Design Of Prospective Clinical Trials Research Articles

Tumor-Stroma Proportion to Predict Chemoresistance in Patients With Ovarian Cancer

Platinum-based chemotherapy is the backbone of standard-of-care treatment for patients with advanced-stage, high-grade serous carcinoma (HGSC), the most common form of ovarian cancer; however, one-third of patients have or acquire chemoresistance toward platinum-based therapies. To demonstrate the utility of tumor-stroma proportion (TSP) as a predictive biomarker of chemoresistance of HGSC, progression-free survival (PFS), and overall survival (OS). This prognostic study leveraged tumors from patients with HGSC in The Cancer Genome Atlas (TCGA) cohort (1993-2013) and an independent cohort of resected clinical specimens from patients with HGSC (2004-2014) available in diagnostic and tissue microarray formats from the University of Tübingen in Germany. Data analysis was conducted from January 2021 to January 2024. Diagnosis of HGSC. Principal outcome measures were the ability of TSP to predict platinum chemoresistance, PFS, and OS. Using hematoxylin and eosin-stained slides from the Tübingen cohort (used for routine diagnostic assessment from surgical specimens) as well as tissue microarrays, representative sections of tumors for scoring of TSP were identified using previously evaluated cutoffs of 50% stroma or greater (high TSP) and less than 50% stroma (low TSP). Digitized slides from the TCGA Cohort were analyzed and scored in a similar fashion. Kaplan-Meier time-to-event functions were fit to estimate PFS and OS. The study included 103 patients (mean [SD] age, 61.6 [11.1] years) from the TCGA cohort and 192 patients (mean [SD] age at diagnosis, 63.7 [11.1] years) from the Tübingen cohort. In the TCGA cohort, there was no significant association of TSP levels with chemoresistance, PFS, or OS. However, in the Tübingen cohort, high TSP was associated with significantly shorter PFS (HR, 1.586; 95% CI, 1.093-2.302; P = .02) and OS (hazard ratio [HR], 1.867; 1.249-2.789; P = .002). Patients with chemoresistant tumors were twice as likely to have high TSP as compared to patients with chemosensitive tumors (HR, 2.861; 95% CI, 1.256-6.515; P = .01). In tissue microarrays from 185 patients from the Tübingen cohort, high TSP was again associated with significantly shorter PFS (HR, 1.675; 95% CI, 1.012-2.772 P = .04) and OS (HR, 2.491; 95% CI, 1.585-3.912; P < .001). In this prognostic study, TSP was a consistent and reproducible marker of clinical outcome measures of HGSC, including PFS, OS, and platinum chemoresistance. Accurate and cost-effective predictive biomarkers of platinum chemotherapy resistance are needed to identify patients most likely to benefit from standard treatments, and TSP can easily be implemented and integrated into prospective clinical trial design and adapted to identify patients who are least likely to benefit long-term from conventional platinum-based cytotoxic chemotherapy treatment at the time of initial diagnosis.

Topical Treatment for Dry Eye Disease Related to Sjögren's Syndrome: A Systematic Review

Abstract&#x0D; Introduction &amp; Objectives : Sjögren’s syndrome (SS) is a systemic autoimmune disorder characterized by dry eyes and dry mouth caused by inflammation in exocrine glands. Dry eye with SS is often more severe than non-SS dry eye and can greatly affect patients’ quality of life, thus treatment modalities must be selected carefully. This study aims to evaluate the recent studies on topical treatment for dry eye disease related to SS and provide evidence based recommendation for clinical practice.&#x0D; Methods : Electronic literature search was performed through the PubMed and Cochrane database from the last 10 years. We only included studies with prospective clinical trial design, a follow-up period of at least 4 weeks, and had outcome parameters among the following: Ocular Surface Disease Index, Schirmer test, tear break up time, tear meniscus height, and corneal fluorescein staining.&#x0D; Results : Fifteen studies were selected from 125 articles retrieved. We identified clinical trials using tacrolimus, cyclosporine, cortisol phosphate, diquafosol, rebamipide, fluorometholone, hydrocortisone, clobetasone butyrate, autologous serum, autologous platelet lysate, artificial tear, and various type of vehicles including hyaluronic acid, sodium hyaluronate, almond oil, ceftazidime,or saline solution.&#x0D; Conclusion : Cyclosporine has comparably equal efficacy to corticosteroid eye drops in improving signs and symptoms of dry eye in SS, but with a better safety for long-term use. Autologous serum is also an effective therapy with the best concentration being 100% serum (no dilution). Diquafosol is a promising therapy but more research is needed to confirm its efficacy and safety.

Arg389Gly beta-1-adrenergic receptor polymorphism determines neutrophil-stunning-associated cardioprotection by metoprolol

Abstract Background Cardioprotective strategies to limit infarct size (IS) have become crucial. The damaged inflicted on the myocardium is the result of the processes of Ischemia and Reperfusion (I/R). In the clinical trial METOCARD-CNIC, it was shown that the intravenous (i.v.) pre-reperfusion administration of the β1-selective antagonist metoprolol reduces IS and improves long-term cardiac function in patients after acute myocardial infarction (1). However, the small sample size precludes a definite conclusion. Despite not having demonstrated a solid clinical benefit in terms of hard endpoints reduction, the clinical guidelines for the management of ST-Elevation Myocardial Infarction (STEMI) recommend the early administration of i.v. β-blockers in patients undergoing Primary Coronary Intervention. Additionally, our group has recently described that the beneficial effect of metoprolol against myocardial I/R injury is due to neutrophil stunning (2), which represents a one-of-a-kind property not shared by other i.v. β-blockers, such as atenolol or propranolol (3). Purpose Since β1-adrenergic receptor (ADRB1) is one of major targets of pharmacological therapy, great efforts are now underway to account for the relevance of the polymorphic variation. Here we explore whether the cardioprotection exerted by metoprolol is dependent on genetic polymorphisms in human ADRB1. Methods Patients included in the METOCARD-CNIC trial were grouped into the different variants for the ADRB1, rs1801252 and rs1801253 (SerGly49 and Arg389Gly, respectively), which might affect their response to the beta-1 modulation exerted by metoprolol on neutrophils and thus its cardioprotective effect. Additionally, the polymorphic-dependent effect of metoprolol on neutrophil migration was evaluated in healthy volunteers, whose neutrophils were exposed across the transwell filter to the CXCL1 in the presence or absence of metoprolol. Drug-receptor interaction properties were evaluated in silico. Results We found that Arg389Gly polymorphism of the human ADRB1 impacts the cardioprotective effect of metoprolol in STEMI patients. Therefore, Arg389 homozygosity was associated with lower infarcts (Figure 1) and better long-term left ventricle ejection fraction when metoprolol was intravenously administered prior reperfusion. Moreover, the disrupting effect of metoprolol on neutrophil migration was only observed in Arg389 homozygote volunteers (Figure 2). These differences were attributed to alterations in the drug-receptor complex stability when Gly residues are present in position 389 of the ADRB1. Conclusions From our perspective, these results are the first showing a polymorphic implication in drug response against myocardial I/R injury. All the data presented refine cardiovascular pharmacotherapy, and have major implications for the prospective clinical trial design aiming at positioning metoprolol as the beta-blocker of choice to reduce hard endpoints in STEMI patients.CardioprotectionNeutrophil migration

Abstract OT3-11-03: The PREDICT Registry Australia: A prospective registry to evaluate the clinical utility of a 7-gene predictive biosignature on treatment decisions in patients with ductal carcinoma in situ

Abstract Background: For women with ductal carcinoma in situ (DCIS) treated with breast conserving surgery (BCS), the benefit of adjuvant radiation therapy (RT) remains controversial. Since there is level 1 evidence supporting the role of RT in reducing the risk of local recurrence, current guidelines generally recommend RT for all women having BCS even though the absolute benefit is variable. In response to the need for prognostic and predictive tools to better assess risk and RT benefit, a 7-gene predictive biosignature (DCISionRT, PreludeDx, Laguna Hills, CA) was developed. The test provides a validated score (DS) for assessing 10-year risk of recurrence and RT benefit using individual tumor biology, as assessed by clinical and pathologic biomarkers. The primary objective of the PREDICT registries is to understand the decision impact such a tool has on treatment decisions. Prospective Clinical Trial Design: This is a multicenter, prospective, observational registry for women diagnosed with DCIS in Australia. After DCIS diagnosis, sites will send the most representative tissue block or sections mounted on charged slides to the PreludeDx lab for biosignature testing. Treating physicians will complete a treatment recommendation survey before and after receiving the biosignature test results. Test results, treatment recommendations, patient preferences and clinicopathologic features will be stored in a de-identified registry for participating institutions from a variety of geographic regions across Australia. Women will then be followed for up to 10 years with completion of a follow-up form. The study has been approved by the North Shore Local Health District Human Research Ethics Committee, St Leonards, NSW, Australia. Universal Trial Number (UTN): U1111-1266-0439; ANZCTR: ACTRN12621000695808; ClinicalTrials.gov: NCT04916808. Eligibility Criteria: The study includes females age 26 or older who are candidates for BCS and eligible for RT and/or systemic treatment. Subjects must not have been previously treated for DCIS or have previous or current invasive or micro-invasive breast cancer. Specific Aims: The primary endpoints are changes in treatment recommendations for surgical, radiation and hormonal therapy. Secondary endpoints are identification of key drivers for treatment recommendations, including age, size, grade, necrosis, hormone receptor status, patient preference and biosignature status. Statistical Methods: Changes in pre- and post-DCISionRT treatment recommendations will be analyzed using McNemar’s test (alpha level = 0.05). Multivariate logistic regression will be used to determine odds ratios of clinicopathologic factors leading to pre- and post-test treatment recommendations. Pre-test covariates include patient age, tumor size, palpability, margin status, hormone receptor status, nuclear grade, tumor necrosis, family history of breast cancer, race, ethnicity and patient preference, as well as physician specialty (surgeons vs. radiation oncologists) and post-test covariates will also include the DCISionRT Decision Score (DS). Differences in recurrence-free and overall survival will be assessed by Kaplan-Meier survival analysis using the log-rank test and/or the Cox Proportional Hazards model. Statistical analyses will be carried out using R (https://www.r-project.org) or SAS. An early interim analysis based on the first 200 enrolled patients is currently underway. Present and Planned Accrual: We are planning to enroll up to 1,500 women from up to 100 sites across Australia. A similar registry has recently completed enrollment of 2,500 women from 68 sites in the US. Citation Format: Yvonne Zissiadis, G Bruce Mann, David Speakman, Christobel Saunders, Christopher Pyke, Daniel De Viana, Melissa Bochner, James R. French, Marcus Dreosti, Sally Baron-Hay, Alexandra Feetham, Kim Kirkham, Shane Ryan, Karuna Mittal, Steven C. Shivers, Troy Bremer. The PREDICT Registry Australia: A prospective registry to evaluate the clinical utility of a 7-gene predictive biosignature on treatment decisions in patients with ductal carcinoma in situ [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 OT3-11-03.

Abstract OT1-20-01: SentiNot 2.0: Avoid unnecessary Sentinel Lymph Node Biopsies in women with DCIS

Abstract Background Approximately 15-30% of women with a preoperative diagnosis of ductal carcinoma in situ (DCIS) will be diagnosed with invasive cancer (IBC) on specimen pathology. Risk of upgrade, and impairment of lymphatic outflow after breast surgery, mainly mastectomy, are drivers for upfront sentinel lymph node dissection (SLND). In the SentiNot feasibility study, marking the SLN by superparamagnetic iron oxide nanoparticles (SPIO) injection during primary surgery minimized unnecessary SLNDs, allowing for delayed SLND (d-SLND) only in those with IBC up to 50 days after primary surgery. This policy resulted in that 78.3% study participants avoided upfront SLND. In the d-SLND setting, SPIO detection outperformed the isotope (98.5 vs 60.6%), regardless of type of breast procedure. Incremental healthcare costs were reduced by 8.5% (485 USD per patient) for the entire trial population (ref 1). Prospective Clinical Trial Design SentiNot 2.0 (ClinicalTrials.gov Identifier: NCT04722692), is currently accruing data, powered to examine the detection rate of SPIO over isotope±blue dye during d-SLND. Trial candidates are: patients with a diagnosis of high-risk DCIS/pLCIS (mass-lesions, microinvasion, grade 3, grade 2 &amp;gt;20mm) regardless of type of breast surgery, and patients with planned breast surgery that precludes safe and accurate axillary mapping at a d-SLND (extensive oncoplastic breast conservation, tumors of the axillary tail and mastectomy). In d-SLND, study patients receive isotope±blue dye and within-patient-randomization is performed for which detection method to start with (SPIO-first vs. isotope-first). The trial is stratified for mastectomy and breast conservation. Secondary outcomes are nodal concordance (SPIO vs. isotope) at d-SLND, quality-of-life and health-economy outcomes. Present and Planned Accrual Total target accrual is 500 d-SLNDs. Insofar, 360 women have been included at six different sites in Sweden, Hong Kong, and the USA. Currently, data accrual and institution recruitment is active and expanding. For more information about the trial please refer to ClinicalTrials.gov Identifier: NCT04722692. For discussion regarding potential participation contact dr Andreas Karakatsanis (andreas.karakatsanis@surgsci.uu.se). Citation Format: Eirini Pantiora, Staffan Eriksson, Lida Pistiolis, Roger Olofsson Bagge, Gyula Nagy, Alastair M. Thompson, Vivian Man, Ava Kwong, Andreas Karakatsanis, Fredrik Wärnberg. SentiNot 2.0: Avoid unnecessary Sentinel Lymph Node Biopsies in women with DCIS [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 OT1-20-01.

CLINICAL AND RADIOGRAPHIC EVALUATION OF NANOHYDROXYAPATITE AND PLATELETS-RICH FIBRIN AS PULPOTOMY MATERIALS FOR PRIMARY MOLARS

Objectives: Pulpotomy works to retain a healthy tooth in the mouth till exfoliation by protecting the radicular pulp. The coronal pulp must be removed, and the radicular pulp must be given medication, in order to maintain the tooths health and function. Subject and Methods: The children who took part in this clinical investigation were chosen aged 4 to 8 years old, following approval from the Ethical Committee and obtaining signed informed consent from their parents. Based on the type of pulpotomy material used, the NHAp group and the PRF group, and 40 mandibular primary teeth that needed pulpotomy treatment were split into two groups (n=20). The split-mouth prospective clinical trial design for this study was authorized. Three distinct follow-up intervals of 6 weeks, six, and twelve months were used to note and evaluate the clinical and radiological outcomes. Results: The teeth treated with PRF had improved clinical and radiographic outcomes at the three distinct follow-up intervals of 6 weeks, 6, and 12 months, but there was no statistically significant difference between them and the teeth treated with NHAp. Conclusion: The results of the pulpotomized primary molars clinical and radiographic outcomes could be improved by using PRF as a pulp dressing agent.

Immune Response and Outcome of High-Risk Neuroblastoma Patients Immunized with Anti-Idiotypic Antibody Ganglidiomab: Results from Compassionate-Use Treatments.

(1) Background: High-risk neuroblastoma (HR-NB) is associated with a poor prognosis despite a multimodal high-intensity treatment regimen, including immunotherapy with anti-GD2 monoclonal antibodies (mAb). Here, we investigated the effects of an anti-idiotypic vaccine based on the mAb ganglidiomab that structurally mimics GD2. (2) Methods: Patients with HR-NB treated with anti-GD2 mAb dinutuximab beta and who achieved complete remission after frontline or salvage therapy were offered the vaccine (0.5 mg ganglidiomab adsorbed to Alhydrogel®). Side effects (CTCAE v4.03) and immune responses were determined on each visit. We also evaluated the time to relapse or progression until the last follow-up. (3) Results: Seven HR-NB patients (five frontlines, two relapsed) received 6-22 subcutaneous injections every two weeks. Six of the seven patients showed an immune response. The non-responding patient had a haploidentical stem cell transplantation as part of the previous treatment. No fever, pain, neuropathy, or toxicities ≥ grade 3 occurred during or post-treatment. All immunized patients did not experience relapses or progressions of their neuroblastoma. (4) Conclusions: This is the first-in-man use of the ganglidiomab vaccine, which was well-tolerated, and all patients not pre-treated by haploidentical transplantation developed vaccine-specific immune responses. These findings provide an important basis for the design of prospective clinical trials.

Mammary analog secretory carcinoma in adults: A systematic review.

e18076 Background: Mammary analog secretory carcinoma (MASC) is a rare malignant salivary gland tumor of the head and neck region that was first described by Skálová et al. in 2010. It histologically mimics breast secretory carcinoma and parotid acinic cell carcinoma, and characterized by ETV6-NTRK3 fusion gene. This review aims to investigate the clinicopathologic features, treatment, and outcomes of MASC in adults. Methods: PubMed search for MASC adults (18+ years) from data inception through 2021, pooled with a case from our institution. Kaplan-Meier analysis was used to plot survival curves. Results: Of the 254 included cases, female:male ratio 1.02:1 with a mean age at diagnosis (±SD, range) of 50.1 (±16.7, 18–86) years. In terms of location, 143 (56.3%) occurred in the parotid gland, 21 (8.3%) in the submandibular gland, 21 (8.3%) in the lip, 15 (5.9%) in the thyroid gland–all (100%) had a component of classical type papillary carcinoma, 15 (5.9%) were cutaneous, 13 (5.1%) in the buccal mucosa, 12 (4.7%) split between hard and soft palate, 4 (1.6%) in the nasal mucosa, 2 (0.8%) in the lung, and remaining 8 (3.1%) each in the conjunctiva, tongue, minor salivary gland, submaxillary gland, maxillary sinus, ethmoid sinus, upper esophagus, and mandible. Patients mostly presented with swelling or growing mass in 95.4% (out of which, 93.3% were painless), followed by a painful ulcer in 1.8%. Median tumor size was 1.9 cm (range 0.3cm–8.5cm). Median duration of symptoms at time of presentation was 12 (range 1-360) months. Tumors were T1 (49.7%), T2 (23.9%), T3 (20.3%), and T4 (6.1%), N0 (81.9%), N1 (10.7%), N2 (7.4%), M0 (97.4%), and M1 (2.6%). Most patients (70.7%) presented as early stage (I or II) which was associated with a high survival probability based on a log-rank test (p-value: 0.0007). All patients had surgical resection, mostly combined with neck dissection (ND) in11.4%, radiation (RT) in 7.8%, ND+RT in 4.7%, ND with platinum-based chemoradiation in 1.0%, and one case reported use of Crizotinib followed by Entrectinib with disease progression at 4.5 and 7 months, respectively. Among patients with reported outcomes, 92.2% were alive with a median follow-up of 26 (range 1-228) months, and 7.8% deceased with a median time-to-death of 29 (range 1-107) months. Eleven (4.3%) reported a high-grade MASC and 18.5% of patients lived for over five years after their diagnosis. Conclusions: Early stage was a notable predictor of higher survival probability in MASC patients. Its rarity, heterogeneity of clinical behaviors, and variable outcomes make it even more challenging. This review serves as real-world evidence to further our understanding of this rare entity and shed light on prospective clinical trial design.

Abstract OT1-11-01: The PREDICT registry Australia: A prospective registry study to evaluate the clinical utility of the DCISionRT test on treatment decisions in patients with DCIS following breast conserving surgery

Abstract Background: The benefit of adjuvant radiation therapy (RT) for women with ductal carcinoma in situ (DCIS) treated with breast conserving surgery (BCS) remains controversial. Since there is level-I evidence supporting the role of RT in reducing the risk of local recurrence, current guidelines generally recommend adjuvant RT for all women having BCS. However, the absolute benefit of RT is variable in women with DCIS and so it is important to develop prognostic and predictive tools to better assess risk and RT benefit. The DCISionRT Test (PreludeDx, Laguna Hills, CA) is a biologic signature that provides a validated score (DS) for assessing 10-year risk of recurrence and RT benefit using individual tumor biology, as assessed by clinical and pathologic biomarkers. The primary objective of the PREDICT registries is to understand the decision impact such a tool would have on treatment decisions. Prospective Clinical Trial Design: This is a multicenter, prospective, non-interventional (observational) cohort study for women diagnosed with DCIS of the breast. After diagnosis of DCIS, sites will send the most representative tissue block or sections mounted on charged slides to PreludeDx for DCISionRT testing. Treating physicians complete a treatment recommendation survey before and after receiving DCISionRT test results. Test results, treatment recommendations, patient preferences and clinicopathologic features will be stored in a de-identified registry for participating institutions from a variety of geographic regions across Australia. Women will then be followed for up to 10 years with completion of a follow-up form. The study has been approved by the North Shore Local Health District Human Research Ethics Committee, St Leonards, NSW, Australia. Universal Trial Number (UTN): U1111-1266-0439; ANZCTR: ACTRN12621000695808; ClinicalTrials.gov: NCT04916808. Eligibility Criteria: The study includes females age 26 or older who are candidates for BCS and eligible for RT and/or systemic treatment. Subjects must not have been previously treated for DCIS or have previous or current invasive or micro-invasive breast cancer. Specific Aims: The primary endpoints are changes in treatment recommendations for surgical, radiation and hormonal therapy. Secondary endpoints are identification of key drivers for treatment recommendations, including age, size, grade, necrosis, hormone receptor status and patient preference. Statistical Methods: Changes in pre- and post-DCISionRT treatment recommendations will be analyzed using McNemar's test (alpha level = 0.05). Multivariate logistic regression will be used to determine odds ratios of clinicopathologic factors leading to pre- and post-test treatment recommendations. Pre-test covariates include patient age, tumor size, palpability, margin status, hormone receptor status, nuclear grade, tumor necrosis, family history of breast cancer, race, ethnicity and patient preference, as well as physician specialty (surgeons vs. radiation oncologists) and post-test covariates will also include the DCISionRT Decision Score (DS). Differences in recurrence-free and overall survival will be assessed by Kaplan-Meier survival analysis using the log-rank test and/or the Cox Proportional Hazards model. Statistical analyses will be carried out using R (https://www.r-project.org) or SAS. An early interim analysis based on the first 200 enrolled patients is planned. Present and Planned Accrual: We are planning to enroll up to 1,500 women from up to 100 sites across Australia. A similar registry in the US has enrolled 1,985 women from 64 sites towards a goal of 2,500. Citation Format: Yvonne Zissiadis, G Bruce Mann, Steven C Shivers, Troy Bremer. The PREDICT registry Australia: A prospective registry study to evaluate the clinical utility of the DCISionRT test on treatment decisions in patients with DCIS following breast conserving surgery [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-11-01.

Individualized quality of life benefit and cost-effectiveness estimates of proton therapy for patients with oropharyngeal cancer

BackgroundProton therapy is a promising advancement in radiation oncology especially in terms of reducing normal tissue toxicity, although it is currently expensive and of limited availability. Here we estimated the individual quality of life benefit and cost-effectiveness of proton therapy in patients with oropharyngeal cancer treated with definitive radiation therapy (RT), as a decision-making tool for treatment individualization.Methods and materialsNormal tissue complication probability models were used to estimate the risk of dysphagia, esophagitis, hypothyroidism, xerostomia and oral mucositis for 33 patients, comparing delivered photon intensity-modulated RT (IMRT) plans to intensity-modulated proton therapy (IMPT) plans. Quality-adjusted life years (QALYs) lost were calculated for each complication while accounting for patient-specific conditional survival probability and assigning quality-adjustment factors based on complication severity. Cost-effectiveness was modeled based on upfront costs of IMPT and IMRT, and the cost of acute and/or long-term management of treatment complications. Uncertainties in all model parameters and sensitivity analyses were included through Monte Carlo sampling.ResultsThe incremental cost-effectiveness ratios (ICERs) showed considerable variability in the cost of QALYs spared between patients, with median $361,405/QALY for all patients, varying from $54,477/QALY to $1,508,845/QALY between individual patients. Proton therapy was more likely to be cost-effective for patients with p16-positive tumors ($234,201/QALY), compared to p16-negative tumors ($516,297/QALY). For patients with p16-positive tumors treated with comprehensive nodal irradiation, proton therapy is estimated to be cost-effective in ≥ 50% of sampled cases for 8/9 patients at $500,000/QALY, compared to 6/24 patients who either have p16-negative tumors or receive unilateral neck irradiation.ConclusionsProton therapy cost-effectiveness varies greatly among oropharyngeal cancer patients, and highlights the importance of individualized decision-making. Although the upfront cost, societal willingness to pay and healthcare administration can vary greatly among different countries, identifying patients for whom proton therapy will have the greatest benefit can optimize resource allocation and inform prospective clinical trial design.

Abstract CT268: CURATE.AI-optimized modulation for multiple myeloma: An N-of-1 randomized trial

Abstract Background: Multiple Myeloma (MM) is an incurable plasma cell neoplasm with an estimated incidence of 32,000 patients per year in the United States. Novel agents and advances in precision medicine for selecting drugs tailored to an individual have increased the likelihood of remission and prolonged survival. To maximize efficacy of the identified drug combinations, dosing strategy should also be tailored to an individual, and dynamically dosed as the individual evolves during treatment. Current dosing strategies are unable to personalize and optimize dosing in a combinatory treatment due to a virtually infinite parameter space as well as stochastic biological behavior. As a result, dose adjustments are instead dictated by treatment tolerability, while the efficacy outcomes remain sub-optimal. In this pilot clinical trial we aim to test if the gap in the dosing strategy for combinatory treatment for MM can be addressed with CURATE.AI - clinically validated deterministic AI-derived platform that generates an individualized profile based only on that individual's data, and recommends the next dose towards optimized efficacy within the pre-identified tolerability range. CURATE.AI has already been used to prospectively modulate dosing strategies for indications ranging from oncology (solid tumor) to infectious diseases (HIV/TB) and immunosuppression (liver transplant). Methods: In this pilot study, CURATE.AI will be used to provide dose recommendations for bortezomib and cyclophosphamide, or bortezomib and thalidomide in the presence of dexamethasone at a fixed dose (VCD, or VTD combinations). The tested hypothesis is: CURATE.AI-driven dosing will result in noninferior efficacy with less toxicity and fewer adverse events. The prospective clinical trial design is a randomized, multiphase (Phase 2/Phase 3), parallel two-arm, single-blinded, N-of-1, exploratory pilot trial with 1:1 allocation, noninferiority, listed under Clinicaltrials.gov identifier NCT03759093. The recruitment is expected to commence in the first quarter of 2020 at National University Hospital in Singapore. Twenty participants fulfilling inclusion criteria (males and females over 21 years [Singapore's legal age for adult consent] with newly diagnosed and evaluable MM, ECOG 0-2, and meeting toxicity criteria within 21 days from the start of the treatment) will be randomly allocated (1:1) into the control or the experimental arm. The subjects will be blinded to the arm allocation. Subjects in the control arm will receive dosing of VCD or VTD according to standard of care - physician following the Singapore Myeloma Study Group Consensus Guidelines. Subjects in the experimental arm will receive fixed dexamethasone dose as in standard of care, while bortezomib and cyclophosphamide (for VCD treatment) or bortezomib and thalidomide (for VTD treatment) doses will be dynamically modulated with CURATE.AI for each subject independently (series of N-of-1) based on that subject's longitudinally collected efficacy output measures. The primary outcome measure is the response rate at the end of cycle 4. The results of this pilot study will additionally inform the logistical and practical suitability of N-of-1 randomized trial designs for testing personalization and dynamic dose modulation for oncology. Citation Format: Agata Blasiak, Theodore Wonpeum Kee, Masturah Bte Mohd Rashid, Edward Kai-Hua Chow, Sanjay De Mel, Wee Joo Chng, Dean Ho. CURATE.AI-optimized modulation for multiple myeloma: An N-of-1 randomized trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT268.

Clinical research in older adults with hematologic malignancies: Opportunities for alignment in the Veterans Affairs

Management of hematologic malignancies in older patients is complex and, with recent and anticipated trends in demographics, increasingly common. As a large, nationally integrated medical system the Veterans Affairs has the potential to lead in research to benefit these patients. In this review we describe the evolving treatment paradigms of hematologic malignancies and how they are best fit with older patients through comprehensive evaluation of key vulnerabilities. We also discuss optimization of supportive care and navigation services to target identified risks and challenges aimed at ameliorating the patient's burden of cancer and treatment. Lastly, we discuss opportunities in design of prospective clinical trials to better align with real-world cases, thereby expanding enrollment of and applicability to older patients with hematologic malignancies.

Partnership for defining the impact of 12 selected rare CNS tumors: a report from the CBTRUS and the NCI-CONNECT.

Population-based cancer statistics, including histology-specific incidence, prevalence, and survival are essential to evaluating the total burden due to disease in a population. The National Cancer Institute's (NCI) Comprehensive Oncology Network Evaluating Rare CNS Tumors (NCI-CONNECT) was developed to better understand tumor biology and patient outcomes for 12 selected brain and other central nervous system (CNS) tumor histologies that are rare in adults to improve approaches to care and treatment. The aim of this study was to determine the incidence, prevalence, and survival of these selected rare histologies. Data from the Central Brain Tumor Registry of the United States (CBTRUS) from 2000 to 2014 were used to calculate average annual age-adjusted incidence rates (AAIR) per 100,000 population overall and by sex, race, ethnicity, and age. NCI's Surveillance, Epidemiology and End Results (SEER) data were used to calculate relative survival (RS) estimates. Point prevalence for 2014 was estimated using annual age-specific incidence and survival from CBTRUS and SEER, respectively. Overall AAIR was 1.47 per 100,000 for all 12 rare histologies combined, with the highest histology-specific incidence in oligodendrogliomas (AAIR = 0.40/100,000). Overall, most histologies were more common in males, adults (age 40 + ), Whites, and non-Hispanics. Ependymomas were the most prevalent histology at 4.11 per 100,000; followed by oligodendrogliomas at 3.68 per 100,000. Relative survival at 1-, 5-, and 10-years was 82.3%, 64.0%, and 55.4%, respectively for all 12 selected brain and other CNS tumor types combined. Ependymomas had the highest RS (1-year = 94.2%, 5-year = 83.9%, 10-year = 78.6%) and gliosarcomas had the lowest relative survival rate (1-year = 42.5%, 5-year = 5.6%, 10-year = 2.9%) at all three time points. Incidence and prevalence of these rare brain and other CNS tumor histologies have not been previously reported. Along with survival, these data provide a statistical foundation to understand the impact of these cancers and provide important disease-specific data for the design of prospective clinical trials.

Carbapenem-Resistant Enterobacteriaceae Infections: Results From a Retrospective Series and Implications for the Design of Prospective Clinical Trials.

BackgroundThe increasing incidence of multidrug-resistant Gram negatives, such as carbapenem-resistant Enterobacteriaceae (CRE), has resulted in a critical need for new antimicrobials. Most studies of new antimicrobials have been performed in patients with nondrug-resistant pathogens. We performed a retrospective analysis of patients with CRE infections to inform the design of phase 3 clinical trials.MethodsThis was a retrospective study at 22 centers in 4 countries. Baseline data, treatment, and outcomes were collected in patients with complicated urinary tract infection (cUTI)/acute pyelonephritis (AP), hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), and bacteremia due to CRE.ResultsTwo hundred fifty-six cases of CRE infection were identified: 75 cUTI/AP, 21 HABP, 20 VABP, and 140 bacteremia. The patient population had significant comorbidities: 32.8% had chronic renal insufficiency, and 26.2% were immunocompromised. Illness severity at presentation was high: 29.3% presented with septic shock. Treatment regimens varied widely; however, a majority of patients received combination therapy. Outcomes were universally poor (28-day mortality was 28.1%) across all sites of infection, particularly in dialysis patients and those with sepsis.ConclusionsThe CRE infections occured in patients with substantial comorbidities and were associated with high mortality and low rates of clinical cure with available antibiotics. Patients with these comorbidities are often excluded from enrollment in clinical trials for registration of new drugs. These results led to changes in the inclusion/exclusion criteria of a phase 3 trial to better represent the patient population with CRE infections and enable enrollment. Observational studies may become increasingly important to guide clinical trial design, inform on the existing standard of care, and provide an external control for subsequent trials.

Commentary on IL-1β associations with posttraumatic epilepsy development: A genetics and biomarker cohort study.

Human posttraumatic epilepsy (PTE), the most common acquired epilepsy in teenagers and young adults1, is an unfortunate natural experiment that may provide insight into epileptogenesis and anti-epileptogenic interventions. In PTE, epilepsy develops weeks to months after traumatic brain injury (TBI), and often in a previously nonepileptic and otherwise healthy brain. Particularly in severe TBI, the injury timing is well-documented, and by necessity for critical care, the patients are closely monitored with access to imaging, electrophysiologic, blood and cerebrospinal fluid (CSF) biomarkers. Yet, the neurobiology of events that take place in the time between TBI and the first seizure of PTE, remains incompletely understood. This gap in knowledge about the mechanisms of posttraumatic epileptogenesis limits our capacity to develop successful antiepileptogenic interventions. As intriguing as the fundamental question of why PTE follows TBI after a seizure-free latent period, are the questions of why only a minority of patients with severe TBI, approximately 20%, develop PTE, and whether a biomarker measure may predict individual PTE likelihood. The selection for the 2015 Epilepsia Prize form Diamond et al., “IL-1β associations with posttraumatic epilepsy development: A genetics and biomarker cohort study2,” addresses these important questions. The authors studied a sizeable (n=256) and relatively homogenous cohort of patients with moderate-to-severe TBI who were part of an otherwise larger group enrolled in a study aimed to evaluate the contributions of genetics and related biomarkers to post-TBI outcomes. PTE developed in 16.4% of this group. Based on a growing literature that implicates autoimmune and inflammatory mechanisms in post-TBI pathophysiology, including in posttraumatic epileptogenesis, they formulated and tested a hypothesis that IL-1β concentrations in the CSF and in serum are predictive of PTE. IL-1β, a proinflammatory cytokine produced by activated microglia and astrocytes, is increased in the CNS after TBI, and may mark a sustained proinflammatory state that contributes to PTE. Further, to study genetic susceptibility to IL-1β-mediated post-traumatic epileptogenesis, the investigators tested whether individual genotypes at selected small nuclear polymorphism (SNPs) of the gene coding for IL-1β (IL-1β) also predicted PTE likelihood. With this approach of studying both the gene and gene product in PTE the authors demonstrate that both a high CSF:serum IL-1β concentration ratio and the specific heterozygous CT genotype in one SNP in the IL-1B gene promoter region, rs1143634, are associated with increased PTE risk. This was the first study to investigate the contributions of both IL-1β levels and IL-1B genetics in a single large TBI patient cohort. While IL-1β has been previously implicated in nontraumatic epilepsy and epileptogenesis, neither its role, nor the role of a specific IL-1β polymorphism as PTE biomarkers have been measured. Interestingly, CSF IL-1β was elevated in all TBI subjects relative to an uninjured control population and did not by itself mark a PTE risk. Thus rather than high CSF IL-1β, a low serum IL-1β concentration in the PTE vs. non-PTE patients with TBI accounted for the increased CSF:serum ratio. This finding underscores the complexity of TBI and PTE biomarker biology where one-dimensional metrics, individual measures that predict the likelihood of PTE with adequate specificity and sensitivity have been elusive. An appropriately cautious discussion in this article suggests an intriguing blood-to-brain IL-1β transport that may account for proinflammatory accumulation of peripheral IL-1β in the CNS. If validated, this would be in contrast to other cytokines and reactive proteins that follow a brain-to-blood transport and concentration gradient. These data thereby suggest that peripheral IL-1β production and transport may present novel therapeutic targets. IL-1β is representative of the larger class of signaling molecules that likely contribute to immune-mediated posttraumatic neuronal dysfunction, and this article expands on its contribution to PTE. The authors also add to their group's prior preclinical research which indicates that levetiracetam, a common first-line antiepileptic drug, suppresses regional posttraumatic IL-1β production and by this mechanism may suppress posttraumatic seizures3. These new data support future design and testing of antiepileptic and antiepileptogenic strategies that target IL-1β-related immune signaling pathways. The authors do not speculate as to the mechanistic contributions to PTE of the rs1143634 SNP CT heterozygous state, and indeed the experiment was not designed to address this question. However, the targeted approach to look simultaneously at the prognostic values IL-1β levels and IL-1B genetics suggests future work that will also incorporate measures of both the gene and the gene product in TBI research. The clinical TBI field and growing body of science dedicated to PTE and post-traumatic epileptogenesis will benefit from this report which is a step toward practical gene and protein biomarkers that predict post-TBI outcomes. These results implicating IL-1β protein and gene in PTE are particularly versatile as they can be incorporated either into future basic preclinical research aimed to elucidate PTE mechanisms and test novel therapies, or into the design of prospective clinical trials.

Radiotherapy for non-malignant disorders: state of the art and update of the evidence-based practice guidelines.

Every year in Germany about 50,000 patients are referred and treated by radiotherapy (RT) for “non-malignant disorders”. This highly successful treatment is applied only for specific indications such as preservation or recovery of the quality of life by means of pain reduction or resolution and/or an improvement of formerly impaired physical body function owing to specific disease-related symptoms. Since 1995, German radiation oncologists have treated non-malignant disorders according to national consensus guidelines; these guidelines were updated and further developed over 3 years by implementation of a systematic consensus process to achieve national upgraded and accepted S2e clinical practice guidelines. Throughout this process, international standards of evaluation were implemented. This review summarizes most of the generally accepted indications for the application of RT for non-malignant diseases and presents the special treatment concepts. The following disease groups are addressed: painful degenerative skeletal disorders, hyperproliferative disorders and symptomatic functional disorders. These state of the art guidelines may serve as a platform for daily clinical work; they provide a new starting point for quality assessment, future clinical research, including the design of prospective clinical trials, and outcome research in the underrepresented and less appreciated field of RT for non-malignant disorders.

A Modern Definition of Mediastinal Compartments

Division of the mediastinum into compartments is used to help narrow the differential diagnosis of newly detected mediastinal masses, to assist in planning biopsy and surgical procedures, and to facilitate communication among clinicians of multiple disciplines. Several traditional mediastinal division schemes exist based upon arbitrary landmarks on the lateral chest radiograph. We describe a modern, computed tomography-based mediastinal division scheme, which has been accepted by the International Thymic Malignancy Interest Group as a new standard. This clinical classification defines a prevascular (anterior), a visceral (middle), and a paravertebral (posterior) compartment, with anatomic boundaries defined clearly by computed tomography. It is our intention that this definition be used in the reporting of clinical cases and the design of prospective clinical trials.

Highlights of This Issue

Manipulation of the apoptosis pathway is an appealing strategy for cancer treatment using BH3 mimetics such as ABT-263, although predictive biomarkers are required to identify patients who may benefit from their use. To investigate this problem, Suryani and colleagues studied the in vivo efficacy of ABT-263 against 31 pediatric acute lymphoblastic leukemia xenografts. High MCL1 expression and function correlated with in vivo ABT-263 resistance, and in vitro assays predicted in vivo ABT-263 responses. These approaches could be included in the design of prospective clinical trials to determine if they can identify patients who may respond to treatment with this class of therapeutic agents.Gastric carcinoma (GC) is the second leading cause of cancer deaths in the world, with many deaths occurring in East Asia. To identify DNA methylation biomarkers for prediction of GC metastasis, scientists, and oncologists from China, the United States, Japan, and Korea have profiled differential methylation patterns in GCs and perform an in-depth characterization of methylation changes in 73 candidate genes. The authors have established a methylation biomarker-set composed of three genes GFRA1, SRF, and ZNF382 that could be used to synergistically predict GC metastasis and patients' overall survival from multiple patient cohorts in China, Japan, and Korea.TAZ, the core component of Hippo signaling pathway, attracts increasing attention as a critical player in tumorigenesis. Using an integrated translational approach, the authors explored the role of TAZ in non-small cell lung cancer (NSCLC). Noguchi and colleagues showed that higher TAZ expression was associated with shorter patient survival, and TAZ promoted lung cancer cell proliferation in vitro and tumor development in vivo. Moreover, TAZ regulated the expression of ErbB ligands and the EGFR signaling pathway was activated in NSCLC tissues with high TAZ expression. This study offers potential therapeutic strategies, either directly against TAZ or indirectly via EGFR pathway.Activation of Wnt-signaling is a common event in colorectal carcinoma (CRC), but its role in CRC metastasis is still under extensive study. In the present study, Zhang and colleagues revealed subcellular redistribution of NAT10 (N-acetyltransferase 10) in CRCs, which correlated well with nuclear translocation of β-catenin and reflected invasive potential of CRC. They demonstrated that inhibition of GSK-3β induced NAT10 redistribution through increasing its stability and nuclear export, which consequently enhanced cytoskeletal remodeling and promoted migration, invasion, and metastasis of cancer cells. These findings suggest NAT10 could be a useful prognostic marker and potential therapeutic target in CRC.

Prospective Randomized Trial to Assess Effects of Continuing Hormone Therapy on Cerebral Function in Postmenopausal Women at Risk for Dementia

The objective of this study was to examine the effects of estrogen-based hormone therapy (HT) on regional cerebral metabolism in postmenopausal women (mean age = 58, SD = 5) at risk for development of dementia. The prospective clinical trial design included pre- and post-intervention neuroimaging of women randomized to continue (HT+) or discontinue (HT−) therapy following an average of 10 years of use. The primary outcome measure was change in brain metabolism during the subsequent two years, as assessed with fluorodeoxyglucose-18 positron emission tomography (FDG-PET). Longitudinal FDG-PET data were available for 45 study completers. Results showed that women randomized to continue HT experienced relative preservation of frontal and parietal cortical metabolism, compared with women randomized to discontinue HT. Women who discontinued 17-β estradiol (17βE)-based HT, as well as women who continued conjugated equine estrogen (CEE)-based HT, exhibited significant decline in metabolism of the precuneus/posterior cingulate cortical (PCC) area. Significant decline in PCC metabolism was additionally seen in women taking concurrent progestins (with either 17βE or CEE). Together, these findings suggest that among postmenopausal subjects at risk for developing dementia, regional cerebral cortical metabolism is relatively preserved for at least two years in women randomized to continue HT, compared with women randomized to discontinue HT. In addition, continuing unopposed 17βE therapy is associated specifically with preservation of metabolism in PCC, known to undergo the most significant decline in the earliest stages of Alzheimer's disease.Trial Registration ClinicalTrials.gov NCT00097058

Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arrays

It is now clear that medulloblastoma (MB), one of the most clinically challenging paediatric brain tumours, is not a single disease entity. Rather, it comprises four distinct molecular subgroups (Wnt pathway activated (WNT), Sonic hedgehog pathway activated (SHH), and the less well-characterised Group 3 and Group 4) [7, 15], which are highly divergent in terms of their patient demographics, underlying biology, and survival outcomes [4, 6]. These subgroups are becoming increasingly important, not only for refining the discovery of prognostic markers or therapeutic targets, but also for the design of prospective clinical trials. Patients with WNT subgroup tumours, for example, generally have a favourable prognosis, and may benefit from a reduction or omission of radiotherapy or chemotherapy to spare neurological side-effects or other toxicities, as is now being prospectively tested in upcoming trials both in North America and Europe. In contrast, patients with poor prognosis Group 3 tumours may benefit from intensification of up-front therapy. Furthermore, many new targeted therapeutics are likely to be efficacious in only one subgroup, such as smoothened inhibitors for SHH pathway-driven MB [1, 2]. A phase III clinical trial randomising SMO inhibition against standard of care in relapsed SHH-MB patients will start recruiting in mid-late 2013. A method for accurate and robust classification into tumour subgroups that is applicable to standard pathology specimens is therefore of key clinical relevance.