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The Art of Diagnosis: Cyto-Histopathological Correlation in Metastatic Lung Cancers - A Rare Case Report
No full textBackground
Metaplastic breast carcinoma (MBC), an exceptionally rare and heterogeneous triple-negative subtype of breast cancer, accounts for less than 1% of all breast carcinomas. This case report exemplifies the pivotal role of cytohistological correlation in diagnosing lung metastasis through fine needle aspiration biopsy. The case of a 90-year-old female with a complex medical history is presented, highlighting the importance of careful clinical assessment in metastatic lung cancers.
Case Information
A 90-year-old female, with a history of metaplastic breast carcinoma following a left mastectomy 20 months ago, was admitted due to a four-week history of progressive dyspnea and fatigue. Despite being a non-smoker, she had a history of essential tremor, dementia, and chronic obstructive pulmonary disease. Extensive diagnostic evaluations, including laboratory results and imaging, revealed pulmonary nodules and partially calcified pleural masses bilaterally along with pleural effusions, raising concerns of metastasis. Thoracentesis initially showed negative pathology findings, along with subsequent CT-guided lung biopsies, prompting an investigation into the patient’s prior oncology history.
The patient's past oncology reports were revisited, uncovering a diagnosis of metaplastic carcinoma with mesenchymal differentiation in the breast. Cytohistological correlation was performed, ultimately confirming the presence of malignant cells in the lung biopsy, leading to the diagnosis of stage IV triple-negative metaplastic breast carcinoma with malignant pleural effusion.
Conclusions
Metaplastic breast carcinoma is characterized by the differentiation of malignant cells toward mesenchymal and squamous elements, making it a rare and heterogeneous cancer. The patient's case, with lung metastasis originating from a metaplastic breast carcinoma, is a rare occurrence, further emphasizing the importance of accurate diagnosis in such unique situations. The report underscores the significance of meticulous medical history collection, interdisciplinary communication, expert consultation, and cyto-histopathological correlation in achieving accurate pathological and clinical diagnoses in metastatic lung cancers.
Metaplastic breast carcinoma's rarity and heterogeneity contribute to its generally poor prognosis, with factors like advanced age, high-grade tumors, and distant metastasis reducing survival rates. In most cases, surgical resection remains the primary treatment approach, followed by platinum-based chemotherapy. Promising treatment avenues, including immunotherapy and molecular targeted therapies, may improve patient outcomes, but these options depend on individual circumstances.
In the case presented here, the patient's age and comorbidities influenced the decision to opt for hospice care, highlighting the importance of tailoring treatment strategies to a patient's unique situation. This case report not only sheds light on a rare occurrence but also serves as a reminder of the importance of comprehensive medical assessments in managing complex clinical scenarios
Taking the Bait: Utilization of Probe-Capture Enrichment in Human Remains Identification
No full textResearch Appreciation Day Award Winner - School of Biomedical Sciences, 2024 Department of Microbiology, Immunology & Genetics (Genetics) Award - 2nd PlacePurpose: Human remains are frequently encountered in forensic laboratories, coming from crime scenes, mass graves, historical samples, mass disasters, and military conflicts. Short tandem repeat (STR) markers evaluated via capillary electrophoresis (CE) are the gold standard for human remains identification (HRID) in forensic investigations due to their high variability and robust database of comparative samples. However, CE excludes valuable sequence-level information both within and around STRs and is often unsuccessful when used on challenged and degraded samples. The problem forensic laboratories face is choosing between depleting sample volumes to repeat individualizing STR analysis or perform costly, time-consuming, and less discriminatory mitochondrial DNA analysis. New DNA sequencing methodologies combined with novel enrichment techniques may provide a more effective platform that overcomes the most common challenges associated with HRID. Our goal for this portion of the project was to design a RNA-baiting assay to capture forensically relevant STRs.
Methods: A custom myBaits panel targeting forensically relevant regions of interest was designed with Arbor Biosciences. DNA extract from whole blood samples was used. Samples were barcoded with Illumina-compatible barcode adapters, pooled, and then probe-captured, resulting in single stranded DNA covering our targeted regions. Fill-in PCR was performed on the captured single stranded DNA using Illumina primers to create DS DNA, which was then sequenced on the MiSeq. Our data was analyzed using our custom script, STRspy, which uses minimap 2 or BWA-mem to align the data to the designated reference database. STRspy then evaluates the reads aligning to each designated loci (forensically relevant STRs in this case), classifying the allele calls as well as the SNPs in the flanking region to create sequence-based genetic profiles. These calls also include the length-based allele designation for each sequence-based allele, therefore allowing the results to be compatible with current CODIS data.
Results: We found that our RNA-baiting assay was successful in capturing our targeted regions of interest. The STR regions targeted for enrichment showed significantly enhanced coverage compared to the coverage across the entire genome.
Conclusions: Our results indicate that probe-capture is a viable enrichment technique for DNA samples.NIJ Award #15PNIJ-22-GG-04414-MUM
Understanding the role of Annexin A2 expression in the incidence of Hepatocellular Carcinoma.
No full textPurpose: Hepatocellular carcinoma (HCC) is a rapidly growing cancer with high mortality rates worldwide, necessitating improved diagnostic and therapeutic strategies. Annexin A2 (AnxA2), a calcium-dependent phospholipid-binding protein and a member of the annexin protein family, holds promise as a diagnostic, prognostic, and therapeutic target in several cancers. This study evaluates the clinical significance of AnxA2 in HCC progression. Methods: The Cancer Genome Atlas (TCGA) data was mined to assess AnxA2 mRNA expression in HCC and its correlation with tumor stage, grade, overall survival, and progression-free survival. Additionally, immunoblot analysis was conducted on tumor tissue samples to determine the AnxA2 expression in HCC patients. Results: Analysis of TCGA data revealed a significant upregulation of AnxA2 mRNA expression in HCC compared to normal liver tissues, correlating with higher pathological grades and stages and poor overall and progression-free survival. The immunoblot analysis further confirmed that the expression of AnxA2 was high in tumor tissues of HCC patients compared to matched adjacent non-tumorigenic liver tissues. Conclusion: These findings underscore the potential of AnxA2 as a biomarker for cancer aggressiveness and prognosis, highlighting its role as a promising therapeutic target
Pulsatile Perfusion Therapy at 0.1 Hz Improves Survival Following Severe Hemorrhage in Rats
No full textPURPOSE: Oscillations in arterial pressure and blood flow at 0.1 Hz are associated with protection of tissue oxygenation during conditions of reduced tissue perfusion. Pulsatile Perfusion Therapy (PPT) is a method we have developed to induce these oscillations, and has been associated with increased tolerance to simulated hemorrhage via lower body negative pressure in humans. However, it is unknown how effective this therapy would be in an actual hemorrhage model. The aim for this study was to test the efficacy of PPT in a rat model of severe hemorrhage. We hypothesized that PPT at 0.1 Hz would protect arterial pressure and cerebral blood flow following severe hemorrhage in rats, subsequently improving survival.
METHODS: Eleven adult Sprague-Dawley rats (six female, five male) were anesthetized via isoflurane, then underwent bilateral carotid artery catheterization for assessment of arterial pressure and carotid artery blood flow, while heart rate was assessed via lead II ECG. Following a 15-min baseline period, all animals were hemorrhaged to 50% of their estimated blood volume over 30-min. Rats were then randomly assigned to the PPT group (3 female, 3 male) or the control group (CON; 3 female, 2 male). PPT was administered via inflatable cuffs attached to both hind limbs, oscillating between 0 mmHg and 250 mmHg every 5-s (10-s cycles or 0.1 Hz) for 30-min immediately following hemorrhage. For the CON group, the leg cuffs were also attached but were not inflated for this 30-min period. All animals were then monitored for an additional 150-min recovery period post-hemorrhage, or until death – defined as the absence of ventricular function on the ECG. Survival time and peak mean arterial pressure (MAP), carotid blood flow, and heart rate were assessed to determine the effectiveness of PPT in protecting hemodynamic responses following hemorrhage.
RESULTS: PPT increased survival time (P = 0.02), with 3 of 6 (50%) rats in the PPT group and 0 of 5 (0%) rats in the CON group surviving the entire 180-min recovery period following hemorrhage. During recovery, PPT protected MAP (PPT: −46.5 ± 12.9% vs. CON: −72.6 ± 19.5% from baseline; P = 0.07) and carotid blood flow (PPT: −61.5 ± 17.7% vs. CON: −83.7 ± 6.7% from baseline; P = 0.04), but did not affect heart rate (PPT: 0.11 ± 6.58% vs. CON: −18.70 ± 29.34% from baseline, P = 0.20), although responses were highly variable between subjects.
CONCLUSIONS: PPT protected arterial pressure and carotid blood flow in rats following severe hemorrhage, subsequently improving survival. These data add further evidence for the use of 0.1 Hz hemodynamic oscillations as a therapeutic intervention for the treatment of hemorrhage.Physiology and Anatomy Department Seed Gran
Utility of Blood Based Biomarkers in Detecting Cerebral Amyloid among Mexican Americans: A HABS-HD Study
No full textBackground: Alzheimer's disease (AD) is the leading cause of dementia in our nation's aging population. Minority groups, such as Hispanics, are 1.5 times more likely than non-Hispanic whites (NHW) to develop AD during their lifetime. Several studies have shown that blood biomarkers can be used to detect dementia related to AD. However, limited research has analyzed the relationship between blood biomarkers and cerebral amyloid, an AD biomarker, in minority groups. This study aims to address this gap and examine the utility of blood-based biomarkers to detect cerebral amyloid and predict AD among NHW and Mexican Americans (MA). Methods: Data were analyzed on 232 participants (n=148 NHW; n=84 MA) from the Health & Aging Brain Study – Health Disparities (HABS-HD) study. Of those selected for inclusion in this study, 46 participants had a positive cerebral amyloid scan, while 186 had a negative scan. Plasma samples were assayed for amyloid beta (Aβ)40, Aβ42, total tau (t-tau), phosphorylated tau (p-tau181), and neurofilament light (NfL) using the Simoa (single molecule array) technology platform (Quanterix.com). PET amyloid imaging was performed using a Neuraceq (florbetaben) tracer to measure cerebral amyloid positivity based on a clinical read and global standardized uptake value ratios (SUVRs). Covariates included age, gender, and education. Certain models were also split by ethnic groups. Correlation models were run separately for each blood biomarker and total cerebral amyloid SUVR. The plasma proteomic profiles were generated without transformations using Random forest (RF) analysis in R package. Regression coefficients examined the relationship between the proteomic biomarkers, the independent variable, and cerebral amyloid, the dependent variable. Logistic regressions were conducted to examine the ability of the proteomic profiles to predict cerebral amyloid positivity status. Results: Biomarkers Aβ40, Aβ42, p-tau181, and NfL were all significantly correlated with cerebral amyloid (ps< 0.05). The entire cohort had a high regression performance (R2=0.905) between the proteomic biomarkers and cerebral amyloid, with p-tau181 as the driving biomarker. Among the MA group, the biomarkers comprising the proteomic profile yielded excellent accuracy in detecting cerebral amyloid (Area Under the Curve [AUC] = 1.00, Sensitivity [SN] = 1.00, Specificity [SP] = 0.97, and positive predictive value [PPV] = 88%). Among the NHW group, the biomarkers also detected cerebral amyloid with a high level of accuracy (AUC = 0.99, SN = 1, SP = 0.99, and PPV = 92%). Cerebral amyloid positivity was predicted with 100% accuracy in both groups, with false positive rates of 1.19% and 2.03% in the MA and NHW groups, respectively. Conclusions: This study supports the application of plasma proteomic profiles to predict cerebral amyloid-related to AD. The findings highlighted that p-tau181 is the most important biomarker for cerebral amyloid detection in the MA population. This is relevant as prior work in NHW have focused on Aβ being the primary biomarker for AD detection. Future work should examine these findings in a larger population subset in order to validate the predictive utility of blood biomarkers as a screening tool in clinical settings for early AD detection.NIH/NIA U19AG07810
Vulvar Crohn’s Disease Progression Over 20 Years: A Case Study
No full textBackground: Vulvar Crohn’s disease (VCD) is a rare cutaneous manifestation of general Crohn’s disease (GCD), characterized by non-caseating granulomas in the vulvar region. VCD occurs independently of fistulization, and in 25% of cases, the vulvar manifestation precedes gastrointestinal symptoms. This case presentation describes the disease course in a patient followed longitudinally over 2 decades. The case report aims to provide insights into the presentation, diagnosis, and management of VCD, as well as highlight the challenges and considerations in clinical practice. Case information: An 18-year-old female initially presented with a two-week history of worsening pain in her vulvar area. (See Figure 1.) She had vaginal discharge and noticed multiple open lesions in the vulvar area. She was sexually active. The patient denied any gastrointestinal symptoms such as abdominal pain, diarrhea, or bloody stool. Primary differentials on initial presentation included donovanosis, lymphogranuloma venereum, hidradenitis suppurative, HIV, and cancer. Biopsy of the vulvar lesions revealed non-caseating granulomas, which are consistent with Crohn’s disease as depicted in Figure 2. The ulcerations spontaneously resolved one year after initial diagnosis as shown in Figure 3. Over the next 20 years, the patient had progressive disease despite use of immunosuppressive agents. The disease has now progressed to a rectovaginal fistula and complete obliteration of the vulvovaginal and anal architecture. (See Figure 4.) Management challenges for this patient included intermittent access to care due to socioeconomic factors and suboptimal response to immunosuppressive therapy. Conclusion: There are fewer than 300 cases of VCD reported in literature. VCD presents a unique diagnostic challenge, often confused with infectious etiologies. The differential of VCD should be considered in patients with vulvar fissures and edema. Management of VCD is more intricate than diagnosis and is not well understood. The literature shows that intestinal disease may be well controlled with a TNF-inhibitor, but VCD may continue to flare. A multidisciplinary approach involving multiple specialists is essential for optimal management. This topic requires further research on therapeutic approaches to improve patient outcomes
Comparing Balance in Patients with Fall History
No full textResearch Appreciation Day Award Winner - SaferCare Texas, 2024 Excellence in Patient Safety Research Award - 2nd PlacePurpose: With falls being the leading cause of mortality with injury, risk factors of falls should be explored further (Lohman). Postural Sway is a method in which you can quantify balance and postural control. Increase in postural sway is shown to be correlated with error in postural control modalities. (Dewan). Having a quantifiable fall-risk metric that can be quickly obtained, could prevent falls, and thereby reduce mortality and surgical interventions necessary. This experiment explores the effect of fall history on postural sway using the Bertec force plate’s measurement of change of pressure, CoP. Methods/Materials: Family Medicine and Geriatric patient participants on a volunteer basis were asked to perform two 30 second intervals of quiet standing on a Bertec force plate as an additional vital sign. Two conditions were performed on firm surfaces: with eyes open (EO) and with eyes closed (EC). Patients were asked to stare at a target for the EO portion and stand still on the force plate for 30 seconds while data was collected. After this, the patient was asked to close their eyes and stand still for another 30 seconds for the eyes closed portion. Postural sway was measured in accordance with CoP using the Clinical Test of Sensory Integration and Balance (mCTSIB) protocol, which describes quiet standing under various conditions to assess fall risk and balance problems. A group of 22 patients with a documented history of a fall was compared against 129 patients without a documented history of a fall. The values of the Range of the CoP in anterior-posterior (AP) direction/axis and medial-lateral (ML) direction/axis were compared using a 2-tail T-test. The values of standard deviation and average of the Radial Distance (RD), the displacement of the CoP points from the center of the stabiligram, a graphical representation of the movements of a person’s quiet standing, were also compared using a 2-tail T-test. Significant values at both conditions, EO and EC, were noted at p < 0.05. Results: The Range of the CoP (AP) was significantly increased in both conditions, EO and EC. The Range of the CoP (ML) was significantly increased in EC, but nonsignificant in EO. The Average RD was significant in EC but nonsignificant in EO, with the Standard Deviation RD with a significant increase in both EO and EC. Conclusion: These findings suggest that there is increased sway in patients with a reported history of a fall compared to those without. This could be a result of error in the vestibular, somatosensory, or visual systems. These errors could point to an increased fall risk. Future studies should investigate the effects these systems have on fall risk as there was more consistent statistical difference of the groups during the eyes closed portion. Some limitations include small sample size, other factors altering sway, and potential non reported fallers in the control group. The ability to measure fall risk quickly and objectively through a simple and non-invasive method like postural sway could prove instrumental in preventing falls with further studies
Renal Oxidative Stress May Explain Sex Differences in Blood Pressure in Adult Offspring Exposed to an Impoverished Environment
No full textNearly 40 million people experience poverty in the U.S. Poverty is linked to adverse childhood experiences (ACEs) which affects ~64% of adults in the U.S. Previous studies indicate that those who experience ACEs are at a higher risk of developing hypertension (HTN) and cardiovascular diseases (CVDs) later in life, with a greater severity and earlier onset in males. The mechanisms behind the ACEs-attributed development of sex differences in HTN later in life is unknown. One plausible mechanism for this sex difference is increased oxidative stress. One rodent model to mimic poverty as an ACE is the limited bed and nesting (LBN) model. This model simulates an impoverished and low resource environment, as observed in poverty, in which the nesting material during weaning is reduced. We hypothesize that male offspring exposed to LBN will have elevated blood pressure and oxidative stress, while females will have no change in blood pressure and reduced oxidative stress.
Pregnant Sprague Dawley rats gave birth naturally and weaned their offspring for 3 weeks. During the weaning period, on Days 2-9, the dams and their respective pups were divided into 2 groups: LBN and control (CON). After LBN treatment, all rats received normal bedding. After weaning, offspring were divided by sex and experimental status: LBN male (n=5), LBN female (n=5), CON male (n=6), and CON female (n=6). At 16-17 weeks, mean arterial pressure (MAP) was measured via carotid catheterization and the kidneys, brain, heart, and plasma were collected to measure antioxidant capacity (AC) via colorimetric biochemical assays.
LBN males had a significant increase (18 mmHg) in MAP compared to CON males (128.17±3.93 vs 110.72± 3.93 mmHg, P>0.001), while female LBN and CON rodents displayed no differences. In males, there were no changes in antioxidant capacity in the brain, heart, and plasma. However, there was a significant 2-fold decrease in renal antioxidant capacity (233±14.0 vs 442±12.3 mM Trolox/mg protein, p>0.0001). In females, there were no changes in the kidneys, heart, and brain antioxidant capacity. Conversely, LBN females showed a trending increase in plasma antioxidant capacity compared to CON (3.33±0.16 vs 2.53±0.35 mM Trolox/mg protein, p=0.053).
Males exposed to an impoverished environment during weaning have elevated blood pressure, while females do not. This difference in blood pressure may be explained by decreases in renal AC in males only. On the other hand, females may be protected from elevated blood pressure because they experience a slight increase in systemic AC. Future studies will examine the role of antioxidants in blood pressure regulation in the kidneys. This is clinically relevant because ACEs affect a large percentage of the American population with ~17% of adults experiencing 4 or more ACEs, with minorities at a greater risk. Understanding the mechanisms on how ACEs contribute to HTN may alleviate some of the racial and ethnic disparities for people with HTN and CVDs. Perhaps, organ and sex-specific antioxidant therapies may prevent or reduce the development of HTN in adults that were exposed to ACEs, like poverty during childhood.This research was supported by start-up funds and the American Heart Association Early Career Development Award [AHA 18CDA34110264 (Cunningham)
Comparing Methylation of CRP and IL-6 Associated Genes in Cognitively Impaired Mexican Americans to Non-Hispanic Whites
No full textPurpose: A large pool of literature shows that Alzheimer’s Disease (AD) results from inflammatory processes and neuronal loss via tau proteins and amyloid-β plaques. Mexican Americans are among those with the highest risk of developing Alzheimer’s and research into the epigenetics of this association is lacking. Methylation alterations are influenced by both genetic and lifestyle factors, which can help us identify the root cause of mild cognitive impairment, a precursor for Alzheimer’s Disease. C-reactive protein and interleukin 6 are well known for their roles in measuring systemic inflammation. This study seeks to explore if there is a significant difference between DNA methylation of CpG Islands for CRP and IL6-associated genes in Cognitively Impaired Mexican Americans (MA) and Non-Hispanic Whites (NHW). Methods: Participants were selected from the Texas Alzheimer’s Research and Care Consortium (TARCC) database. The final cohort (n = 551) consisted of 252 NHW (143 normal cognition (NC), and 109 cognitively impaired (CI)) and 299 MA participants (177 NC and 122 CI). Each participant underwent neurocognitive tests such as Clinical Dementia Rating (CDR) and Mini-Mental State Exam (MMSE) to determine cognitive status. Methylation at CpG sites was measured by array probes as beta values with 0=unmethylated, to 1=fully methylated site. CpG sites associated with CRP are cg06126421, cg10636246, cg18181703, cg19821297, and cg25325512. CpG sites associated with IL6 are cg12929678, cg17412005, cg19638572, cg20789595. Any differences between cognitively impaired participants and normal controls were assessed using the standard two-sample t-test assuming unequal variances in Rstudio. Linear Regression was performed in Rstudio, and covariates that were adjusted for include age, sex, education level (in years), APOE ɛ4 allele status, CD8 T-cells, CD4 T-cells, natural killer cells, B-cells, monocytes, and neutrophils. Results: In Mexican Americans, the CRP-associated sites showed: cg25325512 (gene FGD2) with significant hypomethylation in the CI group (p=0.0003). Cg19821297 (gene DNASE2) with significant hypomethylation in the CI group (p=0.015). Cg10636246 (genes AIM2 & IF116) had significant CI group hypomethylation (p=0.02). In Non-Hispanic Whites, one CRP-associated site showed significant hypermethylation in the CI group, cg06690548 (gene TUBB) (p=0.026). In Mexican Americans, the IL6-associated sites showed: cg17412005 (gene MUTYH & TOE1) with significant hypomethylation in the CI group (p=0.022). Cg19638572 (gene RASSF5) with significant hypermethylation in the CI group (p=0.013). Cg20789595 (gene ADCY5) with significant hypomethylation in the CI group (p<0.001). In Non-Hispanic Whites, zero IL6-associated sites showed any significant methylation between the CI and NC groups. Conclusion: Epigenetics related to AD is still being further investigated. This study suggests an association between hypomethylated CRP and IL6 genes and cognitive impairment in the Mexican American population. Limitations in this study include a limited number of CpG sites investigated, as well as possible comorbidities that should be adjusted for. There were also an unequal number of MA to NHW participants. Further studies should adjust for inflammatory comorbidities, such as metabolic syndrome, and further investigation is warranted into the FGD2 gene and ADCY5 gene as they were strongly correlated with hypomethylation in the cognitively impaired Mexican American population.Research reported in this presentation was supported by the National Institute on Aging of the National Institutes of Health under Award Numbers R01AG054073 and R01AG058533, P41EB015922 and U19AG078109
In vitro characterization of [(125)I]HY-3-24, a selective ligand for the dopamine D3 receptor
No full textINTRODUCTION: Dopamine D3 receptor (D3R) ligands have been studied for the possible treatment of neurological and neuropsychiatric disorders. However, selective D3R radioligands for in vitro binding studies have been challenging to identify due to the high structural similarity between the D2R and D3R. In a prior study, we reported a new conformationally-flexible benzamide scaffold having a high affinity for D3R and excellent selectivity vs. D2R. In the current study, we characterized the in vitro binding properties of a new radioiodinated ligand, [(125)I]HY-3-24. METHODS: In vitro binding studies were conducted in cell lines expressing D3 receptors, rat striatal homogenates, and rat and non-human primate (NHP) brain tissues to measure regional brain distribution of this radioligand. RESULTS: HY-3-24 showed high potency at D3R (K(i) = 0.67 +/- 0.11 nM, IC(50) = 1.5 +/- 0.58 nM) compared to other D2-like dopamine receptor subtypes (D2R K(i) = 86.7 +/- 11.9 nM and D4R K(i) > 1,000). The K(d) (0.34 +/- 0.22 nM) and B(max) (38.91 +/- 2.39 fmol/mg) values of [(125)I]HY-3-24 were determined. In vitro binding studies in rat striatal homogenates using selective D2R and D3R antagonists confirmed the D3R selectivity of [(125)I]HY-3-24. Autoradiography results demonstrated that [(125)I]HY-3-24 specifically binds to D3Rs in the nucleus accumbens, islands of Calleja, and caudate putamen in rat and NHP brain sections. CONCLUSION: These results suggest that [(125)I]HY-3-24 appears to be a novel radioligand that exhibits high affinity binding at D3R, with low binding to other D2-like dopamine receptors. It is anticipated that [(125)I]HY-3-24 can be used as the specific D3R radioligand.The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Institute on Drug Abuse (grant number DA029840)