Screening for Occult Cancer in Unprovoked Venous Thromboembolism.

BACKGROUND: Venous thromboembolism may be the earliest sign of cancer. Currently, there is a great diversity in practices regarding screening for occult cancer in a person who has an unprovoked venous thromboembolism. We sought to assess the efficacy of a screening strategy for occult cancer that included comprehensive computed tomography (CT) of the abdomen and pelvis in patients who had a first unprovoked venous thromboembolism. METHODS: We conducted a multicenter, open-label, randomized, controlled trial in Canada. Patients were randomly assigned to undergo limited occult-cancer screening (basic blood testing, chest radiography, and screening for breast, cervical, and prostate cancer) or limited occult-cancer screening in combination with CT. The primary outcome measure was confirmed cancer that was missed by the screening strategy and detected by the end of the 1-year follow-up period. RESULTS: Of the 854 patients who underwent randomization, 33 (3.9%) had a new diagnosis of occult cancer between randomization and the 1-year follow-up: 14 of the 431 patients (3.2%) in the limited-screening group and 19 of the 423 patients (4.5%) in the limited-screening-plus-CT group (P=0.28). In the primary outcome analysis, 4 occult cancers (29%) were missed by the limited screening strategy, whereas 5 (26%) were missed by the strategy of limited screening plus CT (P=1.0). There was no significant difference between the two study groups in the mean time to a cancer diagnosis (4.2 months in the limited-screening group and 4.0 months in the limited-screening-plus-CT group, P=0.88) or in cancer-related mortality (1.4% and 0.9%, P=0.75). CONCLUSIONS: The prevalence of occult cancer was low among patients with a first unprovoked venous thromboembolism. Routine screening with CT of the abdomen and pelvis did not provide a clinically significant benefit. (Funded by the Heart and Stroke Foundation of Canada; SOME ClinicalTrials.gov number, NCT00773448.).

Risk factors predictive of occult cancer detection in patients with unprovoked venous thromboembolism.

Risk factors predictive of occult cancer detection in patients with a first unprovoked symptomatic venous thromboembolism (VTE) are unknown. Cox proportional hazard models and multivariate analyses were performed to assess the effect of specific risk factors on occult cancer detection within 1 year of a diagnosis of unprovoked VTE in patients randomized in the Screening for Occult Malignancy in Patients with Idiopathic Venous Thromboembolism (SOME) trial. A total of 33 (3.9%; 95% CI, 2.8%-5.4%) out of the 854 included patients received a new diagnosis of cancer at 1-year follow-up. Age ≥ 60 years (hazard ratio [HR], 3.11; 95% CI, 1.41-6.89; ITALIC! P= .005), previous provoked VTE (HR, 3.20; 95% CI, 1.19-8.62; ITALIC! P= .022), and current smoker status (HR, 2.80; 95% CI, 1.24-6.33; ITALIC! P= .014) were associated with occult cancer detection. Age, prior provoked VTE, and smoking status may be important predictors of occult cancer detection in patients with first unprovoked VTE. This trial was registered atwww.clinicaltrials.govas #NCT00773448.

Myositis with prominent B cell aggregates may meet classification criteria for sporadic inclusion body myositis.

The objective of this study was to report the clinical, serological and pathological features of patients with autoimmune myositis other than dermatomyositis, who displayed both muscle weakness on physical examination and prominent B cell aggregates on muscle pathology, defined as ≥ 30 CD20+ cells/aggregate. Specifically, the presence of a brachio-cervical inflammatory myopathies or a sporadic inclusion body myositis (sIBM) phenotype was recorded. Over a three-year period, eight patients were identified from two university neuropathology referral centers. Seven of 8 (88%) patients had an associated connective tissue disease (CTD): rheumatoid arthritis (n=3), systemic sclerosis (n=2), Sjögren's syndrome (n=1) and systemic lupus erythematosus (n=1), while one patient died on initial presentation without a complete serological and cancer investigation. A brachio-cervical phenotype, i.e. neck weakness, proximal weakness more than distal and shoulder abduction weakness greater than hip flexors, was seen in two patients (25%), while one patient had both proximal and diaphragmatic weakness. In contrast, an IBM-like clinical phenotype was seen in the last five patients (63%), who either had finger flexor weakness and/or quadriceps weakness ≤ 4 on the manual muscle testing MRC-5 scale. Although these 5 patients met at least one set of classification criteria for sIBM, an integrated clinico-sero-pathological approach argued against a diagnosis of sIBM. In summary, in a weak patient with myositis plus an associated CTD and lymphoid aggregates at muscle pathology, B cell predominant aggregates may represent a morphological biomarker against a diagnosis of sIBM.

Step down to 6 months of prophylactic-dose low molecular weight heparin after initial full-dose anticoagulation for the treatment of cancer-associated thrombosis (STEP-CAT): A pilot study.

BACKGROUND: Patients with cancer-associated thrombosis (CAT) are treated with full-dose anticoagulation for at least 3 months, but optimal dosing thereafter is unknown. AIM: We explored the feasibility of extended prophylactic-dose low molecular weight heparin (LMWH) treatment following a minimum of 3 months of full-dose LMWH. METHODS: We conducted a multicenter prospective pilot study of patients with CAT who completed at least 3 months of therapeutic-dose LMWH. Patients received 6 months of prophylactic-dose subcutaneous enoxaparin (40 mg once daily). The primary outcome was recurrence of deep vein thrombosis (DVT) or pulmonary embolism (PE), and secondary outcomes included major, clinically relevant non-major (CRNM), and minor bleeding. RESULTS: From August 2016 to May 2019, 52 patients with a mean age of 64.1 years were included. The study was stopped early because of poor recruitment. Breast (23.1%) and colorectal (19.2%) were the most common cancers, and 61.0% had stage IV malignancy. Index CAT consisted of DVT alone in 57.7% of patients and pulmonary embolism (PE) with or without DVT in 42.3%. Patients received a mean of 7.6 months of weight-adjusted LMWH before enrollment. During a mean follow-up of 5.6 months, one patient was diagnosed with recurrent incidental PE (0.0035 events/subject-month). There were no major bleeding events, one CRNM, and one minor bleeding event. Eight (15.4%) patients died; six from cancer and two from respiratory disease unrelated to PE. CONCLUSIONS: These results, in part, provide support for trials of extended reduced-dose anticoagulation for the secondary prevention of CAT. (ClinicalTrials.gov: NCT02752607).

Myositis with prominent B-cell aggregates causing shrinking lung syndrome in systemic lupus erythematosus: a case report.

BACKGROUND: Shrinking lung syndrome (SLS) is a rare manifestation of systemic lupus erythematosus (SLE) characterized by decreased lung volumes and diaphragmatic weakness in a dyspneic patient. Chest wall dysfunction secondary to pleuritis is the most commonly proposed cause. In this case report, we highlight a new potential mechanism of SLS in SLE, namely diaphragmatic weakness associated with myositis with CD20 positive B-cell aggregates. CASE PRESENTATION: A 51-year-old Caucasian woman was diagnosed with SLE and secondary Sjögren's syndrome based on a history of pleuritis, constrictive pericarditis, polyarthritis, photosensitivity, alopecia, oral ulcers, xerophthalmia and xerostomia. Serologies were significant for positive antinuclear antibodies, anti-SSA, lupus anticoagulant and anti-cardiolopin. Blood work revealed a low C3 and C4, lymphopenia and thrombocytopenia. She was treated with with low-dose prednisone and remained in remission with oral hydroxychloroquine. Seven years later, she developed mild proximal muscle weakness and exertional dyspnea. Pulmonary function testing revealed a restrictive pattern with small lung volumes. Pulmonary imaging showed elevation of the right hemidiaphragm without evidence of interstitial lung disease. Diaphragmatic ultrasound was suggestive of profound diaphragmatic weakness and dysfunction. Based on these findings, a diagnosis of SLS was made. Her proximal muscle weakness was investigated, and creatine kinase (CK) levels were normal. Electromyography revealed fibrillation potentials in the biceps, iliopsoas, cervical and thoracic paraspinal muscles, and complex repetitive discharges in cervical paraspinal muscles. Biceps muscle biopsy revealed dense endomysial lymphocytic aggregates rich in CD20 positive B cells, perimysial fragmentation with plasma cell-rich perivascular infiltrates, diffuse sarcolemmal upregulation of class I MHC, perifascicular upregulation of class II MHC, and focal sarcolemmal deposition of C5b-9. Treatment with prednisone 15 mg/day and oral mycophenolate mofetil 2 g/day was initiated. Shortness of breath and proximal muscle weakness improved significantly. CONCLUSION: Diaphragmatic weakness was the inaugural manifestation of myositis in this patient with SLE. The spectrum of myologic manifestations of myositis with prominent CD20 positive B-cell aggregates in SLE now includes normal CK levels and diaphragmatic involvement, in association with SLS.

Colour Doppler ultrasound and the giant cell arteritis probability score for the diagnosis of giant cell arteritis: a Canadian single-centre experience.

OBJECTIVES: The aim was to compare the accuracy of colour Doppler ultrasonography (CDUS) and temporal artery biopsy (TAB) to establish the final diagnosis of GCA and to determine how the GCA probability score (GCAPS) performs as a risk stratification tool. METHODS: Descriptive statistics were performed on a retrospective cohort of patients referred to our vasculitis referral centre between 1 July 2017 and 1 October 2020 for suspected GCA. CDUS, TAB, centre-specific TAB (vasculitis centre vs referring hospitals) and GCAPS were compared against the final diagnosis of GCA as determined by a GCA expert; CDUS was also compared with TAB results. RESULTS: Data from 198 patients were included: 60 patients with GCA and 138 patients without GCA. Sixty-two patients had a TAB. Using the final diagnosis by a GCA expert as a reference, the sensitivity, specificity, positive predictive value and negative predictive value were 93.3%, 98.5%, 96.6% and 97.1% for CDUS and 69.2%, 100%, 100% and 81.8% for TAB, respectively. The false-negative rate was 6.7% for CDUS and 30.8% for TAB. False-negative TAB mostly occurred when performed in referring hospitals (57.1%) as opposed to our vasculitis centre (21.1%). With a cut-off at 9.5 points, sensitivity for GCAPS was 98.3% and specificity 74.3%. CONCLUSION: CDUS of the temporal and axillary arteries showed a high sensitivity and specificity and helped to diagnose GCA in patients with negative TAB. We validated that GCAPS is a useful clinical tool, with a score of <9.5 making the diagnosis of GCA improbable.

Cost effectiveness of the addition of a comprehensive CT scan to the abdomen and pelvis for the detection of cancer after unprovoked venous thromboembolism.

IMPORTANCE: Unprovoked venous thromboembolism (VTE) can be the first manifestation of cancer. It is unclear if extensive screening for occult cancer including a comprehensive computed tomography (CT) scan of the abdomen/pelvis is cost-effective in this patient population. OBJECTIVE: To assess the health care related costs, number of missed cancer cases and health related utility values of a limited screening strategy with and without the addition of a comprehensive CT scan of the abdomen/pelvis and to identify to what extent testing should be done in these circumstances to allow early detection of occult cancers. PARTICIPANTS AND SETTING: Cost effectiveness analysis using data that was collected alongside the SOME randomized controlled trial which compared an extensive occult cancer screening including a CT of the abdomen/pelvis to a more limited screening strategy in patients with a first unprovoked VTE, was used for the current analyses. MAIN OUTCOMES AND MEASURES: Analyses were conducted with a one-year time horizon from a Canadian health care perspective. Primary analysis was based on complete cases, with sensitivity analysis using appropriate multiple imputation methods to account for missing data. RESULTS: Data from a total of 854 patients with a first unprovoked VTE were included in these analyses. The addition of a comprehensive CT scan was associated with higher costs ($551 CDN) with no improvement in utility values or number of missed cancers. Results were consistent when adopting multiple imputation methods. CONCLUSIONS AND RELEVANCE: The addition of a comprehensive CT scan of the abdomen/pelvis for the screening of occult cancer in patients with unprovoked VTE is not cost effective, as it is both more costly and not more effective in detecting occult cancer.

Interrater agreement for two systems used to determine the probability of heparin-induced thrombocytopenia.

PURPOSE: The interrater reliability of the 4T's method and the HIT expert probability (HEP) score for clinical evaluation of suspected heparin-induced thrombocytopenia (HIT) was investigated. METHODS: Patients hospitalized over a three-year period who were tested for HIT via anti-platelet factor 4 (anti-PF4) antigen assay were identified using laboratory data; 127 patient cases met the study inclusion criteria. Nine clinical pharmacists with expertise in HIT management evaluated the 127 cases using two pretest scoring systems: the 4T's score and the HEP score. Each case was independently evaluated using both 4T's and HEP scores. The primary endpoint was interrater agreement of overall 4T's and HEP scores and individual item scores. RESULTS: Raw agreement of values assigned by the two raters for each of the four items comprising the 4T's score ranged from 0.54 to 0.86, with agreement of 0.63 for final patient categorizations. Raw agreement of rater weightings of the eight HEP scoring items ranged from 0.34 to 1.0; for dichotomization of patients at the suggested screening cutoff value (>2.0), agreement was 0.65. Kappa coefficients were 0.15-0.45 for 4T's item scores and 0.17-0.70 for HEP score item scores. With both scoring systems, low rater agreement mainly related to determination of the timing of thrombocytopenia and possible other causes of the disorder. CONCLUSION: In a retrospective study, inter-rater agreement in scoring of HIT probability via the 4T's and HEP scoring systems was relatively low. The HEP score did not increase interrater reliability or correlation with anti-PF4 antibodies compared with the 4T's score.