Sample size calculation for comparing two ROC curves.

Biomarkers are key components of personalized medicine. In this paper, we consider biomarkers taking continuous values that are associated with disease status, called case and control. The performance of such a biomarker is evaluated by the area under the curve (AUC) of its receiver operating characteristic curve. Oftentimes, two biomarkers are collected from each subject to test if one has a larger AUC than the other. We propose a simple non-parametric statistical test for comparing the performance of two biomarkers. We also present a simple sample size calculation method for this test statistic. Our sample size formula requires specification of AUC values (or the standardized effect size of each biomarker between cases and controls together with the correlation coefficient between two biomarkers), prevalence of cases in the study population, type I error rate, and power. Through simulations, we show that the testing on two biomarkers controls type I error rate accurately and the proposed sample size closely maintains specified statistical power.

Percutaneous lumbar interbody fusion results in less perioperative opioid usage compared to minimally invasive transforaminal lumbar interbody fusion: a single institution, multi-surgeon retrospective study.

Background: Ultra-minimally invasive percutaneous lumbar interbody fusion (percLIF) has been demonstrated to further minimize tissue trauma and has been associated with improved clinical outcomes including decreased blood loss, post-operative pain and length of stay when compared to minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) surgery. A single-institution retrospective study was conducted to investigate whether 1-level percLIF is associated with decreased narcotic consumption compared to 1-level MIS-TLIF in the first 24-hour following surgery. Methods: A retrospective study of patients undergoing either single-level percLIF or MIS-TLIF from January 2018 to December 2021. Opioid consumption in the 24-hour following surgery was converted into total morphine milligram equivalents (MME). The primary outcome used univariate and multivariate regression analysis to compare MME consumption between the MIS-TLIF and percLIF groups. Secondary outcome variables included, estimated blood loss, total intraoperative MME, MME at discharge, MME at 30 days post-op, exiting nerve root injury, post-anesthesia care unit (PACU) visual analogue scale (VAS) score at handoff, time to first ambulation, distance ambulated post-operative day one and hospital length of stay. Results: A total of 51 patients (21 percLIF vs. 30 MIS-TLIF) were included in the study. Univariate regression analysis revealed that on average patients who underwent percLIF had a 24-hour postoperative MME -50.8 mg (95% CI: -91.6, -10) lower than those who had MIS-TLIF (P=0.02). On multivariable analysis, after adjusting for sex and age, 24-hour postoperative MME closely failed to meet statistical significance (P=0.06) with an average of -40.8 mg (95% CI: -83.2, 1.6) MME in percLIF patients compared to MIS-TLIF. There was no statistically significant difference in MME between MIS-TLIF and percLIF at the time of discharge and at 30 days post-op. Conclusions: In the setting of the current opioid epidemic in the United States and increased numbers of patients undergoing lumbar interbody fusion, spine surgeons must continue to do their part helping reduce the need for opioid prescriptions for postoperative pain management. New "ultra-MIS" techniques such as percLIF allow surgeons to further decrease tissue trauma, which should lead to reduced need for post-operative narcotic requirements.

Confidence intervals for odds ratio from multistage randomized phase II trials.

A multi-stage randomized trial design can significantly improve efficiency by allowing early termination of the trial when the experimental arm exhibits either low or high efficacy compared to the control arm during the study. However, proper inference methods are necessary because the underlying distribution of the target statistic changes due to the multi-stage structure. This article focuses on multi-stage randomized phase II trials with a dichotomous outcome, such as treatment response, and proposes exact conditional confidence intervals for the odds ratio. The usual single-stage confidence intervals are invalid when used in multi-stage trials. To address this issue, we propose a linear ordering of all possible outcomes. This ordering is conditioned on the total number of responders in each stage and utilizes the exact conditional distribution function of the outcomes. This approach enables the estimation of an exact confidence interval accounting for the multi-stage designs.

Estimation of the odds ratio from multi-stage randomized trials.

A multi-stage design for a randomized trial is to allow early termination of the study when the experimental arm is found to have low or high efficacy compared to the control during the study. In such a trial, an early stopping rule results in bias in the maximum likelihood estimator of the treatment effect. We consider multi-stage randomized trials on a dichotomous outcome, such as treatment response, and investigate the estimation of the odds ratio. Typically, randomized phase II cancer clinical trials have two-stage designs with small sample sizes, which makes the estimation of odds ratio more challenging. In this paper, we evaluate several existing estimation methods of odds ratio and propose bias-corrected estimators for randomized multi-stage trials, including randomized phase II cancer clinical trials. Through numerical studies, the proposed estimators are shown to have a smaller bias and a smaller mean squared error overall.

Efficacy of probiotic treatment as post-exposure prophylaxis for COVID-19: A double-blind, Placebo-Controlled Randomized trial.

BACKGROUND & AIMS: The COVID-19 pandemic continues to pose unprecedented challenges to worldwide health. While vaccines are effective, additional strategies to mitigate the spread/severity of COVID-19 continue to be needed. Emerging evidence suggests susceptibility to respiratory tract infections in healthy subjects can be reduced by probiotic interventions; thus, probiotics may be a low-risk, low-cost, and easily implementable modality to reduce risk of COVID-19. METHODS: In this initial study, we conducted a randomized, double-blind, placebo-controlled trial across the United States testing probiotic Lacticaseibacillus rhamnosus GG (LGG) as postexposure prophylaxis for COVID-19 in 182 participants who had household exposure to someone with confirmed COVID-19 diagnosed within ≤7 days. Participants were randomized to receive oral LGG or placebo for 28 days. The primary outcome was development of illness symptoms within 28 days of COVID-19 exposure. Stool was collected to evaluate microbiome changes. RESULTS: Intention-to-treat analysis showed LGG treatment led to a lower likelihood of developing illness symptoms versus placebo (26.4 % vs. 42.9 %, p = 0.02). Further, LGG was associated with a statistically significant reduction in COVID-19 diagnosis (log rank, p = 0.049) via time-to-event analysis. Overall incidence of COVID-19 diagnosis did not significantly differ between LGG and placebo groups (8.8 % vs. 15.4 %, p = 0.17). CONCLUSIONS: This data suggests LGG is associated with prolonged time to COVID-19 infection, reduced incidence of illness symptoms, and gut microbiome changes when used as prophylaxis ≤7 days post-COVID-19 exposure, but not overall incidence. This initial work may inform future COVID-19 prevention studies worldwide, particularly in developing nations where Lacticaseibacillus probiotics have previously been utilized to reduce other non-COVID infectious-morbidity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04399252, Date: 22/05/2020. https://clinicaltrials.gov/ct2/show/NCT04399252.

A pilot study to assess the feasibility of a remotely monitored high-intensity interval training program prior to allogeneic hematopoietic stem cell transplantation.

INTRODUCTION: Although allogeneic hematopoietic stem cell transplantation (HCT) can be a curative therapy for hematologic disorders, it is associated with treatment-related complications and losses in cardiorespiratory fitness and physical function. High-intensity interval training (HIIT) may be a practical way to rapidly improve cardiorespiratory fitness and physical function in the weeks prior to HCT. The primary aim of this study was to assess the feasibility of implementing a pre-HCT home-based HIIT intervention. The secondary aim was to evaluate pre to post changes in cardiorespiratory fitness and physical function following the intervention. METHODS: This was a single-arm pilot study with patients who were scheduled to undergo allogeneic HCT within six months. Patients were instructed to complete three 30-minute home-based HIIT sessions/week between the time of study enrollment and sign-off for HCT. Sessions consisted of a 5-minute warm-up, 10 high and low intervals performed for one minute each, and a 5-minute cool-down. Prescribed target heart rates (HR) for the high- and low-intensity intervals were 80-90% and 50-60% of HR reserve, respectively. Heart rates during HIIT were captured via an Apple Watch and were remotely monitored. Feasibility was assessed via retention, session adherence, and adherence to prescribed interval number and intensities. Paired t-tests were used to compare changes in fitness (VO2peak) and physical function [Short Physical Performance Battery (SPPB), 30-second sit to stand, and six-minute walk test (6MWT)] between baseline and sign-off. Pearson correlations were used to determine the relationship between intervention length and changes in cardiorespiratory fitness or functional measures. RESULTS: Thirteen patients (58.8±11.6 years) participated in the study, and nine (69.2%) recorded their training sessions throughout the study. Median session adherence for those nine participants was 100% (IQR: 87-107). Adherence to intervals was 92% and participants met or exceeded prescribed high-intensity HR on 68.8±34.8% of intervals. VO2peak improved from baseline to sign-off (14.6±3.1 mL/kg/min to 17.9±3.3 mL/kg/min; p<0.001). 30-second sit to stand and SPPB chair stand scores significantly improved in adherent participants. Improvements in 30-second sit to stand (13.8±1.5 to 18.3±3.3 seconds) and 6MWT (514.4±43.2 to 564.6±19.3) exceeded minimal clinically important improvements established in other chronic disease populations, representing the minimum improvement considered meaningful to patients. CONCLUSIONS: Findings demonstrate that implementing a pre-HCT home-based remotely monitored HIIT program is feasible and may provide benefits to cardiorespiratory fitness and physical function.

Improving patient outcomes with a mobile digital health platform for patients undergoing transcatheter aortic valve replacement.

PURPOSE: ManageMySurgery (MMS) is a digital health application (app) for patients undergoing surgery, including Transcatheter Aortic Valve Replacement (TAVR). Patients using MMS review procedure-specific education, view FAQs, and report patient-reported outcomes. This study assessed the impact of app use on postoperative outcomes. METHODS: Patients who underwent TAVR and invited to use MMS between March 2019 and November 2021 were identified. Patients received standard perioperative care and were defined as App users if they signed into the app at least once and engaged with at least one task or FAQ. Demographics and postoperative outcomes were collected via medical record review. Multivariable logistic regression models were used to determine odds of 90-day readmission, Emergency Room (ER) visits, and complications. RESULTS: 388 patients met inclusion criteria, of which 238 used the app. The average age at surgery was 76.4±7.7 years for users and 78.1±7.6 for non-users. 63.0% of users and 59.3% of non-users were male. App users had significantly lower 90-day readmission rates, (8.8% vs 16.0%, OR=0.51, p=0.0373), ER visit rates (12.6% vs 27.3%, OR=0.36, p=0.0003), and complication rates (Minor: 12.2% vs 20.7%, OR=0.48, P=0.0126; Major: 8.8% vs. 16%, OR=0.47, P=0.0235). CONCLUSIONS: In this non-randomized, retrospective study, we found significant decreases in 90-day readmissions, ER visits, and complications in TAVR patients using an app compared to traditional care. By engaging patients throughout their interventional journey with structured education and tasks, mobile health platforms may mitigate unnecessary use of emergency and inpatient care, thereby improving patient well-being and lowering the burden on healthcare resources.

Timing of Adjuvant Immunotherapy in Stage III Melanoma, Does it Matter?

BACKGROUND: The optimal time to initiate adjuvant immune checkpoint inhibitors (ICI) following resection remains undefined. Herein, we investigated the impact of time to adjuvant ICI on survival in patients with stage III melanoma. METHODS: Patients with resected stage III melanoma receiving adjuvant immune therapy were identified within a multi-institutional retrospective cohort. Patients were stratified by time to adjuvant ICI: within 6 weeks, 6-12 weeks, and greater than 12 weeks from surgery. Recurrence-free survival (RFS) was compared among time strata with Kaplan-Meier and Cox proportional hazards methods in the multi-institutional cohort. RESULTS: Altogether, 626 patients were identified within the multi-institutional cohort: 39% of patients initiated adjuvant ICI within 6 weeks, 42.2% within 6-12 weeks, and 18.8% greater than 12 weeks from surgery. In a multivariate Cox model, adjusting for histology, nodal tumor burden, and pathologic stage, we found that increased time to adjuvant ICI was associated with improved RFS. Patients who initiated adjuvant ICI within 6 weeks of surgery had worse RFS. These findings were preserved in a conditional landmark analysis and separate subgroups of patients with (1) new melanoma diagnoses, (2) occult stage III disease, and (3) those receiving anti-PD-1 monotherapy. CONCLUSIONS: Outcomes for patients with stage III melanoma are not compromised when adjuvant ICI is initiated beyond 6 weeks from resection. Additional work is needed to better understand the underlying mechanisms and implications of timing of adjuvant ICI on long-term outcomes.

Regional anesthesia is associated with improved metastasis free survival after surgical resection of bone sarcomas.

There is increasing evidence that perioperative factors, including type of anesthesia, may be an important consideration regarding oncological disease progression. Previous studies have suggested that regional anesthesia can improve oncological outcomes by reducing the surgical stress response that occurs during tumor resection surgery and that may promote metastatic progression. The purpose of this study is to provide the first robust investigation of the impact of adding regional anesthesia to general anesthesia on oncological outcomes following sarcoma resection. One hundred patients with bone sarcoma were retrospectively analyzed in this study. After adjusting for confounding variables such as age and grade of the tumor, patients with bone sarcoma receiving regional anesthesia in addition to general anesthesia during resection had improved metastasis free survival (multivariate hazard ratio of 0.47 and p = 0.034). Future studies are needed to confer the beneficial effect of regional anesthesia, and to further investigate the potential mechanism. Clinical significance: The results from this study provide evidence that regional anesthesia may be advantageous in the setting of bone sarcoma resection surgery, reducing pain while also improving oncological outcomes and should be considered when clinically appropriate.

Revisiting flow augmentation bypass for cerebrovascular atherosclerotic vaso-occlusive disease: Single-surgeon series and review of the literature.

OBJECTIVE: Despite advances in the nonsurgical management of cerebrovascular atherosclerotic steno-occlusive disease, approximately 15-20% of patients remain at high risk for recurrent ischemia. The benefit of revascularization with flow augmentation bypass has been demonstrated in studies of Moyamoya vasculopathy. Unfortunately, there are mixed results for the use of flow augmentation in atherosclerotic cerebrovascular disease. We conducted a study to examine the efficacy and long term outcomes of superficial temporal artery to middle cerebral artery (STA-MCA) bypass in patients with recurrent ischemia despite optimal medical management. METHODS: A single-institution retrospective review of patients receiving flow augmentation bypass from 2013-2021 was conducted. Patients with non-Moyamoya vaso-occlusive disease (VOD) who had continued ischemic symptoms or strokes despite best medical management were included. The primary outcome was time to post-operative stroke. Time from cerebrovascular accident to surgery, complications, imaging results, and modified Rankin Scale (mRS) scores were aggregated. RESULTS: Twenty patients met inclusion criteria. The median time from cerebrovascular accident to surgery was 87 (28-105.0) days. Only one patient (5%) had a stroke at 66 days post-op. One (5%) patient had a post-operative scalp infection, while 3 (15%) developed post-operative seizures. All 20 (100%) bypasses remained patent at follow-up. The median mRS score at follow up was significantly improved from presentation from 2.5 (1-3) to 1 (0-2), P = .013. CONCLUSIONS: For patients with high-risk non-Moyamoya VOD who have failed optimal medical therapy, contemporary approaches to flow augmentation with STA-MCA bypass may prevent future ischemic events with a low complication rate.

Quantifying the Opportunity Cost of Neurosurgical Resident Education.

BACKGROUND/OBJECTIVE: Education is at the core of neurosurgical residency, but little research in to the cost of neurosurgical education exists. This study aimed to quantify costs of resident education in an academic neurosurgery program using traditional teaching methods and the Surgical Autonomy Program (SAP), a structured training program. METHODS: SAP assesses autonomy by categorizing cases into zones of proximal development (opening, exposure, key section, and closing). All first-time, 1-level to 4-level anterior cervical discectomy and fusion (ACDF) cases between March 2014 and March 2022 from 1 attending surgeon were divided into 3 groups: independent cases, cases with traditional resident teaching, and cases with SAP teaching. Surgical times for all cases were collected and compared within levels of surgery between groups. RESULTS: The study found 2140 ACDF cases, with 1758 independent, 223 with traditional teaching, and 159 with SAP. For 1-level to 4-level ACDFs, teaching took longer than it did with independent cases, with SAP teaching adding additional time. A 1-level ACDF performed with a resident (100.1 ± 24.3 minutes) took about as long as a 3-level ACDF performed independently (97.1 ± 8.9 minutes). The average time for 2-level cases was 72.0 ± 18.2 minutes independently, 121.7 ± 33.7 minutes traditional, and 143.4 ± 34.9 minutes SAP, with significant differences among all groups. CONCLUSIONS: Teaching takes significant time compared with operating independently. There is also a financial cost to educating residents, because operating room time is expensive. Because attending neurosurgeons lose time to perform more surgeries when teaching residents, there is a need to acknowledge surgeons who devote time to training the next generation of neurosurgeons.

Long-term outcomes of aortic root operations in the United States among Medicare beneficiaries.

OBJECTIVE: The best method of aortic root repair in older patients remains unknown given a lack of comparative effectiveness of long-term outcomes data. The objective of this study was to compare long-term outcomes of different surgical approaches for aortic root repair in Medicare patients using The Society of Thoracic Surgeons Adult Cardiac Surgery Database-Centers for Medicare & Medicaid Services-linked data. METHODS: A retrospective cohort study was performed by querying the Society of Thoracic Surgeons Adult Cardiac Surgery Database for patients aged 65 years or more who underwent elective aortic root repair with or without aortic valve replacement. Primary long-term end points were mortality, any stroke, and aortic valve reintervention. Short-term outcomes and long-term survival were compared among each root repair strategy. Additional risk factors for mortality after aortic root repair were assessed with a multivariable Cox proportional hazards model. RESULTS: A total of 4173 patients aged 65 years or more underwent elective aortic root repair. Patients were stratified by operative strategy: mechanical Bentall, stented bioprosthetic Bentall, stentless bioprosthetic Bentall, or valve-sparing root replacement. Mean follow-up was 5.0 (±4.6) years. Relative to mechanical Bentall, stented bioprosthetic Bentall (adjusted hazard ratio, 0.80; confidence interval, 0.66-0.97) and stentless bioprosthetic Bentall (adjusted hazard ratio, 0.70; confidence interval, 0.59-0.84) were associated with better long-term survival. In addition, stentless bioprosthetic Bentall (adjusted hazard ratio, 0.64; confidence interval, 0.47-0.80) and valve-sparing root replacement (adjusted hazard ratio, 0.51; confidence interval, 0.29-0.90) were associated with lower long-term risk of stroke. Aortic valve reintervention risk was 2-fold higher after valve-sparing root replacement compared with other operative strategies. CONCLUSIONS: In the Medicare population, there was poorer late survival and greater late stroke risk for patients undergoing mechanical Bentall and a higher rate of reintervention for valve-sparing root replacement. Bioprosthetic Bentall may be the procedure of choice in older patients undergoing aortic root repair, particularly in the era of transcatheter aortic valve replacement.

Survival and tumor characteristics of patients presenting with single primary versus second primary melanoma lesions.

BACKGROUND: Patients with single primary melanomas have an increased risk of developing subsequent melanomas. Secondary tumors diagnosed within and after 3 months are termed "synchronous" and "asynchronous," respectively. OBJECTIVE: To compare tumor distributions and survival characteristics between patients with second primary melanomas and those with single primary melanomas. METHODS: Retrospective cohort study. Data were collected from an institutional database from 14,029 patients with a diagnosis of a primary melanoma seen between 1970 and 2004. RESULTS: The synchronous and asynchronous cohorts demonstrated significantly improved survival probabilities compared with the single primary cohort (P = .04 and .002, respectively). Single primary lesions (2.2 ± 2.3 mm) were significantly thicker than the first-identified synchronous (2.0 ± 1.7 mm) and asynchronous (1.7 ± 1.3 mm) lesions. Synchronous lesions were more likely to be anatomically concordant compared with asynchronous lesions (55.7% vs 38.2%, P < .001). LIMITATIONS: Single-center study design and incomplete records for second primary melanoma Breslow depth and histopathology. CONCLUSION: Patients with second primary melanomas demonstrated a significant survival advantage and thinner lesions compared with those with single primary melanomas. Our reported tumor distributions support the role of full body skin examinations, with attention to the region of initial diagnosis.

Relevance of Bone Marrow Biopsies for Response Assessment in US National Cancer Institute National Clinical Trials Network Follicular Lymphoma Clinical Trials.

PURPOSE: Bone marrow biopsies (BMB) are performed before/after therapy to confirm complete response (CR) in patients with lymphoma on clinical trials. We sought to establish whether BMB add value in assessing response or predict progression-free survival (PFS) or overall survival (OS) outcomes in follicular lymphoma (FL) subjects in a large, multicenter, multitrial cohort. METHODS: Data were pooled from seven trials of 580 subjects with previously untreated FL through Alliance for Clinical Trials in Oncology (Alliance) and SWOG Cancer Research Network (SWOG) completing enrollment from 2008 to 2016. RESULTS: Only 5/580 (0.9%) had positive baseline BMB, CR on imaging, and subsequent positive BMB (P < .0001). Therefore, BMB were irrelevant to response in 99% of subjects. A sensitivity analysis of 385 FL subjects treated on an Eastern Cooperative Oncology Group study was included. In the Eastern Cooperative Oncology Group cohort, 5/385 (1.3%) had BMB that affected response assessment. Since some subjects do not undergo confirmatory BMB, we performed a landmark survival analysis from first radiologic CR with data from 580 subjects from Alliance and SWOG. Of subjects with CR on imaging (n = 187), PFS and OS were not significantly different among those with negative BMB to confirm CR (n = 47) versus those without repeat BMB (n = 140; PFS: adjusted hazard ratio, 1.10, 95% CI, 0.62 to 1.94, log-rank P = .686; OS: hazard ratio, 0.59, 95% CI, 0.23 to 1.53, log-rank P = .276). CONCLUSION: We conclude that BMB add little value to response assessment in subjects with FL treated on clinical trials and we recommend eliminating BMB from clinical trial requirements. BMB should also be removed from diagnostic guidelines for FL except in scenarios in which it may change management including confirmation of limited stage and assessment of cytopenias. This would reduce cost, patient discomfort, resource utilization, and potentially remove a barrier to trial enrollment.

Optimal designs for phase II clinical trials with heterogeneous patient populations.

We consider single-arm phase II cancer clinical trials with tumor response as the primary outcome. Oftentimes, the patient population of a phase II clinical trial consists of subpopulations with different expected response rates. A well-accepted design in this case is to specify the response rate and the prevalence of each subpopulation, to compute the response rate of the whole population using the weighted (by prevalence) average of the response rates across subpopulations, and to find a standard phase II design, such as Simon's minimax or optimal design, for testing on the response rate of the whole population based on the unstratified binomial test. In such trials, while the response rate is the primary parameter and the prevalence of each subpopulation is a nuisance parameter, the validity of an unstratified statistical test for deciding acceptance or rejection of the experimental treatment is influenced by observed prevalence. In order to avoid bias due to the discrepancy between observed and specified values of the nuisance parameter, we have to use stratified test for such trials. In this paper, we propose optimal and minimax designs for stratified binomial test. We also develop a user-friendly interactive software to visualize the optimal designs and help users make correct statistical decisions.

Nasal Cavity Squamous Cell Carcinoma: Factors Associated With Treatment Outcomes and Potential Organ Preservation.

BACKGROUND: Squamous cell carcinoma of the nasal cavity (NCSCC) is a rare, challenging malignancy. Surgical resection of this tumor can cause significant facial deformity, and indications for adjuvant or organ preservation therapies are not well-described. OBJECTIVE: To examine the impact of treatment regimen on survival outcomes in NCSCC and to compare surgical to non-surgical based therapies. METHODS: The National Cancer Database was queried for NCSCC from 2004 to 2014. Patient demographics, tumor characteristics, and treatment regimen were compared for the entire cohort. Multivariable Cox proportional hazards regression was performed for statistical analysis of treatment regimen and surgical margins on overall survival (OS) for early and late-stage disease. RESULTS: A total of 1883 NCSCC patients were identified. The OS for the cohort was 83 months, and median age at diagnosis was 65 years. NCSCC patients who underwent surgery followed by adjuvant radiation therapy (RT) had a better OS compared to definitive RT (HR: 0.58, P < .001). In early stage NCSCC (T1/T2, N0), there was no significant difference in OS between patients treated with surgery only or surgery with adjuvant RT compared to definitive RT. In advanced stage NCSCC, surgery with adjuvant RT had a better OS compared to definitive chemoradiation. Having positive margins was shown to predict a worse OS when compared to negative margins in surgical patients despite adjuvant RT or chemoradiation. CONCLUSIONS: NCSCC appears to be best treated with surgery followed by adjuvant RT in advanced-stage disease whereas in early-stage disease, surgery does not improve OS compared to definitive RT.

Neoadjuvant Radiation Therapy and Surgery Improves Metastasis-Free Survival over Surgery Alone in a Primary Mouse Model of Soft Tissue Sarcoma.

This study aims to investigate whether adding neoadjuvant radiotherapy (RT), anti-programmed cell death protein-1 (PD-1) antibody (anti-PD-1), or RT + anti-PD-1 to surgical resection improves disease-free survival for mice with soft tissue sarcomas (STS). We generated a high mutational load primary mouse model of STS by intramuscular injection of adenovirus expressing Cas9 and guide RNA targeting Trp53 and intramuscular injection of 3-methylcholanthrene (MCA) into the gastrocnemius muscle of wild-type mice (p53/MCA model). We randomized tumor-bearing mice to receive isotype control or anti-PD-1 antibody with or without radiotherapy (20 Gy), followed by hind limb amputation. We used micro-CT to detect lung metastases with high spatial resolution, which was confirmed by histology. We investigated whether sarcoma metastasis was regulated by immunosurveillance by lymphocytes or tumor cell-intrinsic mechanisms. Compared with surgery with isotype control antibody, the combination of anti-PD-1, radiotherapy, and surgery improved local recurrence-free survival (P = 0.035) and disease-free survival (P = 0.005), but not metastasis-free survival. Mice treated with radiotherapy, but not anti-PD-1, showed significantly improved local recurrence-free survival and metastasis-free survival over surgery alone (P = 0.043 and P = 0.007, respectively). The overall metastasis rate was low (∼12%) in the p53/MCA sarcoma model, which limited the power to detect further improvement in metastasis-free survival with addition of anti-PD-1 therapy. Tail vein injections of sarcoma cells into immunocompetent mice suggested that impaired metastasis was due to inability of sarcoma cells to grow in the lungs rather than a consequence of immunosurveillance. In conclusion, neoadjuvant radiotherapy improves metastasis-free survival after surgery in a primary model of STS.

Sources of bias for single-arm phase II cancer clinical trials.

A phase II trial is conducted to investigate if an experimental therapy is efficacious enough to proceed to a large-scale phase III trial or not. In spite of the fast progress in design and analysis methods, single-arm two-stage design is still the most popular for phase II cancer clinical trials. In this review article, we discuss two design and analysis methods that are popularly used for phase II clinical trials, but that can cause serious bias. One is about using the sample proportion as the estimator of the true response rate from single-arm two-stage trials. For a two-stage design with a futility interim test, the sample proportion is negatively biased by ignoring the two-stage design. The other is about the design and analysis of single-arm phase II trials for patient populations consisting of multiple sub-populations with different response rates. In this case, a standard design method is to project the prevalence of each subpopulation and select a standard two-stage design based on the expected response rate for the whole population. By using an unstratified statistical testing in this case, the standard analysis method can be seriously biased if the observed prevalence is very different from the projected one. In this paper, we review appropriate design and analysis methods that are proposed to avoid these sources of bias.