A pictorial view on false positive findings of 68Ga-PSMA-11 PET/CT and their prognostic value in patients with prostate carcinoma after radical prostatectomy and undetectable PSA values.

OBJECTIVE: Recently, gallium-68-prostate-specific membrane antigen-11 (68Ga-PSMA-11) positron emission tomography/computed tomography (PET/CT) has become a key imaging method in prostate carcinoma staging and biochemical progression, with varying sensitivities in different studies (from 40% to 80%). After four years of experience with 68Ga-PSMA-11 PET/CT, we found that it is possible to detect lesions with increased PSMA expression in patients with undetectable prostate specific antigen (PSA) levels after radical prostatectomy. The key questions we wanted to answer were as follows: if those lesions were malignant and could the early detection of those malignant lesions have a role in patient management? We aimed to identify and follow up PSMA-positive findings for a period of 4 years in patients with prostate cancer after radical prostatectomy and undetectable PSA values at the time of the examination. We also explored false-positive lesions in detail. SUBJECTS AND METHODS: The study included all patients who underwent radical prostatectomy and had undetectable PSA values <0.05ng/mL and who underwent 68Ga-PSMA-11 PET/CT between July 2019 and December 2019. We performed 220 studies and found 40 patients with these characteristics; these patients were included in this study. All of them were followed up until July 2023. Any finding with increased radiopharmaceutical accumulation above the background activity in the respective area was considered a false positive. Prostate-specific membrane antigen accumulation in established lesions was assessed semi-quantitatively by the maximum standardized uptake value (SUVmax) and qualitatively by the four-point visual scale proposed in the E-PSMA recommendations. RESULTS: We found 15/40 (37.5%) patients with PSMA-positive findings. These were predominantly bone changes without a corresponding CT abnormality or discrete cystic or osteoblastic lesions with above-background increased PSMA expression. The mean SUVmax of these non-specific lesions was 3.02 (SD 2.86). After 3.5-4 years of follow-up, biochemical progression was found in only two of the patients.The great sensitivity of the method nowadays is a powerful engine for the development of new therapeutic options. On the other side, the lower specificity due to false positive findings, if misinterpreted, might lead to switching to a higher stage, with the planned radical treatment replaced by palliative treatment. CONCLUSION: The presence of 68Ga-PSMA-11 PET/CT-positive findings in patients after radical prostatectomy and an undetectable PSA had a low predictive value for future progression. The interpretation of 68Ga-PSMA-11 PET/CT should always include a complex assessment of the clinical setting-the risk group, PSA value and degree of PSMA accumulation in the lesions. In these situations, further clarification of PSMA-positive findings is appropriate before deciding to change treatment.

A 14-year-old girl with premature ovarian insufficiency but with a positive pregnancy test.

OBJECTIVES: Childhood cancer survivors are at risk for premature ovarian insufficiency, especially after treatment with alkylating agents. The objective of this report is to highlight a case in which this phenomenon caused a false-positive pregnancy test. CASE PRESENTATION: A workup was performed in a 14-year-old girl with a positive pregnancy test. She was diagnosed with stage IV neuroblastoma of the left adrenal gland at the age of 4 years. She received extensive treatment, including alkylating agents, and had been diagnosed with premature ovarian insufficiency. An LH/hCG suppression test was performed using high dose 17 bèta-estradiol: hCG levels normalized. CONCLUSIONS: The pregnancy test was false-positive due to production of low amounts of hCG by the pituitary gland as a result of high LH concentrations following premature ovarian insufficiency. It may be helpful to perform the LH/hCG suppression test to prove pituitary origin of the hCG overproduction.

False positive findings associated with adenoviral vector-based vaccine underscore the regulatory necessity to eliminate abnormal toxicity test.

Accumulating evidence has shown that the abnormal toxicity test (ATT) is not suitable as a quality control batch release test for biologics and vaccines. The purpose of the current study was to explore the optimal ATT experimental design for an adenoviral vector-based vaccine product to avoid false positive results following the standard test conditions stipulated in the Pharmacopoeias. ATT were conducted in both mice and guinea pigs based on methods in Pharmacopeias, with modifications to assess effects of dose volume and amount of virus particles (VPs). The results showed intraperitoneal (IP) dosing at human relevant dose and volume (i.e., VPs), as required by pharmacopeia study design, resulted in false positive findings not associated with extraneous contaminants of a product. Considering many gene therapy products use adeno associated virus as the platform for transgene delivery, data from this study are highly relevant in providing convincing evidence to show the ATT is inappropriate as batch release test for biologics, vaccine and gene therapy products. In conclusion, ATT, which requires unnecessary animal usage and competes for resources which otherwise can be spent on innovative medicine research, should be deleted permanently as batch release test by regulatory authorities around the world.

False-positive HIV screening test in a healthcare student.

This case report describes a 22-year-old female Ambulance Technician student who displayed human immunodeficiency virus (HIV) false positivity following a recent hepatitis B vaccination. Occupational health clinicians who work in a healthcare setting (with healthcare staff and/or students) should be aware of the possibility of false-positive HIV screening test results, and where a false positive is suspected, they should consider what the underlying cause could be and should consider whether further medical investigation is required.

Predictors of re-attendance at biennial screening mammography following a false positive referral: A study among women in the south of the Netherlands.

AIM: A false positive (FP) referral after screening mammography may influence a woman's likelihood to re-attend the screening program. The impact of having a FP result in the first or subsequent screening round on re-attendance after a FP result was investigated. In addition, we aimed to study differences in re-attendance rates between women who underwent non-invasive and invasive additional examinations as part of the diagnostic work-up following a FP referral. METHODS: A consecutive series of 13,597 women with a FP referral following biennial screening mammography in the south of the Netherlands between 2009 and 2019 was included. RESULTS: The screening re-attendance rate was 81.2% after a FP referral, and 91.3% when also including women who had clinical mammographic follow-up. Women who received a FP referral in the first screening round were less likely to re-attend the screening programme in the following three years, compared to those with a FP test in any subsequent round (odds ratio (OR): 0.59, 95%-confidence interval (CI): 0.51-0.69). Women with a FP referral who underwent invasive examinations after referral were less likely to re-attend the screening programme than those who only received additional imaging (OR, 0.48; 95% CI 0.36-0.64). CONCLUSION: Women with a FP referral are less likely to re-attend the screening programme if this referral occurs at their first screening round or when they undergo invasive diagnostic workup. Hospitals and screening organizations should prioritize informing women about the importance of re-attending the programme following a FP referral.

Sensitivity and specificity of SS-OCT for detecting macular pathologies vs SD-OCT.

PURPOSE: To evaluate the sensitivity and specificity of swept-source optical coherence tomography (SS-OCT) biometer compared with the gold standard spectral-domain optical coherence tomography (SD-OCT) for detecting macular pathology in patients with cataract. SETTING: Eye Centers of Tennessee, Crossville, TN. DESIGN: Prospective, cross-sectional, observational, examiner-masked. METHODS: The study included 132 participants aged 50 years and older, who underwent precataract surgery work-up. All participants underwent fixation check retinal scans using SS-OCT biometer (IOLMaster 700) as well as full macular scans using Cirrus SD-OCT. 3 independent masked examiners evaluated the scans if they were normal or had a suspected pathology. Different measures of diagnostic accuracy were calculated for 3 examiners. RESULTS: True positive rate (sensitivity) ranged from 71.1% (32/45) to 79.2% (42/53), and false negative rate was between 20.8% (11/53) and 28.9% (13/45) for the 3 examiners. True negative rate (specificity) ranged from 86.8% (59/68) to 94.1% (64/68), and false positive rate was between 5.9 (4/68) and 13.2% (9/68). The fitted receiver operating characteristic area ranged from 0.83 to 0.95. CONCLUSIONS: Using retinal SS-OCT biometer scans as a replacement of the dedicated macular SD-OCT for screening or diagnosing macular health would not be appropriate because of its low sensitivity. SS-OCT biometer may potentially fail to identify approximately one-fourth of patients who actually have the disease. Therefore, the final decision on macular health should be based on the gold standard SD-OCT scans. When full macular SD-OCT scans are not accessible, the limited retinal scan information from SS-OCT biometer may still provide useful insights into the macular health.

Evaluating false-positive detection in a computer-aided detection system for colonoscopy.

BACKGROUND AND AIM: Computer-aided detection (CADe) systems can efficiently detect polyps during colonoscopy. However, false-positive (FP) activation is a major limitation of CADe. We aimed to compare the rate and causes of FP using CADe before and after an update designed to reduce FP. METHODS: We analyzed CADe-assisted colonoscopy videos recorded between July 2022 and October 2022. The number and causes of FPs and excessive time spent by the endoscopist on FP (ET) were compared pre- and post-update using 1:1 propensity score matching. RESULTS: During the study period, 191 colonoscopy videos (94 and 97 in the pre- and post-update groups, respectively) were recorded. Propensity score matching resulted in 146 videos (73 in each group). The mean number of FPs and median ET per colonoscopy were significantly lower in the post-update group than those in the pre-update group (4.2 ± 3.7 vs 18.1 ± 11.1; P < 0.001 and 0 vs 16 s; P < 0.001, respectively). Mucosal tags, bubbles, and folds had the strongest association with decreased FP post-update (pre-update vs post-update: 4.3 ± 3.6 vs 0.4 ± 0.8, 0.32 ± 0.70 vs 0.04 ± 0.20, and 8.6 ± 6.7 vs 1.6 ± 1.7, respectively). There was no significant decrease in the true positive rate (post-update vs pre-update: 95.0% vs 99.2%; P = 0.09) or the adenoma detection rate (post-update vs pre-update: 52.1% vs 49.3%; P = 0.87). CONCLUSIONS: The updated CADe can reduce FP without impairing polyp detection. A reduction in FP may help relieve the burden on endoscopists.

Breast Cancer Incidence After a False-Positive Mammography Result.

Importance: False-positive mammography results are common. However, long-term outcomes after a false-positive result remain unclear. Objectives: To examine long-term outcomes after a false-positive mammography result and to investigate whether the association of a false-positive mammography result with cancer differs by baseline characteristics, tumor characteristics, and time since the false-positive result. Design, Setting, and Participants: This population-based, matched cohort study was conducted in Sweden from January 1, 1991, to March 31, 2020. It included 45 213 women who received a first false-positive mammography result between 1991 and 2017 and 452 130 controls matched on age, calendar year of mammography, and screening history (no previous false-positive result). The study also included 1113 women with a false-positive result and 11 130 matched controls with information on mammographic breast density from the Karolinska Mammography Project for Risk Prediction of Breast Cancer study. Statistical analysis was performed from April 2022 to February 2023. Exposure: A false-positive mammography result. Main Outcomes and Measures: Breast cancer incidence and mortality. Results: The study cohort included 497 343 women (median age, 52 years [IQR, 42-59 years]). The 20-year cumulative incidence of breast cancer was 11.3% (95% CI, 10.7%-11.9%) among women with a false-positive result vs 7.3% (95% CI, 7.2%-7.5%) among those without, with an adjusted hazard ratio (HR) of 1.61 (95% CI, 1.54-1.68). The corresponding HRs were higher among women aged 60 to 75 years at the examination (HR, 2.02; 95% CI, 1.80-2.26) and those with lower mammographic breast density (HR, 4.65; 95% CI, 2.61-8.29). In addition, breast cancer risk was higher for women who underwent a biopsy at the recall (HR, 1.77; 95% CI, 1.63-1.92) than for those without a biopsy (HR, 1.51; 95% CI, 1.43-1.60). Cancers after a false-positive result were more likely to be detected on the ipsilateral side of the false-positive result (HR, 1.92; 95% CI, 1.81-2.04) and were more common during the first 4 years of follow-up (HR, 2.57; 95% CI, 2.33-2.85 during the first 2 years; HR, 1.93; 95% CI, 1.76-2.12 at >2 to 4 years). No statistical difference was found for different tumor characteristics (except for larger tumor size). Furthermore, associated with the increased risk of breast cancer, women with a false-positive result had an 84% higher rate of breast cancer death than those without (HR, 1.84; 95% CI, 1.57-2.15). Conclusions and Relevance: This study suggests that the risk of developing breast cancer after a false-positive mammography result differs by individual characteristics and follow-up. These findings can be used to develop individualized risk-based breast cancer screening after a false-positive result.

Long-term psychosocial consequences of false-positive screening mammography: a cohort study with follow-up of 12-14 years in Denmark.

OBJECTIVE: To compare the long-term psychosocial consequences of mammography screening among women with breast cancer, normal results and false-positive results. DESIGN: A matched cohort study with follow-up of 12-14 years. SETTING: Denmark from 2004 to 2019. PARTICIPANTS: 1170 women who participated in the Danish mammography screening programme in 2004-2005. INTERVENTION: Mammography screening for women aged 50-69 years. OUTCOME MEASURES: We assessed the psychosocial consequences with the Consequences Of Screening-Breast Cancer, a condition-specific questionnaire that is psychometrically validated and encompasses 14 psychosocial dimensions. RESULTS: Across all 14 psychosocial outcomes, women with false-positive results averagely reported higher psychosocial consequences compared with women with normal findings. Mean differences were statistically insignificant except for the existential values scale: 0.61 (95% CI (0.15 to 1.06), p=0.009). Additionally, women with false-positive results and women diagnosed with breast cancer were affected in a dose-response manner, where women diagnosed with breast cancer were more affected than women with false-positive results. CONCLUSION: Our study suggests that a false-positive mammogram is associated with increased psychosocial consequences 12-14 years after the screening. This study adds to the harms of mammography screening. The findings should be used to inform decision-making among the invited women and political and governmental decisions about mammography screening programmes.

Cumulative risks of false positive recall and screen-detected breast cancer after multiple screening examinations.

Women tend to make a decision about participation in breast cancer screening and adhere to this for future invitations. Therefore, our study aimed to provide high-quality information on cumulative risks of false-positive (FP) recall and screen-detected breast cancer over multiple screening examinations. Individual Dutch screening registry data (2005-2018) were gathered on subsequent screening examinations of 92 902 women age 49 to 51 years in 2005. Survival analyses were used to calculate cumulative risks of a FP and a true-positive (TP) result after seven examinations. Data from 66 472 women age 58 to 59 years were used to extrapolate to 11 examinations. Participation, detection and additional FP rates were calculated for women who previously received FP results compared to women with true negative (TN) results. After 7 examinations, the cumulative risk of a TP result was 3.7% and the cumulative risk of a FP result was 9.1%. After 11 examinations, this increased to 7.1% and 13.5%, respectively. Following a FP result, participation was lower (71%-81%) than following a TN result (>90%). In women with a FP result, more TP results (factor 1.59 [95% CI: 1.44-1.72]), more interval cancers (factor 1.66 [95% CI: 1.41-1.91]) and more FP results (factor 1.96 [95% CI: 1.87-2.05]) were found than in women with TN results. In conclusion, due to a low recall rate in the Netherlands, the cumulative risk of a FP recall is relatively low, while the cumulative risk of a TP result is comparable. Breast cancer diagnoses and FP results were more common in women with FP results than in women with TN results, while participation was lower.

Low-Value Prostate-Specific Antigen Screening in Older Males.

Importance: The US Preventive Services Task Force guidelines advise against prostate-specific antigen (PSA) screening for prostate cancer in males older than 69 years due to the risk of false-positive results and overdiagnosis of indolent disease. However, this low-value PSA screening in males aged 70 years or older remains common. Objective: To characterize the factors associated with low-value PSA screening in males 70 years or older. Design, Setting, and Participants: This survey study used data from the 2020 Behavioral Risk Factor Surveillance System (BRFSS), a nationwide annual survey conducted by the Centers for Disease Control and Prevention that collects information via telephone from more than 400 000 US adults on behavioral risk factors, chronic illnesses, and use of preventive services. The final cohort comprised male respondents to the 2020 BRFSS survey who were categorized into the following age groups: 70 to 74 years, 75 to 79 years, or 80 years or older. Males with a former or current prostate cancer diagnosis were excluded. Main Outcomes and Measures: The outcomes were recent PSA screening rates and factors associated with low-value PSA screening. Recent screening was defined as PSA testing within the past 2 years. Weighted multivariable logistic regressions and 2-sided significance tests were used to characterize factors associated with recent screening. Results: The cohort included 32 306 males. Most of these males (87.6%) were White individuals, whereas 1.1% were American Indian, 1.2% were Asian, 4.3% were Black, and 3.4% were Hispanic individuals. Within this cohort, 42.8% of respondents were aged 70 to 74 years, 28.4% were aged 75 to 79 years, and 28.9% were 80 years or older. The recent PSA screening rates were 55.3% for males in the 70-to-74-year age group, 52.1% in the 75-to-79-year age group, and 39.4% in the 80-year-or-older group. Among all racial groups, non-Hispanic White males had the highest screening rate (50.7%), and non-Hispanic American Indian males had the lowest screening rate (32.0%). Screening increased with higher educational level and annual income. Married respondents were screened more than unmarried males. In a multivariable regression model, discussing PSA testing advantages with a clinician (odds ratio [OR], 9.09; 95% CI, 7.60-11.40; P < .001) was associated with increased recent screening, whereas discussing PSA testing disadvantages had no association with screening (OR, 0.95; 95% CI, 0.77-1.17; P = .60). Other factors associated with a higher screening rate included having a primary care physician, a post-high school educational level, and income of more than $25 000 per year. Conclusions and Relevance: Results of this survey study suggest that older male respondents to the 2020 BRFSS survey were overscreened for prostate cancer despite the age cutoff for PSA screening recommended in national guidelines. Discussing the benefits of PSA testing with a clinician was associated with increased screening, underscoring the potential of clinician-level interventions to reduce overscreening in older males.

Machine learning to improve false-positive results in the Dutch newborn screening for congenital hypothyroidism.

OBJECTIVE: The Dutch Congenital hypothyroidism (CH) Newborn Screening (NBS) algorithm for thyroidal and central congenital hypothyroidism (CH-T and CH-C, respectively) is primarily based on determination of thyroxine (T4) concentrations in dried blood spots, followed by thyroid-stimulating hormone (TSH) and thyroxine-binding globulin (TBG) measurements enabling detection of both CH-T and CH-C, with a positive predictive value (PPV) of 21%. A calculated T4/TBG ratio serves as an indirect measure for free T4. The aim of this study is to investigate whether machine learning techniques can help to improve the PPV of the algorithm without missing the positive cases that should have been detected with the current algorithm. DESIGN & METHODS: NBS data and parameters of CH patients and false-positive referrals in the period 2007-2017 and of a healthy reference population were included in the study. A random forest model was trained and tested using a stratified split and improved using synthetic minority oversampling technique (SMOTE). NBS data of 4668 newborns were included, containing 458 CH-T and 82 CH-C patients, 2332 false-positive referrals and 1670 healthy newborns. RESULTS: Variables determining identification of CH were (in order of importance) TSH, T4/TBG ratio, gestational age, TBG, T4 and age at NBS sampling. In a Receiver-Operating Characteristic (ROC) analysis on the test set, current sensitivity could be maintained, while increasing the PPV to 26%. CONCLUSIONS: Machine learning techniques have the potential to improve the PPV of the Dutch CH NBS. However, improved detection of currently missed cases is only possible with new, better predictors of especially CH-C and a better registration and inclusion of these cases in future models.

Estimating the lifetime risk of a false positive screening test result.

False positive results in screening tests have potentially severe psychological, medical, and financial consequences for the recipient. However, there have been few efforts to quantify how the risk of a false positive accumulates over time. We seek to fill this gap by estimating the probability that an individual who adheres to the U.S. Preventive Services Task Force (USPSTF) screening guidelines will receive at least one false positive in a lifetime. To do so, we assembled a data set of 116 studies cited by the USPSTF that report the number of true positives, false negatives, true negatives, and false positives for the primary screening procedure for one of five cancers or six sexually transmitted diseases. We use these data to estimate the probability that an individual in one of 14 demographic subpopulations will receive at least one false positive for one of these eleven diseases in a lifetime. We specify a suitable statistical model to account for the hierarchical structure of the data, and we use the parametric bootstrap to quantify the uncertainty surrounding our estimates. The estimated probability of receiving at least one false positive in a lifetime is 85.5% (±0.9%) and 38.9% (±3.6%) for baseline groups of women and men, respectively. It is higher for subpopulations recommended to screen more frequently than the baseline, including more vulnerable groups such as pregnant women and men who have sex with men. Since screening technology is imperfect, false positives remain inevitable. The high lifetime risk of a false positive reveals the importance of educating patients about this phenomenon.

Factors Associated With False-Positive Recalls in Mammography Screening.

BACKGROUND: We aimed to identify factors associated with false-positive recalls in mammography screening compared with women who were not recalled and those who received true-positive recalls. METHODS: We included 29,129 women, aged 40 to 74 years, who participated in the Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) between 2011 and 2013 with follow-up until the end of 2017. Nonmammographic factors were collected from questionnaires, mammographic factors were generated from mammograms, and genotypes were determined using the OncoArray or an Illumina custom array. By the use of conditional and regular logistic regression models, we investigated the association between breast cancer risk factors and risk models and false-positive recalls. RESULTS: Women with a history of benign breast disease, high breast density, masses, microcalcifications, high Tyrer-Cuzick 10-year risk scores, KARMA 2-year risk scores, and polygenic risk scores were more likely to have mammography recalls, including both false-positive and true-positive recalls. Further analyses restricted to women who were recalled found that women with a history of benign breast disease and dense breasts had a similar risk of having false-positive and true-positive recalls, whereas women with masses, microcalcifications, high Tyrer-Cuzick 10-year risk scores, KARMA 2-year risk scores, and polygenic risk scores were more likely to have true-positive recalls than false-positive recalls. CONCLUSIONS: We found that risk factors associated with false-positive recalls were also likely, or even more likely, to be associated with true-positive recalls in mammography screening.

Radioactive Iodine Uptake in Postoperative Seroma: A Cause for False Positivity.

Besides the known physiologic uptake of 131I, the literature describes various false-positive findings on 131I scans in benign lesions, inflammation, traumatic sites, and postsurgical sites, to name a few. However, to the best of our knowledge, no study has shown false-positive uptake of 131I in a postoperative seroma at the postsurgical site. We describe such a case here.

The financial implications of investigating false-positive and true-positive mammograms in a national breast cancer screening program.

Objectives To determine the total annual screening and further-investigation costs of investigating false-positive and true-positive mammograms in the Australian population breast-screening program. Methods This economic analysis used aggregate-level retrospective cohort data of women screened at a breast-screening clinic. Counts and frequencies of each diagnostic workup-sequence recorded were scaled up to national figures and costed by estimating per-patient costs of procedures using screening clinic cost data. Main outcomes and measures estimated were percentage share of total annual screening and further-investigation costs for the Australian population breast-screening program of investigating false-positive and true-positive mammograms. Secondary outcomes determined were average costs of investigating each false-positive and true-positive mammogram. Sensitivity analyses involved recalculating results excluding subgroups of patients below and above the screening age range of 50-74 years. Results Of 8235 patients, the median age was 60.35 years with interquartile range of 54.17-67.17 years. A total of 15.4% (ranging from 13.4 to 15.4% under different scenarios) of total annual screening and further-investigation costs were from investigating false-positive mammograms. This exceeded the share of costs from investigating true-positives (13%). Conclusions We have developed a transparent and non-onerous approach for estimating the costs of false-positive and true-positive mammograms associated with the national breast-screening program. While determining an optimal balance between false-positives and true-positive rates must rely primarily on health outcomes, costs are an important consideration. We recommend that future research adopts and refines similar approaches to facilitate better monitoring of these costs, benchmark against estimates from other screening programs, and support optimal policy development.