Features Of Advanced Disease Research Articles

Changing Clinical Presentation of Pediatric Differentiated Thyroid Cancer in Poland: A Retrospective Cohort Study Spanning 45 Years.

Background: Differentiated thyroid carcinoma (DTC) in children is uncommon; clinical presentation over recent decades is incompletely characterized. Methods: This retrospective cohort study analyzed demographic and disease characteristics of consecutive juveniles with DTC treated from 1970 to 2015 at Poland's largest pediatric DTC referral center, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, who had available records. Sex, age, histopathological characteristics, and DTC stage were documented. We aimed to identify changes in these variables over time and independent risk factors for lymph node or distant metastases. Trends in these variables were assessed using the Cochran-Armitage test and Spearman correlation. Multivariable logistic regression was performed to identify risk factors associated with lymph node or distant metastases. Results: 475 of 479 patients (99.2%) were included in the analysis; roughly half were age ≥15 years, 10%, <10 years. Papillary thyroid carcinoma (PTC) represented 88% of cases and follicular thyroid carcinoma (FTC) 11%. Tumors ≤2 cm constituted 56% of cases with relevant data; those >4 cm accounted for 12%. Multifocality was observed in 37% and extrathyroidal invasion in 22%. Lymph node metastases were noted in 59% and distant metastases in 16%. Over the observation period, significant trends among new cases included: increased proportion of adolescents >15 years; increased frequency of tumors ≤2 cm, decreased multifocality rates, and increased proportion of PTC versus FTC. Extrathyroidal invasion rates remained appreciable throughout, ranging from 17 to 28% during the 5-year study subperiods after 1990. Lymph node metastases significantly increased in frequency in the central neck, remaining consistently common in lateral sites; presence of distant metastases significantly decreased. In multivariable analysis, multifocality, extrathyroidal invasion, and tumor size were independently associated with lateral lymph node metastases and multifocality, larger tumor size, and N1b metastases with distant spread. Conclusions: Our observations of a rising proportion of diagnoses in adolescence, reductions in primary tumor size, and decreased frequency of multifocality and distant metastases may reflect increased detection of patients with less aggressive DTC at earlier disease stages. Nonetheless, we found persistently substantial rates of locoregionally advanced disease features (multifocality, extrathyroidal invasion, and lymph node metastases), which multivariable analyses suggested have significant associations with lateral lymph node and/or distant metastases.

IMPROVING THE KNOWLEDGE, RISK STRATIFICATION AND OUTCOMES IN ADVANCED HEART FAILURE. THE ISMETT HEART FAILURE REGISTRY

Abstract Background Advanced heart failure (AdHF) accounts for approximately 10% of patients in HF clinics worldwide. Clinical management of patients with AdHF remains challenging and most of the available studies focus on chronic but not advanced HF. Registry studies may provide important insights into this specific population. Methods All consecutive patients referred to our centre for AdHF therapies candidacy (left ventricular assist device (LVAD), heart transplant (HTx)) are prospectively studied and enrolled in the registry. On the same day, all patients undergo a comprehensive clinical and instrumental examination, including electrocardiogram, echocardiography, extended laboratory tests and right heart catheterisation. Most patients also undergo a cardiopulmonary exercise test and, in the case of a non–ischaemic aetiology, cardiac magnetic resonance imaging and genetic testing, if not already performed. Echocardiography is also performed to assess advanced echocardiographic measures (biventricular and atrial strain, myocardial work, 3–D chambers assessment). Results Forty–five patients were enrolled from March 1, 2023 to December 22, 2023 (enrolment rate 4.5 patients/month). Mean age was 54 years and 2/3 were male. Median disease duration was 69 (28–165) months. Non–ischemic HF was the most common aetiology with a NYHA IV prevalence of 4% (all others were in NYHA III). 31% of patients had chronic kidney disease and overall liver function was preserved. 67% of patients were treated with sacubitril/valsartan, &amp;gt; 90% were taking beta–blockers (median dose 4.8 mg bisoprolol–equivalent dose) and 84% SGLT2 inhibitors. Both standard and advanced echocardiography showed features of advanced disease. Over a median follow–up of 4 (2 – 6) months 2 (4%) patients died, 5 (11%) underwent urgent HTx and 8 (18%) underwent LVAD implantation. For most variables, there was a trend showing that patients with events were sicker but, currently, the sample size limited the statistical power. Conclusions A systematic comprehensive evaluation of patients with AdHF evaluated for advanced HF therapies could help to reduce the knowledge gap for this high–risk HF population.

Characterization of Thyroid Cancer among Hispanics in California, USA, from 2010 to 2020.

Previous studies on Hispanic thyroid cancer cases show sex disparities and an increased prevalence of large tumor sizes and nodal involvement. Here, we characterized Hispanic thyroid cancer cases in California. We identified thyroid cancer cases from 2010 to 2020 using the California Cancer Registry by sex, race/ethnicity, histology, TNM stage, tumor size, lymph node involvement, and Charlson comorbidity score. The age-adjusted incidence rate (AAIR) and age-adjusted mortality rate (AAMR) for all causes of death were calculated. A Cox proportional hazards regression analysis was performed to evaluate the mortality risk from all causes of death by race. Overall, 56,838 thyroid cancer cases were identified, including 29.75% in Hispanics. Hispanics had the highest female-to-male incidence rate ratio (IRR 3.54) and the highest prevalence of T3/T4 tumor size (28.71%), the highest N1 nodal status (32.69%), and the highest AAMR (0.79 per 100,000 people). After adjusting for demographic and tumor covariates, compared to non-Hispanic White people, Hispanic ethnicity, with an HR of 1.22 (95% CI 1.18-1.25, p < 0.0001), remained a significant independent contributor to mortality risk. Hispanics had the greatest female-to-male IRR ratio, a greater prevalence of advanced disease features at diagnosis, along with the highest AAMR and increased mortality risk despite adjustments for demographic and tumor covariates. Further investigation into other risk factors is needed.

Tumour deposits are independently associated with recurrence in colon cancer.

Tumour deposits are focal aggregates of cancer cells in pericolic fat and mesentery, distinct from vessels, nerves and lymphatics. Their presence upstages lymph node negative patients but is ignored in lymph node positive patients. We investigated the clinicopathological factors associated with tumour deposits and their impact on recurrence in lymph node positive and negative patients. Clinicopathological variables were collected from the medical records of patients with Stage I-III colon cancer who underwent resection in 2017-2019. Pathology was reviewed by a gastrointestinal pathologist. Patients with rectal cancer, metastasis, and concurrent malignancy were excluded. Tumour deposits were noted in 69 (9%) of 770 patients. They were associated with the presence of lymph node metastasis, advanced T category, poorly differentiated tumours, microsatellite stable subtype and lymphovascular and perineural invasion (p < 0.05). The presence of tumour deposits (hazard ratio 2.48, 95% CI 1.49-4.10) and of lymph node metastasis (hazard ratio 3.04, 95% CI 1.72-5.37) were independently associated with decreased time to recurrence. There was a weak correlation (0.27) between the number of tumour deposits and the number of positive lymph nodes. Tumour deposits are associated with more advanced disease and high-risk pathological features. The presence of tumour deposits and lymph node metastasis were found to be independent risk factors for decreased time to recurrence. A patient with both lymph node metastasis and tumour deposits is more than twice as likely to have recurrence compared with a patient with only lymph node metastasis. Tumour deposits independently predict recurrence and should not be ignored in lymph node positive patients.

Kidney Biopsy Findings and Clinical Outcomes of US Veterans with Inflammatory Bowel Disease

Introduction: Patients with inflammatory bowel disease (IBD; ulcerative colitis [UC] and Crohn’s disease [CD]) may have unique patterns of kidney injury related to their underlying or coexisting disease or to medications. We present the kidney biopsy findings and clinical outcomes of veterans with UC or CD from the US Department of Veteran’s Affairs (VA) health system. Methods: Histopathologic and clinical data were extracted by retrospective review of the VA electronic health record of patients with IBD and a kidney biopsy between 2000 and 2018. Incident end-stage kidney disease (ESKD) was defined as requirement of kidney replacement therapy. Statistical analyses were performed using SAS. Results: A total of 140 patients (UC: 91 and CD: 49) underwent kidney biopsy. The three most common diagnoses were IgA nephropathy (17.1%), diabetic nephropathy (14.3%), and acute interstitial nephritis (9.3%). Significant interstitial fibrosis, tubular atrophy, and arteriosclerosis were present in 45% of biopsies. Twenty-six percent of patients with UC and 20% of those with CD progressed to ESKD, with a mean time from kidney biopsy of 3.1 and 1.9 years, respectively. Forty-five percent of patients with UC and 34% of those with CD died, with a mean time from kidney biopsy of 4.3 and 4.6 years, respectively. Conclusion: Among US veterans with IBD who underwent a kidney biopsy, IgA nephropathy, diabetic nephropathy, and interstitial nephritis were among the most common findings. Additionally, features of advanced kidney disease with rapid clinical progression to ESKD or death were observed. These findings suggest a delay and possibly a low rate of diagnosis.

Elexacaftor/Tezacaftor/Ivacaftor Improves Bronchial Artery Dilatation Detected by Magnetic Resonance Imaging in Patients with Cystic Fibrosis.

Rationale: Magnetic resonance imaging (MRI) detects improvements in mucus plugging and bronchial wall thickening, but not in lung perfusion in patients with cystic fibrosis (CF) treated with elexacaftor/tezacaftor/ivacaftor (ETI). Objectives: To determine whether bronchial artery dilatation (BAD), a key feature of advanced lung disease, indicates irreversibility of perfusion abnormalities and whether BAD could be reversed in CF patients treated with ETI. Methods: A total of 59 adults with CF underwent longitudinal chest MRI, including magnetic resonance angiography twice, comprising 35 patients with CF (mean age, 31 ± 7 yr) before (MRI1) and after (MRI2) at least 1 month (mean duration, 8 ± 4 mo) on ETI therapy and 24 control patients with CF (mean age, 31 ± 7 yr) without ETI. MRI was assessed using the validated chest MRI score, and the presence and total lumen area of BAD were assessed with commercial software. Results: The MRI global score was stable in the control group from MRI1 to MRI2 (mean difference, 1.1 [-0.3, 2.4]; P = 0.054), but it was reduced in the ETI group (-10.1 [-0.3, 2.4]; P < 0.001). In the control and ETI groups, BAD was present in almost all patients at baseline (95% and 94%, respectively), which did not change at MRI2. The BAD total lumen area did not change in the control group from MRI1 to MRI2 (1.0 mm2 [-0.2, 2.2]; P = 0.099) but decreased in the ETI group (-7.0 mm2 [-8.9, -5.0]; P < 0.001). This decrease correlated with improvements in the MRI global score (r = 0.540; P < 0.001). Conclusions: Our data show that BAD may be partially reversible under ETI therapy in adult patients with CF who have established disease.

Vascular endothelial profilin-1 drives a protumorigenic tumor microenvironment and tumor progression in renal cancer

Overexpression of actin-binding protein profilin-1 (Pfn1) correlates with advanced disease features and adverse clinical outcome of patients with clear cell renal carcinoma, the most prevalent form of renal cancer. We previously reported that Pfn1 is predominantly overexpressed in tumor-associated vascular endothelial cells in human clear cell renal carcinoma. In this study, we combined invivo strategies involving endothelial cell-specific depletion and overexpression of Pfn1 to demonstrate a role of vascular endothelial Pfn1 in promoting tumorigenicity and enabling progressive growth and metastasis of renal carcinoma cells in a syngeneic orthotopic mouse model of kidney cancer. We established an important role of endothelial Pfn1 in tumor angiogenesis and further identified endothelial Pfn1-dependent regulation of several pro- (VEGF, SERPINE1, CCL2) and anti-angiogenic factors (platelet factor 4) invivo. Endothelial Pfn1 overexpression increases tumor infiltration by macrophages and concomitantly diminishes tumor infiltration by T cells including CD8+ T cells invivo, correlating with the pattern of endothelial Pfn1-dependent changes in tumor abundance of several prominent immunomodulatory cytokines. These data were also corroborated by multiplexed quantitative immunohistochemistry and immune deconvolution analyses of RNA-seq data of clinical samples. Guided by Upstream Regulator Analysis of tumor transcriptome data, we further established endothelial Pfn1-induced Hif1α elevation and suppression of STAT1 activation. In conclusion, this study demonstrates for the first time a direct causal relationship between vascular endothelial Pfn1 dysregulation, immunosuppressive tumor microenvironment, and disease progression with mechanistic insights in kidney cancer. Our study also provides a conceptual basis for targeting Pfn1 for therapeutic benefit in kidney cancer.

Higher estimated plasma volume status is associated with increased thrombotic risk and impaired survival in patients with primary myelofibrosis

Blood plasma represents a large reservoir of cytokines and other mediators of inflammation. Higher estimated plasma volume status (ePVS) has been shown to correlate with increased thrombotic risk in polycythemia vera patients, but its clinical and prognostic associations in patients with myelofibrosis are unknown which we aim to evaluate in this study. We retrospectively analysed a multicentric cohort of 238 patients with primary (PMF) and secondary myelofibrosis (SMF). Estimated plasma volume status was calculated using the Strauss-derived Duarte formula. Overall survival (OS) and time to thrombosis (TTT) considering both arterial and venous thromboses were primary endpoints of interest. Median ePVS was 5.8 dL/g and it did not significantly differ between PMF and SMF patients. Patients with more advanced disease features, more pronounced inflammation and higher comorbidity burden had higher ePVS. Higher ePVS (> 5.6 dL/g) was associated with shorter OS in PMF (unadjusted hazard ratio, HR = 2.8, 95% confidence interval, CI (1.79-4.41), P < 0.001) and SMF (unadjusted HR = 2.55, 95% CI (1.1-5.71), P =0.025) and with shorter TTT in PMF (> 7 dL/g, unadjusted HR = 4.1, 95% CI (1.44-11.59), P = 0.009) patients. Associations with OS diminished in multivariate analyses after adjustments for the dynamic-international-prognostic-scoring-system (DIPSS) and myelofibrosis-secondary-to-PV-and ET-prognostic-model (MYSEC-PM), respectively. Association with TTT remained significant independently of JAK2 mutation, white blood cell count and chronic kidney disease. Myelofibrosis patients with more advanced disease features and more pronounced inflammation have higher ePVS, indicative of expanded plasma volume. Higher ePVS is associated with impaired survival in PMF and SMF and higher thrombotic risk in PMF patients.

IRAK2, an Immune and Radiation-Response Gene, Correlates with Advanced Disease Features but Predicts Higher Post-Irradiation Local Control in Non-Metastatic and Resected Oral Cancer Patients.

Gene Ontology (GO) analysis can provide a comprehensive function analysis for investigating genes, allowing us to identify the potential biological roles of genes. The present study conducted GO analysis to explore the biological function of IRAK2 and performed a case analysis to define its clinical role in disease progression and mediating tumor response to RT. Methods: We performed a GO enrichment analysis on the RNA-seq data to validate radiation-induced gene expression. A total of 172 I-IVB specimens from oral squamous cell carcinoma patients were collected for clinical analysis, from which IRAK2 expression was analyzed by immunohistochemistry. This was a retrospective study conducted between IRAK2 expression and the outcomes of oral squamous cell carcinoma patients after radiotherapy treatment. We conducted Gene Ontology (GO) analysis to explore the biological function of IRAK2 and performed a case analysis to define its clinical role in mediating tumor response to radiotherapy. GO enrichment analysis to validate radiation-induced gene expression was performed. Clinically, 172 stage I-IVB resected oral cancer patients were used to validate IRAK2 expression in predicting clinical outcomes. GO enrichment analysis showed that IRAK2 is involved in 10 of the 14 most enriched GO categories for post-irradiation biological processes, focusing on stress response and immune modulation. Clinically, high IRAK2 expression was correlated with adverse disease features, including pT3-4 status (p = 0.01), advanced overall stage (p = 0.02), and positive bone invasion (p = 0.01). In patients who underwent radiotherapy, the IRAK2-high group was associated with reduced post-irradiation local recurrence (p = 0.025) compared to the IRAK2-low group. IRAK2 plays a crucial role in the radiation-induced response. Patients with high IRAK2 expression demonstrated more advanced disease features but predicted higher post-irradiation local control in a clinical setting. These findings support IRAK2 as a potential predictive biomarker for radiotherapy response in non-metastatic and resected oral cancer patients.

Abstract 5809: Tracking cancer stem cell expression of pancreatic and ampullary cancer organoids in response to chemotherapy

Abstract Background: Cancer stem cells (CSCs) have been described to confer resistance and aggressive disease biology in pancreatic ductal adenocarcinoma (PDAC) and ampullary carcinoma (AMPC). Patient derived cancer organoids (PCOs) are an important model of PDAC that maintain the molecular features of advanced disease and have been shown to predict drug response. This study aimed to determine the dynamics of CSC expression on the oligoclonal culture growth of three independent PCOs models. Methods: PCOs were assayed using low volume 10μL microformat in 96 well design (Ibidi, Inc). PCOs were treated with physiologic FOLFIRINOX or gemcitabine + nab-paclitaxel (nab-pac) including single agent controls. Response was assayed by growth using timecourse data from 0h to 72h using high content imaging (Cytation 5). At 72h, the PCOs were stained using four distinct CSC markers (CD44, CD133, CD117, and EpCAM). Images were aligned using thresholded root mean standard deviation of 75μm and tracked for normalized change in longest diameter. At 72h, CSC markers were tracked using % area positive from brightfield region of interest. Response was tracked by effect size Glass’s Delta (GΔ) defined as the difference between the mean of media control and treatment group normalized to standard deviation of media control. Results: PCOs maintained nuclear atypia and high nuclear-chromatin ratios consistent with matured xenografts. AMPC1 showed similar sensitivity with growth arrest by PCO Δ diameter for gem + nab-pac (mean = +2.2%, GΔ = 1.29) and FOLFIRINOX (mean = 0.0%, GΔ = 1.33). AMPC1 had CSC enrichment for CD44 after treatment with nab-pac (GΔ = 0.93), CD133 expression after treatment with gem + nab-pac (GΔ = 0.75), CD117 after treatment with nab-pac treatment (GΔ = 0.80), and EpCAM after treatment with gem + nab-pac (GΔ = 0.78). In AMPC1, interquartile analysis revealed increased CSC expression conferred reduced growth for CD133 (+72% v. 37%, p&amp;lt;0.005) and CD117 (+81% v. +25%, p&amp;lt;0.005). Normalized Δ diameter across PDAC PCOs revealed PDAC1 had reduced sensitivity to gem + nab-pac (mean = +16.0%, GΔ = 1.2) vs. PDAC2 (Mean = 2.1%, GΔ = 1.65). PDAC1 had CSC enrichment with increased % area of CD44+ after treatment with gem + nab-pac (GΔ = 1.13). In PDAC2, interquartile analysis revealed increased CSC expression conferred decreased growth rate for CD133 (+65% v. +36%, p&amp;lt; 0.005) and CD117 (+75% v. +38%, p&amp;lt;0.005). Conclusions: PDAC and AMPC PCOs reveal oligoclonal expression of CSC markers within a population. Increased CSC expression for CD133 and CD117 within a population consistently revealed decreased growth within an organoid population. CSC expression (CD44, CD133, CD117, and EpCAM) was found to be enriched under therapeutic challenge with gem and nab-pac containing chemotherapy. This work supports the oligoclonal and dynamic nature of CSCs for pancreaticobiliary cancers in response to therapeutic challenge. Citation Format: Eleanor Riedl, Austin Stram, MD Shahadat Hossan, Ethan S. Lin, Luke Koeppel, Jamie Warner, Sam Lubner, Stephanie McGregor, Wei Zhang, Jeremy Kratz. Tracking cancer stem cell expression of pancreatic and ampullary cancer organoids in response to chemotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5809.

CT imaging features regarding ground-glass nodules and solid lesions reflect prognostication of synchronous multiple lung adenocarcinoma.

The prognosis of synchronous multiple lung adenocarcinoma (SMLA) dramatically differs due to its nature of multiple primaries or intrapulmonary metastases. This study aimed to assess computed tomography (CT)-reflected SMLA features regarding ground-glass nodules (GGNs) and solid lesions and their correlation with prognostication. One seventy eight SMLA patients who underwent surgical resection were reviewed. According to preoperative CT features, patients were categorized as: multiple GGN (MG) group: MGs without solid lesions; solid plus GGN (SPG) group: one solid lesion and at least one GGN; multiple solid (MS) group: MS lesions, with or without GGNs. Clinical characteristics, disease-free survival (DFS), and overall survival (OS) were retrieved. Largest tumor size (P < .001) and lymph-node metastasis prevalence (P < .001) were different among three groups, which were highest in the MS group, followed by the SPG group, and lowest in the MG group. Besides, the dominant tumor subtype also varied among the three groups (P < .001), while no difference in other clinical characteristics was discovered. DFS was more deteriorative in the MS group compared to the SPG group (P = .017) and MG group (P < .001), while of no difference between the SPG group and MG group (P = .128). Meanwhile, OS exhibited similar treads among the three groups. Besides, after multivariate Cox analyses adjustment, MS versus MG independently correlated with DFS (P = .030) and OS (P = .027), but SPG versus MG did not. In conclusion, preoperative CT-imaging MS lesions reflect advanced disease features and poor prognosis compared to MG and solid lesion plus GGN in SMLA patients who underwent surgical resection.

Burden, clinical presentation and risk factors of advanced HIV disease in pregnant Mozambican women

BackgroundInformation on the frequency and clinical features of advanced HIV disease (AHD) in pregnancy and its effects on maternal and perinatal outcomes is limited. The objective of this study was to describe the prevalence and clinical presentation of AHD in pregnancy, and to assess the impact of AHD in maternal and perinatal outcomes in Mozambican pregnant women.MethodsThis is a prospective and retrospective cohort study including HIV-infected pregnant women who attended the antenatal care (ANC) clinic at the Manhiça District Hospital between 2015 and 2020. Women were followed up for 36 months. Levels of CD4 + cell count were determined to assess AHD immune-suppressive changes. Risk factors for AHD were analyzed and the immune-suppressive changes over time and the effect of AHD on pregnancy outcomes were assessed.ResultsA total of 2458 HIV-infected pregnant women were enrolled. The prevalence of AHD at first ANC visit was 14.2% (349/2458). Among women with AHD at enrolment, 76.2% (260/341) were on antiretroviral therapy (ART). The proportion of women with AHD increased with age reaching 20.5% in those older than 35 years of age (p < 0.001). Tuberculosis was the only opportunistic infection diagnosed in women with AHD [4.9% (17/349)]. There was a trend for increased CD4 + cell count in women without AHD during the follow up period; however, in women with AHD the CD4 + cell count remained below 200 cells/mm3 (p < 0.001). Forty-two out of 2458 (1.7%) of the women were severely immunosuppressed (CD4 + cell count < 50 cells/mm3). No significant differences were detected between women with and without AHD in the frequency of maternal mortality, preterm birth, low birth weight and neonatal HIV infection.ConclusionsAfter more than two decades of roll out of ART in Mozambique, over 14% and nearly 2% of HIV-infected pregnant women present at first ANC clinic visit with AHD and severe immunosuppression, respectively. Prompt HIV diagnosis in women of childbearing age, effective linkage to HIV care with an optimal ART regimen and close monitoring after ART initiation may contribute to reduce this burden and improve maternal and child survival.

Significance of abnormal blood coagulation in patients with chronic myelomonocytic leukemia.

In aretrospective study, we analyzed the prevalence of subnormal prothrombin time (PT) values in 104patients with chronic myelomonocytic leukemia (CMML), their potential prognostic impact, and potential correlations with clinicolaboratory features. Reduced PT values (< 70%) were found in 45/104 (43%) patients. The median survival of patients with reduced PT values was significantly shorter than in patients with normal PT (19 vs. 49months, p = 0.006). Patients with reduced PT had higher leukocyte counts, ahigher proportion of circulating blast cells, and lower platelet counts. In patients for whom clinical information was available, there was no difference in the incidence of bleeding complications between patients with or without reduced PT. Our results show ahigh prevalence of plasmatic coagulation abnormalities in patients with CMML, which were associated with laboratory features of advanced disease. Moreover, subnormal PT values were identified as anew prognostic marker. Reduced PT values do not seem to have aclinical impact regarding bleeding complications.

MPN-541 Estimated Plasma Volume Status in Patients With Primary Myelofibrosis and Associated Thrombotic and Mortality Risks.

Blood plasma experiences substantial changes in both volume and composition in patients with chronic myeloproliferative neoplasms (MPN) and represents a large reservoir of cytokines and other mediators of inflammation. Higher estimated plasma volume status (ePVS) has recently been shown to correlate with increased thrombotic risk in polycythemia vera patients. To estimate clinical and prognostic associations of ePVS in patients with myelofibrosis. Retrospective cohort study. 6 hematology centers. 238 myelofibrosis patients, 168 with PMF, 34 with post-PV SMF and 36 with post-ET SMF. ePVS was calculated using the Strauss derived Duarte formula: (100-hematocrit (%)/hemoglobin (g/dL) and expressed as dl/g. Overall survival (OS) and time to thrombosis (TTT). Median ePVS was 5.8 dl/g and it did not significantly differ between PMF and SMF patients. Among other associations, higher ePVS was significantly associated with higher degree of bone-marrow fibrosis, absence of JAK2-mutation, lower white blood cells (WBC), platelets and hemoglobin, presence of circulatory blasts, higher C-reactive protein, higher lactate dehydrogenase, lower albumin and higher Charlson comorbidity index in an overall cohort, as well as with more pronounced splenomegaly and higher Dynamic International Prognostic Scoring System (DIPSS) risk in primary myelofibrosis (PMF) and higher Mysec-PM risk in secondary myelofibrosis (SMF) patients (P<0.05 for all analyses). Higher ePVS (>5.6 dl/g) was associated with shorter overall-survival (OS) in PMF (HR=2.8, P<0.001) and SMF (HR=2.55, P=0.025) and with shorter time-to-thrombosis in PMF (>7 dl/g, HR=4.1, P=0.009) patients. Associations with overall survival diminished in multivariate analyses after adjustments for DIPSS and Mysec-PM, respectively. Association with TTT remained significant independently of JAK2, WBC and chronic kidney disease. Myelofibrosis patients with more advanced disease features and more pronounced inflammation have higher ePVS, indicative of expanded plasma volume. Higher ePVS is associated with impaired survival in PMF and SMF and higher thrombotic risk in PMF patients.

Role of uremic toxins in vascular disease—the end of nihilism?

The liver and kidneys are the main organs involved in the metabolism and elimination of carbohydrates, fats, and proteins, as well as their breakdown products. When kidney or liver function is impaired, these metabolites accumulate and contribute to the clinical features of advanced liver disease or end-stage kidney disease (ESKD). The term “uremic toxins” was coined decades ago to describe the compounds that accumulate in ESKD. In 2003, the European Uremic Toxin Work Group listed 90 such solutes.

A Phase 1/2 Study of Single Agent Tagraxofusp, a First-in-Class CD123-Targeted Therapy, in Patients with Myelofibrosis That Is Relapsed/Refractory Following JAK Inhibitor Therapy

A Phase 1/2 Study of Single Agent Tagraxofusp, a First-in-Class CD123-Targeted Therapy, in Patients with Myelofibrosis That Is Relapsed/Refractory Following JAK Inhibitor Therapy

Kidney toxicity of phosphate: is that crystal clear yet?

Hyperphosphatemia is a well-known feature of advanced chronic kidney disease (CKD) and a major risk factor for cardiovascular events in patients with CKD, inducing calcium phosphate supersaturation and vascular calcifications.1 Although the serum phosphate level is not recognized as an independent risk factor for CKD progression, increased urinary phosphate excretion has been associated with CKD progression in small cohort studies.2,3 In experimental studies, exposure to a high-phosphate diet has been shown to accelerate kidney damage in rats with reduced nephron number induced by partial nephrectomy.

COVID-19 pandemic impact on uro-oncological disease outcomes at an Italian tertiary referral center.

PurposeTo assess differences in referral and pathologic outcomes for uro-oncology cases prior to and during the COVID pandemic, comparing clinical and pathological data of cancer surgeries performed at an academic referral center between 2019 and 2020.MethodsWe collected data of 880 prostate biopsies, 393 robot-assisted radical prostatectomies (RARP) for prostate cancer (PCa), 767 trans-urethral resections of bladder tumor (TURB) and 134 radical cystectomies (RC) for bladder cancer (BCa), 29 radical nephro-ureterectomies (RNU) for upper tract urothelial carcinoma, 130 partial nephrectomies (PN) and 12 radical nephrectomies (RN) for renal cancer, and 41 orchifunicolectomies for testicular cancer. Data of patients treated in 2019 (before COVID-19 pandemic) were compared to patients treated in 2020 (during pandemic).ResultsNo significant decline in uro-oncological surgical activity was seen between 2019 and 2020. No significant increase in time between diagnosis and surgery was observed for all considered cancers. No differences in terms of main pathologic features were observed in patients undergoing RARP, TURB, RNU, RN/PN, or orchifunicolectomy. A higher proportion of ISUP grade 3 and 4 PCa were diagnosed in 2020 at biopsy (p = 0.001), but this did not translate into worse pathological grade/stage at RARP. In 2020, more advanced disease features were seen after RC, including lymph node involvement (p = 0.01) and non-organ confined disease (p = 0.02).ConclusionNeither decline in uro-oncologic activity nor delay between diagnosis and treatment was observed at our institution during the first year of COVID-19 pandemic. No significant worsening of cancer disease features was found in 2020 except for muscle-invasive BCa.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00345-021-03842-y.

Modelling human liver fibrosis in the context of non-alcoholic steatohepatitis using a microphysiological system

Non-alcoholic steatohepatitis (NASH) is a common form of chronic liver disease characterised by lipid accumulation, infiltration of immune cells, hepatocellular ballooning, collagen deposition and liver fibrosis. There is a high unmet need to develop treatments for NASH. We have investigated how liver fibrosis and features of advanced clinical disease can be modelled using an in vitro microphysiological system (MPS). The NASH MPS model comprises a co-culture of primary human liver cells, which were cultured in a variety of conditions including+/− excess sugar, fat, exogenous TGFβ or LPS. The transcriptomic, inflammatory and fibrotic phenotype of the model was characterised and compared using a system biology approach to identify conditions that mimic more advanced clinical disease. The transcriptomic profile of the model was shown to closely correlate with the profile of patient samples and the model displayed a quantifiable fibrotic phenotype. The effects of Obeticholic acid and Elafibranor, were evaluated in the model, as wells as the effects of dietary intervention, with all able to significantly reduce inflammatory and fibrosis markers. Overall, we demonstrate how the MPS NASH model can be used to model different aspects of clinical NASH but importantly demonstrate its ability to model advanced disease with a quantifiable fibrosis phenotype.

Maximum Standardized Uptake Value on Positron Emission Tomography is Associated With More Advanced Disease and High-risk Features in Lung Adenocarcinoma

18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) has been widely used for preoperative staging of lung adenocarcinomas. The aim of this study was to determine whether a high maximum standardized uptake value (SUVmax) could correlate with pathological characteristics in those patients. We retrospectively reviewed patients with clinical stage 0-IA lung adenocarcinoma who underwent preoperative 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography followed by curative anatomical resection. To identify more advanced disease and high-risk features, representing visceral pleural involvement, pulmonary metastasis, lymph node involvement, and lymphovascular involvement in resected surgical specimens, univariate and multivariate logistic regression analyses were performed. The optimal cutoff point for the SUVmax was determined by receiver operating characteristic analysis. In 2 groups divided according to the cutoff point, the disease-free survivals were calculated and compared using the Kaplan-Meier method and the log-rank test. More advanced disease and high-risk features were identified in 55 (18.9%) of the 291 patients. SUVmax was significantly correlated with more advanced disease and high-risk features, as did the consolidation/tumor ratio on computed tomography. Only 2 (1.2%) of the 169 patients with a SUVmax <3.20 showed more advanced disease and high-risk features, compared with 43.4% of patients with a SUVmax ≥3.20. The disease-free survival was significantly higher in patients with a SUVmax <3.20 than in those with a SUVmax ≥3.20 (P=0.002). A high SUVmax correlates with more advanced disease and high-risk features in patients with clinical stage 0-IA lung adenocarcinoma. The SUVmax should be considered when deciding treatment strategy in early-stage lung adenocarcinoma.