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Background: Standard surgical techniques result in positive lumpectomy margins 20-40% of the time. These positive margins require surgical re-excision which places significant burden on the healthcare system and patients. The LUM Imaging System consists of a fluorescent drug, a hand-held wide-field detector (LUM Imaging Device) used to image the surgical cavity walls intraoperatively in real-time after the resection of the main lumpectomy specimen, and a proprietary tumor detection algorithm that highlights regions in the tumor bed suspected to contain residual cancer. Methods: The Intraoperative Detection of Residual Cancer in Breast Cancer trial (NCT03321929) is a non-randomized, open-label, multi-site trial. This is a prospective, interventional feasibility study and is a pilot arm to a pivotal study which will further evaluate the safety and efficacy of the LUM Imaging System. This study enrolls women, over the age of 18 and with histologically or cytologically confirmed primary invasive breast cancer (IBC), ductal carcinoma in situ (DCIS) or a combination of IBC/DCIS undergoing a lumpectomy for their breast malignancy. LUM015, a fluorescent drug, is injected prior to the subject’s lumpectomy procedure. Surgeons perform their standard of care lumpectomy followed by intraoperative imaging of the lumpectomy cavity with the LUM Imaging System. In real-time, the LUM Imaging System highlights areas within the tumor bed that may contain, residual abnormal tumor tissue. Surgeons remove additional tissue based on the guidance of the LUM Imaging System. A maximum of two additional tissue shaves may be obtained. All excised tissue specimens are evaluated by routine pathology and correlated to the output of the LUM Imaging System. Results and Discussion: Sixteen medical centers across the United States enrolled 234 subjects into this study. Preliminary data on 141 subjects has been evaluated. The median age of enrolled women undergoing surgery using the Lumicell system was 61 years old. The histology of tumor type in women evaluated in this analysis is representative of the general population, with 21% diagnosed with ductal carcinoma in-situ (DCIS), 11% diagnosed with invasive lobular carcinoma, and 64% diagnosed with invasive ductal carcinoma (with or without DCIS features present). Most women (71%) presented with a palpable mass on physical examination prior to their lumpectomy surgery. Radiological imaging prior to lumpectomy showed scattered areas of fibroglandular density in 49% of the enrolled subjects and heterogeneously dense breast tissue in 42% of the enrolled subjects. The use of the LUM Imaging System positively impacted enrolled subjects; approximately 10% of subjects (N=14) had residual tumor detected and removed from the tumor bed guided by the LUM Imaging System after the standard of care surgery was completed. Without the use of this guidance technology, tumor tissue would have been left behind in this cohort of subjects, potentially requiring additional surgical intervention or other therapy, or local recurrence. The mean absolute volume of tissue removed due to guidance by the Lumicell System was 15 cc corresponding to about 15% of the total tissue removed. The LUM Imaging System correctly identified all positive margins in 28% of subjects with a positive margin after standard of care, and directed excision of additional tissue to create a wider margin. 12% of the patients with positive margins were converted to a negative margin by removing additional tissue guided by this imaging system. Future studies are planned that will measure the sensitivity and specificity of the device. Citation Format: Jorge Ferrer, David Carr, Peter Blumencranz, Daleela Dodge, Nayana Dekhne, Irene Wapnir, Kelly Hunt, Linsey Gold, Stephanie Valente, Peter Beitsch, Donna Dyess, Shelly Hwang, Lynne Clark, Beth-Ann Lesnikoski, Anees Chagpar, Stephen Karp, Brian Schlossberg, Sean Madden, Manna Chang, Kate Smith, David Strasfeld, W David Lee, Barbara Smith. Results from the expansion into multiple institutions for training in the use of the LUM imaging system for intraoperative detection of residual cancer in the tumor bed of female subjects with breast cancer clinical trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-20-06.

Background Breast-conserving surgery is a critical first step in treatment with the goal of removing all cancer cells while minimizing the removal of healthy tissue. 15% to 25% or more of lumpectomy patients have positive margins and require a second surgery to achieve negative margins and reduce the risk of local recurrences. These positive margins are poorly predictive (35% PPV) of cancer left in the cavity, so most second surgeries find no residual cancer. Better detection tools are needed to identify residual cancer in real time during the initial lumpectomy to reduce the number of second operations. LUM015 is a protease-activated fluorescent imaging agent that accumulates in tumor cells and tumor associated macrophages. The LUM Imaging System camera visualizes the intravenously injected LUM015 in the lumpectomy cavity via a hand-held wide field detector and proprietary tumor detection software. This imaging system was previously tested in multiple single-site studies and a large, prospective multi-site study that enrolled 234 patients and showed good ability to detect residual cancer in the lumpectomy cavity. Trial Design The current prospective, multi-center, randomized, blinded study was designed to demonstrate the clinical efficacy, system accuracy, and safety of the LUM Imaging System. It aims to identify residual cancer in the lumpectomy cavity to reduce the rates of positive margins. This study seeks to enroll women with primary invasive breast cancer (IBC), ductal carcinoma in situ (DCIS) or a combination of IBC/DCIS undergoing a lumpectomy for their breast malignancy. Approximately 310 women at 14 US medical centers will be enrolled. This study is powered by an event-driven design that requires 70 patients to be enrolled that have a ‘truth-standard positive' event, which is the identification of cancer in a protocol defined tissue type. To be eligible, patients must not have a history of allergic reaction to polyethylene glycol, intravenous contrast agents, or systemic therapies to treat their cancer. Use of blue dyes before imaging with the LUM System are not allowed. LUM015 is injected prior to the lumpectomy procedure. Surgeons perform standard of care (SOC) lumpectomy and perform blinded intraoperative imaging of the lumpectomy cavity with the LUM Imaging System in regions where SOC shaves will be taken. The patient is then randomized. If the random assignment is to the device arm, the surgeon is directed to excise margins that the LUM System indicates are positive for cancer. Pathologists are blinded to the type of tissue removed when conducting the pathology assessment. Patient reported outcome data is collected as a quality-of-life survey before and after the subject's lumpectomy. Additional detailed eligibility criteria are in the protocol. To date, 166 patients have participated in this trial. This trial is registered as NCT03686215. Citation Format: Jorge Ferrer, David Carr, Peter Blumencranz, Irene Wapnir, Donna Dyess, Shelly Hwang, Nayana Dekhne, Daleela Dodge, Beth-Ann Lesnikoski, Kelly Hunt, Patricia Clark, Stephanie Valente, M. Catherine Lee, Lynne Clark, Brian Schlossberg, Sean Madden, Alejandra Rodriguez, Kate Smith, Manna Chang, Barbara Smith. Pivotal Study of the LUM Imaging System for assisting intraoperative detection of residual cancer in the tumor bed of female patients with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT259.

Background: For many women with breast cancer, breast-conserving surgery is a critical first step in treatment with the goal of removing all cancer cells while minimizing the removal of healthy tissue. 15% to 25% or more of lumpectomy patients have positive margins and require a second surgery to achieve negative margins and reduce the risk of local recurrences. These positive margins are poorly predictive (35% PPV) of cancer left in the cavity, so most second surgeries find no residual cancer. Better detection tools are needed to identify residual cancer in real time during the initial lumpectomy to reduce the number of second operations. LUM015 is a protease-activated fluorescent imaging agent that accumulates in tumor cells and tumor associated macrophages. The LUM Imaging System camera visualizes the intravenously injected LUM015 in the lumpectomy cavity via a hand-held wide field detector and proprietary tumor detection software. This imaging system was previously tested in multiple single-site studies and a large, prospective multi-site study that enrolled 234 patients and showed good ability to detect residual cancer in the lumpectomy cavity. Trial Design: The current prospective multi-center, two-arm randomized, blinded study was designed to demonstrate the clinical efficacy, system accuracy, and safety of the LUM Imaging System. It aims to identify residual cancer in the lumpectomy cavity in order to reduce the rates of positive margins. This study seeks to enroll women with confirmed primary invasive breast cancer (IBC), ductal carcinoma in situ (DCIS) or a combination of IBC/DCIS undergoing a lumpectomy for their breast malignancy. The planned enrollment is 170 women being treated at fifteen medical centers across the US. To be eligible, patients must not have a history of allergic reaction to polyethylene glycol, intravenous contrast agents, or systemic therapies to treat their cancer. Use of blue dyes before imaging with the LUM System are not allowed. LUM015 is injected prior to the lumpectomy procedure. Surgeons perform standard of care (SOC) lumpectomy and perform blinded intraoperative imaging of the lumpectomy cavity with the LUM Imaging System in any regions where SOC shaves will be taken. The patient is then randomized either the further use of device or not. If the random assignment is to the device arm, the surgeon is directed to excise margins that the LUM System indicates are positive for cancer. Pathologists are blinded to the type of tissue removed when conducting the pathology assessment. Patient reported outcome data is collected as a quality of life survey before and after the subject's surgery. Additional detailed eligibility criteria are listed in the protocol. To date, 22 subjects have participated in this trial. This trial is registered as NCT03686215. Citation Format: Jorge Ferrer, David Carr, Irene Wapnir, Kelly Hunt, Peter Blumencranz, Nayana Dekhne, Daleela Dodge, Donna Lynn Dyess, Shelley Hwang, Stephanie Valente, Lynne Clark, Beth-Ann Lesnikoski, Anees Chagpar, Paticia Clark, Marie Catherine Lee, Brian Schlossberg, Sean Madden, Livia Gjylameti, Manna Chang, Kate Smith, Barbara Smith. Pivotal study of the LUM Imaging System for assisting intraoperative detection of residual cancer in the tumor bed of female patients with breast cancer [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 CT281.

Background Physiotherapy, and speech and language therapy are emerging non-pharmacological treatments for refractory chronic cough. We aimed to investigate the efficacy of a physiotherapy, and speech and language therapy intervention (PSALTI) to improve health-related quality of life (HRQoL) and to reduce cough frequency in patients with refractory chronic cough. Methods In this multicentre randomised controlled trial, patients with refractory chronic cough were randomised to four weekly 1:1 sessions of either PSALTI consisting of education, laryngeal hygiene and hydration, cough suppression techniques, breathing exercises and psychoeducational counselling or control intervention consisting of healthy lifestyle advice. We assessed the change in HRQoL at week 4 with the Leicester Cough Questionnaire (LCQ). Secondary efficacy outcomes included 24-hour objective cough frequency (Leicester Cough Monitor) and cough reflex sensitivity. The primary analysis used an analysis of covariance adjusted for baseline measurements with the intention-to-treat population. This study was registered at UK Clinical Research Network (UKCRN ID 10678). Findings Between December 2011 and April 2014, we randomly assigned 75 participants who underwent baseline assessment (34 PSALTI and 41 controls). In the observed case analysis, HRQoL (LCQ) improved on average by 1.53 (95% CI 0.21 to 2.85) points more in PSALTI group than with control (p=0.024). Cough frequency decreased by 41% (95% CI 36% to 95%) in PSALTI group relative to control (p=0.030). The improvements within the PSALTI group were sustained up to 3 months. There was no significant difference between groups in the concentration of capsaicin causing five or more coughs. Interpretation Greater improvements in HRQoL and cough frequency were observed with PSALTI intervention. Our findings support the use of PSALTI for patients with refractory chronic cough. Trial registration number UKCRN ID 10678 and [ISRCTN 73039760][1]; Results. [1]: /external-ref?link_type=ISRCTN&access_num=ISRCTN73039760

Background: Standard surgical techniques result in positive lumpectomy margins 20-40% of the time. These positive margins require surgical re-excision which places significant burden on the healthcare system and patients. The LUM Imaging System consists of a fluorescence-based imaging agent, a hand-held wide-field detector (LUM Imaging Device) used to image the surgical cavity walls intraoperatively in real-time after the resection of the main lumpectomy specimen, and a proprietary tumor detection algorithm that highlights regions in the tumor bed suspected to contain residual cancer. This imaging system was previously tested in a single-site clinical study. The current study is evaluating the imaging system in a multi-study, large patient cohort. Trial Design / Methods This trial (NCT03321929) is a non-randomized, open-label, multi-site trial designed to further refine the tumor detection algorithm utilized by the LUM Imaging System. This is a prospective, interventional feasibility study and is a pilot arm to a pivotal study which will evaluate the safety and efficacy of the LUM Imaging System. Up to 250 adult female breast cancer patients undergoing lumpectomies are being enrolled at sixteen medical centers across the US. LUM015, a fluorescence-based imaging agent, is injected prior to the subject’s lumpectomy procedure. Surgeons perform their standard of care lumpectomy followed by intraoperative imaging of the lumpectomy cavity with the LUM Imaging System. Specific Aims The primary objective is to assess performance characteristics of the LUM Imaging System and to refine the tumor detection algorithm. A secondary objective is to develop and refine the process of implementing the LUM Imaging System into institution-specific workflows during lumpectomies. Eligibility Criteria This study seeks to enroll women, over the age of 18 and with histologically or cytologically confirmed primary invasive breast cancer (IBC), ductal carcinoma in situ (DCIS) or a combination of IBC/DCIS undergoing a lumpectomy for their breast malignancy. In addition to be willing to follow study procedures, participating in an informed consent discussion, signing an informed consent form, and having baseline lab and screening values within protocol limits, enrolled subjects must meet the following key exclusion criteria: have no history of allergic reaction to polyethylene glycol, no history of allergic reaction to intravenous contrast agents, have not undergone any systemic therapies to treat their cancer, and will not be administered methylene blue or other dye for sentinel lymph node detection during their lumpectomy. Additional detailed eligibility criteria are listed in the protocol. Statistical Methods For categorical variables, summary tabulations of the number and percentage of patients within each category (with a category for missing data) of the parameter will be presented. For continuous variables, the number of patients, mean, median, standard deviation, minimum, and maximum values will be presented. The secondary objective will be met by evaluating a robust training and proficiency protocol for all enrolling institutions. Accrual To date, 208 subjects have participated in this LUM Imaging System trial. Contact Information Jorge Ferrer: jmferrer@lumicell.com Kate Smith: kate@lumicell.com Citation Format: Kate Smith, Jorge Ferrer, David Carr, Peter Blumencranz, Daleela Dodge, Nayana Dekhne, Irene Wapnir, Kelly Hunt, Linsey Gold, Stephanie Valente, Peter Beitsch, Donna Dyess, Shelly Hwang, Lynne Clark, Beth-Ann Lesnikoski, Anees Chagpar, Stephen Karp, Brian Schlossberg, Livia Gjylameti, Barbara Smith. Expansion into multiple institutions for training in the use of the LUM Imaging System for intraoperative detection of residual cancer in the tumor bed of female subjects with breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-06-02.

Background Cardiac re-transplantation (re-Tx) among pediatric recipients remains controversial. The purpose of this study is to use the Pediatric Heart Transplant Study (PHTS) database to investigate the incidence of re-Tx and analyze the risk factors and outcomes after transplantation among children. Methods The PHTS database was reviewed for all subjects ≤18 years of age at the time of primary transplant and re-Tx from January 1, 1993 through December 31, 2004. Multivariate analyses in the hazard-function domain were used to identify risk factors for re-Tx and for mortality after re-Tx. Results Risk factors for re-Tx include ventilator support, African-American ethnicity and elevated creatinine. Patient survival was inferior to that after primary transplantation (PTx) with 1-, 3- and 5-year survival probability after re-Tx of 80%, 69% and 60%, respectively ( p = 0.04). Patients re-transplanted for graft coronary artery disease fared better than those re-transplanted for early graft failure. A shorter time period between PTx and re-Tx was a significant risk factor for survival according to univariate analysis. However, risk factors for death after re-Tx by multivariate analysis included only early graft failure and rejection during PTx. Conclusions Survival after pediatric re-Tx is inferior to that after PTx. Re-transplantation for graft failure and rejection are associated with high relative risks for death. Given the limitations of donor availability, re-Tx for early graft failure and rejection appear contraindicated but appears acceptable for those who have survived ≥1 year after their PTx, especially those with graft coronary artery disease.

The Pediatric Heart Transplant Study (PHTS) group was founded in 1991 as a voluntary, collaborative effort dedicated to the advancement of the science and treatment of children following listing for heart transplantation. Since 1993, the PHTS has collected data in an international, prospective, event-driven database that examines risk factors for outcome events following listing for transplantation. The events include transplantation, death, rejection, infection, malignancy, graft vasculopathy, and retransplantation. Over its 12 years of existence, the PHTS has made major contributions to the field of pediatric heart transplantation, especially in the areas of outcome analysis and risk factor assessment for death and other major morbidities after listing and after transplantation. The new challenges facing the PHTS include how to implement the practice of evidence-based medicine in the field of pediatric heart transplantation and how to support ongoing data collection and analysis to provide long-term outcomes as the PHTS subjects enter their second decade after transplantation.

Purpose: Registries and clinical trials have different but overlapping purposes. The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) seeks to enroll all patients in the United States who receive an FDA approved durable mechanically assisted circulatory support device (MCSD). Methods and Materials: The purposed of this investigation is to evaluate INTERMACS data quality and compare to a typical clinical trial. Results: The design of INTERMACS is similar to a clinical trial. The INTERMACS protocol includes enrollment criteria, endpoints, adverse event (AE) definitions, and a study manual. INTERMACS is a collaboration among NHLBI, FDA, CMS, industry, hospitals and researchers. The registry requires IRB approval, participation agreements, conflict of interest forms and informed consent. INTERMACS has 130 hospitals in the United States. This is 90% of the MCSD hospitals. All CMS certified destination therapy hospitals are members. INTERMACS screens 90% of implanted patients in the country and 93% are consented and enrolled for a total of 5690 patients. INTERMACS contains 92% of the required follow-up forms. Data entry requires chart abstraction and does not include medical documents. The Medical Events Committee reviews AE data. Questions are forwarded to monitors who review medical records during on-site audits (30/yr) and quarterly phone audits. Conclusions: INTERMACS surpasses a clinical trial in national coverage, longevity, duration of patient follow-up, and the ability to evaluate approved devices. INTERMACS is similar to a clinical trial in endpoint specification and definitions. The INTERMACS auditing process is similar to a clinical trial but with less frequency. While INTERMACS provides medical review of the major AEs, this does not meet the adjudication rigor of a well-funded device trial. The data quality of INTERMACS is sufficient for FDA post market studies and, under pre-specified conditions, can provide the control arm of an FDA pre-market study.