National Cancer Institute support for targeted alpha-emitter therapy.

BACKGROUND: Radiopharmaceutical targeted therapy (RPT) has been studied for decades; however, recent clinical trials demonstrating efficacy have helped renewed interest in the modality. METHODS: This article reviews National Cancer Institute (NCI)'s support of RPT through communication via workshops and interest groups, through funding extramural programs in academia and small business, and through intramural research, including preclinical and clinical studies. RESULTS: NCI has co-organized workshops and organized interest groups on RPT and RPT dosimetry to encourage the community and facilitate rigorous preclinical and clinical studies. NCI has been supporting RPT research through various mechanisms. Research has been funded through peer-reviewed NCI Research and Program Grants (RPG) and NCI Small Business Innovation Research (SBIR) Development Center, which funds small business-initiated projects, some of which have led to clinical trials. The NCI Cancer Therapy Evaluation Program (CTEP)'s Radiopharmaceutical Development Initiative supports RPT in NCI-funded clinical trials, including Imaging and Radiation Oncology Core (IROC) expertise in imaging QA and dosimetry procedures. Preclinical targeted a-emitter therapy (TAT) research at the NCI's intramural program is ongoing, building on foundational work dating back to the 1980s. Ongoing "bench-to-bedside" efforts leverage the unique infrastructure of the National Institutes of Health's (NIH) Clinical Center. CONCLUSION: Given the great potential of RPT, our goal is to continue to encourage its development that will generate the high-quality evidence needed to bring this multidisciplinary treatment to patients.

Management of severe in-patient hyponatraemia: an audit in two teaching hospitals in Yorkshire, UK.

BACKGROUND: Hyponatraemia, the commonest electrolyte abnormality amongst in-patients, is associated with increased mortality. Until recently, there has been a lack of international consensus management of patients with severe hyponatraemia. AIM: We performed a retrospective study in two teaching hospitals in Yorkshire, UK, to evaluate the management of patients with severe hyponatraemia (serum Na ≤ 110 mmol/L) and to assess the frequency of complications observed in this group, in particular central pontine myelinolysis (CPM) and death. METHODS: Retrospective data collection was performed on all of patients admitted with severe hyponatraemia in a calendar year in two teaching hospitals in Yorkshire. A detailed case note evaluation was conducted to determine the patient clinical characteristics, aetiology, investigations performed, treatment, complications and outcome of patients. RESULTS: We identified 39 patients in total at both sites over a calendar year. There was a notable female predominance (n = 27), with the median (range) age being 65 (45-92) years and median sodium concentration 107 (94-110) mmol/L. Hyponatraemia was classified as acute (onset < 48 h) in six patients, chronic (onset > 48 h) in 20 patients and of unknown duration in 13 patients. Iatrogenic hyponatraemia secondary to drugs, especially thiazides was the most commonly observed aetiology. The mortality rate was 48.7% (n = 19) at the end of one year after admission episode and CPM was seen in 7.6% (n = 3) of patients. CONCLUSIONS: Severe hyponatraemia is associated with significant morbidity and mortality. Drug-induced hyponatraemia was the most common aetiology observed in our group of patients.

Breast cancer detection using high-resolution breast PET compared to whole-body PET or PET/CT.

PURPOSE: To compare the performance characteristics of positron emission mammography (PEM) with those of whole-body PET (WBPET) and PET/CT in women with newly diagnosed breast cancer. METHODS: A total of 178 women consented to PEM for presurgical planning in an IRB-approved protocol and also underwent either WBPET (n = 69) or PET/CT (n = 109) imaging, as per usual care at three centers. Tumor detection sensitivity, positive predictive values, and (18)F-fluorodeoxyglucose (FDG) uptake were compared between the modalities. The effects of tumor size, type, and grade on detection were examined. The chi-squared or Fisher's exact tests were used to compare distributions between groups, and McNemar's test was used to compare distributions for paired data within subject groups, i.e. PEM versus WBPET or PEM versus PET/CT. RESULTS: The mean age of the women was 59 ± 12 years (median 60 years, range 26-89 years), with a mean invasive index tumor size of 1.6 ± 0.8 cm (median 1.5 cm, range 0.5-4.0 cm). PEM detected more index tumors (61/66, 92%) than WBPET (37/66, 56%; p < 0.001) or PET/CT (95/109, 87% vs. 104/109, 95% for PEM; p < 0.029). Sensitivity for the detection of additional ipsilateral malignancies was also greater with PEM (7/15, 47%) than with WBPET (1/15, 6.7%; p = 0.014) or PET/CT (3/23, 13% vs. 13/23, 57% for PEM; p = 0.003). Index tumor detection decreased with decreasing invasive tumor size for both WBPET (p = 0.002) and PET/CT (p < 0.001); PEM was not significantly affected (p = 0.20). FDG uptake, quantified in terms of maximum PEM uptake value, was lowest in ductal carcinoma in situ (median 1.5, range 0.7-3.0) and invasive lobular carcinoma (median 1.5, range 0.7-3.4), and highest in grade III invasive ductal carcinoma (median 3.1, range 1.4-12.9). CONCLUSION: PEM was more sensitive than either WBPET or PET/CT in showing index and additional ipsilateral breast tumors and remained highly sensitive for tumors smaller than 1 cm.

Faecal Immunochemical Test (FIT) Sensitivity; A Five Year Audit.

Introduction: Colorectal cancer has a high prevalence and mortality rate in the United Kingdom. Cancerous colorectal lesions often bleed into the gastrointestinal lumen. The faecal immunochemical test (FIT) detects haemoglobin (Hb) in the faeces of patients and is used as a first line test in the diagnosis of colorectal cancer. Materials and Methods: A retrospective audit of all FIT performed and all colorectal cancers diagnosed in the Hull and East Riding of Yorkshire counties of the United Kingdom (population approximately 609,300) between 2018 and 2022 was conducted. FIT were performed using a HM-JACKarc analyser from Kyowa medical. The predominant symptom suggestive of colorectal cancer which prompted the FIT was recorded. Colorectal cancer was diagnosed using the gold standard of histological biopsy following colonoscopy. Results: Between 2018 and 2022, 56,202 FIT were performed on symptomatic patients. Follow on testing identified 1,511 with colorectal cancer. Of these people, only 450 people with a confirmed colorectal cancer had a FIT within the 12 months preceding their diagnosis. Of these 450 FIT results, 36 had a concentration of <10 µg/g and may be considered to be a false negative. The sensitivity of FIT in the patients identified was 92.00%. The most common reason stated by the clinician for a FIT being performed in patients with colorectal cancer was a change in bowel habits, followed by iron deficient anaemia. The number of patients diagnosed with colorectal cancer decreased in 2020, but increased significantly in 2021. Discussion: This study shows that 8.00% of people diagnosed with colorectal cancer in the Hull and East Riding of Yorkshire regions had a negative FIT. This study also shows that the SARS-CoV-2 pandemic affected the number of people diagnosed with colorectal cancer, and therefore skews the prevalence and pre-test probability of a positive test. There are many reasons why a FIT could produce a false negative result, the most likely being biological factors affecting the stability of haemoglobin within the gastrointestinal tract, or pre-analytical factors influencing faecal sampling preventing the detection of haemoglobin. Some colorectal lesions do not protrude into the gastrointestinal lumen and are less likely to bleed. Conclusion: This is the first study showing data from outside of a structured clinical trial and provides the largest study to date showing the sensitivity of FIT in a routine clinical setting. This study also provides evidence for the impact COVID-19 had on the rate of colorectal cancer diagnosis.

In vitro and in vivo evaluation of osteoporosis therapeutic peptide PTH 1-34 loaded pegylated chitosan nanoparticles.

Oral formulation of human parathyroid hormone 1-34 (PTH 1-34) is an alternative patient compliant route in treating osteoporosis. PTH 1-34 loaded chitosan nanoparticles were PEGylated (PEG-CS-PTH NPs) and characterized by DLS, SEM, TEM and FTIR. PEG-CS-PTH NP aggregates of 200-250 nm which in turn comprised 20 nm individual nanoparticles were observed in SEM and TEM images respectively. The PEG-CS-PTH NP with 40% encapsulation efficiency was subjected to an in vitro release in simulated rat body fluids. PEG-CS-PTH NP treated human primary osteoblast cells, upon PTH 1-34 receptor activation, produced second messenger-cAMP, which downstream stimulated intracellular calcium uptake, production of bone specific alkaline phosphatase, osteocalcin etc., which substantiates the anabolic effect of the peptide. PEG-CS-PTH NPs showed an oral bioavailability of 100-160 pg/mL PTH 1-34 throughout 48 h, which is remarkable compared to the bare PTH 1-34 and CS-PTH NPs. The NIR image of gastrointestinal transit of ICG conjugated PEG-CS-PTH NPs supports this significant finding.

CARE program: NCI and FDA interagency collaborations to support oncology small business entrepreneurs.

The National Cancer Institute's Small Business Innovation Research Development Center (NCI SBIR) supports the commercialization of novel cancer-related technologies by providing resources to 300-400 small businesses each year. Whereas Federal funding is crucial for the translation of technologies to the clinic, the majority of these technologies will need to undergo regulatory review to reach clinical testing. Many small businesses find navigating their regulatory pathway challenging, largely due to lack of regulatory expertise on small startup teams with limited revenue. In collaboration with the US Food and Drug Administration (FDA), NCI SBIR launched a new regulatory assistance program called Connecting Awardees with Regulatory Experts (CARE). The goal of the CARE program is to connect NCI-funded small businesses with the FDA to receive feedback on their regulatory questions during early-stage product development. The program has a multipronged support approach and also educates companies about the FDA process and existing resources. To date, 141 companies have participated in the interagency program. Follow-up surveys indicate that the program guided the companies in planning the next regulatory steps for their technology development (89%) and provided critical information that changed their future NCI small business grant project aims (81%). Overall, companies reported they would recommend the program to other companies (90%). This paper will discuss the CARE program outcomes as well as other NCI and FDA collaborations that support early-stage small businesses, including the joint development of funding opportunities and online resources that focus on the oncology startup community.

Comparative effectiveness of positron emission mammography and MRI in the contralateral breast of women with newly diagnosed breast cancer.

OBJECTIVE: The objective of our study was to compare the performance of positron emission mammography (PEM) with that of MRI in the evaluation of the contralateral breast of women with newly diagnosed cancer. SUBJECTS AND METHODS: Four hundred seventy-two women with newly diagnosed breast cancer offered breast-conserving surgery from September 2006 through November 2008 consented to participate in a multicenter protocol. Participants underwent contrast-enhanced breast MRI and 18F-FDG PEM in randomized order, and the examinations were interpreted independently. The performance characteristics of the imaging modalities were compared using the McNemar test and generalized estimating equations. A retrospective blinded review of PEM images was performed by four experienced observers to understand the reasons for false-negatives. RESULTS: Three hundred sixty-seven women (median age, 58 years; age range, 26-93 years) eligible for analysis completed the appropriate follow-up for study inclusion. Fifteen women (4.1%) were found to have contralateral cancer (11 invasive [mean tumor size, 12 mm; median, 10 mm; range, 1-22 mm] and four ductal carcinoma in situ). Of the 15 cases, both PEM and MRI showed three (20%), only MRI showed 11 (73%), and one (6.7%) was found at prophylactic mastectomy. MRI sensitivity at 14 of 15 (93%; 95% CI, 66-94) was higher than PEM at three of 15 (20%; 95% CI, 5.3-46) (p<0.001). On PEM, three additional cancers were seen prospectively but were considered probably benign and two other cancers were visible in retrospect at the site. Of 352 contralateral breasts without cancer, findings were negative or benign on PEM for 335 (95.2%; 95% CI, 92.2-97.0), which is more than MRI at 315 (89.5%; 95% CI, 85.7-92.4; p=0.002). The positive predictive value (PPV) of PEM-prompted biopsies (3/14 [21%]) was not significantly different from the PPV of MRI (15/54 [28%], p=0.58). On blinded retrospective PEM review of the 15 contralateral cancers, PEM findings for 11 (73%) were considered suspicious. CONCLUSION: Contralateral cancer was found in 15 of 367 women (4.1%), with MRI showing 14 (93%). Eleven contralateral cancers (73%) were visible on PEM, but only three (20%) were recognized prospectively as suspicious. Lesions that are visible on PEM should be viewed as suspicious unless known to be benign by prior breast imaging or biopsy.

Breast cancer: comparative effectiveness of positron emission mammography and MR imaging in presurgical planning for the ipsilateral breast.

PURPOSE: To determine the performance of positron emission mammography (PEM), as compared with magnetic resonance (MR) imaging, including the effect on surgical management, in ipsilateral breasts with cancer. MATERIALS AND METHODS: Four hundred seventy-two women with newly diagnosed breast cancer who were offered breast-conserving surgery consented from September 2006 to November 2008 to participate in a multicenter institutional review board-approved, HIPAA-compliant protocol. Participants underwent contrast material-enhanced MR imaging and fluorine 18 fluorodeoxyglucose PEM in randomized order; resultant images were interpreted independently. Added biopsies and changes in surgical procedure for the ipsilateral breast were correlated with histopathologic findings. Performance characteristics were compared by using the McNemar test and generalized estimating equations. RESULTS: Three hundred eighty-eight women (median age, 58 years; age range, 26-93 years; median estimated tumor size, 1.5 cm) completed the study. Additional cancers were found in 82 (21%) women (82 ipsilateral breasts; median tumor size, 0.7 cm). Twenty-eight (34%) of the 82 breasts were identified with both PEM and MR imaging; 21 (26%) breasts, with MR imaging only; 14 (17%) breasts, with PEM only; and seven (8.5%) breasts, with mammography and ultrasonography. Twelve (15%) cases of additional cancer were missed at all imaging examinations. Integration of PEM and MR imaging increased cancer detection-to 61 (74%) of 82 breasts versus 49 (60%) of 82 breasts identified with MR imaging alone (P < .001). Of 306 breasts without additional cancer, 279 (91.2%) were correctly assessed with PEM compared with 264 (86.3%) that were correctly assessed with MR imaging (P = .03). The positive predictive value of biopsy prompted by PEM findings (47 [66%] of 71 cases) was higher than that of biopsy prompted by MR findings (61 [53%] of 116 cases) (P = .016). Of 116 additional cancers, 61 (53%) were depicted by MR imaging and 47 (41%) were depicted by PEM (P = .043). Fifty-six (14%) of the 388 women required mastectomy: 40 (71%) of these women were identified with MR imaging, and 20 (36%) were identified with PEM (P < .001). Eleven (2.8%) women underwent unnecessary mastectomy, which was prompted by only MR findings in five women, by only PEM findings in one, and by PEM and MR findings in five. Thirty-three (8.5%) women required wider excision: 24 (73%) of these women were identified with MR imaging, and 22 (67%) were identified with PEM. CONCLUSION: PEM and MR imaging had comparable breast-level sensitivity, although MR imaging had greater lesion-level sensitivity and more accurately depicted the need for mastectomy. PEM had greater specificity at the breast and lesion levels. Eighty-nine (23%) participants required more extensive surgery: 61 (69%) of these women were identified with MR imaging, and 41 (46%) were identified with PEM (P = .003). Fourteen (3.6%) women had tumors seen only at PEM.

Positron emission mammography in breast cancer presurgical planning: comparisons with magnetic resonance imaging.

PURPOSE: The objective of this study was to compare the performance characteristics of (18)F-fluorodeoxyglucose (FDG) positron emission mammography (PEM) with breast magnetic resonance imaging (MRI) as a presurgical imaging and planning option for index and ipsilateral lesions in patients with newly diagnosed, biopsy-proven breast cancer. METHODS: Two hundred and eight women >25 years of age (median age = 59.7 ± 14.1 years) with biopsy-proven primary breast cancer enrolled in this prospective, single-site study. MRI, PEM, and whole-body positron emission tomography (WBPET) were conducted on each patient within 7 business days. PEM and WBPET images were acquired on the same day after intravenous administration of 370 MBq of FDG (median = 432.9 MBq). PEM and MRI images were blindly evaluated, compared with final surgical histopathology, and the sensitivity determined. Substudy analysis compared the sensitivity of PEM versus MRI in patients with different menopausal status, breast density, and use of hormone replacement therapy (HRT) as well as determination of performance characteristics for additional ipsilateral lesion detection. RESULTS: Two hundred and eight patients enrolled in the study of which 87% (182/208) were analyzable. Of these analyzable patients, 26.4% (48/182), 7.1% (13/182), and 64.2% (120/182) were pre-, peri-, and postmenopausal, respectively, and 48.4% (88/182) had extremely or heterogeneously dense breast tissue, while 33.5% (61/182) had a history of HRT use. Ninety-two percent (167/182) underwent core biopsy for index lesion diagnosis. Invasive cancer was found in 77.5% (141/182), while ductal carcinoma in situ (DCIS) and/or Paget's disease were found in 22.5% (41/182) of patients. Both PEM and MRI had index lesion depiction sensitivity of 92.8% and both were significantly better than WBPET (67.9%, p < 0.001, McNemar's test). For index lesions, PEM and MRI had equivalent sensitivity of various tumors, categorized by tumor stage as well as similar invasive tumor size predictions with Spearman's correlation coefficient of 0.61 for both PEM and MRI compared to surgical pathology. Menopausal status, breast density, and HRT did not influence the sensitivity of PEM or MRI. For 67 additional unsuspected ipsilateral lesions or multifocal lesions, PEM had sensitivity of 85% (34/40) and specificity of 74%, (20/27) compared to MRI's sensitivity of 98% (39/40) and specificity of 48% (13/27) [p = 0.074, for sensitivity; p = 0.096 for specificity] CONCLUSION: PEM is a good alternative to MRI as a presurgical breast imaging option and its performance characteristics are not affected by patient menopausal/hormonal status or breast density.

Interpretation of positron emission mammography: feature analysis and rates of malignancy.

OBJECTIVE: The purpose of our study was to define and illustrate standard terminology for describing findings on positron emission mammography (PEM) and provide associated rates of malignancy. SUBJECTS AND METHODS: Three hundred eighty-eight women with newly-diagnosed breast cancer anticipating breast-conserving surgery completed a multicenter trial comparing PEM to MRI in assessment of disease extent. Morphologic terminology to describe PEM findings was patterned on BI-RADS for MRI, and investigators were trained in the PEM lexicon. PEM imaging features of known malignancies and additional PEM lesions were recorded and correlated with outcome. The reference standard was biopsy or at least a 6-month follow-up. RESULTS: Of 166 additional lesions on PEM, 54 (33%) proved malignant, with median invasive tumor size 8 mm (range, 2-60 mm). Among 43 round or oval masses, 16 (37%) were malignant, compared with 16 of 21 (76%) of lobulated or irregular masses (p = 0.003). Among 14 findings of focal or regional nonmass uptake, two (14%) were malignant compared with four of 12 (33%) findings of linear-ductal or segmental uptake (p = 0.350). Malignancy rates for BI-RADS-type final assessments were category 2, one of 31 (3.2%); 3, three of 32 (9.4%); 4a, four of 18 (22%); 4b, nine of 33 (27%); 4c, 15 of 24 (63%); and 5, 22 of 28 (79%). On the basis of modeling, irregular or lobulated morphology was the strongest predictor of malignancy, followed by lesion laterality (i.e., ipsilateral to known cancer) then increasing semiquantitative (18)F-FDG uptake. CONCLUSION: Use of standardized terminology to report PEM findings will facilitate effective communication of results and consistent management. A probably benign category 3 assessment carried a substantial rate of malignancy for lesions seen on PEM, and biopsy may be more appropriate than follow-up.

Interpretation of positron emission mammography and MRI by experienced breast imaging radiologists: performance and observer reproducibility.

OBJECTIVE: In preparation for a multicenter trial of positron emission mammography (PEM) and MRI in women with newly diagnosed cancer, the two purposes of this study were to validate training of breast imagers in standardized interpretation of PEM and to validate performance of the same specialists interpreting MRI. MATERIALS AND METHODS: A 2-hour didactic module was developed to train Mammography Quality Standards Act-qualified radiologist observers to interpret PEM images, consisting of a sample feature analysis lexicon analogous to BI-RADS and 12 sample cases. Observers were then asked to review separate interpretive skills tasks for PEM (49 breasts, 20 [41%] of which were malignant) and MRI (32 breasts, 11 [34%] of which were malignant), describe findings, and give assessments analogous to BI-RADS (category 1, 2, 3, 4A, 4B, 4C, or 5). Demographic experience variables were collected for 36 observers from 15 sites. Performance against histopathologic truth was determined, and interobserver agreement for classifying features and final assessments was evaluated using kappa statistics. RESULTS: Across 36 observers, mean sensitivity, specificity, and area under the curve (AUC) for PEM were 96% (range, 75-100%), 84% (range, 66-97%), and 0.95 (range, 0.82-1.0), respectively. Mean sensitivity, specificity, and AUC for the MRI task were 82% (range, 45-100%), 67% (range, 38-91%), and 0.80 (range, 0.48-0.96), respectively. Interobserver agreement for PEM findings ranged from moderate to substantial, with kappa values of 0.57 for lesion type and 0.63 for final assessments. CONCLUSION: With minimal training, experienced breast imagers showed high performance in interpreting PEM images. Performance in MRI interpretation by the same observers validated expected clinical practice.

PET-guided breast biopsy.

Molecular imaging, using positron emission tomography (PET), has become an integral step in the evaluation of many patients with malignancy. However, its use in patients with breast cancer has been limited by the lower levels of (18) F-fluorodeoxyglucose (FDG) uptake in some breast malignancies compared to other cancers, the small size of many breast cancers, and the need for biopsy under PET guidance. High-resolution breast PET, or positron emission mammography (PEM), with biopsy guidance software, now addresses these issues. We report a prospective, multicenter study designed to test the efficacy and safety of PEM biopsy guidance software in women with FDG-avid breast lesions worrisome for malignancy. The intervention chosen was vacuum-assisted core biopsy. Nineteen subjects underwent a total of 24 PEM-guided biopsies. All lesions were successfully targeted and sampled as determined by post-biopsy image scan evaluation, specimen imaging, and pathologic concordance. Invasive cancer was identified in 13 of 24 lesions (54%), while four (17%) were high-risk lesions and three of these were upgraded to malignancy at excision. No serious adverse events occurred and all patients found the procedure to cause only minimal to mild discomfort. High-resolution PEM-guided breast biopsy is both safe and effective for the sampling of PET-depicted breast lesions.

Investor initiatives program: Public-private partnerships to expedite commercialization for NCI-funded small business entrepreneurs.

The National Cancer Institute's Small Business Innovation Research Development Center (NCI SBIR) provides federal research and development funding and commercialization resources to more than 400 small businesses each year developing novel technologies to prevent, diagnose, and treat cancer. Although federal funding is vital for life science startups at the early stage of development, it is often insufficient to translate the technology from discovery to commercial product. Early-stage startups must connect to follow-on capital and resources to bring NCI-funded technologies to patients. Most startups face challenges in securing additional funding due to lack of access to investors and strategic partners and the ability to effectively pitch their technology. In 2015, the NCI SBIR started the Investor Initiatives program to connect funded small businesses with targeted investors and strategic partners to address the aforementioned obstacles. This program leverages an extensive network of investors and partners to conduct business-focused reviews and provide pitch coaching. The program incentivizes earlier collaborations between NCI-funded companies and private investors through various channels. The program has supported 117 companies from years 2016-2019 to attend 27 investor showcase events. Follow-up surveys show that the program and the assistance offered by NCI SBIR have contributed to a total of 32 completed deals as of April 29, 2020. This paper will discuss the Investor Initiatives program and its outcomes from 2016 to 2019 and demonstrate the effectiveness of a federal program that leverages public-private partnerships to assist portfolio companies with raising follow-on funding to accelerate the translation of research into clinical practice.

Development of Novel Radiosensitizers through the National Cancer Institute's Small Business Innovation Research Program.

While radiosensitizing chemotherapy has improved survival for several types of cancer, current chemoradiation regimens remain ineffective for many patients and have substantial toxicities. Given the strong need for the development of novel radiosensitizers to further improve patient outcomes, the Radiation Research Program (RRP) and the Small Business Innovation Research (SBIR) in the National Cancer Institute (NCI) issued a Request for Proposals (RFP) through the NCI SBIR Development Center's contracts pathway. We sought to determine the research outcomes for the NCI SBIR Development Center's funded proposals for the development of radiosensitizers. We identified SBIR-funded contracts and grants for the development of radiosensitizers from 2009 to 2018 using the National Institutes of Health (NIH) Reporter database. Research outcomes of the NCI SBIR Development Center-funded proposals were determined using a comprehensive internet search. We searched PubMed, clinicaltrials.gov, company websites and google.com for research articles, abstracts and posters, clinical trials, press releases and other news, related to progress in the development of funded radiosensitizers. To protect the intellectual property of the investigators and small businesses, all information obtained and reported is publicly available. The SBIR Program has funded four contracts and 11 grants for the development of novel radiosensitizers. Two companies have received phase IIb bridge awards. Overall, 50% of companies (6/12) have successfully advanced their investigational drugs into prospective clinical trials in cancer patients, and all but one company are investigating their drug in combination with radiation therapy as described in the NCI SBIR Development Center proposal. To date, only one company has initiated a randomized trial of standard of care with or without their radiosensitizer. In conclusion, the NCI SBIR Development Center has funded the development of novel radiosensitizers leading to clinical trials of novel drugs in combination with radiation therapy. Continued follow-up is needed to determine if any of these novel radiosensitizers produce improved tumor control and/or overall survival.

Radiation Biomarkers: Can Small Businesses Drive Accurate Radiation Precision Medicine?

Radiation therapy is an essential component of cancer treatment. Currently, tumor control and normal tissue complication probabilities derived from a general patient population guide radiation treatment. Its outcome could be improved if radiation biomarkers could be incorporated into approaches to treatment. A substantial number of cancer patients suffer from side effects of radiation therapy. These side effects can result in treatment interruption. Such unplanned treatment interruptions not only jeopardize anticancer treatment efficacy but also result in poor post-treatment quality-of-life. To develop and translate radiation biomarkers for clinical use, NCI's Radiation Research Program, in collaboration with the Small Business Innovation Research Development Center, funded four small businesses through the request for proposals after peer review during 2015-2019. Here, we summarize publicly available information on intellectual property rights, the status of development, ongoing clinical trials, success in obtaining financing and regulatory approval. An analysis of publicly available information indicates all four companies have completed phase I of SBIR funding and advanced to further development, validation and clinical trials with phase II SBIR funding. These biomarkers are: 1. A panel of genomic biomarkers of radiation response to predict toxicity and radioimmune response (MiraDx Inc., Los Angeles, CA); 2. A multiplex assay for single nucleotide polymorphism (SNP) biomarkers of radiation sensitivity to identify a subset of prostate cancer patients for which radiotherapy is contraindicated (L2 Diagnostics, New Haven, CT); 3. A cell-free DNA assay in blood to measure tissue damage shortly after radiation exposure (DiaCarta Inc., Richmond, CA); and 4. A metabolomic/lipidomic assay to predict late effects that adversely affect quality-of-life among patients treated with radiation for prostate cancer (Shuttle Pharmaceuticals, Rockville, MD). This work also provides a bird's eye view of the process of developing radiation biomarkers for use in radiation oncology clinics, some of the challenges and future directions.

A Retrospective Observational Study to Determine Baseline Characteristics and Early Prescribing Patterns for Patients Receiving Alirocumab in UK Clinical Practice.

BACKGROUND: Alirocumab is a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9) and has been previously shown, in the phase III ODYSSEY clinical trial program, to provide significant lowering of low-density lipoprotein cholesterol (LDL-C) and reduction in risk of major adverse cardiovascular events. However, real-world evidence to date is limited. OBJECTIVE: The primary objective was to describe baseline characteristics, clinical history, and prior lipid-lowering therapy (LLT) use of patients initiated on alirocumab in UK clinical practice following publication of health technology appraisal (HTA) body recommendations. Secondary objectives included description of alirocumab use and lipid parameter outcomes over a 4-month follow-up period. METHODS: In this retrospective, single-arm, observational, multicenter study, data were collected for 150 patients initiated on alirocumab. RESULTS: Mean (standard deviation; SD) age of patients was 61.4 (10.5) years and baseline median (interquartile range; IQR) LDL-C level was 4.8 (4.2-5.8) mmol/l. Alirocumab use occurred predominantly in patients with heterozygous familial hypercholesterolemia (HeFH) (n = 100/150, 66%) and those with statin intolerance (n = 123/150, 82%). Most patients started on alirocumab 75 mg (n = 108/150 [72%]) and 35 (23.3%) were up-titrated to 150 mg. Clinically significant reductions in atherogenic lipid parameters were observed with alirocumab, including LDL-C (median [IQR] change from baseline, - 53.6% [- 62.9 to - 34.9], P < 0.001). CONCLUSION: This study highlights the unmet need for additional LLT in patients with uncontrolled hyperlipidemia and demonstrates the clinical utility of alirocumab in early real-world practice, where dosing flexibility is an important attribute of this therapeutic option.

Advancing Targeted Radionuclide Therapy Through the National Cancer Institute's Small Business Innovation Research Pathway.

The Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programs of the National Cancer Institute (NCI) are congressionally mandated set-aside programs that provide research funding to for-profit small businesses for the development of innovative technologies and treatments that serve the public good. These two programs have an annual budget of $159 million (in 2017) and serve as the NCI's main engine of innovation for developing and commercializing cancer technologies. In collaboration with the NCI's Radiation Research Program, the NCI SBIR Development Center published in 2015-2017 three separate requests for proposals from small businesses for the development of systemic targeted radionuclide therapy (TRT) technologies to treat cancer. TRT combines a cytotoxic radioactive isotope with a molecularly targeted agent to produce an anticancer therapy capable of treating local or systemic disease. This article summarizes the NCI SBIR funding solicitations for the development of TRTs and the research proposals funded through them.

Decreasing the Toxicity of Radiation Therapy: Radioprotectors and Radiomitigators Being Developed by the National Cancer Institute Through Small Business Innovation Research Contracts.

PURPOSE: The use of radioprotectors and radiomitigators could improve the therapeutic index of radiation therapy. With the intention of accelerating translation of radiation-effect modulators (radioprotectors and mitigators), the Radiation Research Program and SBIR (Small Business Innovation Research) Development Center within the National Cancer Institute issued 4 Requests for Proposals (RFPs) from 2010 to 2013. Twelve SBIR contract awards in total were made in response to the 4 RFPs from September 2011 through September 2014. Here, we provide an update on the status of SBIR contract projects for the development of radiation-effect modulators. METHODS AND MATERIALS: To assess the status of research and development efforts under the 4 RFPs on radiation-effect modulators, we searched PubMed for research articles, google.com for published abstracts, clinicaltrials.gov for ongoing or completed clinical trials, and company websites for press releases and other news. All information obtained and reported here is publicly available and thus protects the intellectual property of the investigators and companies. RESULTS: Of the 12 SBIR projects funded, 5 (42%) transitioned successfully from phase 1 to phase 2 SBIR funding, and among the Fast-Track contracts, this rate was 100% (3 of 3). The Internet search identified 3 abstracts and 6 publications related to the aims of the SBIR contracts. One-third of the companies (4 of 12) have successfully launched a total of 8 clinical trials to demonstrate the safety and efficacy of their investigational agents. Two drugs are in clinical trials for their indication as a radioprotector, and 2 drugs are under evaluation for their anticancer properties (an immunomodulator and a small molecule inhibitor). CONCLUSIONS: The National Cancer Institute's SBIR has provided pivotal funding to small businesses for the development of radioprotectors and radiomitigators, which resulted in multiple early-phase clinical trials. Longer follow-up is needed to determine the full impact of these novel therapeutics that enter clinical practice.

Differentiating seizure and convulsive syncope: the importance of history taking.

Distinguishing syncope with convulsions from a seizure disorder remains difficult. Convulsions occurring secondary to syncope typically result in an incorrect diagnosis of a seizure disorder. Available diagnostic testing often does not provide a conclusive answer; to ensure diagnostic accuracy, the careful and experienced clinician should obtain a patient history and physical examination. We present a case report, review the available literature, and analyze the accuracy of diagnostic testing. While no single diagnostic method works perfectly to determine whether loss of consciousness with associated convulsions results from seizure or syncope, accurate history taking is the first step and most sensitive diagnostic tool.