Grim Outcome Research Articles

Low-dose exposure to malathion and radiation results in the dysregulation of multiple neuronal processes, inducing neurotoxicity and neurodegeneration in mouse

Neurodegenerative disorders are a debilitating and persistent threat to the global elderly population, carrying grim outcomes. Their genesis is often multifactorial, with a history of prior exposure to xenobiotics such as pesticides, heavy metals, enviornmental pollutants, ionizing radiation etc,. A holistic molecular insight into their mechanistic induction upon single or combinatorial exposure to different toxicants is still unclear. In the present study, one-month-old C57BL/6 male mice were administered orally with malathion (50 mg/kg body wt. for 14 days) and single whole-body radiation (0.5 Gy) on the 8th day. Post-treatment, behavioural assays for exploratory behaviour, memory, and learning were performed. After sacrifice, brains were collected for histology, biochemical assays, and transcriptomic analysis. Transcriptomic analysis revealed several altered processes like synaptic transmission and plasticity, neuronal survival, proliferation, and death. Signalling pathways like MAPK, PI3K-Akt, Apelin, NF-κB, cAMP, Notch etc., and pathways related to neurodegenerative diseases were altered. Increased astrogliosis was observed in the radiation and coexposure groups, with significant neuronal cell death and a reduction in the expression of NeuN. Sholl analysis, dendritic arborization and spine density studies revealed decreased total apical neuronal path length and dendritic spine density. Reduced levels of the antioxidants GST and GSH and acetylcholinesterase enzyme activity were also detected. However, no changes were seen in exploratory behaviour or learning and memory post-treatment. Thus, explicating the molecular mechanisms behind malathion and radiation can provide novel insights into external factor-driven neurotoxicity and neurodegenerative pathogenesis.

Targeting CREB-Binding Protein (CREBBP) Overcomes Resistance to Azacitidine and Venetoclax Therapy in Acute Myeloid Leukemia (AML)

Acute myeloid leukemia (AML) is a clonal myeloid malignancy arising from hematopoietic stem or progenitor cells (HSPC) within the bone marrow (BM). Despite advancements in our understanding of AML pathogenesis, patients continue to face grim outcomes, with a five-year relative survival rate of approximately 20%. This highlights the pressing need to identify molecular features of AML that are amenable to therapeutic intervention. The ideal molecular targets would be those broadly dysregulated and integral to multiple signaling pathways implicated in AML pathogenesis. Recent therapeutic regimens have incorporated venetoclax, a small molecule inhibitor of BCL2, in combination with hypomethylating agents, showing moderate success. Venetoclax (VEN) acts as a BH3 mimetic, specifically inhibiting BCL2. While clinical outcomes of VEN combined with hypomethylating agents (decitabine or azacitidine - AZA) have been promising, a substantial subset of patients remains refractory or experiences relapse following treatment with these regimens. Due to the molecular and cellular heterogeneity of AML, identifying ideal mechanisms to circumvent resistance remains elusive. In our investigations, we have observed that patient-derived cells from AML exhibit a higher frequency of dysregulated immune and inflammatory pathways than previously appreciated, referred to as “oncogenic immune signaling states.” Furthermore, immune and inflammatory-related pathways are preferentially expressed in AML patients who are resistant/refractory to VEN/AZA compared to those who respond favorably. To identify critical immune and inflammatory-related pathways contributing to VEN/AZA responses, we developed an oncogenic immune signaling-targeted CRISPR-library, aimed at identifying potential therapeutic targets involved in VEN/AZA resistance in AML. Utilizing this targeted CRISPR-screen approach, we successfully identified CREB-binding protein (CREBBP) as the top candidate linked to resistance to VEN/AZA therapy. Notably, CREBBP alterations have been associated with a poor prognosis in de novo AML, making it a compelling target for further investigation. To validate CREBBP's role in VEN/AZA resistance, we treated a VEN/AZA-resistant AML cell line, THP1 (FAB subtype M5, KMT2A-r), with commercially available pharmacologic inhibitors of CREBBP, A485, and CCS1477, and assessed the response. Remarkably, inhibition of CREBBP with either A485 or CCS1477 significantly decreased cell proliferative ability and clonogenic potential. Importantly, co-treatment with either A485 or CCS1477 and VEN/AZA synergistically abrogated cell proliferation and clonogenic potential of THP1 cells, effectively overcoming resistance (Figure 1). Our ongoing studies include validating CREBBP as a potential therapeutic target for overcoming VEN/AZA resistance in AML. We have created CREBBP-knockdown cell lines through genetic manipulation (shRNA) and will utilize these to confirm the specificity of CREBBP in modifying resistance to VEN/AZA. In addition we will utilize patient-derived xenograft studies in immunocompromised (NRG) mouse models. By investigating CREBBP's role in mediating resistance, we aim to unlock new avenues for enhancing the efficacy of VEN/AZA therapy in AML patients, particularly those facing resistance to current therapies. In conclusion, our research highlights the critical involvement of CREBBP in VEN/AZA resistance in AML. Targeting this molecular pathway holds the promise of offering a potential therapeutic approach to improve treatment outcomes for AML patients, particularly those facing resistance to current therapies. Understanding and harnessing CREBBP's influence could pave the way for developing personalized and effective strategies to combat this challenging hematological malignancy.

Midline Gliomas: A Retrospective Study from a Cancer Center in the Middle East.

Midline gliomas are tumors that occur in midline structures and can be circumscribed or diffuse. Classical midline structures include the thalamus, brainstem, and spinal cord. Other midline structures include the corpus callosum, basal ganglia, ventricles, paraventricular structures, and cerebellum. Diffuse midline glioma (DMG) is a diffuse glioma that occurs in the classical midline structures, characterized by a specific genetic alteration, and associated with grim outcome. This study was conducted at King Hussein Cancer Center and reviewed the medical records of 104 patients with circumscribed and diffuse gliomas involving midline structures that underwent biopsy between 2005 and 2022. We included a final cohort of 104 patients characterized by a median age of 23 years and a male-to-female ratio of 1.59-to-1. Diffuse high-grade glioma (DHGG) was the most common pathological variant (41.4%), followed by DMG (28.9%). GFAP was positive in most cases (71.2%). Common positive mutations/alterations detected by surrogate immunostains included H3 K27me3 (28.9%), p53 (25.0%), and H3 K27M (20.2%). Age group, type of treatment, and immunohistochemistry were significantly associated with both the location of the tumor and tumor variant (all; p < 0.05). DMGs were predominantly found in the thalamus, whereas circumscribed gliomas were most commonly observed in the spinal cord. None of the diffuse gliomas outside the classical location, or circumscribed gliomas harbored the defining DMG mutations. The median overall survival (OS) for the entire cohort was 10.6 months. Only the tumor variant (i.e., circumscribed gliomas) and radiotherapy were independent prognosticators on multivariate analysis.

SEOM-GEINO clinical guidelines for high-grade gliomas of adulthood (2022).

High-grade gliomas (HGG) are the most common primary brain malignancies and account for more than half of all malignant primary brain tumors. The new 2021 WHO classification divides adult HGG into four subtypes: grade 3 oligodendroglioma (1p/19 codeleted, IDH-mutant); grade 3 IDH-mutant astrocytoma; grade 4 IDH-mutant astrocytoma, and grade 4 IDH wild-type glioblastoma (GB). Radiotherapy (RT) and chemotherapy (CTX) are the current standard of care for patients with newly diagnosed HGG. Several clinically relevant molecular markers that assist in diagnosis and prognosis have recently been identified. The treatment for recurrent high-grade gliomas is not well defined and decision-making is usually based on prior strategies, as well as several clinical and radiological factors. Whereas the prognosis for GB is grim (5-year survival rate of 5-10%) outcomes for the other high-grade gliomas are typically better, depending on the molecular features of the tumor. The presence of neurological deficits and seizures can significantly impact quality of life.

Intracranial Relapse in Pediatric Sarcoma.

Advances in local control techniques, chemotherapy regimens, and imaging modalities have led to improvements in both morbidity and mortality in pediatric sarcoma patients. However, approximately one-third of patients develop disease relapse and intracranial metastasis was considered rare. The incidence of sarcoma brain metastasis is thought to have increased and is associated with grim outcomes. This was a retrospective study of 3 deidentified patient charts illustrating the possibility of the central nervous system as a potential site for pediatric sarcoma relapse and investigate the patterns of such relapses. We note this is the first report of infantile fibrosarcoma brain metastasis and a rare report of sarcoma lymph node metastasis. In addition, each patient was treated with targeted therapies, including entrectinib, Ruxolitnib, and pazopanib. Caregivers in cases 2 and 3 reported new-onset neurological manifestations before identification of new brain metastasis, indicating a lag in detection of new intracranial relapse in asymptomatic sarcoma patients. We suggest implementing a brief review of systems screening tool focused on concerning neurological manifestations to screen for new brain metastasis.

IDO-1 inhibitor INCB24360 elicits distant metastasis of basal extruded cancer cells in pancreatic ductal adenocarcinoma

Neoplastic cells of non-immunogenic pancreatic ductal adenocarcinoma (PDAC) express indoleamine 2,3-dioxygenase 1 (IDO-1), an immunosuppressive enzyme. The metabolites of IDO-1 in cancers provide one-carbon units that annihilate effector T cells, and recruit immunosuppressive cells. In this study we investigated how IDO-1 affected the neoplastic cell behaviors in PDACs. Using multiple markers co-labeling method in 45-µm-thick tissue sections, we showed that IDO-1 expression was uniquely increased in the neoplastic cells extruded from ducts’ apical or basal domain, but decreased in lymph metastatic cells. IDO-1+ extruding neoplastic cells displayed increased vimentin expression and decreased cytokeratin expression in PDACs, characteristics of epithelial-mesenchymal transition (EMT). However, IDO-1 expression was uncorrelated with immunosuppressive infiltrates and clinicopathological characteristics of grim outcome. We replicated basal extrusion with EMT in murine KPIC PDAC organoids by long-term IFN-γ induction; application of IDO-1 inhibitor INCB24360 or 1-MT partially reversed basal extrusion coupled EMT. Ido-1 deletion in KPIC cells deprived its tumorigenicity in immunocompetent mice, decreased cellular proliferation and macropinocytic ability, and increased immunogenicity. KPIC organoids with IFN-γ-induced basal extrusion did not accelerate distant metastasis, whereas inhibition IFN-γ-induced IDO-1 with INB24360 but not 1-MT in KPIC organoids elicited liver metastasis of subcutaneous KPIC organoid tumors, suggesting that lower IDO-1 activity accelerated distant metastasis, whereas IDO-1 was indispensable for tumorigenicity of PDAC cells and supports the survival of extruding cells.

A deceptive mass on neonatal ultrasound and a fetal brain MRI-confirmed complex dural arteriovenous fistula postnatally: illustrative case.

Dural arteriovenous fistulas (dAVFs) are direct, aberrant connections between dural arteries and cerebral veins. In neonates, delayed diagnosis results in grim outcomes. Treatment involves endovascular management because of its success and tolerability. Here, the authors present a case of a complex dAVF initially recognized with an in utero neurosonogram and fetal magnetic resonance imaging (MRI). A 21-week fetal ultrasound of a nonspecific brain mass was confirmed with fetal MRI as a 2.7-cm T1-hyperintense posterior fossa mass. Although a large flow void in the left middle cranial fossa was present, postnatal computed tomography angiography ultimately revealed a high-flow dAVF communicating with the left transverse sinus. In the early postnatal period, the patient developed hydrocephalus. After successful partial embolization, 6-week postangiogram brain MRI indicated disease progression with the development of a venous varix causing brainstem compression. Repeat embolization resulted in complete cessation of early venous drainage. Neonatal dAVFs are exceedingly rare and result in futile outcomes; however, detection in utero is possible. Although definitive therapy must be performed postnatally, constant monitoring and early delivery can prevent complications. Attention to fetal ultrasound is essential, and knowledge of fetal MRI in the detection of these complex lesions can significantly improve outcomes.

Breast Cancer-Delivered Exosomal miRNA as Liquid Biopsy Biomarkers for Metastasis Prediction: A Focus on Translational Research with Clinical Applicability.

Metastasis represents the most important cause of breast cancer-associated mortality. Even for early diagnosed stages, the risk of metastasis is significantly high and predicts a grim outcome for the patient. Nowadays, efforts are made for identifying blood-based biomarkers that could reliably distinguish patients with highly metastatic cancers in order to ensure a closer follow-up and a more personalized therapeutic method. Exosomes are nano vesicles secreted by cancer cells that can transport miRNAs, proteins, and other molecules and deliver them to recipient cells all over the body. Through this transfer, cancer cells modulate their microenvironment and facilitate the formation of the pre-metastatic niche, leading to sustained progression. Exosomal miRNAs have been extensively studied due to their promising potential as prognosis biomarkers for metastatic breast cancer. In this review, we tried to depict an overview of the existing literature regarding exosomal miRNAs that are already validated as potential biomarkers, and which could be immediately available for the clinic. Moreover, in the last section, we highlighted several miRNAs that have proven their function in preclinical studies and could be considered for clinical validation. Considering the lack of standard methods for evaluating exosomal miRNA, we also discussed the challenges and the technical aspects underlying this issue.

Anticancer Mechanisms of Berberine: A Good Choice for Glioblastoma Multiforme Therapy.

The most typical malignant brain tumor, glioblastoma multiforme (GBM), seems to have a grim outcome, despite the intensive multi-modality interventions. Literature suggests that biologically active phytomolecules may exert anticancer properties by regulating several signaling pathways. Berberine, an isoquinoline alkaloid, has various pharmacological applications to combat severe diseases like cancer. Mechanistically, it inhibits cell proliferation and invasion, suppresses tumor angiogenesis, and induces cell apoptosis. The antitumoral effect of berberine in GBM is increasingly recognized. This review sheds new light on the regulatory signaling mechanisms of berberine in various cancers, proposing its potential role as a therapeutic agent for GBM.

The Impact of Smoking on the Development and Severity of Chronic Pain.

The purpose of this review is to examine the impact of smoking and its role on the development of chronic pain and provide a critical review of recent literature. Recent studies demonstrate the bidirectional and dependent relationship between smoking and chronic pain. Those who are in pain have a more difficult time in the cessation of smoking as well as an increased sensitivity to pain during abstinence, lower confidence, and higher relapse rates. The fear of pain and the anxiety and depression that abstinence causes results in a grim outcome for long-term cessation. The dependent nature between chronic pain and smoking is affected by numerous variables. Providers should consider a multiprong approach to treating chronic pain and targeting smoking cessation treatment by providing motivational therapy, nicotine replacement, and medication therapies to prevent relapse, and providing those who are more likely to relapse with a higher level of care.

Femininity of the murderess. Feminist reading of Alexandros Papadiamantis&amp;#8217; &amp;#919; &amp;#966;&amp;#972;&amp;#957;&amp;#953;&amp;#963;&amp;#963;&amp;#945;

The purpose of this article is an examination of femininity depicted in Papadiamantis’ Φόνισσα through the elaboration on four selected masks of Frankojannou: Mother and Daughter, Christian, Witch, Murderess. The innovative contribution lies in the application of Ardener’s model of the muted group to the society of Skiathos, deeper analysis of the cause of Hadoula’s madness as well as contestation of traditional paradigm. The feminist reading of the text concludes that Papadiamantis associates womanhood with death which returns as a reoccurring motif throughout the story. Despite the grim outcome, the novel is presented as a positive example of an androtext.

Energy dissipation characteristics for AA6061 extrusions subjected to hybrid cutting/clamping at impact velocities up to 32 m/s

Novel deformation modes with favorable energy absorbing properties are critical to improving the grim outcomes associated with traffic collisions, and an understanding of the dynamic performance is necessary for practical implementation. Dynamic testing of AA6061 extrusions in T6 and T4 temper conditions subjected to hybrid cutting/clamping deformation modes was conducted utilizing a pneumatically accelerated testing apparatus with impact velocities ranging from 14 m/s to 32 m/s (1.13 kJ and 5.89 kJ of kinetic energy, respectively). This range replicated the loading conditions associated with traffic accidents and provided new insights into the previously unconsidered dynamic performance of this novel deformation mode. Complementary axial crushing tests were performed to compare the instantaneous force responses and key energy absorption performance metrics between the cutting/clamping mode and current state-of-the-art under impact. Thin-walled (ro/t≥10) circular extrusions subjected to quasi-static, 10-bladed cutting exhibited 50% greater energy absorbing capacity compared to progressive folding. However, the energy absorbing potential was approximately equal for identical extrusions subjected to 22 m/s impact velocities and thick-walled (ro/t<10) extrusions were generally outperformed by the crushing mode. The trend of reduced cutting forces with increasing velocities was attributed to a degrading extrusion/blade interface, confirmed by post-test optical examinations of the cut surfaces, and a corresponding reduction in the associated contact forces. Enhanced analytical and numerical (Eulerian) models were developed which accurately replicated the experimental findings by implementing a newly obtained velocity dependent, degrading friction coefficient with average cumulative errors of 0.084 and 0.102, respectively.

Tissue Infiltrating Immune Cells and Endometrial Cancer Prognosis

The number of patients diagnosed with endometrial cancer surpasses that of any other gynaecological cancer. This disease is usually detected early after disease onset and with current therapy 80 percent of patients with early-stage disease reach a five-year survival milestone. However, patients with advanced or recurrent disease have a grim outcome and the five-year survival rate for these patients is only about 16 percent. In several cancer types there is accumulating evidence that immune cells play a crucial role in the initiation, progression and outcome of disease. In order to provide novel and effective immunotherapeutic treatments for advanced disease endometrial cancer, an understanding of the relevance of immune cells needs to be addressed. This review briefly discusses current knowledge in the area of immune cells and how they may alter the course of endometrial cancer, as well as the implications of these cells for novel therapy and outcome.

Comprehensive Genomic Subtyping of Glioma Using Semi-Supervised Multi-Task Deep Learning on Multimodal MRI

High grade glioma (HGG) are the most common, highly infiltrative brain tumors usually with a grim outcome with low survival. Recent comprehensive genomic profiling has greatly elucidated the molecular markers in gliomas that include the mutations in isocitrate dehydrogenase (IDH), 1p/19q co-deletion and alterations in O6 methyl-guanine methyltransferase (MGMT). Prognosis of these markers can support early clinical decision making that can consequently improve the survival outcomes. Multi-modal MRI based phenotypic tools such as radiomics based multi-variate models and state-of-art convolutional neural networks (CNNs) have shown promise in identifying these genotypes. However, current techniques do not facilitate comprehensive genomic profiling of the HGG as these are focused only on a single mutation. Moreover, the models are trained on small datasets and cannot employ unlabeled data, which is abundant as pathological labelling is invasive, expensive and inaccessible in many places. In this work, we build a semi-supervised hierarchical multi-task model that can incorporate unlabeled glioma data and learn to predict multiple molecular markers simultaneously. Our framework employs the latent space from an encoder to incorporate the unlabeled data while the hierarchical multi-task model accounts for the similarity between tasks and utilizes the shared information, resulting in inductive learning that facilitates precise delineation of IDH, MGMT, 1p/19q and grade. We applied our framework to 120 labeled, 149 semi-labeled and 48 unlabeled data using T1-contrast enhanced, T2 and FLAIR images and illustrate that our model performs with an average test accuracy of 82.35% and verified the results using task wise and modality wise ablation analysis. Moreover, the class activation maps computed from each local task branch provide clinical interpretability.

Black Mental Health Matters: Bridging the Mental Health Gap in the Black Community

18 | BLACK HISTORY BULLETIN VOL. 84, NO. 2 84 No.2 BLACK MENTAL HEALTH MATTERS: BRIDGING THE MENTAL HEALTH GAP IN THE BLACK COMMUNITY By Erika Lourenco de Freitas, Ashley Franco, and Annette Teasdell Throughout the course of 2020, the world saw how the COVID-19 pandemic impacted the way people go about their daily lives. COVID-19 and its social isolation protocols have forced individuals worldwide to reevaluate their interactions with friends and family and how they take care of their physical, emotional, and psychological well-being. With such rapidly changing dynamics, it is no surprise that the pandemic has harmed both the physical and mental health of communities around the world, particularly Blacks and African Americans , as they anxiously await a return to normalcy. The effects of racism represent a serious mental health issue that stems from people being treated differently because of their phenotype (skin color, eye color, hair color, etc.).1 Due to its usefulness in analyzing racial and ethnic relations in social and institutional systems in terms of patterns and relationships between race, culture, gender, and social structures, this paper applies critical race structuralism (CRS) as a theoretical framework.2 As a theory of social change, CRS mitigates against racism and other forms of oppression and emphasizes social justice to advocate for equitable representation , access, and resources for underserved populations in education and beyond. Thus, this article’s guiding research question is: How are the COVID-19 pandemic and systemic racism impacting Black mental health? In the purview of CRS, Black health and wellness is a social justice issue that is heightened by institutionalized racism in schools and society. As the COVID-19 pandemic unfolds, more data regarding testing, infection, hospitalization, and mortality rates are becoming available, shedding light on the disparate ways the crisis is affecting specific demographic groups. The move to online learning because of COVID-19 revealed a digital divide that has led to unequal educational access for poor and minoritized students. This health crisis demonstrated the need for culturally responsive online teaching that empowers students intellectually, culturally, socially, and emotionally.3 Poor mental health has been associated with high suicide rates, such as in the historical case of Ota Benga, a Mbuti African whose maltreatment and display as an “animal” in the monkey house of the Bronx Zoo in 1906 led to his ultimate suicide.4 Despite the assumption that such overt racist practices would be socially unacceptable nowadays, the impacts of harmful attitudes or behaviors toward Black students continue to lead to disastrous health outcomes. As such, in 2019, US Representative Bonnie Watson Coleman established the Congressional Black Caucus Emergency Taskforce on Black Youth Suicide and Mental Health. Their report, Ring the Alarm: The Crisis of Black Youth Suicide in America,5 was released in December 2019 and points to the bleak reality of Black youth in the US: “Over the past decade, increases in the suicide death rate for Black youth have seen the rate rising from 2.55 per 100,000 in 2007 to 4.82 per 100,000 in 2017. Black youth under 13 years are twice as likely to die by suicide and when comparing by sex, Black males, 5 to 11 years, are more likely to die by suicide compared to their White peers.”6 In the light of such grim outcomes, one can argue that racism itself results from the poor mental health condition of those who dehumanize others and make fallacious claims of cultural and/or racial superiority. Per CRS, this is a conditioned reflex of those who hold power and use it to racialize, dehumanize, and “other” people as a conduit of their own lack of self-efficacy and ignorance. In this sense, those who de- BLACK HISTORY BULLETIN VOL. 84, NO. 2 | 19 84 No.2 humanize operate in toxic mental spaces, exhibited by racist behaviors. These actions can also be expressed in behaviors imitated from the dominant group, as internalized domination and degradation among minority groups. Thus, the oppressor and oppressed may both be impacted psychologically and physically by the perils of White racism. In the era of COVID-19, more attention should be paid to health and wellness, both...

Brazil and a Tragedy Foretold

The way Brazil handled their pandemic crisis has been an active matter of discussion worldwide. Researchers across the country, as well as the international press, have highlighted that the grim outcomes the country is experiencing are largely a consequence of the current administration’s approach to minimize the impact of the pandemic, undermining science and neglecting basic public health needs. Fifteen months into the pandemic, while many parts of the world are starting to see a return to normalcy, in Brazil, an unjustifiable delay in vaccine availability and refusal to implement or advocate for mitigating strategies has led to a continuous surge in the number of cases and deaths. The country comprises numerous areas of highly vulnerable populations, marginally protected by a fragile healthcare and social system. Behind the mantra of “The economy must come first”, individuals were discouraged from staying home, avoiding crowds, or even wearing masks (1).

COVID-19 and cardiovascular disease

Coronavirus disease 2019 (COVID-19), a spectrum of disease spanning from a barely symptomatic infection to critical illness, is caused by the new coronavirus - severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although lung injury and acute respiratory distress syndrome have been at a centre stage as the most dreadful complications of COVID-19, the heart damage has recently emerged as yet another grim outcome in the virus’s repertoire of possible complications. The cardiac involvement occurs as a direct invasion of cardiomyocytes by the virus via the angiotensin‐converting enzyme 2 (ACE2) receptors and also indirectly by the inflammatory reaction due to cytokine storm. COVID-19 increases the severity of an already pre-existing heart disease and also unmasks the cardiac symptoms in a previously undiagnosed heart disease as well. Apart from this the drugs that are repurposed and are supposed to have a preventive or a therapeutic potential are also supposedly causing cardiac side effects. In the absence of substantial database all these seem to be a hypothetical correlation and one needs to rely on clinical skills and acumen. Keywords: COVID-19; SARS-CoV-2; cardiovascular disease; acute respiratory distress syndrome

S3447 Atypical Symptomatology, a Call to Keep an Open Differential List

INTRODUCTION: Appropriate suspicion with atypical presentations can serve as a screen for dangerous conditions, especially important as these conditions may have grim outcomes. This case depicts a primary mediastinal choriocarcinoma (CCA) in a male; a rare tumor often with complicated diagnosis and treatment. According to reported cases, these neoplasms often metastasize early and can be rapidly fatal even with treatment. Of note, this malignancy was detected via thorough history taking at a gastrointestinal (GI) clinic visit. We would like to highlight the importance of maintaining awareness for rarer entities while pursuing the more common differentials. CASE DESCRIPTION/METHODS: The patient is a 42 year old male who was referred to a GI clinic for symptoms including epigastric pain and hematemesis with positive H. pylori stool antigen and initiation on quadruple therapy for the H. pylori. At the GI appointment, he reported persistent symptoms despite treatment. Upon further questioning, he also reported recent weight loss and clarified he had hemoptysis rather than hematemesis. In response to his atypical symptoms, a more ominous disease process was considered with ordering of a chest x-ray. Unfortunately, this imaging demonstrated a mediastinal lung mass with metastases. The patient was referred for further evaluation at an emergency department. A CT scan confirmed the findings and alpha-fetoprotein and beta-HCG levels were markedly elevated suggesting CCA. Testicular ultrasound did not show a primary testicular mass. Due to long term GI symptoms, the patient had endoscopic studies performed with benign results. Initial biopsies of a pulmonary mass were read as squamous cell carcinoma but repeat biopsies yielded results consistent with stage IIIC CCA. Chemotherapy was promptly initiated and now four months post-initiation of treatment, he has had improvement in symptoms, labs, and imaging markers. DISCUSSION: Primary mediastinal CCAs are exceedingly rare tumors often with poor prognoses. In this case, the malignancy was detected by a gastroenterologist recognizing an atypical presentation. The patient is now showing improved symptoms after treatment initiation. The patient could have had rapid deterioration and an ultimately fatal outcome in these past few months following had his atypical symptoms not elicited suspicion with further investigation. This report is meant to serve as a call to action to keep a broad differential when evaluating patients keeping in mind that while rare, zebras do exist.

Postoperative circulating tumor cells: An early predictor of extrahepatic metastases in patients with hepatocellular carcinoma undergoing curative surgical resection.

Postoperative extrahepatic metastases (EHM) contribute to a grim outcome in patients with hepatocellular carcinoma (HCC) who are undergoing curative surgical resection. The current study investigated the clinical value of circulating tumor cells (CTCs) in predicting EHM after curative surgery. A total of 197 patients with HCC who were undergoing curative surgical resection were assigned to a retrospective training cohort (144 patients) or a prospective validation cohort (53 patients). The CELLSEARCH system was used for the detection of CTCs prior to surgical resection and 1month thereafter. The cutoff value of CTCs was estimated using receiver operating characteristic analysis. Bonferroni correction was applied for multiple testing in a Cox proportional hazards regression model. In the training cohort, EHM was found to be associated with a higher postoperative CTC burden compared with no EHM (mean: 4.33 vs 0.52; P < .001). Receiver operating characteristic analysis demonstrated a postoperative CTC count ≥3 as the optimal cutoff value for the prediction of EHM. Patients with a postoperative CTC count ≥3 experienced a higher EHM risk (56.3% vs 5.5%) and a shorter median overall survival (31.25months vs not reached) (all P<.001). The prognostic significance of a postoperative CTC count ≥3 also applied to patient subgroups with a low EHM risk, such as those with an α-fetoprotein level ≤400ng/mL, absence of vascular invasion, well differentiation, and early tumor stage, and its predictive value was retained in patients with a continuous normal α-fetoprotein level during postoperative follow-up (all P<.05). The results were confirmed in the validation cohort. A postoperative CTC count ≥3 appears to be a surrogate marker for the prediction of EHM after curative surgical resection of HCC. More careful surveillance should be recommended to patients with a high CTC load to ensure the greater possibility of early interventions for postoperative EHM.

Incoming International Medical Graduates and the COVID-19 Pandemic: More Than Meets the Eye.

Incoming International Medical Graduates and the COVID-19 Pandemic: More Than Meets the Eye.