Forgotten clientele: A systematic review of patient-centered pathology reports.

CONTEXT: Patient portals, designed to give ready access to medical records, have led to important improvements in patient care. However, there is a downside: much of the information available on portals is not designed for lay people. Pathology reports are no exception. Access to complex reports often leaves patients confused, concerned and stressed. We conducted a systematic review to explore recommendations and guidelines designed to promote a patient centered approach to pathology reporting. DESIGN: In consultation with a research librarian, a search strategy was developed to identify literature regarding patient-centered pathology reports (PCPR). Terms such as "pathology reports," "patient-centered," and "lay-terms" were used. The PubMed, Embase and Scopus databases were searched during the first quarter of 2023. Studies were included if they were original research and in English, without date restrictions. RESULTS: Of 1,053 articles identified, 17 underwent a full-text review. Only 5 studies (≈0.5%) met eligibility criteria: two randomized trials; two qualitative studies; a patient survey of perceived utility of potential interventions. A major theme that emerged from the patient survey/qualitative studies is the need for pathology reports to be in simple, non-medical language. Major themes of the quantitative studies were that patients preferred PCPRs, and patients who received PCPRs knew and recalled their cancer stage/grade better than the control group. CONCLUSION: Pathology reports play a vital role in the decision-making process for patient care. Yet, they are beyond the comprehension of most patients. No framework or guidelines exist for generating reports that deploy accessible language. PCPRs should be a focus of future interventions to improve patient care.

Use of Artificial Intelligence Chatbots in Interpretation of Pathology Reports.

Importance: Anatomic pathology reports are an essential part of health care, containing vital diagnostic and prognostic information. Currently, most patients have access to their test results online. However, the reports are complex and are generally incomprehensible to laypeople. Artificial intelligence chatbots could potentially simplify pathology reports. Objective: To evaluate the ability of large language model chatbots to accurately explain pathology reports to patients. Design, Setting, and Participants: This cross-sectional study used 1134 pathology reports from January 1, 2018, to May 31, 2023, from a multispecialty hospital in Brooklyn, New York. A new chat was started for each report, and both chatbots (Bard [Google Inc], hereinafter chatbot 1; GPT-4 [OpenAI], hereinafter chatbot 2) were asked in sequential prompts to explain the reports in simple terms and identify key information. Chatbot responses were generated between June 1 and August 31, 2023. The mean readability scores of the original and simplified reports were compared. Two reviewers independently screened and flagged reports with potential errors. Three pathologists reviewed the flagged reports and categorized them as medically correct, partially medically correct, or medically incorrect; they also recorded any instances of hallucinations. Main Outcomes and Measures: Outcomes included improved mean readability scores and a medically accurate interpretation. Results: For the 1134 reports included, the Flesch-Kincaid grade level decreased from a mean of 13.19 (95% CI, 12.98-13.41) to 8.17 (95% CI, 8.08-8.25; t = 45.29; P < .001) by chatbot 1 and 7.45 (95% CI, 7.35-7.54; t = 49.69; P < .001) by chatbot 2. The Flesch Reading Ease score was increased from a mean of 10.32 (95% CI, 8.69-11.96) to 61.32 (95% CI, 60.80-61.84; t = -63.19; P < .001) by chatbot 1 and 70.80 (95% CI, 70.32-71.28; t = -74.61; P < .001) by chatbot 2. Chatbot 1 interpreted 993 reports (87.57%) correctly, 102 (8.99%) partially correctly, and 39 (3.44%) incorrectly; chatbot 2 interpreted 1105 reports (97.44%) correctly, 24 (2.12%) partially correctly, and 5 (0.44%) incorrectly. Chatbot 1 had 32 instances of hallucinations (2.82%), while chatbot 2 had 3 (0.26%). Conclusions and Relevance: The findings of this cross-sectional study suggest that artificial intelligence chatbots were able to simplify pathology reports. However, some inaccuracies and hallucinations occurred. Simplified reports should be reviewed by clinicians before distribution to patients.

Sarcoidosis Versus Lymphoma: A Clinical Diagnostic Dilemma in a Patient With Extensive Lymphadenopathy.

Sarcoidosis is a granulomatous disease involving multiple organ systems. In its classic form, sarcoidosis is associated with non-caseating granuloma. Several differential diagnostic entities exist for sarcoidosis, including tuberculosis (TB), as well as lymphomas. In this report, we present a case of sarcoidosis in a 55-year-old male with diffuse lymphadenopathy and hepatosplenic involvement, highlighting the differential diagnostic point for this disease.

When a Lump is More Than Just a Lump: Anaplastic Large Cell Lymphoma Presenting as a Pediatric Breast Mass.

Anaplastic large cell lymphoma (ALCL) is a rare non-Hodgkin T-cell lymphoma characterized by a cluster of differentiation-30 positivity. Subtypes are characterized by positive or negative anaplastic lymphoma kinase (ALK) expression. ALCLs account for about 10% to 15% of all pediatric non-Hodgkin lymphomas and more than 90% of the cases are ALK-positive. We report a rare case of pediatric systemic ALK-negative ALCL with an atypical presentation as a painful breast mass. Despite the general benign features of most pediatric breast masses, it is important to consider malignant systemic diagnoses like the one reported here.

Pediatric Eosinophilic Esophagitis: Searching for Serologic Markers.

OBJECTIVE: Eosinophilic esophagitis (EoE) is a Th2 disease that presently is diagnosed and followed by clinical symptoms in the presence of endoscopic biopsies documenting elevated esophageal eosinophilia. To simplify clinical care, multiple studies have attempted to identify a disease specific serologic marker. None have been successful. The goal of this study was to employ custom designed Luminex multiplex bead assays to identify a reliable serologic marker for EoE. METHODS: Luminex assays were employed to measure serum levels of 11 analytes associated with EoE (IL-5, lL13, periostin, eotaxin-3, thymic stromal lymphopoietin, and immunoglobulins) in a cohort of pediatric patients consisting of active EoE (n=30), EoE in remission (n=13), and controls (n=34). RESULTS: No analyte was found to be elevated or depressed in active EoE compared to the other groups. Additionally, among the cohort with active EoE, none of the 11 analytes correlated with peak esophageal eosinophilia, endoscopic features of EoE quantitatively defined by an EoE validated endoscopic reference score (EREFS), or esophageal thickness as determined by endosonography. CONCLUSION: This is the largest prospective survey of heterogeneous markers studied in a consecutive cohort to determine whether they could diagnose or follow EoE. Although none were identified in this cohort, Luminex provides a rapid, economical tool to simultaneously screen multiple sera for proteins that are increased or decreased in disease states.

Anatomic location of colorectal cancer presents a new paradigm for its prognosis in African American patients.

Among all racial groups in the U.S., African Americans (AA) have the highest incidence of and mortality from colorectal cancer (CRC). Although socioeconomic factors, as the major contributors to racial disparity of CRC, have been widely investigated, there is a dearth of information germane to understanding its biological basis. To better elucidate the clinicopathologic features we extracted demographic, clinical, pathologic and molecular features of 500 consecutive cases of CRC diagnosed at our institution which has an AA-predominant patient population (75% of all patients). We compared data from our AA patients with those of white patients both from our institution and from SEER and the published literature for meaningful comparison. AA patients were more likely to be at an advanced disease stage (25.9% vs. 20.8%, p = 0.041), have low grade tumors (89.2% vs. 77.5%, p<0.001) in cecum (18.7% vs. 16.2%, p<0.001) and <60-years-old than white patients (31.8% vs. 26.3%, p = 0.015). The frequency of KRAS mutation was higher in AA patients than in white patients (56.8% vs. 20.7%, p<0.001). Amongst subtypes of KRAS tested in CRC, codon 12 mutation is more common in AA than white patients (85.2% vs. 68.9%, p = 0.020). Compared with other racial groups, we found AA patients to have worse disease-free survival (HR = 3.682, p = 0.035). Also, AA patients with CRC in distal (sigmoid and rectum) or proximal (cecum) colon have worse overall survival than those with CRC in middle colon (HR = 2.926, p = 0.014), a finding not observed in white patients. In both racial groups, advanced stage, perforation, and hypertension were independent prognostic factors for overall survival (p<0.05). Similarly, low body-mass index at presentation, mucinous adenocarcinoma, lymphovascular invasion, perineural invasion and KRAS mutations were independent factors significantly associated with poor disease-free survival. Collectively, our data provide new insights into the roles of clinicopathologic features, especially anatomic distribution, in predicting outcomes of CRC in AA population.

Emerging Insights on Caspases in COVID-19 Pathogenesis, Sequelae, and Directed Therapies.

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a significant global health emergency with new variants in some cases evading current therapies and approved vaccines. COVID-19 presents with a broad spectrum of acute and long-term manifestations. Severe COVID-19 is characterized by dysregulated cytokine release profile, dysfunctional immune responses, and hypercoagulation with a high risk of progression to multi-organ failure and death. Unraveling the fundamental immunological processes underlying the clinical manifestations of COVID-19 is vital for the identification and design of more effective therapeutic interventions for individuals at the highest risk of severe outcomes. Caspases are expressed in both immune and non-immune cells and mediate inflammation and cell death, including apoptosis and pyroptosis. Here we review accumulating evidence defining the importance of the expression and activity of caspase family members following SARS-CoV-2 infection and disease. Research suggests SARS-CoV-2 infection is linked to the function of multiple caspases, both mechanistically in vitro as well as in observational studies of individuals with severe COVID-19, which may further the impact on disease severity. We also highlight immunological mechanisms that occur in severe COVID-19 pathology upstream and downstream of activated caspase pathways, including innate recognition receptor signaling, inflammasomes, and other multiprotein complex assembly, inflammatory mediators IL-1ß and IL-18, and apoptotic and pyroptotic cell death. Finally, we illuminate discriminate and indiscriminate caspase inhibitors that have been identified for clinical use that could emerge as potential therapeutic interventions that may benefit clinical efforts to prevent or ameliorate severe COVID-19.

Evaluation of the incidence and clinical significance of WT-1 expression in uterine serous carcinoma.

BACKGROUND: Wilms tumor gene 1 (WT1) expression is a hallmark of ovarian serous carcinoma and considered to be diagnostic marker of these tumors, differentiating them from uterine serous carcinoma (USC), historically thought to rarely express WT1. However, more recent data indicates a significant percentage of USC may express WT1. The clinical implications of WT1 positivity in USC remain unclear. METHODS: A multicenter retrospective analysis of patients with USC was conducted from 2000 to 2019. Inclusion criteria were patients who had undergone comprehensive surgical staging/tumor debulking with archival tissue available for WT1 assessment via immunohistochemistry (IHC). Chemosensitive patients were defined as those recurring >6 months from last platinum-based chemotherapy. Progression free survival (PFS) and overall survival (OS) analysis was performed using Kaplan-Meier estimates. Multivariate analysis (MVA) was performed using Cox proportional hazards model. RESULTS: WT1 status was evaluated in 61 patients with USC. 13 (21.3%) were positive for WT1 by IHC. Stage distribution included 32% stage I, 5% stage II, 25% stage III and 38% stage IV. There was no difference in the stage (p = 0.158), race (p = 0.227) or distribution of recurrence sites (p = 0.581) between WT1 positive and WT1 negative tumors. The majority of patients were chemosensitive (63%). Chemosensitivity was significantly improved in WT1 positive (92.3%) vs. WT1 negative tumors (55.8%) (p = 0.016). We observed a trend towards improved PFS among WT1 positive tumors (21 vs. 16-months, respectively) (p = 0.544). On MVA, stage (p < 0.001) and chemosensitivity (p < 0.001) were independent predictors of PFS. CONCLUSIONS: WT1 positivity is observed in over 20% of USC. WT1 expression is associated with improved chemosensitivity which may contribute to improvements in PFS.

Caspases and therapeutic potential of caspase inhibitors in moderate-severe SARS-CoV-2 infection and long COVID.

BACKGROUND: COVID-19 can present with lymphopenia and extraordinary complex multiorgan pathologies that can trigger long-term sequela. AIMS: Given that inflammasome products, like caspase-1, play a role in the pathophysiology of a number of co-morbid conditions, we investigated caspases across the spectrum of COVID-19 disease. MATERIALS & METHODS: We assessed transcriptional states of multiple caspases and using flow cytometry, the expression of active caspase-1 in blood cells from COVID-19 patients in acute and convalescent stages of disease. Non-COVID-19 subject presenting with various comorbid conditions served as controls. RESULTS: Single-cell RNA-seq data of immune cells from COVID-19 patients showed a distinct caspase expression pattern in T cells, neutrophils, dendritic cells, and eosinophils compared with controls. Caspase-1 was upregulated in CD4+ T-cells from hospitalized COVID-19 patients compared with unexposed controls. Post-COVID-19 patients with lingering symptoms (long-haulers) also showed upregulated caspase-1activity in CD4+ T-cells that ex vivo was attenuated with a select pan-caspase inhibitor. We observed elevated caspase-3/7levels in red blood cells from COVID-19 patients compared with controls that was reduced following caspase inhibition. DISCUSSION: Our preliminary results suggest an exuberant caspase response in COVID-19 that may facilitate immune-related pathological processes leading to severe outcomes. Further clinical correlations of caspase expression in different stages of COVID-19 will be needed. CONCLUSION: Pan-caspase inhibition could emerge as a therapeutic strategy to ameliorate or prevent severe COVID-19.

A Perplexing Case of Recurrent Abscess-Like Lesions: Insights Into Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type.

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is one of the rarest forms of primary cutaneous lymphomas (PCLs) and it confers a poor prognosis. Diagnosis of PCDLBCL-LT can be challenging and complex as it can manifest with a myriad of dermatological presentations. However, early treatment with chemo-radiation leads to an appropriate response. We present the case of a 66-year-old female with a history of polymyositis and interstitial lung disease on immunosuppression who presented to our institution with recurrent abscess-like lesions localized to buttocks that were later biopsied and diagnosed as the leg-type variant of PCL. She received chemotherapy with the rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen and subsequent involved-site radiation therapy (ISRT), which resulted in complete remission. The patient was later followed up and remained in remission for years.

Usefulness of the Eosinophilic Esophagitis Histologic Scoring System in Distinguishing Active Eosinophilic Esophagitis From Remission and Gastroesophageal Reflux Disease.

BACKGROUND: Eosinophilic esophagitis (EoE) is defined as esophageal dysfunction in the presence of > 15 intraepithelial eosinophils per high-power field (eos/hpf) in either the mid or distal esophagus. The current focus of EoE pathologic evaluation is the peak eosinophil count (PEC), although histologic features other than eosinophilic inflammation are also commonly observed. In addition, histologic variance between the mid and distal esophagus in EoE has not been rigorously studied. The aim of our study was to utilize a recently developed EoE histologic scoring system (EoEHSS) to compare the mid and the distal esophageal histology in patients with active EoE (EoE-A), EoE in remission (EoE-R), and gastroesophageal reflux disease (GERD). METHODS: EoEHSS was used to prospectively evaluate the severity and extent of changes in multiple histopathologic features (PEC; basal zone hyperplasia (BZH); eosinophilic abscesses (EA); eosinophil surface layering (ESL); dilated intercellular spaces (DIS); surface epithelial alteration (SEA); dyskeratotic epithelial cells (DEC); lamina propria fibrosis (LPF)) in the mid and distal esophageal biopsies in 85 pediatric patients at a tertiary medical center. These patients were divided into three cohorts: EoE-A (n = 36), EoE-R (n = 12) and GERD (n = 37). RESULTS: Total grade (severity) and stage (extent) scores were significantly higher in EoE-A compared to EoE-R and GERD patients in both the mid and the distal esophagus. The mean total grade scores in the mid esophagus, but not the distal esophagus remained higher in EoE-R as compared to GERD patients. Specific histopathologic features independent of PEC were different in distal and mid esophagus in EoE-A. About one-half of children with active EoE had different EoEHSS scores in their mid and distal esophageal biopsies. CONCLUSIONS: EoEHSS yields histologic insights beyond those derived from PEC and helps in more objective, reproducible and accurate diagnosis of EoE and GERD. It also provides a more comprehensive understanding into the pathophysiology of EoE.

Mixed and nonvaccine high risk HPV types are associated with higher mortality in Black women with cervical cancer.

We studied the incidence of HPV genotypes in mostly Black women with cervical carcinoma and correlated histopathologic tumor characteristics, immune markers and clinical data with survival. Disease-free survival (DFS) and overall survival (OS) were recorded for 60 months post-diagnosis. Fifty four of the 60 (90%) patients were Black and 36 (60%) were < 55 years of age. Of the 40 patients with typeable HPV genotypes, 10 (25%) had 16/18 HPV genotypes, 30 (75%) had one of the non-16/18 HPV genotypes, and 20 (50%) had one of the 7 genotypes (35, 39, 51, 53, 56, 59 and 68) that are not included in the nonavalent vaccine. Mixed HPV infections (≥ 2 types) were found in 11/40 (27.5%) patients. Patients infected with non-16/18 genotypes, including the most common genotype, HPV 35, had significantly shorter DFS and OS. PD-L1 (p = 0.003), MMR expression (p = 0.01), clinical stage (p = 0.048), histologic grade (p = 0.015) and mixed HPV infection (p = 0.026) were independent predictors of DFS. A remarkably high proportion of cervical cancer cells in our patients expressed PD-L1 which opens the possibility of the use of immune checkpoint inhibitors to treat these cancers. Exclusion of the common HPV genotypes from the vaccine exacerbates mortality from cervical cancer in underserved Black patients.

Long-term immunosuppression and multiple transplants predispose systemic lupus erythematosus patients with cytopenias to hematologic malignancies.

ABSTRACT: Cytopenias in systemic lupus erythematosus (SLE) require clinical and laboratory workup and bone marrow (BM) examination to determine the cause and for appropriate patient management. Common causes include an increase in SLE activity, immune-mediated hemolysis, iron deficiency, antiphospholipid antibody syndrome, infection, or the effect of medications. We retrospectively evaluated the clinical and laboratory findings of patients with SLE and cytopenias who had undergone BM studies to determine the indicators of malignancy.We retrospectively reviewed medical records of patients with SLE who presented with cytopenias for their disease course, medications, laboratory parameters and documented the spectrum of morphological changes in BM including CD34 expression.Twenty patients with SLE had undergone BM biopsy for evaluation of cytopenias. 14/20 (70%) of the patients had reactive BM, and the rest had hematologic malignancies involving the BM. Of these 14 patients, 8 had hypocellular marrow with loss of precursor cells (low CD34), 4 had left shift in myeloid lineage, 3 had serous atrophy, and 1had multilineage dysplasia. The 6 patients with hematologic malignancies included 2 with diffuse large B cell lymphoma, and one each of natural killer/T cell lymphoma, post-transplant lymphoproliferative disorder, Hodgkin lymphoma, and myelodysplastic syndrome evolving to acute myelogenous leukemia. The presence of autoantibodies, SLE activity, and lupus nephritis were comparable in patients with and without neoplasia. However, the duration of the use of multiple immunosuppressants, years since renal transplant (22 vs 10), multiple transplants, and the presence of other autoimmune diseases were greater in those with neoplasia. Two of the 14 patients with non-neoplastic BM and 1 with the neoplastic BM had nonhematological malignancy.Clinical and laboratory findings, the number of transplants, and the use of immunosuppressive agents can guide physicians to identify patients with a higher risk of developing hematologic malignancy. BM findings of cytopenia in SLE are often due to increased disease activity causing global cell death and dysmaturation. SLE patients presenting with cytopenias, with a history of long-term exposure to immunosuppressive drugs, should be regularly screened for hematologic and nonhematologic malignancies.

Validation of inducible basophil biomarkers: Time, temperature and transportation.

BACKGROUND: The short stability window of several hours from blood collection to measuring basophil activation has limited the use of flow cytometry-based basophil activation assays in clinical settings. We examine if it is possible to extend this window to 1 day allowing for shipment of samples between laboratories. Several options exist for reporting the results including reporting all the measured values directly, calculating ratios and reporting a single value covering all measured results. Each of these options have different stability and value to the physician. METHODS: Whole blood samples from peanut allergic patients were stimulated with four different peanut concentrations at Day 0, Day 1, and Day 2. Samples were stored under temperature-controlled conditions. Flow cytometry was used to analyze the samples. The basophil activation and degranulation were measured as percentage of positive CD63 basophils and CD203c MFI fold change. Shipped samples were transported under ambient conditions. RESULTS: The results show that CD63 is a stable marker at Day 1. The CD203c ratio decreases significantly at Day 1. Calculating the CD63/IgE ratio proves to be more stable than CD63 alone. The most stable readouts are the semi-quantitative results and the trajectory of the dose response curve. Finally, we confirmed that the stability can be extended to samples shipped overnight to the laboratory. CONCLUSIONS: It is possible to extend the stability of the basophil activation assay to 1 day for samples stored at 18-25°C as well as samples shipped under ambient conditions as long as the temperature is within the 2-37°C range.

Higher comorbidities and early death in hospitalized African-American patients with Covid-19.

BACKGROUND: African-Americans/Blacks have suffered higher morbidity and mortality from COVID-19 than all other racial groups. This study aims to identify the causes of this health disparity, determine prognostic indicators, and assess efficacy of treatment interventions. METHODS: We performed a retrospective cohort study of clinical features and laboratory data of COVID-19 patients admitted over a 52-day period at the height of the pandemic in the United States. This study was performed at an urban academic medical center in New York City, declared a COVID-only facility, serving a majority Black population. RESULTS: Of the 1103 consecutive patients who tested positive for COVID-19, 529 required hospitalization and were included in the study. 88% of patients were Black; and a majority (52%) were 61-80 years old with a mean body mass index in the "obese" range. 98% had one or more comorbidities. Hypertension was the most common (79%) pre-existing condition followed by diabetes mellitus (56%) and chronic kidney disease (17%). Patients with chronic kidney disease who received hemodialysis were found to have lower mortality, than those who did not receive it, suggesting benefit from hemodialysis Age > 60 years and coronary artery disease were independent predictors of mortality in multivariate analysis. Cox proportional hazards modeling for time to death demonstrated a significantly high ratio for COPD/Asthma, and favorable effects on outcomes for pre-admission ACE inhibitors and ARBs. CRP (180, 283 mg/L), LDH (551, 638 U/L), glucose (182, 163 mg/dL), procalcitonin (1.03, 1.68 ng/mL), and neutrophil:lymphocyte ratio (8.3:10.0) were predictive of mortality on admission and at 48-96 h. Of the 529 inpatients 48% died, and one third of them died within the first 3 days of admission. 159/529patients received invasive mechanical ventilation, of which 86% died and of the remaining 370 patients, 30% died. CONCLUSIONS: COVID-19 patients in our predominantly Black neighborhood had higher in-hospital mortality, likely due to higher prevalence of comorbidities. Early dialysis and pre-admission intake of ACE inhibitors/ARBs improved patient outcomes. Early escalation of care based on comorbidities and key laboratory indicators is critical for improving outcomes in African-American patients.

SARS-CoV-2 specific antibody and neutralization assays reveal the wide range of the humoral immune response to virus.

Development of antibody protection during SARS-CoV-2 infection is a pressing question for public health and for vaccine development. We developed highly sensitive SARS-CoV-2-specific antibody and neutralization assays. SARS-CoV-2 Spike protein or Nucleocapsid protein specific IgG antibodies at titers more than 1:100,000 were detectable in all PCR+ subjects (n = 115) and were absent in the negative controls. Other isotype antibodies (IgA, IgG1-4) were also detected. SARS-CoV-2 neutralization was determined in COVID-19 and convalescent plasma at up to 10,000-fold dilution, using Spike protein pseudotyped lentiviruses, which were also blocked by neutralizing antibodies (NAbs). Hospitalized patients had up to 3000-fold higher antibody and neutralization titers compared to outpatients or convalescent plasma donors. Interestingly, some COVID-19 patients also possessed NAbs against SARS-CoV Spike protein pseudovirus. Together these results demonstrate the high specificity and sensitivity of our assays, which may impact understanding the quality or duration of the antibody response during COVID-19 and in determining the effectiveness of potential vaccines.

Comparative Genomics Reveals Distinct Immune-oncologic Pathways in African American Men with Prostate Cancer.

PURPOSE: The role of immune-oncologic mechanisms of racial disparities in prostate cancer remains understudied. Limited research exists to evaluate the molecular underpinnings of immune differences in African American men (AAM) and European American men (EAM) prostate tumor microenvironment (TME). EXPERIMENTAL DESIGN: A total of 1,173 radiation-naïve radical prostatectomy samples with whole transcriptome data from the Decipher GRID registry were used. Transcriptomic expressions of 1,260 immune-specific genes were selected to assess immune-oncologic differences between AAM and EAM prostate tumors. Race-specific differential expression of genes was assessed using a rank test, and intergene correlational matrix and gene set enrichment was used for pathway analysis. RESULTS: AAM prostate tumors have significant enrichment of major immune-oncologic pathways, including proinflammatory cytokines, IFNα, IFNγ, TNFα signaling, ILs, and epithelial-mesenchymal transition. AAM TME has higher total immune content score (ICSHIGH) compared with 0 (37.8% vs. 21.9%, P = 0.003). AAM tumors also have lower DNA damage repair and are genomically radiosensitive as compared with EAM. IFITM3 (IFN-inducible transmembrane protein 3) was one of the major proinflammatory genes overexpressed in AAM that predicted increased risk of biochemical recurrence selectively for AAM in both discovery [HRAAM = 2.30; 95% confidence interval (CI), 1.21-4.34; P = 0.01] and validation (HRAAM = 2.42; 95% CI, 1.52-3.86; P = 0.0001) but not in EAM. CONCLUSIONS: Prostate tumors of AAM manifest a unique immune repertoire and have significant enrichment of proinflammatory immune pathways that are associated with poorer outcomes. Observed immune-oncologic differences can aid in a genomically adaptive approach to treating prostate cancer in AAM.

CCR5 inhibition in critical COVID-19 patients decreases inflammatory cytokines, increases CD8 T-cells, and decreases SARS-CoV2 RNA in plasma by day 14.

OBJECTIVE: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is now a global pandemic. Emerging results indicate a dysregulated immune response. Given the role of CCR5 in immune cell migration and inflammation, we investigated the impact of CCR5 blockade via the CCR5-specific antibody leronlimab on clinical, immunological, and virological parameters in severe COVID-19 patients. METHODS: In March 2020, 10 terminally ill, critical COVID-19 patients received two doses of leronlimab via individual emergency use indication. We analyzed changes in clinical presentation, immune cell populations, inflammation, as well as SARS-CoV-2 plasma viremia before and 14 days after treatment. RESULTS: Over the 14-day study period, six patients survived, two were extubated, and one discharged. We observed complete CCR5 receptor occupancy in all donors by day 7. Compared with the baseline, we observed a concomitant statistically significant reduction in plasma IL-6, restoration of the CD4/CD8 ratio, and resolution of SARS-CoV2 plasma viremia (pVL). Furthermore, the increase in the CD8 percentage was inversely correlated with the reduction in pVL (r = -0.77, p = 0.0013). CONCLUSIONS: Our study design precludes clinical efficacy inferences but the results implicate CCR5 as a therapeutic target for COVID-19 and they form the basis for ongoing randomized clinical trials.

Three metachronous primary lung cancers in a chronic smoker: A case report and review of the literature.

RATIONALE: Lung cancer is a leading cause of cancer-related deaths. Smoking is major risk factor for initial and subsequent lung cancer especially in active smokers. Treatment of subsequent lung cancer depends on whether it is synchronous or metachronous. We report a rare case of triple metachronous lung cancer and review of literature of patients with triple metachronous cancers. This will be the second case reported of triple metachronous lung cancer. PATIENT CONCERNS: A 60-year-old male, active smoker with diabetes mellitus, chronic obstructive pulmonary disease (COPD) and peripheral arterial disease presented with cough and hemoptysis. Initial computed tomography (CT) scan showed right upper lobe spiculated mass. DIAGNOSIS: He underwent transthoracic needle biopsy for right upper lobe mass, showing primary lung adenocarcinoma (ADC)-Stage-IIIA. He continued to smoke and 9-years later had new left upper lobe spiculated nodule, which on surgical resection showed squamous cell carcinoma (SCC)-Stage-IA1. Despite counselling on smoking cessation, he was unable to quit. Six months later, he presented with shortness of breath and CT chest showing right hilar adenopathy in right upper and lower lobes. He underwent transbronchial biopsies of lesion which showed small cell lung carcinoma (SCLC). INTERVENTIONS: His initial lung ADC-Stage-IIIA, was treated with chemotherapy, weekly thoracic radiation and additional chemotherapy cycles. Nine years later, his left upper lobe mass showing SCC-Stage-IA1 was deemed curative after apical resection and he was kept on surveillance. Six months later, after diagnosis of SCLC in right upper and lower lobe, patient was not a candidate for systemic chemotherapy due to poor performance status and opted for hospice care. OUTCOMES: His initial lung ADC-Stage-IIIA showed complete radiological response with chemotherapy and radiation. Subsequent SCC-Stage-IA1 was deemed curative after resection. Due to his poor performance status, he was not a candidate for chemotherapy for SCLC and patient opted for hospice care. LESSONS: Smoking is a major risk factor for developing lung cancer and with continued smoking, patients are at higher risk for developing subsequent primary lung cancers. We recommend, patients with lung cancer must quit smoking, and those who do not, should remain on long-term surveillance.

Immune-Related Gene Expression and Cytokine Secretion Is Reduced Among African American Colon Cancer Patients.

Background: Colorectal cancer is the third most deadly cancer among African Americans (AA). When compared to Caucasian Americans (CA), AA present with more advanced disease and lower survival rates. Here, we investigated if differences in tumor immunology could be contributive to disparities observed between these populations. Methods: We examined gene expression of tumor and non-tumor adjacent tissues from AA and CA by whole transcriptome sequencing, and generated scores for immune cell populations by NanoString. In addition, we utilized "The Cancer Genome Atlas" (TCGA) database from AA and CA as a validation cohort. Finally, we measured the secretion of cytokines characteristic of effector T helper cell (Th) subsets by ELISA using plasma from each AA and CA participant. Results: Colon tumors from AA patients showed significant fold-change increase in gene expression when compared to CA for FOXP3 (6.22 vs. 3.22), IL1B (103 vs. 11.4) and IL8 (220 vs. 28.9) (p < 0.05). In contrast, among CA we observed statistically higher gene expression of markers associated with antitumor activity such as GZMB (Granzyme B), IFNG and the immunotherapy targets PDL1 (CD274) and CTLA4 (p < 0.05). TCGA data validated our observed higher gene expression of GZMB and PDL1 in CA patients when compared to AA. Notably, our observations on immune cell populations show that AA tumors have significantly higher number of exhausted CD8+ cells (p < 0.01), mast cells (p < 0.02) and increased T regulatory cells when compared to CA. AA colon cancer patients differed from CA in cytokine production patterns in plasma (i.e., reduced IL-12). Conclusions: Our study demonstrates significant differences of the immunological profiles of colon tumors from AA compared to CA that suggest a deficiency of appropriate immune defense mechanisms in terms of gene expression, recruitment of immune cells and systemic secretion of cytokines. As such, these immune differences could be mitigated through population-specific therapeutic approaches.