Risk of cancer and serious disease in Danish patients with urgent referral for serious non-specific symptoms and signs of cancer in Funen 2014-2021.

BACKGROUND: In 2011, as the first European country, Denmark introduced the non-organ-specific cancer patient pathway (CPP) for patients presenting with non-specific symptoms and signs of cancer (NSSC). The proportion of patients with cancer over time is unknown. METHODS: A retrospective cohort study of all patients with a NSSC-CPP investigational course in the province of Funen to the Diagnostic Centre in Svendborg from 2014 to 2021 was performed to evaluate the proportion of patients with cancer and serious disease over time. RESULTS: A total of 6698 patients were referred to the NSSC-CPP of which 20.2% had cancer. While the crude referral rate increased from 114 per 100,000 people in 2014 and stabilised to around 214 in 2017-2021, the cancer detection rate of the total yearly new cancers in Funen diagnosed through the NSSC-CPP in DC Svendborg increased from 3 to 6%. CONCLUSIONS: With now high and stable conversion and crude referral rates, the NSSC-CPP is one of the largest CPPs in Denmark as measured by the number of new cancer cases found. Similar urgent referral programmes in other countries might fill an unmet medical need for patients presenting with serious non-specific symptoms and signs of cancer in general practice.

Exploring diagnostic events and first referrals in cancer patient pathways in primary care. A questionnaire survey.

BACKGROUND: Cancer diagnostic pathways in general practice are often nonlinear, and several events can delay timely diagnosis. OBJECTIVES: To explore cancer diagnostic processes in general practice, examining how patients' symptom presentations, sex, and age are associated with the occurrence of predefined potentially delaying events and the first referrals. METHOD: General practices in 3 Danish Regions were invited to participate in a questionnaire survey, addressing patient's symptom presentation, diagnostic process events, and first referral. The general practitioners (GPs) received a list of their incident cancer patients from the preceding 2 years. RESULTS: In total 187 general practices participated, including 5,908 patients with the cancer diagnostic pathways initiated in general practice. Presenting with nonspecific symptoms was associated with potentially delaying events, even when the patient also had specific symptoms. Almost half of the patients were referred to a cancer patient pathway (CPP) first, men more often than women, and 10% were referred for acute hospitalization. In 23% of the diagnostic processes, GPs initially treated or referred patients on suspicion of another disease rather than cancer and waited due to normal examinations in 1 out of 20 patients. Excluding sex-specific cancers, these 2 events were more prevalent in women. Men less often complied to the follow-up agreement. Younger patients were less often first referred to a CPP and together with older patients more often first acutely hospitalized. CONCLUSION: In cancer diagnostic processes in general practice, first referrals and the occurrence of potentially delaying events are associated with the patient's age, sex, and specificity of symptoms.

Exploring GPs' assessments of their patients' cancer diagnostic processes: a questionnaire study.

BACKGROUND: Most cancer diagnostic pathways start from primary care and several factors affect the diagnostic processes. AIM: To analyse the associations between patient characteristics, symptom presentation, and cancer type and the GP's assessment of the diagnostic processes. DESIGN AND SETTING: General practices in the North, Central, and Southern regions of Denmark were invited to participate in a questionnaire survey. METHOD: Participating GPs received a list of patients with incident cases of cancer in the period between 1 March 2019 and 28 February 2021 based on administrative hospital data. A questionnaire was completed for each patient, addressing symptom presentation and the GP's assessment of the diagnostic process both overall and in four subcategories (the patient's role, the GP's role, the transition between primary and secondary care, and the secondary sector's role). RESULTS: A total of 187 general practices informed on 8240 patients. For 5868 patients, diagnostic pathways started in general practice. Almost half (48.3%, 2837/5868) presented with specific cancer symptoms. GPs assessed 55.6% (3263) and 32.3% (1897) of the diagnostic processes as 'very good' and 'predominantly good', respectively; 11.9% (700) were 'predominantly poor' or 'very poor' for these 5868 patients. Long symptom duration of ≥2 months prior to GP contact and presenting with non-specific or a combination of non-specific and specific symptoms were associated with a poor overall assessment of the diagnostic process. Assessment in the four subcategories showed that the patient's role was assessed less positively than the other three categories. CONCLUSION: A longer symptom duration and presenting without cancer-specific symptoms were associated with GPs assessing the diagnostic process as poor.

2-[18F]FDG-PET/CT in Cancer of Unknown Primary Tumor-A Retrospective Register-Based Cohort Study.

We investigated the impact of 2-[18F]FDG-PET/CT on detection rate (DR) of the primary tumor and survival in patients with suspected cancer of unknown primary tumor (CUP), comparing it to the conventional diagnostic imaging method, CT. Patients who received a tentative CUP diagnosis at Odense University Hospital from 2014-2017 were included. Patients receiving a 2-[18F]FDG-PET/CT were assigned to the 2-[18F]FDG-PET/CT group and patients receiving a CT only to the CT group. DR was calculated as the proportion of true positive findings of 2-[18F]FDG-PET/CT and CT scans, separately, using biopsy of the primary tumor, autopsy, or clinical decision as reference standard. Survival analyses included Kaplan-Meier estimates and Cox proportional hazards regression adjusted for age, sex, treatment, and propensity score. We included 193 patients. Of these, 159 were in the 2-[18F]FDG-PET/CT group and 34 were in the CT group. DR was 36.5% in the 2-[18F]FDG-PET/CT group and 17.6% in the CT group, respectively (p = 0.012). Median survival was 7.4 (95% CI 0.4-98.7) months in the 2-[18F]FDG-PET/CT group and 3.8 (95% CI 0.2-98.1) in the CT group. Survival analysis showed a crude hazard ratio of 0.63 (p = 0.024) and an adjusted hazard ratio of 0.68 (p = 0.087) for the 2-[18F]FDG-PET/CT group compared with CT. This study found a significantly higher DR of the primary tumor in suspected CUP patients using 2-[18F]FDG-PET/CT compared with patients receiving only CT, with possible immense clinical importance. No significant difference in survival was found, although a possible tendency towards longer survival in the 2-[18F]FDG-PET/CT group was observed.

Clinical presentation and treatment response in patients with polymyalgia rheumatica and giant cell arteritis during a 40-week follow-up.

OBJECTIVES: The aim was to study the clinical features of PMR/GCA and clinical predictors of treatment response during a 40-week follow-up period. METHODS: Clinical data on 77 patients with newly diagnosed PMR/GCA who were treated with oral glucocorticoids were gathered at baseline and during a 40-week follow-up period. A unilateral temporal artery biopsy (TAB) and 18F-fluorodeoxyglucose (18F-FDG) PET/CT were undertaken at diagnosis. In total, each patient was seen on five occasions (i.e. baseline and weeks 4, 16, 28 and 40). Treatment response was assessed by considering clinical evaluations and results of inflammatory markers. RESULTS: Of 77 patients [49 (63.6%) female; mean age 71.8 (8.0) years], 64 (83.1%) patients had pure PMR, 10 (13.0%) concomitant PMR and GCA, and 3 (3.9%) pure GCA. The patients reported that clinical symptoms, apart from scalp pain and duration of morning stiffness, improved significantly at week 4 and remained lower at week 40 compared with the relative frequencies at baseline. Besides, all components of physical examination showed significant improvement and remained lower at week 40 compared with the baseline. A complete response was seen in 68.7, 62.9, 44.1 and 33.3% of patients at weeks 4, 16, 28 and 40, respectively. Several clinical features, including female biological sex, younger age, fewer relapses and a lower level of baseline ESR, were significantly associated with a better treatment response. Treatment response during the follow-up period was independent of TAB results and fluorodeoxyglucose uptakes on 18F-FDG PET/CT at diagnosis. CONCLUSION: Obtaining valid disease-specific outcome measures for evaluating treatment efficacy in PMR and GCA that can be applied universally is clearly an unmet clinical need. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02985424.

Benefits and harms of implementing [18F]FDG-PET/CT for diagnosing recurrent breast cancer: a prospective clinical study.

BACKGROUND: [18F]-fluorodeoxyglucose-positron emission tomography/computed tomography ([18F]FDG-PET/CT) has been implemented sporadically in hospital settings as the standard of care examination for recurrent breast cancer. We aimed to explore the clinical impact of implementing [18F]FDG-PET/CT for patients with clinically suspected recurrent breast cancer and validate the diagnostic accuracy. METHODS: Women with suspected distant recurrent breast cancer were prospectively enrolled in the study between September 2017 and August 2019. [18F]FDG-PET/CT was performed, and the appearance of incidental benign and malignant findings was registered. Additional examinations, complications, and the final diagnosis were registered to reflect the clinical consequence of such findings. The diagnostic accuracy of [18F]FDG-PET/CT as a stand-alone examination was analyzed. Biopsy and follow-up were used as a reference standard. RESULTS: [18F]FDG-PET/CT reported breast cancer metastases in 72 of 225 women (32.0%), and metastases were verified by biopsy in 52 (52/225, 23.1%). Prior probability and posterior probability of a positive test for suspected metastatic cancer and incidental malignancies were 27%/85% and 4%/20%, respectively. Suspected malignant incidental findings were reported in 46 patients (46/225, 20.4%), leading to further examinations and final detection of nine synchronous cancers (9/225, 4.0%). These cancers originated from the lung, thyroid, skin, pancreas, peritoneum, breast, kidney, one was malignant melanoma, and one was hematological cancer. False-positive incidental malignant findings were examined in 37/225 patients (16.4%), mainly in the colon (n = 12) and thyroid gland (n = 12). Ten incidental findings suspicious for benign disease were suggested by [18F]FDG-PET/CT, and further examinations resulted in the detection of three benign conditions requiring treatment. Sensitivity, specificity, and AUC-ROC for diagnosing distant metastases were 1.00 (0.93-1.0), 0.88 (0.82-0.92), and 0.98 (95% CI 0.97-0.99), respectively. CONCLUSION: [18F]FDG-PET/CT provided a high posterior probability of positive test, and a negative test was able to rule out distant metastases in women with clinically suspected recurrent breast cancer. One-fifth of patients examined for incidental findings detected on [18F]FDG-PET/CT were diagnosed with clinically relevant conditions. Further examinations of false-positive incidental findings in one of six women should be weighed against the high accuracy for diagnosing metastatic breast cancer. Trial registration Clinical.Trials.gov. NCT03358589. Registered 30 November 2017-Retrospectively registered, http://www.ClinicalTrials.gov.

Prognostic impacts of glucocorticoid treatment in patients with polymyalgia rheumatica and giant cell arteritis.

Identifying comorbidities in polymyalgia rheumatica/giant cell arteritis (PMR/GCA) is crucial for patients' outcomes. The present study aimed to evaluate the impact of the inflammatory process and glucocorticoid treatment on aortic arterial stiffness and body composition in PMR/GCA. 77 patients with newly diagnosed PMR/GCA were treated with oral glucocorticoids and followed for 40 weeks. Aortic pulse wave velocity (PWV) was measured at baseline and during the follow-up period and compared to the results of temporal artery biopsy (TAB) and 18F-FDG PET/CT. Body composition was assessed by total body DXA at baseline and the end of the study. Of 77 patients (49 (63.6%) female, mean of age: (71.8 ± 8.0)), 64 (83.1%) had pure PMR, 10 (13.0%) concomitant PMR and GCA, and 3 (3.9%) pure GCA. Compared to baseline values, aortic PWV was initially decreased at week 16 (p = 0.010) and remained lower than baseline at week 28 (p = 0.002) and week 40 (p < 0.001), with no association with results of TAB and 18F-FDG PET/CT. Aortic PWV was significantly associated with age, male gender, left systolic and diastolic blood pressure, right diastolic blood pressure, and CRP. Total bone mineral content (BMC) was decreased in both genders (p < 0.001), while fat mass (FM) was significantly increased (p < 0.001). However, lean body mass did not significantly change during the study. Changes in FM were correlated with cumulative prednisolone dose (rho: 0.26, p = 0.031). Glucocorticoid treatment of patients with PMR/GCA had several prognostic impacts. Arterial stiffness was decreased due either to the treatment or a reduction in the inflammatory load. Additionally, treatment led to changes in body composition, including a decrease in BMC and FM excess.

Prevalence of Newly Diagnosed Malignancies in Patients with Polymyalgia Rheumatica and Giant Cell Arteritis, Comparison of 18F-FDG PET/CT Scan with Chest X-ray and Abdominal Ultrasound: Data from a 40 Week Prospective, Exploratory, Single Centre Study.

The aim of the study was to identify the prevalence of newly diagnosed malignancies in patients with polymyalgia rheumatica (PMR) and giant cell arteritis (GCA), with the aid of 18F-FDG PET/CT scan compared to conventional imaging techniques: Chest X-ray (CXR) and abdominal ultrasound (US). Secondarily, to examine the relative diagnostic accuracy of these two imaging modalities for the detection of cancer. Eighty consecutive patients with newly diagnosed PMR, GCA, or concomitant PMR and GCA, were included and followed up for 40 weeks. All patients underwent an 18F-FDG PET/CT scan, CXR, and abdominal US at diagnosis. Imaging findings were dichotomously categorized into malignant or benign. Among 80 patients, three patients were diagnosed with seronegative rheumatoid arthritis and were excluded from the analysis. Of the remaining 77, 64 (83.1%) patients were diagnosed with pure PMR, 3 (3.9%) with pure GCA, and 10 (13.0%) with concomitant PMR and GCA. Five types of cancer that were more prevalent than the one-year prevalence of 1.2% among the background population were found in four (5.2%; 95%CI: 1.4-12.8%) patients. CXR/abdominal US could detect the solid cancer in one patient, whereas 18F-FDG PET/CT could identify all four solid cancers. Furthermore, four (5.2%; 95%CI: 1.4-12.8%) cases of monoclonal gammopathy of undetermined significance (MGUS) were found. An increase in C reactive protein (CRP) implicated an increased risk for cancer of 2.4% (OR: 1.024, 95%CI: 1.001-1.047; p = 0.041). 18F-FDG PET/CT can reveal occult cancers at an early stage with a high negative predictive value, and it is specifically beneficial in PMR/GCA patients with nonspecific symptoms.

The Utility of 18F-FDG PET/CT in Patients With Clinical Suspicion of Polymyalgia Rheumatica and Giant Cell Arteritis: A Prospective, Observational, and Cross-sectional Study.

OBJECTIVE: To define the proportions of agreement between fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT), clinical diagnosis, and temporal artery biopsy (TAB) in patients with polymyalgia rheumatica (PMR) and giant cell arteritis (GCA). Furthermore, the association of 18F-FDG PET/CT uptake patterns and clinical presentation of newly diagnosed PMR and GCA was investigated. METHODS: Eighty patients newly suspected of having PMR, GCA, or concomitant PMR and GCA were included and followed for 40 weeks. Every patient underwent an 18F-FDG PET/CT scan before or within 3 days of initiation of steroids in case of GCA. FDG uptakes in 8 paired articular/periarticular sites and 14 arterial segments were evaluated based on a 4-point visual grading scale. RESULTS: Of the 80 patients (female: 50 [62.5%]; mean age ± SD: 72.0 ± 7.9), 64 (80.0%) patients were diagnosed with pure PMR, 3 (3.7%) with pure GCA, and 10 (12.5%) with concomitant PMR and GCA. Additionally, three (3.7%) patients were diagnosed with seronegative rheumatoid arthritis during the follow-up period. For the diagnosis of PMR, 18F-FDG PET/CT had a proportion of agreement of 75.3 (64.2-84.4), compared with clinical diagnosis. When comparing findings of 18F-FDG PET/CT with TAB, 18F-FDG PET/CT had a proportion of agreement of 93.0 (84.3-97.7) in all included patients and 69.2 (38.6-90.9) in the subgroup of patients with vasculitis. C-reactive protein was significantly higher in patients with PMR activity on 18F-FDG PET/CT compared with those without 18F-FDG PET/CT activity (P value = 0.006). CONCLUSIONS: 18F-FDG PET/CT is a powerful imaging technique in PMR and GCA that was in good agreement with clinical diagnosis and TAB.

Polymyalgia rheumatica and giant cell arteritis-three challenges-consequences of the vasculitis process, osteoporosis, and malignancy: A prospective cohort study protocol.

INTRODUCTION: Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are common inflammatory conditions. The diagnosis of PMR/GCA poses many challenges since there are no specific diagnostic tests. Recent literature emphasizes the ability of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) to assess global disease activity in inflammatory diseases. 18F-FDG PET/CT may lead to the diagnosis at an earlier stage than conventional imaging and may also assess response to therapy. With respect to the management of PMR/GCA, there are 3 significant areas of concern as follows: vasculitis process/vascular stiffness, malignancy, and osteoporosis. METHODS AND ANALYSIS: All patients with suspected PMR/GCR referred to the Rheumatology section of Medicine Department at Svendborg Hospital, Denmark. The 4 separate studies in the current protocol focus on: the association of clinical picture of PMR/GCA with PET findings; the validity of 18F-FDG PET/CT scan for diagnosis of PMR/GCA compared with temporal artery biopsy; the prevalence of newly diagnosed malignancies in patients with PMR/GCA, or PMR-like syndrome, with the focus on diagnostic accuracy of 18F-FDG PET/CT scan compared with conventional workup (ie, chest X-ray/abdominal ultrasound); and the impact of disease process, and also steroid treatment on bone mineral density, body composition, and vasculitis/vascular stiffness in PMR/GCA patients. ETHICS AND DISSEMINATION: The study has been approved by the Regional Ethics Committee of the Region of Southern Denmark (identification number: S-20160098) and Danish Data Protection Agency (J.nr 16/40522). Results of the study will be disseminated via publications in peer-reviewed journals, and presentation at national and international conferences.

Leptospirosis-Associated Severe Pulmonary Hemorrhagic Syndrome with Lower Back Pain as an Initial Symptom.

BACKGROUND Leptospirosis is a zoonosis transmitted through urine of infected animals. Symptoms range from mild influenza-like symptoms to severe pulmonary hemorrhagic syndrome (SPHS); the latter are often fatal. The serogroup distribution in Denmark has changed from 1988 to 2012, with Icterohaemorrhagiae and Sejroe now being predominant. CASE REPORT A 45-year-old Danish woman living in an area endemic for Hanta virus, without prior medical history, was admitted because of lower back pain radiating to the left hip, fever, headache, nausea, and malaise. Two weeks before admission she had been bitten by a mouse or a rat. Blood tests revealed raised white cells and CRP, electrolyte imbalances, raised creatinine, low thrombocytes, and a slightly decreased clotting factor (II, VII, and X). Treatment with broad-spectrum intravenous antibiotics and supporting therapy was initiated very quickly. Eight hours after admission she died from respiratory failure where severe hemoptysis was observed. Leptospiral DNA was later detected in a urine sample. CONCLUSIONS This case represents leptospirosis with severe pulmonary hemorrhagic syndrome. In spite of immediate treatment with broad-spectrum antibiotics, the patient died a few hours after hospital admission.

Glucose effectiveness and insulin sensitivity measurements derived from the non-insulin-assisted minimal model and the clamp techniques are concordant.

BACKGROUND: We investigated the concordance between glucose effectiveness (SG) and insulin sensitivity (SI), derived from the unmodified dynamic non-insulin-assisted intravenous glucose tolerance test (IVGTT) implemented by SG(MM) and SI(MM); simulation analysis and modelling/conversational interaction (SAAM/CONSAM) versus the eu/hyperglycaemic basal insulinaemic and the euglycaemic hyperinsulinaemic clamp (SG(CLAMP) and SI(CLAMP)). METHODS: Twenty-seven of 30 normoglycaemic subjects completed a (1) euglycaemic hyperinsulinaemic clamp, (2) 6-h eu/hyperglycaemic near-normoinsulinaemic pancreatic clamp with hyperglycaemia present over the final 2 h of the clamp (Day 2 study), (3) identical clamp to (2) but with euglycaemia maintained over the entire 6 h (Day 3 study) and (4) IVGTT. SG(CLAMP) was calculated in two ways based on data from study (2) alone (Day 2 SG(CLAMP210-240')) or from data from study day (2) and (3) (Day 2-3 SG(CLAMP330-360')). RESULTS: SG(MM) was unrelated to the magnitude of endogenous insulin release (AIR). The single-day (Day 2) and two-day (Day 2 and 3) SG(CLAMP) protocols correlated (r = 0.72, p = 0.003), but SG(CLAMP210-240') was significantly (p = 0.001) higher than SG(CLAMP330-360'). Employing the Day 2 and 3 SG(CLAMP) protocol, the whole body SG(CLAMP330-360') was similar to SG(MM) (1.80 ± 0.82 versus 1.73 ± 0.58 dL/min) and correlated (r = 0.45, p < 0.02). SG(CLAMP210-240') did not correlate with SG(MM) (r = 0.24). SI(MM) and SI(CLAMP) were similar (0.093 ± 0.060 versus 0.087 ± 0.029 dL/min per mU/L) and correlated (r = 0.76, p < 0.001). CONCLUSIONS: The time-dependent increase in glucose disposal observed during a prolonged 6-h clamp significantly influences the estimation of SG(CLAMP), and significant concordance coefficients are observed between SG(MM), and SG(CLAMP330-360'), and SI(MM) and SI(CLAMP).

Effect of short-term hyperglycemia per se on nociceptive and non-nociceptive thresholds.

Previous animal and human studies have indicated that nociceptive thresholds are decreased by acute hyperglycemia. The results of these studies may be challenged due to methodological problems. We therefore conducted a double-blind, controlled, cross-over study on the effect of acute hyperglycemia on nociceptive and non-nociceptive thresholds in 10 type 1 (insulin-dependent) diabetic patients (diabetes < 5 years) without symptoms or clinical signs of peripheral neuropathy. During an overnight fast, blood glucose concentration was normalized by refract insulin injections. Then, blood glucose was kept at 6 mmol/l for 3 h by an intravenous infusion of glucose and insulin. On one study day, blood glucose was kept at 6 mmol/l for a further 3 h and on another day, blood glucose was elevated to 12 mmol/l during 0.5 h by additional glucose infusion and kept at that level for 2.5 h. Sensory testing was carried out twice during the initial 3 h with euglycemia and 3 times during the following period with either hyper- or euglycemia. The test procedure included determination of pain detection and pain tolerance thresholds to heat (wrists) and pressure (fingers) as well as detection thresholds to warmth/cooling (wrist), vibration (finger), and mechanical (wrist) stimulation. The changes in neither nociceptive nor non-nociceptive thresholds showed any statistically significant differences between the 2 study days. The pressure pain detection and tolerance thresholds showed, however, minor decreases at each of the test days, probably due to cutaneous sensitization caused by the repeated measurements. Compared to baseline, the pressure pain thresholds decreased significantly on the day with hyperglycemia. None of the other thresholds showed such changes.(ABSTRACT TRUNCATED AT 250 WORDS)