Anxiety and depression in patients with non-site-specific cancer symptoms: data from a rapid diagnostic clinic.

Background: Rapid diagnostic clinics (RDCs) provide a streamlined holistic pathway for patients presenting with non-site specific (NSS) symptoms concerning of malignancy. The current study aimed to: 1) assess the prevalence of anxiety and depression, and 2) identify a combination of patient characteristics and symptoms associated with severe anxiety and depression at Guy's and St Thomas' Foundation Trust (GSTT) RDC in Southeast London. Additionally, we compared standard statistical methods with machine learning algorithms for predicting severe anxiety and depression. Methods: Patients seen at GSTT RDC between June 2019 and January 2023 completed the General Anxiety Disorder Questionnaire (GAD-7) and Patient Health Questionnaire (PHQ-8) questionnaires, at baseline. We used logistic regression (LR) and 2 machine learning (ML) algorithms (random forest (RF), support vector machine (SVM)) to predict risk of severe anxiety and severe depression. The models were constructed using a set of sociodemographic and clinical variables. Results: A total of 1734 patients completed GAD-7 and PHQ-8 questionnaires. Of these, the mean age was 59 years (Standard Deviation: 15.5), and 61.5% (n:1067) were female. Prevalence of severe anxiety (GAD-7 score ≥15) was 13.8% and severe depression (PHQ-8 score≥20) was 9.3%. LR showed that a combination of previous mental health condition (PMH, Adjusted Odds Rario (AOR) 3.28; 95% confidence interval (CI) 2.36-4.56), symptom duration >6 months (AOR 2.20; 95%CI 1.28-3.77), weight loss (AOR 1.88; 95% CI 1.36-2.61), progressive pain (AOR 1.71; 95%CI 1.26-2.32), and fatigue (AOR 1.36; 95%CI 1.01-1.84), was positively associated with severe anxiety. Likewise, a combination PMH condition (AOR 3.95; 95%CI 2.17-5.75), fatigue (AOR 2.11; 95%CI 1.47-3.01), symptom duration >6 months (AOR 1.98; 95%CI 1.06-3.68), weight loss (AOR 1.66; 95%CI 1.13-2.44), and progressive pain (AOR 1.50; 95%CI 1.04-2.16), was positively associated with severe depression. LR and SVM had highest accuracy levels for severe anxiety (LR: 86%, SVM: 85%) and severe depression (SVM: 89%, LR: 86%). Conclusion: High prevalence of severe anxiety and severe depression was found. PMH, fatigue, weight loss, progressive pain, and symptoms >6 months emerged as combined risk factors for both these psychological comorbidities. RDCs offer an opportunity to alleviate distress in patients with concerning symptoms by expediting diagnostic evaluations.

Real-world data evaluating Guy's rapid diagnostic clinic as an alternate pathway for patients with FIT levels below 10.

OBJECTIVE: To analyse the effectiveness of rapid diagnostic clinics (RDCs) as an alternative pathway for patients with concerning symptoms and a faecal immunochemical test (FIT) result <10. Our primary endpoint was rate of colorectal cancer (CRC) detection. Second endpoints were rates of other cancers and gastrointestinal (GI) serious benign conditions. Finally, we analysed the specific pathway followed by FIT <10 patients with cancer at Guy's and St Thomas NHS Foundation Trust (GSTT) RDC. DESIGN: A retrospective and prospective cohort study. SETTING: GSTT RDC, one of England's largest single-centre RDCs. Sociodemographic and clinical characteristics of FIT <10 patients were analysed descriptively. PARTICIPANTS: Patients with an FIT result <10, seen at GSTT RDC between 1 January 2020 and 5 May 2023. RESULTS: A total of 1299 patients with an FIT<10 were seen at GSTT RDC between January 2020 and May 2023. Of these, 66% (n=861) reported weight loss, 62% (n=805) pain, 37% (n=481) fatigue, 34% (n=444) were anaemic and 23% (n=301) had nausea and vomiting. Among these patients, 7% (n=88) received a cancer diagnosis, 36% (n=462) were identified as having a serious benign condition. Within the patients with cancer, 9% (n=8) were diagnosed with CRC. Among patients with serious benign conditions, 7% (n=31) were referred to colorectal, hepatopancreatobiliary, or upper GI specialists. CONCLUSION: This study demonstrates the effectiveness of RDCs as an alternate pathway for FIT <10 patients with ongoing clinical concerns. These results contribute to enhancing patient care and optimising resource allocation within the healthcare system.

CTP Synthase 1 Is a Novel Therapeutic Target in Lymphoma.

Lymphoma is the most common hematological malignancy and is among the 10 most prevalent cancers worldwide. Although survival has been improved by modern immunochemotherapeutic regimens, there remains a significant need for novel targeted agents to treat both B-cell and T-cell malignancies. Cytidine triphosphate synthase 1 (CTPS1), which catalyzes the rate-limiting step in pyrimidine synthesis, plays an essential and nonredundant role in B-cell and T-cell proliferation but is complemented by the homologous CTPS2 isoform outside the hemopoietic system. This report describes the identification and characterization of CTPS1 as a novel target in B- and T-cell cancers. A series of small molecules have been developed which show potent and highly selective inhibition of CTPS1. Site-directed mutagenesis studies identified the adenosine triphosphate pocket of CTPS1 as the binding site for this small molecule series. In preclinical studies, a potent and highly selective small molecule inhibitor of CTPS1 blocked the in vitro proliferation of human neoplastic cells, showing the highest potency against lymphoid neoplasms. Importantly, pharmacological CTPS1 inhibition induced cell death by apoptosis in the majority of lymphoid cell lines tested, thus demonstrating a cytotoxic mechanism of action. Selective CTPS1 inhibition also inhibited the growth of neoplastic human B- and T- cells in vivo. These findings identify CTPS1 as a novel therapeutic target in lymphoid malignancy. A compound from this series is in phase 1/2 clinical studies for the treatment of relapsed/refractory B- and T-cell lymphoma (NCT05463263).

The effectiveness of the Guy's Rapid Diagnostic Clinic (RDC) in detecting cancer and serious conditions in vague symptom patients.

BACKGROUND: Rapid Diagnostic Clinics (RDC) are being expanded nationally by NHS England. Guy's RDC established a pathway for GPs and internal referrals for patients with symptoms concerning for malignancy not suitable for a site-specific 2WW referral. However, little data assessing the effectiveness of RDC models are available in an English population. METHODS: We evaluated all patients referred to Guy's RDC between December 2016 and June 2019 (n = 1341) to assess the rate of cancer diagnoses, frequency of benign conditions and effectiveness of the service. RESULTS: There were 96 new cancer diagnoses (7.2%): lung (16%), haematological (13%) and colorectal (12%)-with stage IV being most frequent (40%). Median time to definitive cancer diagnosis was 28 days (IQR 15-47) and treatment 56 days (IQR 32-84). In all, 75% were suitable for treatment: surgery (26%), systemic (24%) and radiotherapy (14%). Over 180 serious non-neoplastic conditions were diagnosed (35.8%) of patients with no significant findings in two-third of patients (57.0%). CONCLUSIONS: RDCs provide GPs with a streamlined pathway for patients with complex non-site-specific symptoms that can be challenging for primary care. The 7% rate of cancer diagnosis exceeds many 2WW pathways and a third of patients presented with significant non-cancer diagnoses, which justifies the need for rapid diagnostics. Rapid Diagnostic Centres (RDCs) are being rolled out nationally by NHS England and NHS Improvement as part of the NHS long-term plan. The aim is for a primary care referral pathway that streamlines diagnostics, patient journey, clinical outcomes and patient experience. This pilot study of 1341 patients provides an in-depth analysis of the largest single RDC in England. Cancer was diagnosed in 7% of patients and serious non-cancer conditions in 36%-justifying the RDC approach in vague symptom patients.

Derivatisation of parthenolide to address chemoresistant chronic lymphocytic leukaemia.

Parthenolide is a natural product that exhibits anti-leukaemic activity, however, its clinical use is limited by its poor bioavailability. It may be extracted from feverfew and protocols for growing, extracting and derivatising it are reported. A novel parthenolide derivative with good bioavailability and pharmacological properties was identified through a screening cascade based on in vitro anti-leukaemic activity and calculated "drug-likeness" properties, in vitro and in vivo pharmacokinetics studies and hERG liability testing. In vitro studies showed the most promising derivative to have comparable anti-leukaemic activity to DMAPT, a previously described parthenolide derivative. The newly identified compound was shown to have pro-oxidant activity and in silico molecular docking studies indicate a prodrug mode of action. A synthesis scheme is presented for the production of amine 7 used in the generation of 5f.

Diabetes mellitus and female lower urinary tract symptoms: a review.

Diabetes mellitus (DM) has reached epidemic proportions world wide. Many chronic complications of DM, including neuropathy, retinopathy and nephropathy, have been well studied and although urologic complications have been recognized since 1935, little is known about DM as a pathophysiological risk factor for development of lower urinary tract symptoms (LUTS) in women. Diabetic nephropathy, a life-threatening condition, has received considerable attention in the last few years. Diabetic cystopathy, on the other hand, has received far less attention despite having a significant impact on quality of life, and with significant individual health risks. Initial studies suggested that long standing DM causes paralysis of the detrusor muscle leading to voiding difficulties and this has been the received wisdom regarding diabetic cystopathy for many years. In this review, we discuss what is currently known about lower urinary tract function and urinary incontinence in diabetic females, with a critical analysis of the available evidence and suggest areas for future research.