hounsfield units (HU) of the soft tissue component were increased by > 50% in 7 cases. The signal intensity (SI) ratios of tumor/muscle in T2WI of plain MRI were decreased by > 10% in 60% of the cases. Shrinkage of soft tissue mass by > 10% was observed in 4 cases. The mean duration of operation was 575 ± 174 min, and the mean estimated blood loss (EBL) was 2790 ± 1934 ml. No obvious adhesion to dura mater or major vessels was encounter intraoperatively. There is no tumor collapse or breakage during surgery. Multinucleated giant cells were decreased in 6 cases (60%) with the remaining 4 cases showing absence of multinucleated giant cells. Mononuclear stromal cells existed in most of the cases (8 cases, 80%). New bone formation was noticed in 8 cases (80%). No patient had a worsening of neurologic function after surgery. No tumor recurrence was noticed within the mean follow-up of 24 ± 20 months.ConclusionShort-term neoadjuvant denosumab could yield radiological and histological responses and might facilitate en bloc spondylectomy by hardening the tumor and causing less adhesion to segmental vessels, major vessels and nerve roots, which was beneficial to achieve the optimal oncological and functional outcomes.

Effects of Bedaquiline Combined with Fluoroquinolone and/or Clofazimine on QT Interval in Patients with Multidrug-Resistant Tuberculosis: a Retrospective Study.

With the application of bedaquiline (Bdq), the success rate of multidrug-resistant tuberculosis (MDR-TB) treatment has been significantly improved; however, the cardiac safety of the patients during treatment cannot be ignored. Hence, this study compared the effects of bedaquiline alone and bedaquiline combined with fluoroquinolones (FQs) and/or clofazimine (CFZ) on the QT interval. This single-center retrospective cohort study analyzed the clinical data of MDR-TB patients treated with bedaquiline for 24 weeks from January 2020 to May 2021 in Xi'an Chest Hospital and compared the changes in QTcF between the two groups. Eighty-five patients were included in the study and grouped by types of anti-TB drugs affecting the QT interval they used. Group A included bedaquiline (n = 33), and group B included bedaquiline in combination with fluoroquinolones and/or clofazimine (n = 52). Out of patients with available corrected QT interval by Fridericia's formula (QTcF) data, 2.4% (2/85) experienced a postbaseline QTcF of ≥500 ms, and 24.7% (21/85) had at least one change of QTcF of ≥60 ms from baseline. In group A, 9.1% (3/33) had at least one ΔQTcF of >60 ms, as did 34.6% (18/52) of group B. Multivariate Cox regression analysis showed that the adjusted risk of QT prolongation was 4.82 times higher in group B (95% confidence interval [CI], 1.406 to 16.488). Bedaquiline combined with other anti-TB drugs affecting QT interval significantly increased the incidence of grade 3 or 4 QT prolongation; however, no serious ventricular arrhythmia and permanent drug withdrawal occurred. The use of bedaquiline combined with fluoroquinolone and/or clofazimine is an independent risk factor affecting QT interval. IMPORTANCE Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis. The emergence of MDR-TB is caused by an organism that is resistant to at least isoniazid and rifampin and is currently considered the major challenge for the global control of TB. Bedaquiline is the first new TB drug in 50 years with a unique mechanism of action, strong anti-M. tuberculosis activity. Yet unexplained excess deaths in the bedaquiline arms have been found in some phase II clinical trials; thus, the FDA has issued a "boxed warning." However, the cardiac safety of the patients during treatment cannot be ignored. Accordingly, further investigations are needed to establish whether bedaquiline combined with clofazimine, fluoroquinolones, or anti-TB drugs affecting the QT interval in a long-course or short-course treatment increases the risk of QT prolongation.

Short versus long course of colistin treatment for carbapenem-resistant A. baumannii in critically ill patients: A propensity score matching study

BackgroundCarbapenem-resistant Acinetobacter baumannii (CRAB) is one of the most commonly found nosocomial infections in critically ill patients. However, the appropriate treatment period for a specific group of critically ill patients with CRAB infection is currently being debated. Therefore, our study aimed to evaluate the optimal courses of therapy for critically ill patients with CRAB infection by comparing the outcomes of colistin therapy of short duration (<14 days) versus long duration (≥ 14 days). MethodsA retrospective cohort study was conducted at Nakornping Hospital on critically ill patients with CRAB infection who received either a short or long course of colistin treatment between 2015 and 2022. The primary outcome was the 30-day mortality rate while secondary outcomes were clinical response, microbiological response, and nephrotoxicity. Propensity score matching with a 1: 1 ratio was performed to reduce potential biases. Furthermore, a logistic regression model was used to estimate the odds ratio (OR). ResultsA total of 374 patients met the inclusion criteria. Two hundred and forty-eight patients were recruited after utilizing propensity scores to match patients at a 1: 1 ratio. The results from the propensity score matching analysis demonstrated that the long-course therapy group had a lower 30-day mortality rate compared to the short-course therapy group (adjusted OR (aOR) = 0.46, 95% CI: 0.26–0.83, p = 0.009). The clinical response and microbiological response rates were higher in patients who received the long course of colistin therapy compared to those receiving the short course (aOR = 3.24, 95% CI: 1.78–5.92, p = 0.001; aOR = 3.01, 95% CI: 1.63–5.57, p = 0.001). There was no significant different in the occurrence of nephrotoxicity (aOR = 1.28, 95% CI: 0.74–2.22, p = 0.368) between the two treatment groups. ConclusionA long course of colistin therapy resulted in a lower 30-day mortality rate in critically ill patients, and better clinical and microbiological outcomes, but similar nephrotoxicity as compared to a short course of colistin therapy. Therefore, a specific subset of critically ill patients who had CRAB infection needed to be considered for a long course of therapy.

Update on the diagnosis and treatment of tuberculosis

According to World Health Organization estimates, more than 1 million patients aged less than 15 years develop tuberculosis (TB) each year worldwide. In some regions, up to 25% of new TB cases are caused by drug-resistant strains. Although Spain is considered a low-incidence country, several hundred children and adolescents develop TB each year. The importance of paediatric TB has been minimized for years due to the lack of microbiological confirmation in many patients and because these patients are not usually contagious. Nevertheless, in the past 15 years there have been major improvements in the epidemiological reporting of TB in children and adolescents, new immunodiagnostic tests have been developed, molecular methods that allow rapid microbiological diagnosis and detection of variants associated with drug resistance have become available, novel second-line antituberculosis drugs have been discovered, including for paediatric use, and the results of clinical trials have validated shorter courses of treatment for some patients. This document, developed by a group of experts from the Sociedad Española de Infectología Pediátrica and the Sociedad Española de Neumología Pediátrica, updates and complements the previous guidelines for the diagnostic and therapeutic management of children with TB in Spain based on the newly available scientific evidence.

A randomized, open-label study of the tolerability and efficacy of one or three daily doses of ivermectin plus diethylcarbamazine and albendazole (IDA) versus one dose of ivermectin plus albendazole (IA) for treatment of onchocerciasis.

Onchocerciasis ("river blindness") has been targeted for elimination. New treatments that kill or permanently sterilize female worms could accelerate this process. Prior studies have shown that triple drug treatment with ivermectin plus diethylcarbamazine and albendazole (IDA) leads to prolonged clearance of microfilaremia in persons with lymphatic filariasis. We now report results from a randomized clinical trial that compared the tolerability and efficacy of IDA vs. a comparator treatment (ivermectin plus albendazole, IA) in persons with onchocerciasis. The study was performed in the Volta region of Ghana. Persons with microfiladermia and palpable subcutaneous nodules were pre-treated with two oral doses of ivermectin (150 μg/kg) separated by at least 6 months prior to treatment with either a single oral dose of ivermectin 150 μg/kg plus albendazole 400 mg (IA), a single oral dose of IDA (IDA1, IA plus diethylcarbamazine (DEC. 6 mg/kg) or three consecutive daily doses of IDA (IDA3). These treatments were tolerated equally well. While adverse events were common (approximately 30% overall), no severe or serious treatment-emergent adverse events were observed. Skin microfilariae were absent or present with very low densities after all three treatments through 18 months, at which time nodules were excised for histological assessment. Nodule histology was evaluated by two independent assessors who were masked regarding participant infection status or treatment assignment. Significantly lower percentages of female worms were alive and fertile in nodules recovered from study participants after IDA1 (40/261, 15.3%) and IDA3 (34/281, 12.1%) than after IA (41/180, 22.8%). This corresponds to a 40% reduction in the percentage of female worms that were alive and fertile after IDA treatments relative to results observed after the IA comparator treatment (P = 0.004). Percentages of female worms that were alive (a secondary outcome of the study) were also lower after IDA treatments (301/574, 52.4%) than after IA (127/198, 64.1%) (P = 0.004). Importantly, some comparisons (including the reduced % of fertile female worms after IDA1 vs IA treatment, which was the primary endpoint for the study) were not statistically significant when results were adjusted for intraclass correlation of worm fertility and viability for worms recovered from individual study participants. Results from this pilot study suggest that IDA was well tolerated after ivermectin pretreatment. They also suggest that IDA was more effective than the comparator treatment IA for killing or sterilizing female O. volvulus worms. No other short-course oral treatment for onchocerciasis has been demonstrated to have macrofilaricidal activity. However, this first study was too small to provide conclusive results. Therefore, additional studies will be needed to confirm these promising findings. The study is registered at Cinicaltrials.gov under the number NCT04188301.

Current Hepatitis C Vaccine Candidates Based on the Induction of Neutralizing Antibodies.

The introduction of direct-acting antivirals (DAAs) has revolutionized hepatitis C treatment. Short courses of treatment with these drugs are highly beneficial to patients, eliminating hepatitis C virus (HCV) without adverse effects. However, this outstanding success is tempered by the continuing difficulty of eradicating the virus worldwide. Thus, access to an effective vaccine against HCV is strongly needed to reduce the burden of the disease and contribute to the elimination of viral hepatitis. The recent failure of a T-cell vaccine based on the use of viral vectors expressing the HCV non-structural protein sequences to prevent chronic hepatitis C in drug users has pointed out that the induction of neutralizing antibodies (NAbs) will be essential in future vaccine candidates. To induce NAbs, vaccines must contain the main target of this type of antibody, the HCV envelope glycoproteins (E1 and E2). In this review, we summarize the structural regions in E1 and E2 proteins that are targeted by NAbs and how these proteins are presented in the vaccine candidates currently under development.

Optimizing (O) rifapentine-based (RI) regimen and shortening (EN) the treatment of drug-susceptible tuberculosis (T) (ORIENT) using an adaptive seamless design: study protocol of a multicenter randomized controlled trial

BackgroundStandard treatment for drug-susceptible tuberculosis (DS-TB) includes a multidrug regimen requiring at least 6 months of treatment, and this lengthy treatment easily leads to poor adherence. There is an urgent need to simplify and shorten treatment regimens to reduce interruption and adverse event rates, improve compliance, and reduce costs.MethodsORIENT is a multicenter, randomized controlled, open-label, phase II/III, non-inferiority trial involving DS-TB patients to evaluate the safety and efficacy of short-term regimens compared with the standardized six-month treatment regimen. In stage 1, corresponding to a phase II trial, a total of 400 patients are randomly divided into four arms, stratified by site and the presence of lung cavitation. Investigational arms include 3 short-term regimens with rifapentine 10 mg/kg, 15 mg/kg, and 20 mg/kg, while the control arm uses the standardized six-month treatment regimen. A combination of rifapentine, isoniazid, pyrazinamide, and moxifloxacin is administered for 17 or 26 weeks in rifapentine arms, while a 26-week regimen containing rifampicin, isoniazid, pyrazinamide, and ethambutol is applied in the control arm. After the safety and preliminary effectiveness analysis of patients in stage 1, the control arm and the investigational arm meeting the conditions will enter into stage 2, which is equivalent to a phase III trial and will be expanded to recruit DS-TB patients. If all investigational arms do not meet the safety conditions, stage 2 will be canceled. In stage 1, the primary safety endpoint is permanent regimen discontinuation at 8 weeks after the first dose. The primary efficacy endpoint is the proportion of favorable outcomes at 78 weeks after the first dose for both two stages.DiscussionThis trial will contribute to the optimal dose of rifapentine in the Chinese population and suggest the feasibility of the short-course treatment regimen containing high-dose rifapentine and moxifloxacin for DS-TB.Trial registrationThe trial has been registered on ClinicalTrials.gov on 28 May 2022 with the identifier NCT05401071.

Short-course treatment after complete response to pembrolizumab in metastatic urothelial bladder cancer: a case series.

Background: The optimal duration of treatment for metastatic patients who achieve a complete response with immune checkpoint inhibitors is unknown. Methods: The outcome for sixmetastatic bladder cancer patients who received short course of pembrolizumab is reported. Results: A median number of sevencycles of pembrolizumab was given. After a median follow-up of 38months, progressive disease was confirmed in three patients. All patients relapsed in lymph nodes and underwent pembrolizumab rechallenge: oneachieved a complete response, another a partial response. Conclusion: Our case series paves the way for discontinuation of pembrolizumab in patients who achieve a complete response since threeout of six patients remain free of disease after 3-year follow-up. Prospective studies are required to confirm our results.

Effect of tannin fruit extracts on Candida albicans yeast

Background: The results of the chemical detection showed that the active groups in the fruit extracts of the tannin plant contained glycosides, saponins, flavonoids, tannins, terpene and phenols.&#x0D; Aim: To evaluate Tannins inhibition activity against Candida albicans. &#x0D; Materials and methods: A number of aqueous, alcoholic and acetone fruit extracts of Tannins were prepared, and their effect on inhibition of Candida albicans was tested. Four concentrations were used [10, 20, 30, 40 (mg / ml)].&#x0D; Results: The effect of tested extracts on yeast varied in terms of concentration and type of extract. The inhibition diameter was positively correlated to the increase in extract concentration. The results showed that the acetone extract was with a very high effectiveness and demonstrate higher inhibition effect against C. albicans, with an average inhibition diameter of 15.5 and 20 mm at a concentration of 10 and 20 mg / ml, respectively, while it was increased to reach 24.5 and 28 mm at a concentration 30 and 40 mg/ml, respectively. The alcoholic extract came in the second inhibition effect.&#x0D; Conclusion: The acetone extract shows a higher inhibitory activity than alcoholic and aqueous extracts. The interesting finding of this study was the inhibition against C. albicans was exhibited in the first 24 hours, while the nystatin inhibitory effect started in after 48 hours. The inhibition timing was vital as it lead to short course of treatment and less possibility for resistance induction

Cost-Effectiveness of Short Course of Ceftazidime/Avibactam for K. pneumoniae-KPC Bloodstream Infections in Italy

Background: Evidence has shown that short courses of antibiotic therapy are at least as effective as long courses with better clinical outcomes. CAZ/AVI has demonstrated its clinical efficacy in treating K. pneumoniae-KPC infections. Methods: We conducted an analysis based on the real-life data of our ten years retrospective cohort to assess the cost-effectiveness and cost-utility of a short course of CAZ/AVI plus source control compared to a long course plus source control. A Markov model was structured. Patient transition between health states was modeled, each transition has a probability, and each state has a cost and a utility. Incremental cost-effectiveness ratios (ICERs) were obtained by dividing the difference in costs by the difference in utilities between the two courses. Input parameter uncertainty was investigated through sensitivity analysis. We launched 1000 Monte Carlo simulations by iteratively perturbing variables within estimated variation ranges, obtaining an ICER result for each simulation. Results: In the first model (old appropriate treatment), a short course of treatment was associated with reduced costs per patient per year of €4818.60 and reduced effects (0.10 QALYs), compared to a long course. In the CAZ/AVI model, the short course was associated with increased costs of €1297.9 and with increased effects (0.04 QALYs), resulting in an ICER of €32,317.82 per QALY gained, below the WTP threshold of €40,000. Conclusions: Our findings highlight additional evidence regarding the cost-effectiveness of CAZ/AVI for policy-makers. We outline that CAZ/AVI could be cost-effective compared to old appropriate antibiotic therapies for KPC-Kp BSI.

Actualización del diagnóstico y tratamiento de la tuberculosis

According to WHO estimates, more than 1 million patients aged less than 15 years develop tuberculosis (TB) each year worldwide. In some regions, up to 25% of new TB cases are caused by drug-resistant strains. Although Spain is considered a low-incidence country, several hundred children and adolescents develop TB each year. The importance of paediatric TB has been minimized for years due to the lack of microbiological confirmation in many patients and because these patients are not usually contagious. Nevertheless, in the past 15 years there have been major improvements in the epidemiological reporting of TB in children and adolescents, new immunodiagnostic tests have been developed, molecular methods that allow rapid microbiological diagnosis and detection of variants associated with drug resistance have become available, novel second-line antituberculosis drugs have been discovered, including for paediatric use, and the results of clinical trials have validated shorter courses of treatment for some patients. This document, developed by a group of experts from the Sociedad Española de Infectología Pediátrica and the Sociedad Española de Neumología Pediátrica, updates and complements the previous guidelines for the diagnostic and therapeutic management of children with TB in Spain based on the newly available scientific evidence.

Association between prolonged corticosteroids use in COVID-19 and increased mortality in hospitalized patients: a retrospective study with inverse probability of treatment weighting analysis

BackgroundPrevious studies have demonstrated a beneficial effect of early use of corticosteroids in patients with COVID-19. This study aimed to compare hospitalized patients with COVID-19 who received short-course corticosteroid treatment with those who received prolonged-course corticosteroid treatment to determine whether prolonged use of corticosteroids improves clinical outcomes, including mortality.MethodsThis is a retrospective cohort study including adult patients with positive testing for Sars-CoV-2 hospitalized for more than 10 days. Data were obtained from electronic medical records. Patients were divided into two groups, according to the duration of treatment with corticosteroids: a short-course (10 days) and a prolonged-course (longer than 10 days) group. Inverse probability treatment weighting (IPTW) analysis was used to evaluate whether prolonged use of corticosteroids improved outcomes. The primary outcome was in-hospital mortality. Secondary outcomes were hospital infection and the association of different doses of corticosteroids with hospital mortality. Restricted cubic splines were used to assess the nonlinear association between mortality and dose and duration of corticosteroids use.ResultsWe enrolled 1,539 patients with COVID-19. Among them, 1127 received corticosteroids for more than 10 days (prolonged-course group). The in-hospital mortality was higher in patients that received prolonged course corticosteroids (39.5% vs. 26%, p < 0.001). The IPTW revealed that prolonged use of corticosteroids significantly increased mortality [relative risk (RR) = 1.52, 95% confidence interval (95% CI): 1.24–1.89]. In comparison to short course treatment, the cubic spline analysis showed an inverted U-shaped curve for mortality, with the highest risk associated with the prolonged use at 30 days (RR = 1.50, 95% CI 1.21–1.78).ConclusionsProlonged course of treatment with corticosteroids in hospitalized patients with COVID-19 was associated with higher mortality.

Abstract 6625: Mathematical modeling of single-cell data reveals the key role of stochasticity - not fitness - in determining the clonal origins of relapse in childhood leukemia

Abstract Acute lymphoblastic leukemia (cALL) is the most common pediatric cancer, and since up to 20% of children relapse after initially responding to chemotherapy treatment, the largest cause of cancer-related childhood deaths in the western world. With the idea that dissecting the evolutionary population dynamics leading to relapse would help explain treatment failure from a mechanistic standpoint, several studies have performed comparisons of genetic heterogeneity at diagnosis and relapse. These showed that as many as 70% of relapses are dominated by a single diagnostic subclone or one of its evolutionary progeny; leading to the prevailing view that treatment selection in cALL primarily operates at the genotype level. However, a crucial caveat of these studies is their reliance, due primarily to technical and economic constraints, on very limited data timepoints. While the dynamics linking said timepoints are often interpreted based on simple intuition. To overcome this sparse data challenge and reconstruct the entire spatial and temporal evolutionary trajectories of individual cALL cells from diagnosis to relapse, we have integrated experimental data with an in silico model. Single-cell WGS and RNAseq data were obtained from primary and xenografted leukemic cells before and after chemotherapy. These were then used to parameterize an agent-based mathematical model allowing tracking of the genotype and evolving phenotype of individual cells over time. When short treatment courses akin to those we delivered in vivo were used, the in silico model closely recapitulated the experimental results. Since cALL treatment lasts several years, it cannot be entirely modelled in vivo. Due to the rarity of post-treatment residual cells and the lack of universal cell surface markers to isolate them, direct analysis of clinical samples is also challenging. However, based on the initial treatment data, our calibrated model provided a unique opportunity to simulate longer remission-relapse dynamics of several leukemias. Mechanistic analysis of the collected data showed that, strikingly, in most cases, clonal dominance at relapse results from stochastic sweeps rather than deterministic differences in clonal fitness. Indeed, independent treatment of the same leukemia with an identical drug regimen more frequently ended with a considerably different clonal landscape (either polyclonal disease or a different dominant clone) than with the same outcome initially observed. Rather than genotype differences, the size of residual disease and a founder effect linked to the stochastic exit, post-treatment, of individual cells from quiescence were the key determinants of the relapse genetic landscape. Altogether, our data highlight the misinterpretation risk associated with snapshot analysis and might inform promising alternative treatment schedules. Citation Format: Virginia Turati, Javier Herrero, Mark Robertson-Tessi, Tariq Enver, Andriy Marusyk, Alexander RA Anderson. Mathematical modeling of single-cell data reveals the key role of stochasticity - not fitness - in determining the clonal origins of relapse in childhood leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6625.

Abstract 3279: Systemic immune response invoked by short-course oxaliplatin-based chemotherapy (FLOX) for efficacy of sequential immune checkpoint blockade (ICB; nivolumab) in microsatellite-stable (MSS) metastatic colorectal cancer (mCRC)

Abstract Purpose: Most mCRC patients harbor MSS disease without inherent immunogenicity. The METIMMOX study (NCT03388190) explored an unconventional concept, that patients with previously untreated, unresectable abdominal metastases from MSS-CRC may achieve therapeutic efficacy from short-course oxaliplatin-based chemotherapy (FLOX) and sequential ICB (nivolumab). Among study patients who were assigned this highly experimental treatment, 15% obtained long-lasting complete response and more than a half met an early occurring radiologic signal of ICB responsiveness predicting significantly extended progression-free survival (PFS) compared to study control arm patients given standard FLOX chemotherapy [PMID: 36229579]. The aim of the present study was to verify if systemic tumor-defeating immunity had been invoked by the short-course FLOX treatment in the responding patients. The fms-related tyrosine kinase-3 ligand (Flt3L) is a circulating factor that reflects the direct cytotoxic effects of chemotherapy and also activates dendritic cells that present the shed tumor antigens to tumor-targeting T-cells. Procedures: Study patients were randomly assigned to the control arm of FLOX (oxaliplatin 85 mg/m2 on day 1 and bolus 5-fluorouracil 500 mg/m2 and folinic acid 100 mg on days 1 and 2) Q2W or the experimental arm of repeat sequential cycles of 2 FLOX Q2W and 2 nivolumab (240 mg) Q2W. Radiologic response assessment was done every 8 weeks with PFS as the primary endpoint. Patients were categorized into those with target lesion (TL) reduction of ≥10% or &amp;lt;10% at the first post-baseline assessment (8 weeks) [PMID: 36229579]. Serum Flt3L was measured at baseline and following the initial 2 FLOX cycles (at 4 weeks) using a Luminex assay. Results: For all subjects, median Flt3L was 103.8 pg/ml (range 24.6-306.1) at baseline and 162.4 pg/ml (range 53.3-503.8) at 4 weeks. For the experimental arm patients (n = 34), the higher 4-week Flt3L level, the deeper overall radiologic response (rho = -0.39, p = 0.022, Spearman correlation). The 4-week Flt3L level was higher in patients who obtained ≥10% TL reduction (n = 18; median 233.5 pg/ml, range 94.9-466.7) than in those who did not meet this 8-week predictive signal of extended PFS (n = 16; median 161.9 pg/ml, range 53.3-374.8; p = 0.022, Mann-Whitney U test). Selecting a 160 pg/ml cut-off, patients with 4-week Flt3L values above (n = 21) obtained longer PFS (median of 13.6 months, 95% CI 7.6-19.7) than those with serum values below (n = 13; median PFS of 5.9 months, 95% CI 2.4-9.3; p = 0.046, log-rank test). Conclusions: High circulating Flt3L after initial short-course FLOX chemotherapy, as a proxy of invoked tumor-defeating immunity, was associated with an early radiologic signal of ICB responsiveness and improved PFS in patients with MSS-mCRC. Citation Format: Sebastian Meltzer, Kjersti Flatmark, Anniken J. Fuglestad, Hanne M. Hamre, Christian Kersten, Eva Hofsli, Marianne G. Guren, Halfdan Sorbye, Anne Negård, Anne Hansen Ree. Systemic immune response invoked by short-course oxaliplatin-based chemotherapy (FLOX) for efficacy of sequential immune checkpoint blockade (ICB; nivolumab) in microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3279.

Stereotactic Magnetic Resonance-Guided Adaptive and Non-Adaptive Radiotherapy on Combination MR-Linear Accelerators: Current Practice and Future Directions.

Stereotactic body radiotherapy (SBRT) is an effective radiation therapy technique that has allowed for shorter treatment courses, as compared to conventionally dosed radiation therapy. As its name implies, SBRT relies on daily image guidance to ensure that each fraction targets a tumor, instead of healthy tissue. Magnetic resonance imaging (MRI) offers improved soft-tissue visualization, allowing for better tumor and normal tissue delineation. MR-guided RT (MRgRT) has traditionally been defined by the use of offline MRI to aid in defining the RT volumes during the initial planning stages in order to ensure accurate tumor targeting while sparing critical normal tissues. However, the ViewRay MRIdian and Elekta Unity have improved upon and revolutionized the MRgRT by creating a combined MRI and linear accelerator (MRL), allowing MRgRT to incorporate online MRI in RT. MRL-based MR-guided SBRT (MRgSBRT) represents a novel solution to deliver higher doses to larger volumes of gross disease, regardless of the proximity of at-risk organs due to the (1) superior soft-tissue visualization for patient positioning, (2) real-time continuous intrafraction assessment of internal structures, and (3) daily online adaptive replanning. Stereotactic MR-guided adaptive radiation therapy (SMART) has enabled the safe delivery of ablative doses to tumors adjacent to radiosensitive tissues throughout the body. Although it is still a relatively new RT technique, SMART has demonstrated significant opportunities to improve disease control and reduce toxicity. In this review, we included the current clinical applications and the active prospective trials related to SMART. We highlighted the most impactful clinical studies at various tumor sites. In addition, we explored how MRL-based multiparametric MRI could potentially synergize with SMART to significantly change the current treatment paradigm and to improve personalized cancer care.

Patient-Specific Considerations, the GABA Pathway, and New Clinical Trial Data on Neuroactive Steroids in MDD and PPD

Major depressive disorder (MDD) and major depressive episode with peripartum onset, commonly referred to as postpartum depression (PPD), are among the most common psychiatric illnesses and are leading contributors to disability and suicide. Standard of care antidepressants are the cornerstone of MDD treatment; however, nonadherence to antidepressants has been widely recognized as one of the reasons for treatment failure in MDD. Delayed response in current therapies can take up to 4 or even 8 weeks for patients to experience therapeutic benefits. Low treatment response rates are seen in a considerable amount of patients, with early-stage treatment-resistant depression (TRD) affecting 50% of patients receiving first-line treatments and 30% developing into substantive TRD. Given these treatment gaps, there is an urgent need to develop novel antidepressants with a faster onset of action and shorter treatment course, which could improve adherence and treatment response rates. The neurobiology of depression is multifactorial, with different pathways converging on the development of the neurocircuit dysfunction characteristic of depression. Neuroactive steroids play an important role in modulating acute and chronic stress via their phasic and tonic inhibitory effects on select GABAA receptors, ultimately modulating neurocircuit function. With clinical recognition of the importance of neurosteroids in the modulation of GABAA signaling pathways, researchers have developed novel neuroactive steroid-based pharmacotherapies that have been tested in clinical studies. Given their rapid onset of action and shorter treatment course, these novel antidepressants have the potential to change the treatment paradigm for MDD and PPD.

Well-Circumscribed Intramuscular Lipoma of Superior Rectus Muscle

Extraocular muscle lipoma is a rare benign mesenchymal tumor of the orbit. We report a case of a 37-year-old woman who presented with chronic progressive proptosis and inferior globe displacement of left eye. External eye examination revealed a yellowish mass at the superior bulbar conjunctiva. Magnetic resonance imaging showed a well-circumscribed mass confined in the superior rectus muscle belly and tendon with a fat signal. Debulking surgery was performed using the transconjunctival and vertical lid split approach. A pathological study demonstrated matured adipose tissue cells encapsulated by a thin layer of fibrous tissue, in addition to the chronic non-specific inflammation of the tenon capsule tissue sample. Histopathological findings of the mass were consistent with a well-circumscribed intramuscular lipoma. The symptoms of the patient were significantly improved 3 months after surgical and short-course systemic steroid treatments. However, long-term surveillance is needed.

Abstract PD13-01: PD13-01 Elacestrant in postmenopausal women with estrogen receptor positive and HER2-negative early breast cancer: primary efficacy and safety analysis of the preoperative, window of opportunity SOLTI-1905-ELIPSE trial

Abstract Introduction Elacestrant is the first oral, non-steroidal, selective estrogen receptor degrader (SERD) to demonstrate improved efficacy compared to standard of care endocrine treatment, with greater relative benefit in ESR1-mutated tumors, and manageable safety profile in pretreated patients with metastatic breast cancer (BC) (Bidard F.C., JCO 2022). SOLTI ELIPSE trial (NCT04797728) is a prospective, multicenter, window of opportunity trial designed to assess whether a short-course of preoperative elacestrant may suppress tumor proliferation in postmenopausal women with estrogen receptor positive (ER+)/HER2-negative early BC (Vidal M., SABCS 2021). Here, we present the results of the primary efficacy and safety study analysis. Methods Eligible patients with operable, untreated ER+/HER2-negative BC that were T1c (≥1.5 cm)-T3 by ultrasound, clinically or radiologically N0 and had a locally assessed Ki67 ≥10%, received elacestrant 400 mg once a day continuously for a total of 4 weeks. At the study treatment completion, patients were treated according to local practice. Centralized assessment of post-treatment (D28) Ki67 from surgical specimen or tumor biopsy was required for the primary endpoint evaluation. Primary efficacy endpoint was complete cell cycle arrest (CCCA), defined as Ki67≤2.7%, at D28. Ki67 geometric relative change, variation in tumor infiltrating lymphocytes (TILs), switch in PAM50 subtypes and differential expression of 192 genes from baseline (D1) to D28 was also explored. Adverse events (AEs) were graded according to CTCAE v5.0. Results Between April 2021 and February 2022, 24 patients were enrolled and 22 were evaluable for the primary endpoint. Baseline characteristics were: mean age 69 years (range 50-81); ductal histology 74%; T1c 61%; T2 39%; grade 1-2 83%; median local Ki67 20% (10-70). Baseline PAM50 subtypes distribution was: Luminal A (n=12), Luminal B (n=8), Basal-like (n=1), Normal-like (n=1). At D28, CCCA was achieved in the 27% (n=6) of the patients. Fourteen patients (64%) had D28 Ki67 ≤10%. Paired centralized Ki67 was available in 19 patients. A statistically significant 41% (95% CI, -24 to -58) Ki67 relative reduction (rr) from D1 was observed (p=0.007). CCCA rate was 31% and 17% in patients with D1 Ki67 &amp;lt; 20% (n=13) and D1 Ki67 ≥20% (n=6), respectively. Ki67 varied consistently in both Ki67 &amp;lt; 20% (rr=-38%; 95% CI, -16 to -60) and Ki67 ≥20% (rr=-46%; 95% CI, -20 to -72) groups. Overall, elacestrant was associated with a shift towards a more endocrine sensitive and less proliferative phenotype based on PAM50 gene signatures. CCCA occurred in 45% of Luminal A tumors, whereas no CCCA was observed among Luminal B tumors. Levels of TILs were significantly higher at D28 (mean difference, +3.73; p=0.004). Elacestrant induced high expression of immune-response genes including IGJ, GZMB, CD4, CD8a and suppressed proliferation (e.g., UBE2T, MYBL2, BIRC5, MK67) and estrogen-signaling (e.g., ESR1, PGR, CCND1, BRCA2) genes (false discovery rate 5%). These changes in gene expression were observed both in tumors with D28 Ki67≤2.7% and in those with D28 Ki67 &amp;gt;10%. Overall, 87% of the patients reported any grade AEs. Treatment-related AE occurred in 1 patient (grade 3 cutaneous rash) and led to treatment discontinuation. Most frequently reported AEs (all grade 1) were hot flush (n=6), dyspepsia (n=2), anemia (n=2) and constipation (n=2). No serious AEs were reported. Conclusions In untreated ER+/HER2-negative early BC a short-course preoperative treatment with elacestrant was associated with relevant biological and molecular response and with manageable safety profile. Globally, these findings support further exploration of this highly potent, novel oral SERD in early BC. Citation Format: Maria Vidal, Tomás Pascual, Claudette Falato, Rodrigo Sanchez-Bayona, Montserrat Muñoz, Isaac Cerbrecos, Xavier Gonzalez-Farré, Tomás Cortadellas, Mireia Margelí, Miguel Angel Luna, Christian Siso, Kepa Amillano, Patricia Galván, Fernando Salvador, Alejandra Espinosa, Laia Paré, Esther Sanfeliu, Aleix Prat, Meritxell Bellet Ezquerra. PD13-01 Elacestrant in postmenopausal women with estrogen receptor positive and HER2-negative early breast cancer: primary efficacy and safety analysis of the preoperative, window of opportunity SOLTI-1905-ELIPSE trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-01.