Unusual case of Reinke's oedema.

This case report describes a man in his mid 40s, with a history of chronic smoking, who presented with dysphonia. He underwent microlaryngoscopy and biopsy for a suspicious lesion on the anterior right vocal cord. Mask ventilation proved difficult on induction of general anaesthesia due to a solid lesion acting as a ball valve into the glottis. This mass was LASER debulked and sent for histopathology. This demonstrated a haematoma, likely traumatic in origin, with some polypoidal features, consistent with advanced Reinke's oedema. Reinke's oedema is a benign condition where chronic inflammation causes fluid accumulation within the vocal cords. Long-standing inflammation leads to disarrangement of the vocal cord lamina propria, causing fluid accumulation and thereby resulting oedema of the vocal cords. This process can subsequently lead to polyp formation and can cause gravelly voice. This case report describes the potential airway sequelae of this benign condition.

Accuracy of a Smartphone Software Application Compared With a Handheld Goniometer for Measuring Shoulder Range of Motion in Asymptomatic Adults.

Background: Typically, shoulder range of motion (ROM) measurements are performed in a clinic setting, where physicians, physical therapists (PTs), and occupational therapists make use of a goniometer. Purpose: To determine the accuracy of a smartphone-based ROM software application (app) in assessing active shoulder ROM and compare the measurements with traditional goniometry as measured by a PT. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: This prospective, nonblinded study was conducted at a single institution with adult asymptomatic participants with full active ROM of both shoulders. Participants were enrolled between June 1 and 15, 2021. Each participant self-assessed their active shoulder ROM using the PeerWell smartphone app. A single PT concurrently measured each participant's active shoulder ROM using a handheld universal goniometer. Bilateral shoulder ROM (forward flexion, abduction [AB], external rotation, internal rotation [IR], and extension) was measured 2 times for each participant. Interrater reliability between the smartphone app and PT measurements as well as intrarater reliability for each method of measurement were assessed using the intraclass correlation coefficient (ICC), and limits of agreement were analyzed for the difference in measurement methods. Results: Data were analyzed for 60 shoulders (30 right, 30 left) from 30 participants (mean age, 31.4 ± 11.7 years; 73% female). The interrater reliability between the 2 methods was excellent for all movements (ICCs, 0.90-0.96). For all movements except shoulder AB, the mean difference in the measurements between the 2 methods was <1.3°; the mean difference in AB ROM was 2.08°. For all movements except IR, both PTs and the app showed excellent intrarater reliability (ICCs >0.90); for IR, good intrarater reliability (ICC ≥0.75) was observed. Conclusion: The PeerWell smartphone app provided measurements comparable with manual measurements taken by a PT using a goniometer. These data provide evidence that the smartphone app is a reliable and valid tool for measuring shoulder ROM and show promise for measuring and monitoring patient ROM remotely.

A scoping review of digital health interventions for combating COVID-19 misinformation and disinformation.

OBJECTIVE: We provide a scoping review of Digital Health Interventions (DHIs) that mitigate COVID-19 misinformation and disinformation seeding and spread. MATERIALS AND METHODS: We applied our search protocol to PubMed, PsychINFO, and Web of Science to screen 1666 articles. The 17 articles included in this paper are experimental and interventional studies that developed and tested public consumer-facing DHIs. We examined these DHIs to understand digital features, incorporation of theory, the role of healthcare professionals, end-user experience, and implementation issues. RESULTS: The majority of studies (n = 11) used social media in DHIs, but there was a lack of platform-agnostic generalizability. Only half of the studies (n = 9) specified a theory, framework, or model to guide DHIs. Nine studies involve healthcare professionals as design or implementation contributors. Only one DHI was evaluated for user perceptions and acceptance. DISCUSSION: The translation of advances in online social computing to interventions is sparse. The limited application of behavioral theory and cognitive models of reasoning has resulted in suboptimal targeting of psychosocial variables and individual factors that may drive resistance to misinformation. This affects large-scale implementation and community outreach efforts. DHIs optimized through community-engaged participatory methods that enable understanding of unique needs of vulnerable communities are urgently needed. CONCLUSIONS: We recommend community engagement and theory-guided engineering of equitable DHIs. It is important to consider the problem of misinformation and disinformation through a multilevel lens that illuminates personal, clinical, cultural, and social pathways to mitigate the negative consequences of misinformation and disinformation on human health and wellness.

Association of VDBP (rs4588 and rs7041) gene polymorphisms with susceptibility to postpartum depression in South Indian population: A cross-sectional study.

Low vitamin D levels have been implicated in postpartum depressive disorders (PPD). Our study aimed to demonstrate the association of Vitamin D Binding Protein (VDBP) genetic variants rs7041 and rs4588 with susceptibility to PPD and to investigate their possible relationship with serum vitamin D and VDBP levels in Indian women with PPD. A cross-sectional study involved 330 cases and 330 controls. Depressive symptoms were assessed using Edinburg Postnatal Depression Scale. Genotyping of SNPs was done by Taqman 5'allelic discrimination assay. Estimation of serum 25 hydroxyvitamin D [25(OH) D] and VDBP levels were done by ELISA. Serum total, free and bioavailable 25(OH) D levels were significantly lower in cases compared to controls, with similar levels of VDBP between the two groups. The study results showed that the VDBP rs4588 variant genotype AA was significantly associated with lower circulating levels of total 25(OH) D in cases. Also, the VDBP rs7041 variant TT genotype demonstrated significantly lower levels of total, free and bioavailable 25(OH) D levels in controls. However, VDBP rs7041 and rs4588 variants were not associated with PPD susceptibility. Also, VDBP haplotypes showed no association with PPD susceptibility. Our results demonstrated that VDBP polymorphisms rs4588 and rs7041 and their haplotypes are not associated with PPD susceptibility in the South Indian population. However, vitamin D levels were found to be influenced by the risk genotypes of VDBP SNPs rs4588 and rs7041.

Comparison of a Smartphone App to Manual Knee Range of Motion Measurements.

Background: Digital technology has emerged as a useful tool for preoperative and postoperative patient engagement and for remote patient monitoring. Smartphones are equipped with motion-sensing technology, and apps can be designed which use these features to create a simple method for measuring range of motion. The purpose of this study was to determine the accuracy of digital technology in assessing knee range of motion using a smartphone app, compared to traditional goniometric measurements in an office setting. Methods: Fifty-three (53) patients in a clinical practice were enrolled between October 2019 and March 2020. Three separate measurements were taken during the patient encounter: (1) the surgeon, (2) the app, and (3) the physical therapist. Intraclass correlations were computed to assess the agreement between (1) the surgeon and app and (2) that between the physical therapist and surgeon. Results: When measuring flexion, the correlation between either the surgeon or therapist with the app was good, whereas the comparison between the surgeon and therapist was moderate. All extension measurement comparisons, between the app, surgeon, and therapist, showed moderate correlation. Limits of agreements showed that 80% of the difference between surgeon and app is within 10 degrees for extension and 11 degrees for flexion. Body mass index did not affect the accuracy of the measurements. Conclusion: Digital app measurements were comparable to measurements made by either a surgeon or physical therapist with a manual goniometer in the clinical setting and may be beneficial for measuring and monitoring patients' range of motion remotely.

Recurrent Facial Paralysis-an Unusual Initial Presentation of Temporal Bone Metastasis in Case of Advanced Prostate Malignancy.

Metastasis into temporal bone is uncommon. Involvement of facial nerve is rarer. We report an unusual case of metastatic prostatic carcinoma presenting initially as facial nerve palsy in an 82 year old male. Diagnostic pitfalls have been discussed. Radiological evaluation followed by biopsy was diagnostic.

Quantifying Patient Engagement in Total Joint Arthroplasty Using Digital Application-Based Technology.

BACKGROUND: Digital patient engagement has been suggested as a mean to increase patient activation and patient satisfaction after total joint arthroplasty. The purpose of this study was to assess patient engagement with application-based educational tools and to explore what content was most useful to patients in the perioperative period surrounding total hip arthroplasty (THA) and total knee arthroplasty (TKA), respectively. METHODS: Patients undergoing THA and TKA between October 2017 and January 2020 were enrolled to use an application-based digital technology. The App provides comprehensive patient education using a series of modules delivered at set intervals preoperatively and postoperatively. Patient engagement was defined as patients viewing at least one time the modules that were sent, or marking them as completed. Patient satisfaction was assessed using an in-application survey. RESULTS: Complete data were available on 207 patients of which 95 (46%) underwent THA and 112 (54%) underwent TKA. The average age was 60 years. 54% with patients invited to the program completed registration. An average compliance rate of 48% (41 modules engaged out of 83) was observed. Of all modules completed, the top three most popular categories included physical therapy/exercise videos, health literacy, and anxiety/stress/pain management. The least viewed category was nutrition planning and education. CONCLUSION: When presented educational material related to THA and TKA, patients had a high rate of compliance. Digital technology platforms provide a scalable, meaningful approach to engaging patients throughout the continuum of joint replacement care and may serve as a cost-effective adjunct to traditional methods.

Cross-sectional association between vitamin B12 status and probable postpartum depression in Indian women.

BACKGROUND: Vitamin B12 is an essential micronutrient for neurological function, as it leads to the regeneration of methionine from homocysteine, which is precursor of biologically active molecule S-Adenosyl Methionine (SAM). Pregnancy is a state of increased demand and delayed postpartum repletion of nutrients may predispose women to depression. METHODS: We included women who visited the hospital at 6-weeks postpartum for a regular checkup. Inclusion criteria were age (18-50 years), and willingness to donate venous sample for analysis. Exclusion criteria included previous history of mood disorders or antidepressant medication use, and any systemic illness like hypothyroidism, epilepsy, diabetes, and hypertension. Based on EPDS score of 10 as a cutoff, 217 women with probable postpartum depression (PPD) and equal number of age and BMI matched controls were included. Plasma total vitamin B12, holotranscobalamin (holotc), homocysteine (hcy), methyl malonic acid (MMA), 5-methyl tetrahydrofolate (THF), SAM and serotonin levels were estimated using commercially available ELISA kits. Combined B12 (cB12) score was calculated from study parameters. Multivariate analysis was performed to assess the risk of probable postpartum depression. RESULTS: Total vitamin B12 and combined B12 score were found to be significantly lower (p = 0.001) and MMA (p = 0.002) and 5-methyl THF (p < 0.001) levels were higher in women with probable depression than women without probable PPD. Women in the lowest vitamin B12 quartile had 4.53 times higher likelihood of probable postpartum depression (p < 0.001). Multivariate analysis demonstrated that decreasing vitamin B12 (OR = 0.394; 95% CI: 0.189-0.822) and cB12 (OR = 0.293; 95% CI: 0182-0.470) and increasing MMA (OR = 2.14; 95% CI: 1.63-2.83) and 5-methyl THF levels (OR = 3.29; 95% CI: 1.59-6.83) were significantly associated with the risk of probable PPD. CONCLUSION: Low vitamin B12 may contribute to depressive symptoms in vulnerable postpartum period.

Reduced Maternal Serum Total, Free and Bioavailable Vitamin D Levels and its Association with the Risk for Postpartum Depressive Symptoms.

BACKGROUND: Low vitamin D levels have been implicated in postpartum depressive disorders. However, studies on bioavailable vitamin D levels in postpartum depression are limited. Our study aimed to assess the serum concentrations of total, free and bioavailable 25-hydroxyvitamin D (25(OH)D) levels in women with postpartum depressive symptoms (PPD) and the association between 25(OH)D levels and PPD at 6 week post-delivery. METHODS: In this cross-sectional study, a total of 330 cases and 330 age and BMI matched controls were recruited from the tertiary care hospital in South India. Women with depressive symptoms were assessed using the validated Edinburg Postnatal Depression Scale (EPDS) and cut-off score ≥10 was used. Serum 25(OH)D and VDBP levels were measured using commercially available ELISA kits. RESULTS: Serum total, free and bioavailable 25(OH)D levels were significantly lower in postpartum depressive women compared to non-depressive women (p <0.001, p = 0.01). A significant negative correlation was observed between 25(OH)D, free 25(OH)D and bioavailable 25(OH)D with EPDS score in total study subjects (p <0.001, r = -0.19; p <0.001, r = -0.14 and p <0.001, r = -0.14). Multivariate linear regression analysis further confirmed a significant association between serum total, free and bioavailable 25(OH)D levels and EPDS score (p <0.001∗). CONCLUSIONS: Our study demonstrated that lower serum total, free and bioavailable 25(OH)D levels were associated with postpartum depressive symptoms. Hypovitaminosis D after delivery may be a risk factor for postpartum depression.

Continuous Temperature-Monitoring Socks for Home Use in Patients With Diabetes: Observational Study.

BACKGROUND: Over 30 million people in the United States (over 9%) have been diagnosed with diabetes. About 25% of people with diabetes will experience a diabetic foot ulcer (DFU) in their lifetime. Unresolved DFUs may lead to sepsis and are the leading cause of lower-limb amputations. DFU rates can be reduced by screening patients with diabetes to enable risk-based interventions. Skin temperature assessment has been shown to reduce the risk of foot ulceration. While several tools have been developed to measure plantar temperatures, they only measure temperature once a day or are designed for clinic use only. In this report, wireless sensor-embedded socks designed for daily wear are introduced, which perform continuous temperature monitoring of the feet of persons with diabetes in the home environment. Combined with a mobile app, this wearable device informs the wearer about temperature increases in one foot relative to the other, to facilitate early detection of ulcers and timely intervention. OBJECTIVE: A pilot study was conducted to assess the accuracy of sensors used in daily wear socks, obtain user feedback on how comfortable sensor-embedded socks were for home use, and examine whether observed temperatures correlated with clinical observations. METHODS: Temperature accuracy of sensors was assessed both prior to incorporation in the socks, as well as in the completed design. The measured temperatures were compared to the reference standard, a high-precision thermostatic water bath in the range 20°C-40°C. A total of 35 patients, 18 years of age and older, with diabetic peripheral neuropathy were enrolled in a single-site study conducted under an Institutional Review Board-approved protocol. This study evaluated the usability of the sensor-embedded socks and correlated the observed temperatures with clinical findings. RESULTS: The temperatures measured by the stand-alone sensors were within 0.2°C of the reference standard. In the sensor-embedded socks, across multiple measurements for each of the six sensors, a high agreement (R2=1) between temperatures measured and the reference standard was observed. Patients reported that the socks were easy to use and comfortable, ranking them at a median score of 9 or 10 for comfort and ease of use on a 10-point scale. Case studies are presented showing that the temperature differences observed between the feet were consistent with clinical observations. CONCLUSIONS: We report the first use of wireless continuous temperature monitoring for daily wear and home use in patients with diabetes and neuropathy. The wearers found the socks to be no different from standard socks. The temperature studies conducted show that the sensors used in the socks are reliable and accurate at detecting temperature and the findings matched clinical observations. Continuous temperature monitoring is a promising approach as an early warning system for foot ulcers, Charcot foot, and reulceration.

Low serum levels of High-Density Lipoprotein cholesterol (HDL-c) as an indicator for the development of severe postpartum depressive symptoms.

Postpartum depression (PPD) is a psychiatric complication of childbirth affecting 10-20% of new mothers and has negative impact on both mother and infant. Serum lipid levels have been related to depressive disorders, but very limited literatures are available regarding the lipid levels in women with postpartum depression. The present study is aimed to examine the association of serum lipids with the development of postpartum depressive symptoms. This is a cross sectional study conducted at a tertiary care hospital in South India. Women who came for postpartum check-up at 6th week post-delivery were screened for PPD (September 2014-October 2015). Women with depressive symptoms were assessed using EPDS (Edinburgh Postnatal Depression Scale). The study involved 186 cases and 250 controls matched for age and BMI. Serum levels of lipid parameters were estimated through spectrophotometry and the atherogenic indices were calculated in all the subjects. Low serum levels of Total Cholesterol (TC) and High Density Lipoprotein cholesterol (HDL-c) were significantly low in PPD women with severe depressive symptoms. The study recorded a significant negative correlation between HDL-c and the EPDS score in PPD women (r = -0.140, p = 0.05). Interestingly, the study also observed a significant negative correlation between Body Mass Index (BMI) and EPDS scores in case group (r = -0.146, p = 0.047), whereas a positive correlation between the same in controls (r = 0.187, p = 0.004). Our study demonstrated that low levels of serum HDL-c is correlated with the development of severe depressive symptoms in postpartum women. Study highlights the role of lipids in the development of postpartum depressive symptoms.

Pulmonary arterial intimal sarcoma with retrograde extension: report of a case and review of literature.

Most of the pulmonary arterial sarcomas arise from multi-potential mesenchymal intimal cells and are designated as intimal sarcomas. These tumors grow in the direction of blood flow into peripheral arteries producing clinical features mimicking pulmonary thromboembolism. Retrograde extension is rare. We report one such case of intimal sarcoma that had a retrograde extension into the right ventricular outflow tract, and review such a presentation in the last ten years.

A multicenter study directly comparing the diagnostic accuracy of gene expression profiling and immunohistochemistry for primary site identification in metastatic tumors.

Metastatic tumors with an uncertain primary site can be a difficult clinical problem. In tens of thousands of patients every year, no confident diagnosis is ever issued, making standard-of-care treatment impossible. Gene expression profiling (GEP) tests currently available to analyze these difficult-to-diagnose tumors have never been directly compared with the diagnostic standard of care, immunochemistry (IHC). This prospectively conducted, blinded, multicenter study compares the diagnostic accuracy of GEP with IHC in identifying the primary site of 157 formalin-fixed paraffin-embedded specimens from metastatic tumors with known primaries, representing the 15 tissues on the GEP test panel. Four pathologists rendered diagnoses by selecting from 84 stains in 2 rounds. GEP was performed using the Pathwork Tissue of Origin Test. Overall, GEP accurately identified 89% of specimens, compared with 83% accuracy using IHC (P=0.013). In the subset of 33 poorly differentiated and undifferentiated carcinomas, GEP accuracy exceeded that of IHC (91% to 71%, P=0.023). In specimens for which pathologists rendered their final diagnosis with a single round of stains, both IHC and GEP exceeded 90% accuracy. However, when the diagnosis required a second round, IHC significantly underperformed GEP (67% to 83%, P<0.001). GEP has been validated as accurate in diagnosing the primary site in metastatic tumors. The Pathwork Tissue of Origin Test used in this study was significantly more accurate than IHC when used to identify the primary site, with the most pronounced superiority observed in specimens that required a second round of stains and in poorly differentiated and undifferentiated metastatic carcinomas.

Gene expression microarray-based assay to determine tumor site of origin in a series of metastatic tumors to the ovary and peritoneal carcinomatosis of suspected gynecologic origin.

The origin of the primary tumor is sometimes difficult to determine in peritoneal and ovarian metastases. A series of 25 metastatic tumors to the ovary and 7 cases of peritoneal carcinomatosis of suspected gynecologic origin were collected. Total RNA was extracted from frozen tumor tissue and studied by the Tissue of Origin-Frozen test, a microarray-based gene expression test from Pathwork Diagnostics (Redwood City, CA). Independently, formalin-fixed, paraffin-embedded tumor tissue was subjected to pathologic analysis. Immunohistochemical stains included keratins 7 and 20, estrogen and progesterone receptors, CDX2, villin, CEA, WT-1, TTF-1, mammoglobin, GCDF-15, and CD31. Clinical data were considered as gold standard, and after clinicopathologic evaluation, the tissue of origin was found in 29 cases. The Tissue of Origin-Frozen test correctly identified the ovary as site of origin in 7 of 7 peritoneal carcinomatosis cases, whereas immunohistochemical stains only allowed appropriate recognition in 5. In addition, the Tissue of Origin-Frozen test identified correctly the site of origin in 18 of the 22 metastatic tumors to the ovary with known origin. In the remaining 4 tumors, the correct origin was the second option in 2 cases and was not determined in the other 2. Immunohistochemistry correctly identified the site of origin in 17 of these 22 ovarian metastases. A combination of Tissue of Origin-Frozen and immunohistochemistry correctly identified the site of origin in 19 of 22 ovarian metastases of known origin. Although conventional pathologic examination and immunohistochemistry are commonly used for assessing the tumor site of origin, Tissue of Origin testing can be useful in difficult cases.

Comparison of histopathology to gene expression profiling for the diagnosis of metastatic cancer.

BACKGROUND: Determining the primary site of metastatic cancer with confidence can be challenging. Pathologists commonly use a battery of immunohistochemical (IHC) stains to determine the primary site. Gene expression profiling (GEP) has found increasing use, particularly in the most difficult cases. In this pilot study, a direct comparison between GEP and IHC-guided methods was performed. METHODS: Ten archived formalin-fixed paraffin embedded metastatic tumor samples for which the primary site had been clinically determined were selected. Five pathologists who were blinded to the diagnosis were asked to determine the primary site using IHC and other stains selected from a panel of 84 stains. Each pathologist was provided patient sex, biopsy site and gross sample description only. Slides were digitized using ScanScope®XT at 0.25 µm/pixel. Each evaluating pathologist was allowed to provide a diagnosis in three stages: initial (after reviewing the H&E image), intermediate (after reviewing images from the first batch of stains) and final diagnosis (after the second batch of stains if requested). GEP was performed using the only FDA-cleared test for this intended use, the Pathwork Tissue of Origin Test. No sample information was provided for GEP testing except for patient sex. Results were reported as the tumor tissue type with the highest similarity score. RESULTS: In this feasibility study, GEP determined the correct primary site in 9 of the 10 cases (90%), compared to the IHC-guided method which determined the correct primary site for 32 of 50 case evaluations (average 64%, range 50% to 80%). The five pathologists directing the IHC-guided method ordered an average of 8.8 stains per case (range 1 to 18). GEP required an average of 3 slides per case (range 1 to 4). CONCLUSIONS: Results of the pilot study suggest that GEP provides correct primary site identification in a higher percentage of metastatic cases than IHC-guided methods, and uses less tissue. A larger comparative effectiveness study using this study design is needed to confirm the results. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1749854104745508.

Unique patterns of metastases in common and rare types of malignancy.

This review on the unique patterns of metastases by common and rare types of cancer addresses regional lymphatic metastases but also demonstrates general principles by consideration of vital organ metastases. These general features of successfully treated metastases are relationships to basic biological behavior as illustrated by disease-free interval, organ-specific behavior, oligo-metastatic presentation, genetic control of the metastatic pattern, careful selection of patients for surgical resection, and the necessity of complete resection of the few patients eligible for long-term survival after resection of vital organ metastasis. Lymph node metastases, while illustrating these general features, are not related to overall survival because lymph node metastases themselves do not destroy a vital organ function, and therefore have no causal relationship to overall survival. When a cancer cell spreads to a regional lymph node, does it also simultaneously spread to the systemic site or sites? Alternatively, does the cancer spread to the regional lymph node first and then it subsequently spreads to the distant site(s) after an incubation period of growth in the lymph node? Of course, if the cancer is in its incubation stage in the lymph node, then removal of the lymph node in the majority of cases with cancer cells may be curative. The data from the sentinel lymph node era, particularly in melanoma and breast cancer, is consistent with the spectrum theory of cancer progression to the sentinel lymph node in the majority of cases prior to distant metastasis. Perhaps, different subsets of cancer may be better defined with relevant biomarkers so that mechanisms of metastasis can be more accurately defined on a molecular and genomic level.

Gene expression profiling from formalin-fixed, paraffin-embedded tissue for tumor diagnosis.

BACKGROUND: Molecular profiling assays have emerged as a promising tool in tumor diagnosis. Recent advances have allowed the use of formalin-fixed, paraffin-embedded (FFPE) tissues in such assays involving the use of microarrays. The Pathwork Tissue of Origin (TOO) Test was developed for use with FFPE tissue to aid tumor diagnosis. We sought to determine the performance of the TOO test on routine specimens from an independent laboratory. METHODS: Forty-five blinded, archived clinical specimens from the UCSF Department of Pathology were tested. Total RNA was processed to prepare labeled cDNA for hybridization to Pathchip microarrays. Hybridization data was analyzed with a 2000-gene classification model to quantify similarity between RNA expression of the study specimens and the 15 tissues on the test panel. RESULTS: 44/45 (98%) specimens were successfully processed. 37 cases met study inclusion criteria. Of these, 35 (95%) gave results which were in agreement with the reference diagnosis. In no case was the reference diagnosis ruled out. CONCLUSIONS: The Tissue of Origin Test gave a high agreement with the reference diagnosis when archived clinical specimens from UCSF were assessed. Molecular profiling assays are highly accurate, and can be a useful tool in cancer diagnosis.

Validation and reproducibility of a microarray-based gene expression test for tumor identification in formalin-fixed, paraffin-embedded specimens.

Tumors whose primary site is challenging to diagnose represent a considerable proportion of new cancer cases. We present validation study results for a gene expression-based diagnostic test (the Pathwork Tissue of Origin Test) that aids in determining the tissue of origin using formalin-fixed, paraffin-embedded (FFPE) specimens. Microarray data files were generated for 462 metastatic, poorly differentiated, or undifferentiated FFPE tumor specimens, all of which had a reference diagnosis. The reference diagnoses were masked, and the microarray data files were analyzed using a 2000-gene classification model. The algorithm quantifies the similarity between RNA expression patterns of the study specimens and the 15 tissues on the test panel. Among the 462 specimens, overall agreement with the reference diagnosis was 89% (95% CI, 85% to 91%). In addition to the positive test results (ie, rule-ins), an average of 12 tissues for each specimen could be ruled out with >99% probability. The large size of this study increases confidence in the test results. A multisite reproducibility study showed 89.3% concordance between laboratories. The Tissue of Origin Test makes the benefits of microarray-based gene expression tests for tumor diagnosis available for use with the most common type of histology specimen (ie, FFPE).

Gene expression profiles help identify the tissue of origin for metastatic brain cancers.

BACKGROUND: Metastatic brain cancers are the most common intracranial tumor and occur in about 15% of all cancer patients. In up to 10% of these patients, the primary tumor tissue remains unknown, even after a time consuming and costly workup. The Pathwork Tissue of Origin Test (Pathwork Diagnostics, Redwood City, CA, USA) is a gene expression test to aid in the diagnosis of metastatic, poorly differentiated and undifferentiated tumors. It measures the expression pattern of 1,550 genes in these tumors and compares it to the expression pattern of a panel of 15 known tumor types. The purpose of this study was to evaluate the performance of the Tissue of Origin Test in the diagnosis of primary sites for metastatic brain cancer patients. METHODS: Fifteen fresh-frozen metastatic brain tumor specimens of known origins met specimen requirements. These specimens were entered into the study and processed using the Tissue of Origin Test. Results were compared to the known primary site and the agreement between the two results was assessed. RESULTS: Fourteen of the fifteen specimens produced microarray data files that passed all quality metrics. One originated from a tissue type that was off-panel. Among the remaining 13 cases, the Tissue of Origin Test accurately predicted the available diagnosis in 12/13 (92.3%) cases. DISCUSSION: This study demonstrates the accuracy of the Tissue of Origin Test when applied to predict the tissue of origin of metastatic brain tumors. This test could be a very useful tool for pathologists as they classify metastatic brain cancers.

A gene expression signature of CD34+ cells to predict major cytogenetic response in chronic-phase chronic myeloid leukemia patients treated with imatinib.

In chronic-phase chronic myeloid leukemia (CML) patients, the lack of a major cytogenetic response (< 36% Ph(+) metaphases) to imatinib within 12 months indicates failure and mandates a change of therapy. To identify biomarkers predictive of imatinib failure, we performed gene expression array profiling of CD34(+) cells from 2 independent cohorts of imatinib-naive chronic-phase CML patients. The learning set consisted of retrospectively selected patients with a complete cytogenetic response or more than 65% Ph(+) metaphases within 12 months of imatinib therapy. Based on analysis of variance P less than .1 and fold difference 1.5 or more, we identified 885 probe sets with differential expression between responders and nonresponders, from which we extracted a 75-probe set minimal signature (classifier) that separated the 2 groups. On application to a prospectively accrued validation set, the classifier correctly predicted 88% of responders and 83% of nonresponders. Bioinformatics analysis and comparison with published studies revealed overlap of classifier genes with CML progression signatures and implicated beta-catenin in their regulation, suggesting that chronic-phase CML patients destined to fail imatinib have more advanced disease than evident by morphologic criteria. Our classifier may allow directing more aggressive therapy upfront to the patients most likely to benefit while sparing good-risk patients from unnecessary toxicity.