Equivocal Diagnosis Research Articles

Diffusion weighted imaging as adjunct modality to distinguish benign and malignant breast lesions in resource constrained settings: A single institute experience

Objectives To establish the accuracy of the “targeted DWI/ADC sequence” as an adjunct to mammography and sonography for differentiating malignant and benign breast masses in an underdeveloped population, in correlation with histopathology. Materials and Methods The study population was predominantly rural and from underdeveloped regions. It included 108 female patients of various ages who presented with breast masses with equivocal diagnoses on mammography and sonography. These patients were unwilling to return for additional investigations. The targeted lesions were then further evaluated using diffusion weighted imaging (DWI)/apparent diffusion coefficient (ADC) maps and ADC values. The final diagnosis was later confirmed by histopathology examination. Results A total of 108 patients having 115 lesions were targeted based on mammography and sonography findings and subjected to DWI. The cut-off ADC value was established for these lesions to be 1.2 × 10–3 mm2/s through receiver operating characteristic curve analysis. This value exhibited a sensitivity of 98.7% and specificity of 91.9% in the present study. DWI overdiagnosed malignancy by 2.6%. Conclusion In the present study, the “targeted DWI/ADC sequence” has proven useful with a sensitivity of 98.7% and specificity of 91.9% using a cut-off value of 1.2 × 10–3 mm2/s. Targeted DWI/ADC in combination with mammography and sonography accurately identified all malignant lesions with overdiagnosis of malignancy in 2.6% of cases. In India, where the demographic is largely rural and underdeveloped, social and economic limitations, along with a lack of awareness, make adherence to ideal diagnostic protocols challenging. This ultimately results in losing the patient to follow-up and missing the cancer. This novel approach of targeted DWI/ADC sequence in combination with mammography and sonography is highly effective in such scenarios, enabling the identification of the likely nature of the disease during the same visit. This empowered healthcare professionals to counsel patients confidently and initiate early management.

Evidence-Based Approaches to Food Allergy Diagnosis

The prevalence of food allergy has increased in the past decades. However, most studies are based on self-reported clinical history of food allergy rather than food challenge-confirmed ones; these may overestimate the prevalence of food allergy. Food allergy has been identified as one of the most common causes of anaphylaxis, especially among children. Like other studies, the study by Rosero et al., published in this issue, identified that food is the most common trigger for anaphylaxis among pediatric patients admitted to a tertiary hospital.1 The incidence of food-induced anaphylaxis in children worldwide is varied, with a range of 1 to 77 per 100,000 person‐years.2 Moreover, almost half of all patients with food allergies experienced anaphylaxis in any previous reaction (46%, 2556/5587), based on the Food Allergy Research & Education (FARE) Patient Registry.3 The most common food triggers causing anaphylaxis in adults are crustaceans and eggs, cow’s milk, nuts, wheat, and shellfish among children.4,5 A detailed allergy-focused clinical history is the first step in the diagnostic work-up among patients suspected to have food allergies. The allergy-focused history will serve as a guide to the allergy tests that will be done. Skin prick tests (SPT) to allergen extracts and fresh food, serum-specific IgE (sIgE) to allergen extracts and individual allergen components, and basophil activation test (BAT) are recommended tests to support the diagnosis of IgE-mediated allergy.6 These tests have high to moderate sensitivity (negative result rules out FA) and specificity (positive result rules in FA) to a variety of food.7 BAT is suggested to support the diagnosis of food allergy among those with an equivocal diagnosis of IgE-mediated allergy to peanut and sesame. The gold standard for diagnosing food allergy is the oral food challenge (OFC). However, the OFC is resource-intensive and may pose severe allergic reactions. In the EAACI guidelines on diagnosing IgE-mediated FA, OFC is the recommended reference diagnostic procedure to confirm or exclude FA.6 Based on the same guidelines, the double-blind placebo-controlled food challenge is suggested if an open OFC outcome is indeterminate and in research studies. There are tests available in laboratories that lack evidence of diagnostic validity and do not show a correlation with food allergy. Patients will seek physicians' opinions regarding these tests or will come to the clinic with the results of these tests marketed as food allergy or food intolerance tests. Society guidelines and practice parameters do not recommend unvalidated tests to diagnose food allergy.6,8-10 These tests, such as IgG or IgG4 antibody level, hair analysis, electrodermal testing, antigen leukocyte antibody test, mediator release test, and kinesiology.11 The Philippine Society of Allergy, Asthma, and Immunology does not recommend food-specific IgG testing to identify or predict adverse reactions to food.9 The production of food-specific IgG or IgG4 is a normal immunologic response linked to the development of tolerance, not food allergy or intolerance. Identifying the food trigger through an allergy-focused clinical history and validated diagnostic tests is essential to prevent future adverse reactions, eliminate unnecessary food elimination, prevent nutritional deficiencies, and improve quality of life.

Endoscopic ultrasound-guided needle-based confocal laser endomicroscopy for pancreatic cystic lesions: current status and future prospects.

Pancreatic cystic lesions (PCLs) have increased in prevalence due to the increased usage and advancements in cross-sectional abdominal imaging. Current diagnostic techniques cannot distinguish between PCLs requiring surgery, close surveillance, or expectant management. This has increased the morbidity and healthcare costs from inappropriately aggressive and conservative management strategies. Endoscopic ultrasound (EUS) needle-based confocal laser endomicroscopy (nCLE) allows for microscopic examination and delineation of the surface epithelium of PCLs. Landmark studies have identified characteristics distinguishing various types of PCLs, confirmed the high diagnostic yield of EUS-nCLE (especially for PCLs with an equivocal diagnosis), and shown that EUS-nCLE helps to change management and reduce healthcare costs. Refining procedure technique and reducing procedure length have improved the safety of EUS-nCLE. The utilization of artificial intelligence and its combination with other EUS-based advanced diagnostic techniques would further improve the results of EUS-based PCL diagnosis. A structured training program and device improvements to allow more complete mapping of the pancreas cyst epithelium will be crucial for the widespread adoption of this promising technology.

Diagnostic discordance among histopathological reviewers of melanocytic lesions.

Histopathological examination is adequate for the diagnosis of most cutaneous melanocytic neoplasms. However, there is a subset that is either difficult to definitively diagnose or would have diagnostic disagreement upon review by multiple dermatopathologists if a more exhaustive review was performed. Melanocytic lesions underwent an independent, blinded diagnostic histopathological review of hematoxylin and eosin-stained sections. Each lesion was reviewed by three to six dermatopathologists and categorized as benign, malignant, or unknown malignant potential (UMP). Diagnoses were grouped as concordant (all the same designation); opposing (received benign and malignant designations); majority (single designation with the highest number of diagnoses, no benign/malignant opposing designations); and non-definitive (equal number of non-opposing designations [i.e., benign/UMP or malignant/UMP]). Lesions with equivocal designations (concordant or majority UMP, opposing, majority, and non-definitive) were utilized in a patient treatment model of projected surgical treatment discrepancies. In total, 3317 cases were reviewed, and 23.8% of lesions received equivocal diagnoses. Of these, 7.3% were majority benign, 4.8% were majority malignant, 2.7% were majority UMP, 0.5% were concordant UMP, 6.9% were opposing, and 1.6% were non-definitive. Patient treatment models of those with equivocal lesions (n = 788) revealed a potential of overall surgical treatment variations ranging from 18% to 72%, with the highest variation amongst lesions with opposing, non-definitive, or majority UMP (40%-72%) diagnoses. Histopathologic review in this large cohort demonstrated substantial diagnostic variation, with 23.8% of cases receiving equivocal diagnoses. We identified diagnostic ambiguity even in lesions where a definitive diagnosis was previously rendered by a single real-world dermatopathologist. The combined clinical impact of diagnostic discordance or a final diagnosis of UMP is highlighted by high diagnosis-dependent treatment variation in the patient treatment model, which could be underreported in a real-world setting, where review by more than one to two dermatopathologists is relatively rare.

Enhancing upper tract urothelial carcinoma diagnosis: Utility of cytokeratin 17 and CK20/CD44/p53 immunohistochemical panel

Upper tract urothelial carcinoma (UTUC) presents diagnostic challenges due to small biopsy specimen size, poor orientation, and technical obstacles that can yield equivocal diagnoses. This uncertainty often mandates repeated biopsies to evaluate the necessity of nephroureterectomy. Prior studies have suggested cytokeratin 17 (CK17) immunostain as an adjunctive tool for diagnosing bladder urothelial neoplasia in both urine cytology and tissue biopsy specimens. We evaluated the utility of CK17 in differentiating UTUC from benign urothelium and its ability to stratify low-grade from high-grade neoplasia. Our study involved a cohort of previously diagnosed cytology (n = 29) and tissue specimens from biopsies and resections (n = 85). We evaluated CK17 staining percentage in cytology and tissue samples and localization patterns in biopsy/resection samples. Our findings showed a statistically significant distinction (p < 0.05) between UTUC and benign tissue specimens based on full thickness localization pattern (odds ratio 8.8 [95% CI 1.53–67.4]). The percentage of CK17 staining failed to significantly differentiate neoplastic from non-neoplastic cases in cytology or tissue samples. Additionally, based on prior research showing the efficacy of CK20/CD44/p53 triple panel in bladder urothelial neoplasia, we utilized tissue microarrays to evaluate if these markers could distinguish UTUC from benign urothelium. We found that CK20/CD44/p53, individually or in combination, could not distinguish urothelial neoplasia from non-neoplasia. Full thickness CK17 urothelial localization by immunohistochemistry was highly reproducible with excellent interobserver agreement and may play a supplementary role in distinguishing upper tract urothelial neoplasia from benign urothelium.

Atypical squamous cells of undetermined significance cervical cytology in Bahrain: Reporting rates, high-risk HPV testing, and cytologic and histopathologic follow-up findings.

Atypical squamous cells of undetermined significance cytology (ASC-US) is a challenging and equivocal diagnosis for pathologists in cervical Pap smears. The data on ASC-US cervical cytology in Bahrain are deficient. This study reviewed and identified the reporting rates, high-risk human papillomavirus (HPV) testing results, histopathologic follow-up findings, and the cytologic progression of patients diagnosed with ASC-US in Bahrain. A retrospective chart review was conducted on the medical records of 23,888 women who had Pap smear test results between January 2019 and March 2022 at the main referral tertiary hospital in Bahrain to identify the ASC-US cases. High-risk HPV (hrHPV) genotype was identified, and the histopathological results of the cervical biopsy was recorded. In addition, cytologic follow-up Pap smear tests conducted within 1 year of ASC-US diagnosis were tracked to monitor the progression or regression of ASC-US. In this study, 259 out of 23,888 women reported to have ASC-UC cytology results with a reporting rate of 1.1%. The mean age of the ASC-US cases was 43 ± 11.6. Thirty percent of the ASC-US cases tested positive for hrHPV, and they were predominantly infected with the other hrHPV genotype (75%). When the histopathological changes of the cervix were analyzed, 82.1% had normal histopathologic findings. However, low-grade cervical intraepithelial neoplasia-1 was reported in 2 cases (7.1%), and high-grade cervical lesions (cervical intraepithelial neoplasia-2 and higher) were reported in 3 cases (10.7%). Regarding the cytologic follow-up, most of the ASC-US cases were negative for intraepithelial lesion or malignancy (NILM) (73.8%) or had persistent ASC-US (17.9%). The remaining minority of cases progressed into either low-grade squamous intraepithelial lesions (6%) or high-grade squamous intraepithelial lesions (2.4%). There was a statistically significant and relatively strong association between the cytology follow-up findings and the hrHPV test results (χ2 [2] = 8.869, P < 0.012, Cramer's V = 0.417). This is the first and largest study to characterize the ASC-US cytology cases in Bahrain. The reporting rates of ASC-US fell within the worldwide reported range. Although most of the ASC-US cases regressed into NILM, ASC-US showed progression into more advanced cervical cytologic diagnoses or contributed to the malignant transformation of cervical tissue, especially in the presence of hrHPV infection which was positive in 30% of the ASC-US cases. This emphasizes the role of cotesting (combination of hrHPV genotyping and Pap smear test) and the importance of colposcopic evaluation of those women with cytologic follow-up tests at 1 year of diagnosis. Implementing these recommendations in the cervical cancer screening practice in Bahrain will help in having a better management plan for women diagnosed with ASC-US cervical cytology.

Comparison of the Diagnostic Yield of Intracoronary Acetylcholine Infusion and Acetylcholine Bolus Injection Protocols During Invasive Coronary Function Testing

Coronary endothelial dysfunction (CED) and coronary artery spasm (CAS) are causes of angina in patients with no obstructive coronary arteries (ANOCA). Both can be diagnosed by invasive coronary function testing (ICFT) using Acetylcholine (ACh). This study aimed to evaluate the diagnostic yield of a 3-minute ACh infusion as compared to a 1-minute ACh bolus injection protocol in testing CED and CAS. In total 220 consecutive ANOCA patients underwent ICFT using continuous Doppler flow measurements. Per protocol, 110 patients were tested using 3-minute infusion and thereafter 110 patients using 1-minute bolus injections, due to a protocol change. CED was defined as a <50% increase in coronary blood flow or any epicardial vasoconstriction in reaction to low dose ACh and CAS according to the COVADIS criteria, both with and without T-wave abnormalities, in reaction to high dose ACh. The prevalence of CED was equal in both protocols (78% vs 79%; p=0.869). Regarding the endotypes of CAS according to COVADIS, the equivocal endotype was diagnosed less often in the 3-minutes vs 1-minute protocol (24% vs 44%; p=0.004). Including T-wave abnormalities to the COVADIS criteria resulted in a similar diagnostic yield of both protocols. Hemodynamic changes from baseline to the low or high ACh doses were comparable between the protocols for each endotype. In conclusion, ICFT using 3-minute infusion or 1-minute bolus injections of ACh showed a similar diagnostic yield of CED. When using the COVADIS criteria, a difference in the equivocal diagnosis was observed. Including T-wave abnormalities as diagnostic criterion reclassified equivocal test results into CAS and decreased this difference. For clinical practice, we recommend the inclusion of T-wave abnormalities as diagnostic criterion for CAS and the 1-minute bolus protocol for practicality.

Ultrasound and magnetic resonance imaging neurography assessment of diagnostic criteria in patients with carpal tunnel syndrome using electrophysiological tests as gold standard: A prospective study.

Evaluating peripheral neuropathy mainly relies on physical examination, patient history, and electrophysiological studies. High-resolution ultrasound is a fast, noninvasive modality for dynamic nerve assessment that enables the length of the nerve to be examined. Magnetic resonance imaging is preferred for examining deeper nerves with a high contrast resolution; its use shows excellent benefit in patients with atypical presentation, equivocal diagnosis, suspected secondary causes, and postsurgical relapse. We aimed to assess the measurements and criteria for both ultrasound and magnetic resonance neurography for the diagnosis of carpal tunnel syndrome, based mainly on the three measurements assessed by Buchberger et al. This prospective study was conducted to test diagnostic accuracy. Thirty-two patients who presented clinically with, and were diagnosed by electrophysiological tests as having, carpal tunnel syndrome participated. Superficial ultrasound of the wrist joint was performed on all participants, followed by magnetic resonance imaging within 1 week of ultrasonography. The three main parameters of cross-sectional area measurement, distal nerve flattening, and flexor retinaculum bowing indices showed positive occurrences of 93.7%, 59.4%, and 59.4%, respectively; 90.6% of patients had decreased nerve echotexture. The diagnostic ability of magnetic resonance imaging was decreased when cross-sectional area measurements were used: positive results were achieved in 81.2% of patients, but the positive results showing the distal tunnel nerve increased flattening and bowed flexor retinaculum slightly decreased to 56.2% for each. A high T2 signal of the median nerve was observed in 90.6% of patients. In an agreement analysis, we found a statistically significant difference that supported the use of ultrasound as a primary diagnostic modality for carpal tunnel syndrome. However, magnetic resonance imaging improved tissue characterization and was a good diagnostic modality, with a statistically significant difference, for cases of secondary carpal tunnel syndrome, detection of the underlying entrapping cause, and early abnormality detection in the innervated muscle. Our results demonstrate that ultrasound examination can be used as the first imaging modality after physician evaluation, with results comparable to those of electrophysiological studies for evaluating carpal tunnel syndrome and determining its cause. Magnetic resonance neurography examination is the second step in detecting secondary causes in cases with suspected early muscle denervation changes that cannot be elicited by ultrasound or in cases with equivocal results.

Individualized tumor-informed circulating tumor DNA analysis for postoperative monitoring of non-small cell lung cancer.

We report a personalized tumor-informed technology, Patient-specific pROgnostic and Potential tHErapeutic marker Tracking (PROPHET) using deep sequencing of 50 patient-specific variants to detect molecular residual disease (MRD) with a limit of detection of 0.004%. PROPHET and state-of-the-art fixed-panel assays were applied to 760 plasma samples from 181 prospectively enrolled early stage non-small cell lung cancer patients. PROPHET shows higher sensitivity of 45% at baseline with circulating tumor DNA (ctDNA). It outperforms fixed-panel assays in prognostic analysis and demonstrates a median lead-time of 299days to radiologically confirmed recurrence. Personalized non-canonical variants account for 98.2% with prognostic effects similar to canonical variants. The proposed tumor-node-metastasis-blood (TNMB) classification surpasses TNM staging for prognostic prediction at the decision point of adjuvant treatment. PROPHET shows potential to evaluate the effect of adjuvant therapy and serve as an arbiter of the equivocal radiological diagnosis. These findings highlight the potential advantages of personalized cancer techniques in MRD detection.

Analysis of Discordant Findings between 3T Magnetic Resonance Imaging and Arthroscopic Evaluation of the Knee Meniscus.

Numerous studies have assessed the performance of magnetic resonance imaging (MRI) in detecting tears of the knee menisci using arthroscopy results as the gold standard, but few have concentrated on the nature of discordant findings. The purpose of this study was to analyze the discordances between 3T MRI and arthroscopic evaluation of the knee meniscus. Medical records of 112 patients who underwent 3T MRI and subsequent arthroscopy of the knee were retrospectively analyzed to determine the accuracy of diagnoses of meniscal tear. Compared with arthroscopy, there were 22 false-negative and 14 false-positive MR interpretations of meniscal tear occurring in 32 patients. Images with errors in diagnosis were retrospectively reviewed by two musculoskeletal radiologists in consensus and all errors were categorized as either unavoidable, equivocal or as interpretation error. Of 36 MR diagnostic errors, there were 16 (44%) unavoidable, 5 (14%) interpretation errors and 15 (42%) equivocal for meniscal tear. The largest categories of errors were unavoidable false-positive MRI diagnoses (71%) and equivocal false-negative MRI diagnoses (50%). All meniscal tears missed by MRI were treated with partial meniscectomy (n = 14) or meniscal repair (n = 8). Discordant findings between 3T MRI and arthroscopic evaluation of the knee meniscus remain a concern and primarily occur due to unavoidable and equivocal errors. Clinicians involved in the diagnosis and treatment of patients with meniscal tears should understand why and how the findings seen on knee MRI and arthroscopy may sometimes differ.

Abstract 1039: Individualized tumor-informed circulating tumor DNA (ctDNA) analysis for postoperative monitoring of non-small cell lung cancer (NSCLC) - the MEDAL study

Abstract Background: Through parallel testing and comparison of personalized and fixed panel minimal residual disease (MRD) assays, to establish the best technique and application strategy of dynamic MRD detection for prognosis prediction and disease assessment among non-small cell lung cancer (NSCLC) patients. Method: We analyzed 760 plasma samples from prospectively enrolled 181 patients with NSCLC recruited to the MEDAL study (NCT03634826), with disease stage I (63%), II (19%) and III (18%). 80% were adenocarcinomas. Plasma samples were collected at baseline (n=157), landmark 3-day and 1-month (n=334), and longitudinal points (n=248) were analyzed. Additional plasma was collected after relapse for 14 patients (n=21). Median follow-up was 1092 days, and 48 patients progressed. We employed a novel personalized tumor-informed technology named PROPHET using deep sequencing of 50 patient-specific variants. The PROPHET was developed to detect MRD with a limit of detection (LoD) of 0.004% and sample-level specificity of greater than 99% in the analytical validation. Detection and quantification of MRD through tumor-informed (TI) and tumor-agnostic (TA) fixed panel assays in the same samples were conducted for a head-to-head comparison. Results: ctDNA was detected by PROPHET prior to treatment in 45% of samples (83%, 75% and 23% for disease stage III, II and I), and showed a higher positive rate than the TI and TA assays (22% and 19%). PROPHET identified 30 more ctDNA positive patients with a median ctDNA fraction of 0.01% at baseline. From the landmark single test, the sensitivity was 45%; integrating longitudinal time points increased the sensitivity to 85%. Landmark PROPHET status was the only risk factor other than clinical features to predict the clinical relapse (p&amp;lt;0.001, multivariate Cox model). MRD positive patients defined by non-canonical variants (n=8) had similar disease-free survival (DFS) as MRD positive patients defined by canonical variants (n=9). Landmark PROPHET-based MRD status combined with clinical TNM stage outperformed TNM stage for prediction of prognosis (p&amp;lt;0.001). Longitudinal MRD achieved negative predictive value (NPV) of 99% with an interval of 150 days, and demonstrated 299 days of longer lead-time than other state-of-the-art fixed-panel assays. Among 16 patients with equivocal radiological diagnosis, all the MRD positive patients relapsed (n=6). Among relapsed patients received next-line treatments, 7 ctDNA negative patients survived or died other disease, 67% (2/3) ctDNA positive patients died from cancer. Sensitivity for bone and brain metastasis was 100% (11/11) and 50% (2/4), respectively. Conclusion: The sensitive tumor-informed personalized MRD approach could provide advantages in prognosis prediction at landmark and disease assessment during surveillance for NSCLC patients. Citation Format: Kezhong Chen, Chenyang Wang, Haifeng Shen, Xi Li, Yichen Jin, Shuailai Wu, Fujun Qiu, Qiang Lu, Di Peng, Shuai Fang, Bing Li, Juan Lv, Jinlei Song, Yang Wang, Shannon Chuai, Zhihong Zhang. Individualized tumor-informed circulating tumor DNA (ctDNA) analysis for postoperative monitoring of non-small cell lung cancer (NSCLC) - the MEDAL study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1039.

Large-scale longitudinal comparison of urine cytological classification systems reveals potential early adoption of The Paris System criteria.

Urine cytology is used to screen for urothelial carcinoma in patients with hematuria or risk factors (eg, smoking, industrial dye exposure) and is an essential clinical triage and longitudinal monitoring tool for patients with known bladder cancer. However, urine cytology is semisubjective and thus susceptible to issues including specimen quality, interobserver variability, and "hedging" towards equivocal ("atypical") diagnoses. These factors limit the predictive value of urine cytology and increase reliance on invasive procedures (cystoscopy). The Paris System for Reporting Urine Cytology (TPS) was formulated to provide more quantitative/reproducible endpoints with well-defined criteria for urothelial atypia. TPS is often compared to other assessment techniques to justify its adoption. TPS results in decreased use of the atypical category and better reproducibility. Previous reports comparing diagnoses pre- and post-TPS have not considered temporal differences between diagnoses made under prior systems and TPS. By aggregating across time, studies may underestimate the magnitude of differences between assessment methods. We conducted a large-scale longitudinal reassessment of urine cytology using TPS criteria from specimens collected from 2008 to 2018, prior to the mid-2018 adoption of TPS at an academic medical center. Findings indicate that differences in atypical assignment were largest at the start of the period and these differences progressively decreased towards insignificance just prior to TPS implementation. This finding suggests that cytopathologists had begun to utilize the quantitative TPS criteria prior to official adoption, which may more broadly inform adoption strategies, communication, and understanding for evolving classification systems in cytology.

The economic burden of malaria inpatients and its determinants during China's elimination stage.

Malaria burden is still worrisome, while empirical evidence from malaria-eliminated countries including China may provide inspiration for the world. This study aimed to investigate China's malaria hospitalization costs and explore its determinants. Stratified multistage sampling across provincial, municipal, and county hospitals was conducted in 2017. All the malaria medical records were retrieved from 2014 to 2016 in 70 hospitals. Parametric and non-parametric methods were employed to estimate hospitalization costs, and the non-parametric bootstrap was used to compare hospitalization costs among sample areas and assessed the uncertainty of its differences. Quantile regressions were conducted to identify the determinants of hospitalization costs. The median hospitalization costs of 1633 malaria inpatients were 628 USD. Medication and laboratory tests accounted for over 70% of total expenditure. The median reimbursement rate was 41.87%, and this number was even lower in higher-level hospitals (<35%) and among the New Rural Cooperative Medical Scheme (<40%). Finally, health insurance type, hospital tier, clinical units, unknown fever, and comorbidity were the main determinants of hospitalization costs. The disparity of health protection for malaria hospitalization between rural and urban areas was noteworthy. Equivocal diagnosis and comorbidity are contributors of high cost as well. A reasonable payment system and enhanced capacities to treat malaria in a cost-effective way are suggested to reassure malaria economic burden.

The role of apparent diffusion coefficient histogram metrics for differentiating pediatric medulloblastoma histological variants and molecular groups

Medulloblastoma, a high-grade embryonal tumor, is the most common primary brain malignancy in the pediatric population. Molecular medulloblastoma groups have documented clinically and biologically relevant characteristics. Several authors have attempted to differentiate medulloblastoma molecular groups and histology variants using diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) maps. However, literature on the use of ADC histogram analysis in medulloblastomas is still scarce. This study presents data from a sizable group of pediatric patients with medulloblastoma from a single institution to determine the performance of ADC histogram metrics for differentiating medulloblastoma variants and groups based on both histological and molecular features. In this retrospective study, we evaluated the distribution of absolute and normalized ADC values of medulloblastomas. Tumors were manually segmented and diffusivity metrics calculated on a pixel-by-pixel basis. We calculated a variety of first-order histogram metrics from the ADC maps, including entropy, minimum, 10th percentile, 90th percentile, maximum, mean, median, skewness and kurtosis, to differentiate molecular and histological variants. ADC values of the tumors were also normalized to the bilateral cerebellar cortex and thalami. We used the Kruskal-Wallis and Mann-Whitney U tests to evaluate differences between the groups. We carried out receiver operating characteristic (ROC) curve analysis to evaluate the areas under the curves and to determine the cut-off values for differentiating tumor groups. We found 65 children with confirmed histopathological diagnosis of medulloblastoma. Mean age was 8.3 ± 5.8 years, and 60% (n = 39) were male. One child was excluded because histopathological variant could not be determined. In terms of medulloblastoma variants, tumors were classified as classic (n = 47), desmoplastic/nodular (n = 9), large/cell anaplastic (n = 6) or as having extensive nodularity (n = 2). Seven other children were excluded from the study because of incomplete imaging or equivocal molecular diagnosis. Regarding medulloblastoma molecular groups, there were: wingless (WNT) group (n = 7), sonic hedgehog (SHH) group (n = 14) and non-WNT/non-SHH (n = 36). Our results showed significant differences among the molecular groups in terms of the median (P = 0.002), mean (P = 0.003) and 90th percentile (P = 0.002) ADC histogram metrics. No significant differences among the various medulloblastoma histological variants were found. ADC histogram analysis can be implemented as a complementary tool inthe preoperative evaluation of medulloblastoma in children. This technique can provide valuable information for differentiating among medulloblastoma molecular groups. ADC histogram metrics can help predict medulloblastoma molecular classification preoperatively.

Predicting and Decreasing Bladder Tumor Recurrence Following Nephroureterectomy

Following radical nephroureterectomy for upper tract urothelial carcinoma, bladder tumor recurrence is a common event occurring in up to 22-47% of cases within the first post-operative year. In this review, we summarize the current knowledge on predictors of bladder tumor recurrence after radical nephroureterectomy and methods for reducing the risk of bladder tumor recurrence. Risk factors can be classified as modifiable and non-modifiable. Of these, the treating urologist has the greatest potential to decrease bladder tumor recurrence by focusing on treatment specific risk factors. Procedures which may decrease the risk of bladder tumor recurrence include limiting diagnostic ureteroscopy with biopsy to cases with equivocal diagnosis, use of perioperative intravesical chemotherapy, and complete distal ureterectomy with bladder cuff excision. Ongoing studies evaluating the timing and choice of intravesical chemotherapy during/after radical nephroureterectomy may help to further reduce bladder tumor recurrence in the future.

Known Benefits and Unknown Risks of Active Surveillance of Cervical Intraepithelial Neoplasia Grade 2.

Cervical intraepithelial neoplasia grade 2 (CIN 2) is an equivocal diagnosis with high interobserver variation. Owing to high regression rates of 50%, many countries recommend active surveillance of CIN 2, especially in women younger than age 25-30 years, where regression rates are even higher (ie, 60%). Additionally, excisional treatment is associated with increased risk of reproductive harm, particularly preterm birth. Active surveillance typically consists of semi-annual follow-up visits for up to 2 years, including colposcopy and either cytology, testing for human papillomavirus, or both. Excisional treatment is recommended for progression or persistent disease after 2 years. Because active surveillance in younger women is relatively new, knowledge on subsequent risk of cervical cancer is limited. Considering human papillomavirus latency, women undergoing active surveillance might be at higher risk of cervical cancer than women undergoing excisional treatment. Furthermore, there are limited data describing preferences of women for the management of CIN 2, and it is also unclear how active surveillance may affect planning for future pregnancy. In this context, biomarkers for risk stratification of CIN 2 into either high or low probability of progression would allow for targeted treatment. Currently, immunohistochemical staining for p16 is used to clarify the histologic diagnosis, but whether it or other biomarkers can be used for risk-stratification in clinical management of women with CIN 2 remains unknown. In conclusion, active surveillance of CIN 2 needs further investigation, including understanding the long-term cervical cancer risk and evaluation of markers that may enable risk stratification of CIN 2.

Deconvolution microscopy: A platform for rapid on-site evaluation of fine needle aspiration specimens that enables recovery of the sample.

ContextRapid on‐site evaluation (ROSE) optimises the performance of cytology, but requires skilled handling, and smearing can make the material unavailable for some ancillary tests. There is a need to facilitate ROSE without sacrificing part of the sample.ObjectiveWe evaluated the image quality of inexpensive deconvolution fluorescence microscopy for optically sectioning non‐smeared fine needle aspiration (FNA) tissue fragments.DesignA portion of residual material from 14 FNA samples was stained for 3 min in Hoechst 33342 and Sypro™ Red to label DNA and protein respectively, transferred to an imaging chamber, and imaged at 200× or 400× magnification at 1 micron intervals using a GE DeltaVision inverted fluorescence microscope. A deconvolution algorithm was applied to remove out‐of‐plane signal, and the resulting images were inverted and pseudocoloured to resemble H&E sections. Five cytopathologists blindly diagnosed 2 to 4 representative image stacks per case (total 70 evaluations), and later compared them to conventional epifluorescent images.ResultsAccurate definitive diagnoses were rendered in 45 (64%) of 70 total evaluations; equivocal diagnoses (atypical or suspicious) were made in 21 (30%) of the 70. There were two false positive and two false negative “definite” diagnoses in three cases (4/70; 6%). Cytopathologists preferred deconvolved images compared to raw images (P < 0.01). The imaged fragments were recovered and prepared into a ThinPrep or cell block without discernible alteration.ConclusionsDeconvolution improves image quality of FNA fragments compared to epifluorescence, often allowing definitive diagnosis while enabling the ROSE material to be subsequently triaged.

Bile cytology diagnosis in challenging cases: Validation of diagnostic bile cytology criteria and extensive study for immunocytochemical markers.

Bile cytology is useful in diagnosing biliary tract lesions, albeit often challenging due to equivocal findings. To achieve better diagnoses for clinical decisions, we conducted cytomorphological and immunocytochemical studies of bile cytology cases. We re-evaluated 40 bile cytology cases with initial equivocal diagnoses, taken from the cytology records of Jichi Medical University Hospital, including 1778 bile cytology specimens. First, we assessed the cases by the diagnostic bile cytology criteria of the Japanese Society of Clinical Cytology. Second, we searched for useful immunocytochemical markers by extensive immunohistochemical analyses using tissue microarray for 10 antibodies: S100P, IMP3, GLUT1, p53, S100A4, Mapsin, MUC17, CD10, MDM2, and SMAD4. Microarrays were from 257 extrahepatic bile duct carcinoma cases. To elucidate the utility of immunocytochemistry, we applied selected markers to immunocytochemical evaluation of the equivocal cases after cell transfer. The criteria indicated a sensitivity 60%, specificity 87%, and accuracy 70%. Irregularly overlapping (88%), arranged (96%), and shaped (76%) nuclei were more common in malignant cases, while enlarged nuclei were more frequent in benign cases (67% vs. 28%). We applied S100P and IMP3, which showed higher accuracy (88% and 77%) in tissue microarray, to immunocytochemistry. The sensitivity of S100P and IMP3 were 69% and 70%, respectively. The specificity of S100P and IMP3 were 50% and 100%, respectively. The criteria showed a certain effectiveness even in challenging cases, and some pitfalls associated with reactive changes of benign cells. Although comprehensive diagnosis including cytomorphology seems preferable, S100P and IMP3 are promising immunocytochemical markers.

Papillary Lesions of Breast- A Retrospective Analysis of Cytomorphological Features with Histopathology Concordance

Introduction: Papillary lesions of the breast include a spectrum of entities ranging from benign papilloma to malignant papillary carcinoma. The overlapping morphological features in benign and malignant lesions make their accurate sub categorization difficult. Definitive surgical management decisions on papillary lesions of breast based on fine needle aspiration cytology report alone is a matter of concern. Aim: To evaluate the cytomorphological features of papillary lesions of breast and its concordance with histopathology. Materials and Methods: This retrospective study was conducted in Department of Pathology at Regional Cancer Centre, Thiruvananthapuram, Kerala, India (tertiary cancer centre) from January 2017 to June 2017. Total 28 cases diagnosed as papillary lesions/neoplasm on nipple discharge/fine needle aspiration cytology (FNAC) from January 2014 to December 2016 were reviewed and concordance with histopathology where ever available was analysed. Cytomorphological features that were analysed included cellularity, complex folded and branching epithelial sheets, stromal bare nuclei, cyst macrophages, single cells and atypia. Results: Total 28 cases of papillary lesions diagnosed by cytology were identified with mean age of 51 years. Out of 28, 22 cases had histopathology concordance. Most common diagnosis in cytology was papillary neoplasm, accurate categorization into benign or malignant could not be done in cytology in most of the cases. Most common diagnosis in histopathology was carcinoma, in-situ and invasive. Of total 22 cases,16 cases showed true papillae. Majority of the cytomorphological features assessed were statistically insignificant in differentiating benign and malignant lesions. Fifteen cases out of the total 22 cases turned out to be malignant in final histopathology. Out of the total 22 cases wherein histopathology correlation was available, cytology could give a conclusive diagnosis of malignancy in two cases and could give a suggestion of malignancy in seven cases. Out of these nine cases where cytology favoured malignancy, one case turned out to be benign in histopathology while the rest eight cases were malignant. In five cases cytology gave benign diagnosis, one of these turned out to be malignant in histopathology, rest four cases histopathological diagnosis was in concordance with cytology. In eight cases cytology gave an equivocal diagnosis of papillary neoplasm, where further categorisation into benign and malignant category was not possible. Out of these equivocal cases, six turned out to be malignant in histopathology and two were benign. Conclusion: Cytomorphological features of papillary lesions of the breast are not unique and are inadequate for consistent categorization into benign and malignant lesions. Excision biopsy with adequate sampling and immunostaining with myoepithelial markers and oestrogen and progesterone receptors (ER and PR) are essential for accurate categorization of papillary neoplasms of breast.

Proton Density Fat Fraction Spine MRI for Differentiation of Erosive Vertebral Endplate Degeneration and Infectious Spondylitis

Vertebral Modic type 1 (MT1) degeneration may mimic infectious disease on conventional spine magnetic resonance imaging (MRI), potentially leading to additional costly and invasive investigations. This study evaluated the diagnostic performance of the proton density fat fraction (PDFF) for distinguishing MT1 degenerative endplate changes from infectious spondylitis. A total of 31 and 22 patients with equivocal diagnosis of MT1 degeneration and infectious spondylitis, respectively, were retrospectively enrolled in this IRB-approved retrospective study and examined with a chemical-shift encoding (CSE)-based water-fat 3D six-echo modified Dixon sequence in addition to routine clinical spine MRI. Diagnostic reference standard was established according to histopathology or clinical and imaging follow-up. Intravertebral PDFF [%] and PDFFratio (i.e., vertebral endplate PDFF/normal vertebrae PDFF) were calculated voxel-wise within the single most prominent edematous bone marrow lesion per patient and examined for differences between MT1 degeneration and infectious spondylitis. Mean PDFF and PDFFratio of infectious spondylitis were significantly lower compared to MT1 degenerative changes (mean PDFF, 4.28 ± 3.12% vs. 35.29 ± 17.15% [p < 0.001]; PDFFratio, 0.09 ± 0.06 vs. 0.67 ± 0.37 [p < 0.001]). The areas under the curve (AUC) and diagnostic accuracies were 0.977 (p < 0.001) and 98.1% (cut-off at 12.9%) for PDFF and 0.971 (p < 0.001) and 98.1% (cut-off at 0.27) for PDFFratio. Our data suggest that quantitative evaluation of vertebral PDFF can provide a high diagnostic accuracy for differentiating erosive MT1 endplate changes from infectious spondylitis.