Talus-derived reference coordinate system for 3D calcaneal assessment: A novel approach to improve morphological measurements.

In 3D-analysis of the calcaneus, a consistent coordinate system aligned with the original anatomical directions is crucial for pre- and postoperative analysis. This importance stems from the calcaneus's key role in weight-bearing and biomechanical alignment. However, defining a reliable coordinate system based solely on fractured or surgically reconstructed calcanei presents significant challenges. Given its anatomical prominence and consistent orientation, the talus offers a potential solution to this challenge. Our work explores the feasibility of talus-derived coordinate systems for 3D-modeling of the calcaneus across its various conditions. Four methods were tested on nonfractured, fractured and surgically reconstructed calcanei, utilizing Principal Component Analysis, anatomical landmarks, bounding box, and an atlas-based approach. The methods were compared with a self-defined calcaneus reference coordinate system. Additionally, the impact of deviation of the coordinate system on morphological measurements was investigated. Among methods for constructing nonfractured calcanei coordinate systems, the atlas-based method displayed the lowest Root Mean Square value in comparison with the reference coordinate system. For morphological measures like Böhler's Angle and the Critical angle of Gissane, the atlas talus-based system closely aligned with ground truth, yielding differences of 0.6° and 1.2°, respectively, compared to larger deviations seen in other talus-based coordinate systems. In conclusion, all tested methods were feasible for creating a talus derived coordinate system. A talus derived coordinate system showed potential, offering benefits for morphological measurements and clinical scenarios involving fractured and surgically reconstructed calcanei. Further research is recommended to assess the impact of these coordinate systems on surgical planning and outcomes.

A Comparison of Pneumatic Actuators for Soft Growing Vine Robots.

Soft pneumatic actuators are used to steer soft growing "vine" robots while being flexible enough to undergo the tip eversion required for growth. In this study, we compared the performance of three types of pneumatic actuators in terms of their ability to perform eversion, quasi-static bending, dynamic motion, and force output: the pouch motor, the cylindrical pneumatic artificial muscle (cPAM), and the fabric pneumatic artificial muscle (fPAM). The pouch motor is advantageous for prototyping owing to its simple manufacturing process. The cPAM exhibits superior bending behavior and produces the highest forces, whereas the fPAM actuates fastest and everts at the lowest pressure. We evaluated a range of dimensions for each actuator type. Larger actuators can produce more significant deformations and forces, but smaller actuators inflate faster and can evert at a lower pressure. Because vine robots are lightweight, the effect of gravity on the functionality of different actuators is minimal. We developed a new analytical model that predicts the pressure-to-bending behavior of vine robot actuators. Using the actuator results, we designed and demonstrated a 4.8 m long vine robot equipped with highly maneuverable 60 × 60 mm cPAMs in a three-dimensional obstacle course. The vine robot was able to move around sharp turns, travel through a passage smaller than its diameter, and lift itself against gravity.

A quantitative gibberellin signaling biosensor reveals a role for gibberellins in internode specification at the shoot apical meristem.

Growth at the shoot apical meristem (SAM) is essential for shoot architecture construction. The phytohormones gibberellins (GA) play a pivotal role in coordinating plant growth, but their role in the SAM remains mostly unknown. Here, we developed a ratiometric GA signaling biosensor by engineering one of the DELLA proteins, to suppress its master regulatory function in GA transcriptional responses while preserving its degradation upon GA sensing. We demonstrate that this degradation-based biosensor accurately reports on cellular changes in GA levels and perception during development. We used this biosensor to map GA signaling activity in the SAM. We show that high GA signaling is found primarily in cells located between organ primordia that are the precursors of internodes. By gain- and loss-of-function approaches, we further demonstrate that GAs regulate cell division plane orientation to establish the typical cellular organization of internodes, thus contributing to internode specification in the SAM.

POLARIS: A phase 2 trial of encorafenib plus binimetinib evaluating high-dose and standard-dose regimens in patients with BRAF V600-mutant melanoma with brain metastasis.

Background: POLARIS (phase 2 [ph2]; NCT03911869) evaluated encorafenib (BRAF inhibitor) in combination with binimetinib (MEK1/2 inhibitor) in BRAF/MEK inhibitor-naïve patients with BRAF V600-mutant melanoma with asymptomatic brain metastases. Methods: The safety lead-in (SLI) assessed tolerability for high-dose encorafenib 300 mg twice daily (BID) plus binimetinib 45 mg BID. If the high dose was tolerable in ph2, patients would be randomized to receive high or standard dose (encorafenib 450 mg once daily [QD] plus binimetinib 45 mg BID). Otherwise, standard dose was evaluated as the recommended ph2 dose (RP2D). Patients who tolerated standard dosing during Cycle 1 could be dose escalated to encorafenib 600 mg QD plus binimetinib 45 mg BID in Cycle 2. Safety, efficacy, and pharmacokinetics were examined. Results: RP2D was standard encorafenib dosing, as >33% of evaluable SLI patients (3/9) had dose-limiting toxicities. Overall, of 13 safety-evaluable patients (10 SLI, 3 ph2), 9 had prior immunotherapy. There were 9 treatment-related adverse events in the SLI and 3 in ph2. Of the SLI efficacy-evaluable patients (n = 10), 1 achieved complete response and 5 achieved partial responses (PR); the brain metastasis response rate (BMRR) was 60% (95% CI: 26.2, 87.8). In ph2, 2 of 3 patients achieved PR (BMRR, 67% [95% CI: 9.4, 99.2]). Repeated encorafenib 300 mg BID dosing did not increase steady-state exposure compared with historical 450 mg QD data. Conclusions: Despite small patient numbers due to early trial termination, BMRR appeared similar between the SLI and ph2, and the ph2 safety profile appeared consistent with previous reports of standard-dose encorafenib in combination with binimetinib.

Atp1a2 and Kcnj9 are candidate genes underlying oxycodone behavioral sensitivity and withdrawal in C57BL/6 substrains.

Opioid use disorder is heritable, yet its genetic etiology is largely unknown. Analysis of addiction model traits in rodents (e.g., opioid behavioral sensitivity and withdrawal) can facilitate genetic and mechanistic discovery. C57BL/6J and C57BL/6NJ substrains have extremely limited genetic diversity, yet can show reliable phenotypic diversity which together, can facilitate gene discovery. The C57BL/6NJ substrain was less sensitive to oxycodone (OXY)-induced locomotor activity compared to the C57BL/6J substrain. Quantitative trait locus (QTL) mapping in an F2 cross identified a distal chromosome 1 QTL explaining 7-12% of the variance in OXY locomotor sensitivity and anxiety-like withdrawal in the elevated plus maze. We identified a second QTL for withdrawal on chromosome 5 near the candidate gene Gabra2 (alpha-2 subunit of GABA-A receptor) explaining 9% of the variance. Next, we generated recombinant lines from an F2 founder spanning the distal chromosome 1 locus (163-181 Mb), captured the QTL for OXY sensitivity and withdrawal, and fine-mapped a 2.45-Mb region (170.16-172.61 Mb). There were five striatal cis-eQTL transcripts in this region (Pcp4l1, Ncstn, Atp1a2, Kcnj9, Igsf9), two of which were confirmed at the protein level (KCNJ9, ATP1A2). Kcnj9, a.k.a., GIRK3, codes for a potassium channel that is a major effector of mu opioid receptor signaling. Atp1a2 codes for a subunit of a Na+/K+ ATPase enzyme that regulates neuronal excitability and shows adaptations following chronic opioid administration. To summarize, we identified genetic sources of opioid behavioral differences in C57BL/6 substrains, two of the most widely and often interchangeably used substrains in opioid addiction research.

Stress-induced dysfunction of neurovascular astrocytes contributes to sex-specific behavioral deficits.

Astrocytes form an integral component of the neurovascular unit, ensheathing brain blood vessels with projections high in aquaporin-4 (AQP4) expression. These AQP4-rich projections facilitate interaction between the vascular endothelium, astrocytes, and neurons, and help stabilize vascular morphology. Studies using preclinical models of psychological stress and post-mortem tissue from patients with major depressive disorder (MDD) have reported reductions in AQP4, loss of astrocytic structures, and vascular impairment in the prefrontal cortex (PFC). Though compelling, the role of AQP4 in mediating stress-induced alterations in blood vessel function and behavior remains unclear. Here, we address this, alongside potential sex differences in chronic unpredictable stress (CUS) effects on astrocyte phenotype, blood-brain barrier integrity, and behavior. CUS led to pronounced shifts in stress-coping behavior and working memory deficits in male -but not female- mice. Following behavioral testing, astrocytes from the frontal cortex were isolated for gene expression analyses. We found that CUS increased various transcripts associated with blood vessel maintenance in astrocytes from males, but either had no effect on-or decreased-these genes in females. Furthermore, CUS caused a reduction in vascular-localized AQP4 and elevated extravasation of a small molecule fluorescent reporter (Dextran) in the PFC in males but not females. Studies showed that knockdown of AQP4 in the PFC in males is sufficient to disrupt astrocyte phenotype and increase behavioral susceptibility to a sub-chronic stressor. Collectively, these findings provide initial evidence that sex-specific alterations in astrocyte phenotype and neurovascular integrity in the PFC contribute to behavioral and cognitive consequences following chronic stress.

Feasibility and Safety of Oral Risperidone to Treat Prehospital Agitation.

Objective: Agitation is a common prehospital problem and frequently presents without a clear etiology. Given the dynamic environment of the prehospital setting, there has historically been a varied approach to treating agitation with a heavy reliance on parenteral medications. Newer best practice guidelines recommend the incorporation of oral medications to treat patients experiencing agitation. Therefore, we evaluated the use of oral risperidone in a single system after a change in protocol occurred.Methods: This was conducted as a retrospective chart review of an urban/suburban Emergency Medical Services system over the period of 8 months. The first day this medication was implemented throughout the service was included. Charts were included for selection if they included risperidone oral dissolving tablet (ODT) as a charted medication. The primary outcome was administration of additional medications to treat agitation. Exploratory outcome measures included acceptance of medication, documented injury to paramedics, documented injuries to patients, scene times, and adverse events that could possibly be linked to the medication.Results: A total of 552 records were screened for inclusion. Risperidone was offered to 530 patients and accepted by 512 (96.6%). Of these 512 patients, the median age of included patients was 39 years old (IQR 29-52 years old) with a range of 18-89 years old. Rescue or additional medications for agitation were required in 9 (1.8%) cases. There were a total of 4 (0.8%) potential complications following administration of risperidone. There were no reported assaults with subsequent injuries to prehospital personnel or injuries sustained by patients reported in this study.Conclusions: Risperidone ODT was found to be a safe and effective medication to treat mild agitation in a large urban and suburban EMS system. The need for additional medications to treat agitation was rare and there were no documented injuries to either patients or paramedics.

Comparison of Cyclic and Linear PEG Conjugates.

Bioconjugation of polymers to proteins is a method to impart improved stability and pharmacokinetic properties to biologic systems. However, the precise effects of polymer architecture on the resulting bioconjugates are not well understood. Particularly, cyclic polymers are known to possess unique features such as a decreased hydrodynamic radius when compared to their linear counterparts of the same molecular weight, but have not yet been studied. Here, we report the first bioconjugation of a cyclic polymer, poly(ethylene glycol) (PEG), to a model protein, T4 lysozyme, containing a single engineered cysteine residue (V131C). We compare the stability and activity of this conjugate with those of a linear PEG-T4 lysozyme analogue of similar molecular weight. Furthermore, we used molecular dynamics (MD) simulations to determine the behavior of the polymer-protein conjugates in solution. We introduce cyclic polymer-protein conjugates as potential candidates for the improvement of biologic therapeutics.

HIV infection and ART exposure impact tumor T-cell receptor repertoire of diffuse large B-cell lymphoma.

The most common subtype of lymphoma globally, diffuse large B-cell lymphoma (DLBCL) is a leading cause of cancer death in people with HIV (HIV+). The restructuring of the T-cell compartment due to HIV infection and antiretroviral therapy (ART) may have implications for modern treatment selection, but current understanding of these dynamic interactions is limited. Here, we investigated the T-cell response to DLBCL by sequencing the T-cell receptor (TCR) repertoire in a cohort of HIV-negative (HIV-), HIV+/ART-experienced and HIV+/ART-naïve DLBCL patients. HIV+/ART-naïve tumor TCR repertoires were more clonal and more distinct from each other than HIV- and HIV+/ART-experienced. Further, increased overlap between tumor and blood TCR repertoires was associated with improved survival and HIV/ART status. Our study describes TCR repertoire characteristics for the first time in an African DLBCL cohort and demonstrates contributions of HIV infection and ART exposure to the DLBCL TCR repertoire.

Probing Metal Ion Adduction in the ESI Charged Residue Mechanism via Gas-Phase Ion/Ion Chemistry.

The final stages of the charged residue mechanism/model (CRM) for ion generation via electrospray ionization (ESI) involves the binding of excess charge onto analyte species. Ions of both polarities can bind to the analyte with an excess of ions of the same polarity as the droplet. For large biomolecule/biocomplex ions, which are commonly the species of interest in native mass spectrometry (MS), the binding of acids and salts onto the analyte can lead to extensive broadening of ion signals due to adduction. Therefore, heating step(s) to facilitate desolvation and salt adduct removal are commonplace. In this work, we describe an approach to study the final stages of CRM using gas-phase ion/ion reactions to generate analyte ion/salt clusters of well-defined composition, followed by gas-phase collision-induced dissociation (CID). While there are many variables that can be studied systematically via this approach, the work described herein is focused on salt clusters of the form [Na10X11]-, where X = acetate (Ac-), chloride (Cl-), or nitrate (NO3-), in reaction with a common charge state of ubiquitin as well as several model peptides. Experiments in which equimolar quantities of each salt (i.e., NaAc, NaCl, and NaNO3) are subjected to ESI with ubiquitin (Ubi) and gas-phase ion/ion reaction studies involving [Na10X11]- and [Ubi + 6H]6+ show similar trends, in terms of the extent of sodium ion incorporation into the protein ions. Ion/ion reaction studies using model peptides show that the acetate-containing salt transfers significantly more Na+ ions into the peptide ions. Exchange of Na+ for H+ is shown to occur at the C-terminus and at up to all of the amide linkages using [Na10X11]-, whereas only the C-terminus engages in Na+/H+ exchange with [Na10Cl11]- and [Na10(NO3)11]-. In the latter cases, an additional Na+ is taken up as the excess positive charge, presumably due to solvation of the charge by multiple sites (e.g., carbonyl oxygens and basic sites).

Fluid flow overcomes antimicrobial resistance by boosting delivery.

Antimicrobial resistance is an emerging global threat to humanity. As resistance outpaces development, new perspectives are required. For decades, scientists have prioritized chemical optimization, while largely ignoring the physical process of delivery. Here, we used biophysical simulations and microfluidic experiments to explore how fluid flow delivers antimicrobials into communities of the highly resistant pathogen Pseudomonas aeruginosa . We discover that increasing flow overcomes bacterial resistance towards three chemically distinct antimicrobials: hydrogen peroxide, gentamicin, and carbenicillin. Without flow, resistant P. aeruginosa cells generate local zones of depletion by neutralizing all three antimicrobials through degradation or chemical modification. As flow increases, delivery overwhelms neutralization, allowing antimicrobials to regain effectiveness against resistant bacteria. Additionally, we discover that cells on the edge of a community shield internal cells, and cell-cell shielding is abolished in higher flow regimes. Collectively, our quantitative experiments reveal the unexpected result that physical flow and chemical dosage are equally important to antimicrobial effectiveness. Thus, our results should inspire the incorporation of flow into the discovery, development, and implementation of antimicrobials, and could represent a new strategy to combat antimicrobial resistance.

Exploring the chemical dynamics of phenanthrene (C14H10) formation via the bimolecular gas-phase reaction of the phenylethynyl radical (C6H5CC) with benzene (C6H6).

The exploration of the fundamental formation mechanisms of polycyclic aromatic hydrocarbons (PAHs) is crucial for the understanding of molecular mass growth processes leading to two- and three-dimensional carbonaceous nanostructures (nanosheets, graphenes, nanotubes, buckyballs) in extraterrestrial environments (circumstellar envelopes, planetary nebulae, molecular clouds) and combustion systems. While key studies have been conducted exploiting traditional, high-temperature mechanisms such as the hydrogen abstraction-acetylene addition (HACA) and phenyl addition-dehydrocyclization (PAC) pathways, the complexity of extreme environments highlights the necessity of investigating chemically diverse mass growth reaction mechanisms leading to PAHs. Employing the crossed molecular beams technique coupled with electronic structure calculations, we report on the gas-phase synthesis of phenanthrene (C14H10)-a three-ring, 14π benzenoid PAH-via a phenylethynyl addition-cyclization-aromatization mechanism, featuring bimolecular reactions of the phenylethynyl radical (C6H5CC, X2A1) with benzene (C6H6) under single collision conditions. The dynamics involve a phenylethynyl radical addition to benzene without entrance barrier leading eventually to phenanthrene via indirect scattering dynamics through C14H11 intermediates. The barrierless nature of reaction allows rapid access to phenanthrene in low-temperature environments such as cold molecular clouds which can reach temperatures as low as 10 K. This mechanism constitutes a unique, low-temperature framework for the formation of PAHs as building blocks in molecular mass growth processes to carbonaceous nanostructures in extraterrestrial environments thus affording critical insight into the low-temperature hydrocarbon chemistry in our universe.

In-Depth Analysis of the Species and Transformations during Sol Gel-Assisted V2PC Synthesis.

The sol-gel reaction mechanism of 211 MAX phases has proven to be very complex when identifying the intermediate species, chemical processes, and conversions that occur from a mixture of metal salts and gelling agent into a crystalline ternary carbide. With mostly qualitative results in the literature (Cr2GaC, Cr2GeC, and V2GeC), additional analytical techniques, including thermal analysis, powder diffraction, total scattering, and various spectroscopic methods, are necessary to unravel the identity of the chemical compounds and transformations during the reaction. Here, we demonstrate the combination of these techniques to understand the details of the sol-gel synthesis of MAX phase V2PC. The metal phosphate complexes, as well as amorphous/nanocrystalline vanadium phosphate species (V in different oxidation states), are identified at all stages of the reaction and a full schematic of the reaction process is suggested. The early amorphous vanadium species undergo multiple changes of oxidation states while organic species decompose releasing a variety of small molecule gases. Amorphous oxides, analogous to [NH4][VO2][HPO4], V2PO4O, and VO2P2O7 are identified in the dried gel obtained during the early stages of the heating process (300 and 600 °C), respectively. They are carbothermally reduced starting at 900 °C and subsequently react to crystalline V2PC with the excess carbon in the reaction mixture. Through CHN analysis, we obtain an estimate of left-over amorphous carbon in the product which will guide future efforts of minimizing the amount of carbon in sol gel-produced MAX phases which is important for subsequent property studies.

Incidentally diagnosed superior vena cava narrowing prompted by screening mammography.

An adult woman with a prior history of treated non-Hodgkin's lymphoma presented for screening mammography, which incidentally demonstrated dilated veins throughout the bilateral breasts. Concern for a superior vena cava stenosis or obstruction was raised despite the patient being asymptomatic; the patient underwent further imaging with chest CT, which revealed focal stenosis of the superior vena cava, attributed to fibrosis secondary to prior radiation therapy. Superior vena cava syndrome (SVCS), the spectrum of disease caused by superior vena cava narrowing or obstruction, requires prompt investigation given its association with intrathoracic malignancy, primary lung cancer and poor outcomes. This report explores the benign and malignant causes, signs and symptoms, preferred investigations, and treatment of SVCS. This case highlights the potential importance of screening mammography in revealing unexpected ancillary diagnoses, especially in high-risk patients.

Primary intraosseous xanthoma of the frontal bone in a child: illustrative case.

BACKGROUND: Skull lesions are a common finding in children, with dermoid cysts and eosinophilic granulomas observed most frequently. However, primary intraosseous xanthomas of the calvaria, which are lytic, expansile lesions that develop without underlying hyperlipidemic disease, are rare in children, with only one prior case reported. OBSERVATIONS: The authors describe the case of a healthy 6-year-old male who presented with a 2-month history of an enlarging midline skull mass that developed after a recent minor trauma. Imaging showed a full-thickness, lytic frontal bone lesion with an aggressive appearance and heterogeneous contrast enhancement. The patient underwent gross-total resection of the lesion with placement of a mesh cranioplasty. Histopathology revealed a primary intraosseous xanthoma. The patient was discharged on postoperative day 2 and required no further treatment at the 1-month follow-up. LESSONS: This is the first reported case of a primary intraosseous xanthoma in the frontal bone of a pediatric patient. It emphasizes the need to include primary xanthomas in the differential diagnosis for pediatric skull lesions, particularly when the lesion has an aggressive radiographic appearance or the patient has a history of focal trauma. Furthermore, our findings indicate that resection, together with subsequent monitoring for lesion reccurrence, is an adequate first-line treatment.

The Effect of Neoadjuvant Systemic Therapy on Surgical Outcomes After Lymph Node Dissections for Stage III Melanoma; An Australian Cohort.

BACKGROUND: Neoadjuvant systemic therapy (NAST) for patients with stage III melanoma achieves high major pathologic response rates and high recurrence-free survival rates. This study aimed to determine how NAST with targeted therapies (TTs) and immune checkpoint inhibitors (ICIs) influences surgical outcomes after lymph node dissection in terms of complications, morbidity, and textbook outcomes. METHODS: Patients who underwent a lymph node dissection after either NAST in a clinical trial or upfront surgery for stage III melanoma between 2014 and 2022 were identified from an institutional research database. RESULTS: The study included 89 NAST-treated patients and 79 upfront surgery-treated patients. The rate of postoperative complications did not differ between the NAST- and upfront surgery-treated patients (55% vs. 51%; p = 0.643), and steroid treatment for drug toxicity did not influence the complication rate (odds ratio [OR], 1.1; 95% confidence interval [CI], 0.4-3; p = 0.826). No significant differences in postoperative morbidity were observed in terms of seroma (23% vs. 11%; p = 0.570) or lymphedema (36% vs. 51%; p = 0.550). The rate of achieving a textbook outcome was comparable for the two groups (61% vs. 57%; p = 0.641). CONCLUSIONS: The surgical outcomes after lymph node dissections were comparable between the patients who received NAST and those who had upfront surgery, indicating that surgery can be safely performed after NAST with TT or ICI for stage III melanoma.

Different clinical characteristics and outcomes of adult hospitalized SARS-CoV-2 pneumonia patients complicated by cardiovascular events during the first, delta and omicron waves of COVID-19.

Background: The effects of SARS-CoV-2 have varied between significant waves of hospitalization. Research question: Are cardiovascular complications different among the first, delta and omicron waves of hospitalized COVID-19 pneumonia patients? Study design and methods: This was a multi-centre retrospective study of patients hospitalized with SARS-CoV-2 pneumonia: 632 were hospitalized during the first wave (March-July 2020), 1013 during the delta wave (September 2020-March 2021), and 323 during the omicron wave (January 2022-July 2022). Patients were stratified by wave and occurrence of cardiovascular events. Results: Among all hospitalized patients with cardiovascular events, patients in the omicron wave were younger (62.4 ± 14 years) than patients in the first wave (67.4 ± 7.8 years) and the delta wave (66.9 ± 12.6 years) and had a higher proportion of non-Hispanic White people than in the first wave (78.6% vs. 61.7%). For COVID-19 patients who suffered from cardiovascular events, the omicron wave patients had significantly higher neutrophil/lymphocyte ratio, white blood cell and platelet counts when compared to the first wave. Omicron wave patients had significantly lower albumin and B-type natriuretic peptide levels (only 5.8% of the first wave and 14.6% of the delta wave) when compared to either the first wave or delta wave patients. In COVID-19 patients who suffered cardiovascular events during hospitalization, mortality rate in the omicron wave (26.8%) was significantly lower than the first wave (48.3%), time to mortality for non-survivors of COVID-19 patients who suffered cardiovascular events was significantly longer in the omicron wave (median 16 days) than in the first wave (median 10 days). Conclusions: Younger and white patients were affected with cardiovascular complications more often by the omicron variant. Despite higher neutrophil/lymphocyte ratio and WBC counts, the omicron patients with cardiovascular events showed lower heart injuries, lower mortality and longer time to mortality for non-survivors when compared to the first and delta waves.

Upstrapping to determine futility: predicting future outcomes nonparametrically from past data.

BACKGROUND: Clinical trials often involve some form of interim monitoring to determine futility before planned trial completion. While many options for interim monitoring exist (e.g., alpha-spending, conditional power), nonparametric based interim monitoring methods are also needed to account for more complex trial designs and analyses. The upstrap is one recently proposed nonparametric method that may be applied for interim monitoring. METHODS: Upstrapping is motivated by the case resampling bootstrap and involves repeatedly sampling with replacement from the interim data to simulate thousands of fully enrolled trials. The p-value is calculated for each upstrapped trial and the proportion of upstrapped trials for which the p-value criteria are met is compared with a pre-specified decision threshold. To evaluate the potential utility for upstrapping as a form of interim futility monitoring, we conducted a simulation study considering different sample sizes with several different proposed calibration strategies for the upstrap. We first compared trial rejection rates across a selection of threshold combinations to validate the upstrapping method. Then, we applied upstrapping methods to simulated clinical trial data, directly comparing their performance with more traditional alpha-spending and conditional power interim monitoring methods for futility. RESULTS: The method validation demonstrated that upstrapping is much more likely to find evidence of futility in the null scenario than the alternative across a variety of simulations settings. Our three proposed approaches for calibration of the upstrap had different strengths depending on the stopping rules used. Compared to O'Brien-Fleming group sequential methods, upstrapped approaches had type I error rates that differed by at most 1.7% and expected sample size was 2-22% lower in the null scenario, while in the alternative scenario power fluctuated between 15.7% lower and 0.2% higher and expected sample size was 0-15% lower. CONCLUSIONS: In this proof-of-concept simulation study, we evaluated the potential for upstrapping as a resampling-based method for futility monitoring in clinical trials. The trade-offs in expected sample size, power, and type I error rate control indicate that the upstrap can be calibrated to implement futility monitoring with varying degrees of aggressiveness and that performance similarities can be identified relative to considered alpha-spending and conditional power futility monitoring methods.

Anti-PD-1 alone or in combination with anti-CTLA-4 for advanced melanoma patients with liver metastases.

BACKGROUND: The combination of anti-PD-1 and anti-CTLA-4 has been associated with improvement in response and survival over anti-PD-1 monotherapy in unselected patients with advanced melanoma. Whether patients with liver metastases also benefit from the combination of anti-PD-1 and anti-CTLA-4 over anti-PD-1, is unclear. In this study, we sought to assess whether the combination of anti-PD-1 and anti-CTLA-4 leads to better response, progression-free survival and overall survival, compared with anti-PD-1 monotherapy for patients with liver metastases. METHODS: We have conducted an international multicentre retrospective study. Patients with advanced melanoma with liver metastases treated with 1st line anti-PD1 monotherapy or with anti-CTLA-4 were included. The endpoints of this study were: objective response rate, progression-free survival and overall survival. RESULTS: With a median follow-up from commencement of anti-PD-1 monotherapy or in combination with anti-CTLA-4 of 47 months (95% CI, 42-51), objective response rate was higher with combination therapy (47%) versus anti-PD-1 monotherapy (35%) (p = 0.0027), while progression-free survival and overall survival were not statistically different between both treatment groups. However, on multivariable analysis with multiple imputation for missing values and adjusting for predefined variables, combination of anti-PD1 and anti-CTLA-4 was associated with higher objective response (OR 2.21, 1.46 - 3.36; p < 0.001), progression-free survival (HR 0.73, 0.57 - 0.92; p = 0.009) and overall survival (HR 0.71, 0.54 - 0.94; p = 0.018) compared to anti-PD1 monotherapy. CONCLUSIONS: Findings from this study will help guide treatment selection for patients who present with liver metastases, suggesting that combination therapy should be considered for this group of patients.