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.

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.

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.

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.

Dedicated Breast Gamma Camera Imaging and Breast PET: Current Status and Future Directions.

Recent advances in nuclear medicine instrumentation have led to the emergence of improved molecular imaging techniques to image breast cancer: dedicated gamma cameras using γ-emitting 99mTc-sestamibi and breast-specific PET cameras using 18F-fluorodeoxyglucose. This article focuses on the current role of such approaches in the clinical setting including diagnosis, assessing local extent of disease, monitoring response to therapy, and, for gamma camera imaging, possible supplemental screening in women with dense breasts. Barriers to clinical adoption and technologies and radiotracers under development are also discussed.

Use of Breast-Specific PET Scanners and Comparison with MR Imaging.

The goals of this article are to discuss the role of breast-specific PET imaging of women with breast cancer, compare the clinical performance of positron emission mammography (PEM) and MR imaging for current indications, and provide recommendations for when women should undergo PEM instead of breast MR imaging.

Comparison of method-related reference intervals for thyroid hormones: studies from a prospective reference population and a literature review.

Introduction Reference intervals are dependent on the reference population, the analytical methods and the way the data are handled statistically. Individual method-related differences have been studied but the comparative differences in reference intervals have not. Methods We studied a reference population of healthy adult subjects and measured free thyroxine and thyroid-stimulating hormone by the four most commonly used analytical platforms used in the UK. Subjects were excluded if they were > 65 years or had positive thyroid peroxidase antibodies. We also performed a systematic literature review of thyroid hormone reference interval studies in non-pregnant adults. Results In total, 303 subjects were recruited and 42 excluded. The central 95th centile values for thyroid-stimulating hormone (mIU/L) were Abbott Architect (0.51-3.67); Beckman Unicel DxI (0.57-3.60); Roche Cobas (0.60-4.31) and Siemens Advia Centaur XP (0.63-4.29). The 95th centile values for thyroxine (pmol/L) were Abbott Architect (10.6-15.5); Beckman Unicel DxI (7.9-13.0); Roche Cobas (12.5-19.6) and Siemens Advia Centaur XP (11.8-19.0). We identified 55 papers describing thyroid reference intervals in male and non-pregnant female adults. The values for upper and lower reference intervals by manufacturer varied but were not significantly different for thyroid-stimulating hormone but were for thyroxine. Discussion Our study demonstrates clearly that there are marked variations in the reference intervals for thyroid hormones between analytical platforms. There is an urgent need for standardization of thyroid hormone assays to permit transferability of results. Until then, guidelines will need to reflect this method-related difference.

Evaluation of the effect of clinical validation of out of hours critical laboratory results.

AIM: The aim of the study was to review the clinical validation process of out of hours critical biochemistry results by a clinical biochemist and its effect on primary care services. METHODS: A prospective study was conducted of all critical results for primary care patients who were analysed out of hours. The nine-month study period was conducted between June 2013 and February 2014. The data collected include patients' age, clinical details, critical results and the urgency of result communicated. The patients' subsequent attendance rate at the emergency department in the local hospital was reviewed. RESULTS: A total of 311 out of hours critical results were identified in the laboratory. After clinical validation, 110 (35.4%) results were telephoned urgently and 155 (49.8%) results were deferred to the next day. Forty-six (14.8%) results were not telephoned. Following the urgent result communication, 53/110 (48.2%) patients attended the hospital emergency department within 24 h and 17/110 (15.5%) had their repeat blood test by their general practitioner surgery within 48 h. When the result was telephoned during working hours the next day, only 15/155 (9.7%) attended the hospital acute services within 48 h and 16/155 (10.3%) had repeat blood test at their general practitioner surgery. CONCLUSION: In our practice, the clinical validation of out of hours critical results by a clinical biochemist is associated with a reduction in the number of results telephoned when compared against the critical limits list recommended by the Royal College of Pathologists and may focus out of hours clinical activity on more suitable patients.

Radioprotectors and Radiomitigators for Improving Radiation Therapy: The Small Business Innovation Research (SBIR) Gateway for Accelerating Clinical Translation.

Although radiation therapy is an important cancer treatment modality, patients may experience adverse effects. The use of a radiation-effect modulator may help improve the outcome and health-related quality of life (HRQOL) of patients undergoing radiation therapy either by enhancing tumor cell killing or by protecting normal tissues. Historically, the successful translation of radiation-effect modulators to the clinic has been hindered due to the lack of focused collaboration between academia, pharmaceutical companies and the clinic, along with limited availability of support for such ventures. The U.S. Government has been developing medical countermeasures against accidental and intentional radiation exposures to mitigate the risk and/or severity of acute radiation syndrome (ARS) and the delayed effects of acute radiation exposures (DEARE), and there is now a drug development pipeline established. Some of these medical countermeasures could potentially be repurposed for improving the outcome of radiation therapy and HRQOL of cancer patients. With the objective of developing radiation-effect modulators to improve radiotherapy, the Small Business Innovation Research (SBIR) Development Center at the National Cancer Institute (NCI), supported by the Radiation Research Program (RRP), provided funding to companies from 2011 to 2014 through the SBIR contracts mechanism. Although radiation-effect modulators collectively refer to radioprotectors, radiomitigators and radiosensitizers, the focus of this article is on radioprotection and mitigation of radiation injury. This specific SBIR contract opportunity strengthened existing partnerships and facilitated new collaborations between academia and industry. In this commentary, we assess the impact of this funding opportunity, outline the review process, highlight the organ/site-specific disease needs in the clinic for the development of radiation-effect modulators, provide a general understanding of a framework for gathering preclinical and clinical evidence to obtain regulatory approval and provide a basis for broader venture capital needs and support from pharmaceutical companies to fully capitalize on the advances made thus far in this field.

Hepatocellular carcinoma in variegate porphyria: a case report and literature review.

Variegate porphyria is an autosomal dominant acute hepatic porphyria characterized by photosensitivity and acute neurovisceral attacks. Hepatocellular carcinoma has been described as a potential complication of variegate porphyria in case reports. We report a case of a 48-year-old woman who was diagnosed with hepatocellular carcinoma following a brief history of right upper quadrant pain which was preceded by a few months of blistering lesions in sun-exposed areas. She was biochemically diagnosed with variegate porphyria, and mutational analysis confirmed the presence of a heterozygous mutation in the protoporphyrinogen oxidase gene. Despite two hepatic resections, she developed pulmonary metastases. She responded remarkably well to Sorafenib and remains in remission 16 months after treatment. A review of the literature revealed that hepatocellular carcinoma in variegate porphyria has been described in at least eight cases. Retrospective and prospective cohort studies have suggested a plausible association between hepatocellular carcinoma and acute hepatic porphyrias. Hepatic porphyrias should be considered in the differential diagnoses of hepatocellular carcinoma of uncertain aetiology. Patients with known hepatic porphyrias may benefit from periodic monitoring for this complication.

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.

Versatile carboxymethyl chitin and chitosan nanomaterials: a review.

Biocompatibility, biodegradability, and low cost of chitin and chitosan have drawn immense attention in many fields including medicine, bioinspired material science, pharmaceuticals, and agriculture. Their handling and processing are difficult owing to its insolubility in neutral aqueous solution or organic solvents. One of the methods used to improve the solubility characteristics of chitin and chitosan is chemical modification. Introducing a carboxymethyl group is the most advantageous method of increasing the solubility of chitosan at neutral and alkaline pH. Carboxymethyl chitin (CMC) and carboxymethyl chitosan (CMCS) are water soluble derivatives formed by introducing CH2COOH function into the polymer which endows it with better biological properties. The functional group makes CMC/CMCS nanoparticles (NPs) efficient vehicles for the delivery of DNA, proteins, and drugs. This review provides an overview of the characteristics of CMC/CMCS NPs as well as fulfills the task of describing and discussing its important roles primarily in cancer nanomedicine detailing the targeted drug delivery aspect. The application of these NPs in imaging, agriculture, and textiles has also been highlighted. The review also elaborates the advantages of using the CMC and CMCS NPs for drug and gene delivery.