Unfavorable Disease Research Articles

Stereotactic Body Radiation Therapy and High-Dose Rate Brachytherapy Boost in Combination with Intensity Modulated Radiation Therapy for Localized Prostate Cancer: A Single-Institution Cohort Study

The use of dose-escalated external beam radiation (EBRT) and brachytherapy (BT) boost with ADT has emerged as an option with superior biochemical control compared to dose-escalated EBRT alone. BT is traditionally delivered using low-dose rate techniques, but more recently high-dose rate (HDR) BT has also emerged as a boost option for these patients with promise of low toxicity rates. SBRT is a favorable modality for monotherapy for low and intermediate risk group patients, however its safety and efficacy as a boost in combination with EBRT is less well understood. The aim of this study is to compare SBRT boost, HDR boost and LDR boost for localized prostate cancer. A single-institution retrospective chart review was performed of men receiving EBRT delivered using intensity modulated RT and either SBRT boost (650cGy x 3), HDR-BT boost (1500cGy x 1), or LDR boost with I-125 (110Gy). Of patients treated w/ SBRT boost, 39 (80%) were treated with an SIB to the MRI-detectable lesion(s) to 700cGy x 3. Treatment characteristics for each strategy were reviewed and on-treatment toxicity outcomes for each of the cohorts were compared using Chi-square tests. From 2017-2022, 49 patients were treated with EBRT+SBRT boost, 44 patients received EBRT+ HDR-BT boost, and 46 patients received EBRT+ LDR-BT boost. The average age of patients included in the study was 71.2 years (median age 69.55 years, range 51.42-83.70 years) with average baseline PSA of 11 (median 7.6, range 3.3-64). In addition, 55% of the patients had high-risk/very high-risk disease, 39% had unfavorable intermediate disease and 6% had favorable intermediate disease. 139 patients received androgen deprivation therapy (93%). There were no differences in these baseline demographics and clinical or treatment factors between SBRT, HDR and LDR boost (p>0.05). The median dose/fx of EBRT was 4500cGy/25 fx (range 4500-5040cGy/23-28 fractions). At the end of treatment, 69% of the patients had 0-1 change in nocturia. There is an increase in nocturia episodes of 2-3 from baseline in 27% of the patients, while 4% had an increase in nocturia episodes of 4 or more from baseline with no difference between the SBRT, HDR and LDR boost. At baseline 36 patients (26%) reported urinary frequency symptoms, increasing to 80 patients (58%) by end of treatment with no difference between the SBRT, HDR and LDR boost. Similarly, there was a trend to increased use of urinary modifiers at end of treatment in patients treated with EBRT+HDR boost compared to EBRT+SBRT and EBRT+ LDR boost (89% vs. 71% v 72% respectively). There was no significant difference in acute urinary toxicity and nocturia between SBRT, HDR and LDR boost (p>0.05).

Mitochondrial dysfunction, lipids metabolism, and amino acid biosynthesis are key pathways for COVID-19 recovery

The metabolic alterations caused by SARS-CoV-2 infection reflect disease progression. To analyze molecules involved in these metabolic changes, a multiomics study was performed using plasma from 103 patients with different degrees of COVID-19 severity during the evolution of the infection. With the increased severity of COVID-19, changes in circulating proteomic, metabolomic, and lipidomic profiles increased. Notably, the group of severe and critical patients with high HRG and ChoE (20:3) and low alpha-ketoglutaric acid levels had a high chance of unfavorable disease evolution (AUC= 0.925). Consequently, patients with the worst prognosis presented alterations in the TCA cycle (mitochondrial dysfunction), lipid metabolism, amino acid biosynthesis, and coagulation. Our findings increase knowledge regarding how SARS-CoV-2 infection affects different metabolic pathways and help in understanding the future consequences of COVID-19 to identify potential therapeutic targets.

Predictors of disease course and long-term outcomes of idiopathic intracranial hypertension in children and adolescents.

This study provides insights into predictive factors for an unfavorable disease course, persistent headaches, and poor visual outcomes in patients with childhood IIH. Patients with persistent headaches may have a variant of a chronic pain syndrome warranting a different therapeutic approach. • Childhood-onset Idiopathic Intracranial hypertension (IIH) is a heterogenous disease. The knowledge on disease trajectory and long-term outcomes and its predictors is limited. • A higher opening pressure and factors suggestive of the metabolic syndrome predict an unfavorable disease coursewhereasfemale sex and disease recurrence are significantly associated with poor visual outcomes • A third of the patients diagnosed with IIH experience ongoing headachesdespite achieving favorable visual outcomes.This subset, characterized by lower disease-severity indicators at onset may represent a distinct subgroup warranting a different therapeutic approach.

Characteristics of euthyroid sick syndrome in patients with breast cancer

Purpose. Determination of thyroid hormones (TH) and cortisol levels in blood in patients with breast cancer (BC) without previously detected endocrine pathology in the anamnesis.Patients and methods. Twenty-five primary luminal A breast cancer patients before and aſter surgical removal of the tumour and 25 breast cancer patients with secondary metastatic brain lesions were examined. The levels of total and free forms of TH (T4, FT4, T3 FT3) and cortisol were determined in serum by RIA method.Results. Before treatment in all patients with breast cancer the level of T3 was decreased 1.3 times and FT3 was increased 1.3 times (p < 0.05) against the background of normal TTH content. In 80 % of patients, blood cortisol concentration was 2 times higher than normal, and in 16 % of patients, T4 level was 1.8 times higher than normal (p < 0.05). Aſter tumour removal, FT3 levels in all patients and cortisol levels in 40 % of patients did not differ from normal. T4 content in 40 % of patients, and T3 and TTH in 28 % of women were above normal. A distinctive feature of patients with brain metastases of breast cancer was low T4 and cortisol levels in 36 % of patients against the background of low T3 levels.Conclusions. Euthyroid sick syndrome was detected in all patients with BC: low serum T3 levels against the background of normal serum levels of TTH. Patients with primary BC were characterized by high concentrations of FT3 and cortisol, which could promote proliferation of malignant cells and decrease antitumour immunity. The condition of 1/3 of patients with brain metastases was aggravated by low levels of T4 and cortisol which could indicate the depletion of the main regulatory systems and an unfavorable disease prognosis.

Mild Crigler-Najjar Syndrome with Progressive Liver Disease-A Multicenter Retrospective Cohort Study.

Crigler-Najjar Syndrome (CNS) with residual activity of UDP-glucuronosyltransferase 1A1 (UGT1A1) and no need for daily phototherapy is called mild Crigler-Najjar Syndrome. Most of these patients need medical treatment for enzyme induction (phenobarbital) to lower blood levels of unconjugated bilirubin (UCB). Apart from this, no long-term problems have been described so far. The phenotype of patients with the homozygous pathogenic variant c.115C>G p.(His39Asp) in UGT1A1 is described as variable. Clinical observations of our patients led to the assumption that patients with variant c.115C>G have a mild CNS phenotype while having a high risk of developing progressive liver disease. For mild CNS disease, progressive liver disease has not been described so far. Therefore, we conducted a retrospective multicenter analysis of 14 patients with this particular variant, aiming for better characterization of this variant. We could confirm that patients with variant c.115C>G have a high risk of progressive liver disease (seven of fourteen), which increases with age despite having a very mild CNS phenotype. Earlier predictors and causes for an unfavorable disease course are not detectable, but close follow-up could identify patients with progressive liver disease at the beginning. In conclusion, these patients need close and specialized follow-up. Our study questions whether fibrosis in the CNS is really driven by high amounts of UCB or phototherapy.

Antibodies against angiotensin II receptor type 1 and endothelin A receptor are increased in COVID-19 patients.

Increased titers of autoantibodies targeting the G-protein-coupled receptors angiotensin II type 1 receptor (AT1R) and endotelin-1 type A receptor (ETAR) are associated with severe coronavirus disease 2019 (COVID-19) infection. The aim of this study was to determine whether 1) these antibodies are specifically related to COVID-19 disease pathogenesis or increased during any severe respiratory illness, 2) if they are formed during illness, and 3) if they correlate with inflammatory markers or long-term symptoms. Antibodies against AT1R, ETAR, and antinuclear antibodies (ANAs) were measured in n=40 prospectively enrolled COVID-19 patients and n=207 COVID-19 patients included in a biobank. Clinical and laboratory findings were prospectively and retrospectively assessed in both cohorts, and results were combined for analysis. The presence of auto-antibodies against AT1R or ETAR in peripheral blood was compared between hospitalized patients with COVID-19 and controls (n=39). Additionally, AT1R and ETAR titers were compared between patients with an unfavorable disease course, defined as intensive care admission and/or death during hospital admission (n=121), to those with a favorable disease course (n=126). A subset of intubated patients with severe COVID-19 were compared to intubated patients with acute respiratory distress syndrome (ARDS) due to any other cause. Significantly increased AT1R and ETAR antibody titers were found in COVID-19 patients compared to controls, while titers were equal between favorable and unfavorable COVID-19 disease course groups. On ICU, intubated patients with COVID-19 had significantly increased AT1R and ETAR titers compared to patients with ARDS due to any other cause. The titers did not correlate with baseline inflammatory markers during admission or with diffusion capacity, cognitive impairment, or fatigue measured at 3 months follow-up. In patients hospitalized for COVID-19, antibodies against AT1R and ETAR are increased compared to controls and patients with ARDS due to other causes than COVID-19. The baseline antibody titers do not correlate with inflammatory markers or long-term symptoms in this study.

Efficacy of olaparib maintenance therapy in <i>BRCA1</i> germline mutations in familial pancreatic cancer patient

Pancreatic cancer (PaCa) is one of the most aggressive and unfavourable current oncological diseases. The vast majority of patients have unresectable or metastatic disease at diagnosis. Despite considerable achievements in the drug therapy of most malignant tumours, the immediate and long-term results of the treatment of PaCa still remain extremely unsatisfactory, as overall survival at 5 years does not exceed 10%. The high molecular genetic heterogeneity, which is characteristic of pancreatic adenocarcinomas, the low frequency of driver changes, the diagnostic difficulties, and the rapid progressive deterioration of the general health condition of most patients are just a few of the reasons for the lack of highly specific treatment. Understanding that about 10–15% of pancreatic tumours are a manifestation of genetically determined syndromes has changed the pharmaceutical treatment options for this cohort of patients. BRCA1/2 mutation carrier status is one of these reasons, while the relative risk of PaCa is 2.36 in BRCA1 mutation and 3.34 in BRCA2, respectively. The PARP inhibitor therapy experience and proven efficacy allowed to successfully use this group of drugs in the treatment of BRCA-mutated ovarian and breast cancers. The double-blind, placebo-controlled phase III POLO trial showed the benefit of olaparib as maintenance therapy in BRCA-mutated PaCa. This article presents a clinical case report of the use of olaparib in a patient with familial BRCA1-mutated metastatic PaCa.

Dosiahnennia kardiolohii u vyvchenni predyktoriv prohnozuvannia hostroi livoshlunochkovoi ta kryteriiv narostannia tiazhkosty khronichnoi sertsevoi nedostatnosty pid chas khvorob sertsia (ohliad literatury; rezultaty vlasnykh doslidzhen)

Introduction. Few works have been published in the literature on the prediction of predictors of acute and chronic heart failure. The aim of the study. Аnalyze the achievements of cardiology in the field of studying the predictors of predicting acute left ventricular failure and the criteria for the progression of CHF with various CVD. Materials and methods. Vikoristani 51 published an article and presented the results of public research in the field of predicting acute respiratory failure and progression of CHF in heart disease. Results. In most patients, the term after the transferred MI is associated with an increase in end-diastolic volume and end-systolic volume, which are prognostically unfavorable signs. In these cases, the development of LV remodeling is of great importance, as well as accepting the same name as MI, stroke, and HF. Predictors of unfavorable cardiovascular diseases dynamics: changes in EDV, ESV and left ventricular ejection fraction. It should be noted that GLS and diastolic dysfunction are important predictors of cardiovascular complications and SCD. The apparent mitral regurgitation increased the risk of death for 5 years of birth. On the basis of our research, we proved for the first time in 1991 that 4 pathogenetically related mechanisms play a leading role in the development of the initial stage of HF in SCD: central, regional pulmonary hemodynamics, microcirculation, and tissue exchange with the development of arteriolar hypoxemia, venous hyperoxia, reduction of ABB by O2 and utilization of oxygen by tissues, reduction of aerobic processes occurring in the H. A. Krebs cycle and replenishment of energy deficit due to increased glycolysis and pentose phosphate shunt (activities of succinate dehydrogenase and cytochrome oxidase). Conclusions. Based on the given data and own results of the study, predictors of predicting acute CHF and progression are: AMI, UA severe form, stable angina pectoris 3-4 FC, cardiac aneurysm, SBP more than 180 mm Hg. and is less than 100 mm Hg, age 70 years and older, AF, TP, VE of 3-5 gradations, “pirouette”-type VT, significant increase in EDV, ESV and decrease in LVEF. The study of predictors of acute progression and criteria for predicting CHF is of primary importance. Key words: predictor of acute left ventricular insufficiency, chronic heart failure

Profiling of patients with type 2 diabetes based on medication adherence data.

Type 2 diabetes mellitus (T2DM) is a complex, chronic disease affecting multiple organs with varying symptoms and comorbidities. Profiling patients helps identify those with unfavorable disease progression, allowing for tailored therapy and addressing special needs. This study aims to uncover different T2DM profiles based on medication intake records and laboratory measurements, with a focus on how individuals with diabetes move through disease phases. We use medical records from databases of the last 20 years from the Department of Endocrinology and Diabetology of the University Medical Center in Maribor. Using the standard ATC medication classification system, we created a patient-specific drug profile, created using advanced natural language processing methods combined with data mining and hierarchical clustering. Our results show a well-structured profile distribution characterizing different age groups of individuals with diabetes. Interestingly, only two main profiles characterize the early 40-50 age group, and the same is true for the last 80+ age group. One of these profiles includes individuals with diabetes with very low use of various medications, while the other profile includes individuals with diabetes with much higher use. The number in both groups is reciprocal. Conversely, the middle-aged groups are characterized by several distinct profiles with a wide range of medications that are associated with the distinct concomitant complications of T2DM. It is intuitive that the number of profiles increases in the later age groups, but it is not obvious why it is reduced later in the 80+ age group. In this context, further studies are needed to evaluate the contributions of a range of factors, such as drug development, drug adoption, and the impact of mortality associated with all T2DM-related diseases, which characterize these middle-aged groups, particularly those aged 55-75. Our approach aligns with existing studies and can be widely implemented without complex or expensive analyses. Treatment and drug use data are readily available in healthcare facilities worldwide, allowing for profiling insights into individuals with diabetes. Integrating data from other departments, such as cardiology and renal disease, may provide a more sophisticated understanding of T2DM patient profiles.

377 Real-world use of OPZELURA™: safety analysis at 1 year

Abstract OPZELURA™ (ruxolitinib cream) became the first approved topical Janus kinase inhibitor (JAKi) in the USA on September 21, 2021, for treatment of mild to moderate atopic dermatitis and on July 18, 2022 for nonsegmental vitiligo. This study aims to review postmarketing safety encompassing nearly 14,000 patient-years of treatment during the first year of market approval through September 20, 2022. The Incyte global safety database and the US Food and Drug Administration (FDA) Adverse Event Reporting System were queried for adverse event (AE) reports received for OPZELURA between September 21, 2021 and September 20, 2022. Search of these databases found 294 postmarketing individual case safety reports (ICSRs) containing 585 nonserious AEs, four serious AEs and no fatal AEs. Of the 294 ICSRs, 220 (75%) were received from spontaneous sources and 74 (25%) were received from noninterventional/solicited sources. Consumers reported 221 ICSRs (75%) and 73 (25%) were medically confirmed by a healthcare professional (i.e. nurse, pharmacist and physician). Gender was reported in 257 ICSRs; of these, 81 (32%) involved male patients and 176 (68%) involved female patients. Age was reported in 64 ICSRs (22%), with a median age of 39 years. The AEs (any unfavorable sign, symptom or disease) with frequency >2% out of all events included application site pain (16 events), dermatitis atopic, skin irritation (15 events each), scratch (14 events) and condition aggravated (13 events). Application site pain, skin irritation and scratch were mostly related to an initial issue with cream texture that was rapidly addressed. ‘Dermatitis atopic’ and ‘condition aggravated’ reflected worsening of the underlying condition or lack of improvement. The four serious AEs were skin cancer (two events), pericarditis and thrombocytopenia (one event each), all of which had insufficient information for assessment of relatedness to OPZELURA. Because indications for OPZELURA are inflammatory conditions, OPZELURA has been subject to the same class warnings as oral JAKi that include the risk of serious infections, mortality, malignancy, major adverse cardiovascular events and thrombosis, imposed by FDA subsequent to the ORAL Surveillance trial of tofacitinib in rheumatoid arthritis (Kragstrup et al., RMD Open, 2022; 8:e002236). Topical application of OPZELURA results in low systemic bioavailability of ruxolitinib, and serious AEs associated with oral JAKi were not reported with OPZELURA. Safety data from the first year of marketing confirm that OPZELURA is well tolerated, without significant systemic AEs, and with a low incidence of application site reactions.

Do Post-harvest Losses Affect the Farmers’ Income? - Post-Harvest Loss Estimation for Major Vegetables in South India

Over the last two decades, India’s food system with population surge has been undergoing a transformation with increase in demand for high value fruits and vegetables. However, farmers are not benefitted from these transitions as the post-harvest losses are fairly high due to poorly developed post-harvest management practices. The present study aims to estimate the nature and extent of losses and also analysed the determinants of post-harvest losses for major vegetables (gourds) in South India. Palakkad district of Kerala was chosen for the study as it contributes the most, for the state’s vegetable area and production. Multi-stage random sampling techniques were adopted and the vegetables selected were based on their annual production in the study area. The total loss observed in bitter gourd at farm level was about 12.46 percent (34.53 qtl/ha). At trader level, the physiological loss contributed to almost 45 percent of the total losses. Hence, the total loss in bitter gourd was observed to be 21.88 per cent. Likewise in snake gourd, the extent of losses at farm level was found to be 9 percent (26.1 qtl/ha), where the highest losses (4.74 percent) were due to biotic factors like pests and diseases prevailing in the study area. Therefore, the total loss estimated in snake gourd was 13.89 percent which included 4.89 percent loss at trader level. Regression analyses delineated that in bitter gourd, area under cultivation, unfavourable weather conditions, pests and diseases and use of packing materials like jute sacks and wooden baskets were found as major determinants for losses. Whereas, area under cultivation, experience in farming and prevailing pests and diseases in snake gourd were found to affect the volume of post-harvest losses at farm level. The study found that adoption of proper post-harvest handling practices by farmers would help minimizing the losses to a remarkable extent. Besides, analysis of farmers’ perception, brought out the fact that the farmers aware of losses incurred only to a limited extent.

Unfavorable early-stage Hodgkin lymphoma: assessment of patient characteristics in a real-world setting.

Aim: Unfavorable prognostic factors among classical Hodgkin lymphoma (cHL) patients in the real-world setting have yet to be fully characterized. Methods: In this retrospective study using the ConcertAI Oncology Dataset, patient characteristics, unfavorable prognostic factorsand treatment patterns were evaluated among patients diagnosed with cHL. Results: Among 324 adult cHL patients diagnosed 2016-2021, 16.1% were classified as early favorable, 32.7% early unfavorableand 51.2% advanced disease. Early unfavorable patients were younger and had a larger nodal mass. The prognostic factor B symptoms was most frequently documented in early unfavorable patients (59.4%), followed by bulky disease (46.2%), >3 involved lymph node regions (31.1%), and erythrocyte sedimentation rate ≥50 (25.5%). Conclusion: In this analysis of real-world data, we found that nearly a third of newly diagnosed cHL patients had early unfavorable disease. Our analysis also showed differences in the proportion of patients for each unfavorable factor among patients with early-stage unfavorable cHL.

Efficacy and safety of switching other tyrosine kinase inhibitors to regorafenib combined with primary PD-1 antibodies in patients with hepatocellular carcinoma.

e14612 Background: Currently, formal tyrosine kinase inhibitors (TKIs) such as sorafenib or lenvatinib in combination with PD-1/PD-L1 immune checkpoint inhibitor had achieved promising results in patients with hepatocellular carcinoma (HCC). However, a portion of patients experienced drug-resistant tumor progression and/or severe adverse events associated with TKIs during the course of treatment, resulting in unfavorable disease control and poorer overall survival. Therefore, a better medication strategy is urgently needed in aim to improve the prognosis of these patients who experienced discontinuing medication of TKIs. Methods: We reviewed the medical data of 23 HCC patients with disease progression after received sorafenib or lenvatinib combined with PD-1 antibodies from Jan Feb 2020 to Sep 2021 at the Fifth Medical Center of PLA General Hospital in China. These patients had switched to regorafenib PO for 3 weeks on/1 week off combined with primary PD-1 antibodies after experienced tumor progression and/or severe adverse events with respect to sorafenib or Lenvatinib. All patients were followed up regularly. Changes of tumor lesions, survival data and adverse events (AEs) were detailed recorded after switched. All AEs were evaluated according to the CTCAE v5. Results: Initially, 20 (87.0%) patients were treated with lenvatinib and 3 (13.0%) patients were treated with sorafenib before switched to regorafenib. Of all patients, tumor progression caused 15 (65.2%) switching and severe AEs caused 8 (34.8%) switching, and the initial daily dose of regorafenib were 80mg (95.6%) and 40 mg (4.4%), respectively. Before switched to regorafenib, the most common mild AEs were hypertension, hypothyroidism and granulocytopenia, and the most common severe AEs were rash, hepatitis, and lung infections. In contrast, the most common AEs was mild hoarseness after switched to regorafenib. During the follow-up, 12 (52.2%) patients died, 3 (13.0%) patients lost and 8 (34.8%) patients sustained survival. The overall median survival time (MST) was 22.47 months [95% confidence interval (CI): 2.98 months to 41.96 months], the MST after switched to regorafenib was 10.53 months (95% CI: 0.257 months to 20.81 months). Of note, size of tumor lesion decreased in 7 (30.4%) patients and increased in 3 (13.0%) patients, and the other 13 (56.6%) patients could not be evaluated due to incomplete data after switching to regorafenib. Conclusions: For patients who are resistant to other TKIs, switching to regorafenib showed good efficacy and manageable safety. Therefore, this treatment protocol can be considered as a potential treatment for patients without clinical benefits after first or second-line combination therapy.

COVID-19 and smoking: Considerations after two years

COVID-19 and smoking: Considerations after two years

Immunoglobulin genes and stereotyped antigenic receptors in chronic lymphocytic leukemia and other lymphoproliferative diseases

Introduction. The mutational status of immunoglobulin heavy chain variable region genes (IGHV) is the most important prognostic factor in chronic lymphocytic leukemia (CLL). Furthermore, a significant narrowing of the IGHV gene repertoire is found in CLL and other lymphoproliferative diseases. Aim — to review the publication data on the IGHV genes repertoire and mutational status in CLL and other lymphoproliferative diseases regarding their clinical significance. General information. Nucleotide sequence of rearranged IGHV genes is a unique marker of a tumor clone. CLL patients with unmutated IGHV genes have an extremely unfavorable disease outcome in contrast to the patients with mutated IGHV genes. Patients with mutated IGHV genes benefit from conventional immunochemotherapy, while non-mutated IGHV patients require therapy escalation with new targeted drugs. The study of IGHV genes and stereotyped antigen receptors repertoire makes possible to identify additional groups of CLL patients with specific genetic and clinical features. Stereotype receptors are also detected in other lymphoproliferative diseases, but their clinical significance has not yet been defined. However, stereotyped receptors are found to be disease-specific.

A Novel Nomogram to Identify Candidates for Focal Therapy Among Patients with Localized Prostate Cancer Diagnosed via Magnetic Resonance Imaging–Targeted and Systematic Biopsies: A European Multicenter Study

BackgroundSuitable selection criteria for focal therapy (FT) are crucial to achieve success in localized prostate cancer (PCa). ObjectiveTo develop a multivariable model that better delineates eligibility for FT and reduces undertreatment by predicting unfavorable disease at radical prostatectomy (RP). Design, setting, and participantsData were retrospectively collected from a prospective European multicenter cohort of 767 patients who underwent magnetic resonance imaging (MRI)-targeted and systematic biopsies followed by RP in eight referral centers between 2016 and 2021. The Imperial College of London eligibility criteria for FT were applied: (1) unifocal MRI lesion with Prostate Imaging-Reporting and Data System score of 3–5; (2) prostate-specific antigen (PSA) ≤20 ng/ml; (3) cT2–3a stage on MRI; and (4) International Society of Urological Pathology grade group (GG) 1 and ≥6 mm or GG 2–3. A total of 334 patients were included in the final analysis. Outcome measurements and statistical analysisThe primary outcome was unfavorable disease at RP, defined as GG ≥4, and/or lymph node invasion, and/or seminal vesicle invasion, and/or contralateral clinically significant PCa. Logistic regression was used to assess predictors of unfavorable disease. The performance of the models including clinical, MRI, and biopsy information was evaluated using the area under the receiver operating characteristic curve (AUC), calibration plots, and decision curve analysis. A coefficient-based nomogram was developed and internally validated. Results and limitationsOverall, 43 patients (13%) had unfavorable disease on RP pathology. The model including PSA, clinical stage on digital rectal examination, and maximum lesion diameter on MRI had an AUC of 73% on internal validation and formed the basis of the nomogram. Addition of other MRI or biopsy information did not significantly improve the model performance. Using a cutoff of 25%, the proportion of patients eligible for FT was 89% at the cost of missing 30 patients (10%) with unfavorable disease. External validation is required before the nomogram can be used in clinical practice. ConclusionsWe report the first nomogram that improves selection criteria for FT and limits the risk of undertreatment. Patient summaryWe conducted a study to develop a better way of selecting patients for focal therapy for localized prostate cancer. A novel predictive tool was developed using the prostate-specific antigen (PSA) level measured before biopsy, tumor stage assessed via digital rectal examination, and lesion size on magnetic resonance imaging (MRI) scans. This tool improves the prediction of unfavorable disease and may reduce the risk of undertreatment of localized prostate cancer when using focal therapy.

A pilot study to determine the relationship of changes in the characteristics of β1- and β2-adrenoreceptors against the background of the use of β2-agonists with clinically significant parameters in patients with cardiovascular pathology

Background: Comorbid cardiovascular and bronchoobstructive diseases worsens disease course and prognosis and causes difficulties in therapy. Effectiveness 2-agonists (cornerstone of bronchoobstructive pathology treatment) depends on -adrenoreceptors state. Therefore, a detailed study of the functional state of beta-adrenoreceptors is necessary. Aim: to evaluate the relationship of changes in the characteristics of 1- and 2-adrenoreceptors, against the background of the use of 2-agonists in patients with cardiovascular and bronchoobstructive diseases with clinically significant parameters. Methods: In the pilot single-center prospective study during 2.5 years 45 patients (15 with cardiovascular and 30 with bronchoobstructive diseases) were included. Anamnestic data and complaints were collected and laboratory and instrumental studies were performed. Modified radioligand analysis on blood T-lymphocytes using radiolabeled Cyanopindolol and unlabeled selective ligands (ICI 118551, CGP 20712) before and after salbutamol and formoterol was performed and the binding activity of 1- and 2-adrenoreceptors was determined. Results: The correlation analysis between clinically significant parameters and changes in the specific binding index of 1- and 2-adrenoreceptors confirmed its clinical relevance. In test with beta-agonists in cardiovascular and bronchoobstructive diseases patients, an increase in the specific binding index of 1-adrenoreceptors is associated with clinical, laboratory and instrumental parameters of a favorable course of the disease, and an increase in the specific binding index of 2-adrenoreceptors is associated with negative. In the cardiovascular group without bronchoobstructive diseases with salbutamol an increase in the specific binding index of 1-adrenoreceptors was associated with parameters of unfavorable disease course, while an increase in the specific binding index of 2-adrenoreceptors did not have a clear associative relationship with clinical characteristics. Conclusions: The association of changes in the specific binding index of 1- and 2-adrenoreceptors in patients with cardiovascular and bronchoobstructive diseases with clinically significant parameters during acute tests with short- and long-acting 2-agonists was revealed, which in the future may provide an opportunity to identify patients with an unfavorable course of the disease.

Abstract 4758: SETD4 transcription levels correlates with leukemic burden and SMYD2 transcription in acute lymphoblastic leukemia

Abstract Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy worldwide. It has a history of great rates of success in treatment, but adults and infants still share a dismal prognosis. This condition makes the development of new prognostic markers linked to effective therapeutic strategies a matter of pressing concern. While cancer has traditionally been viewed as a genetic disease derived from alterations in oncogenes and tumor suppressors, it is well known nowadays that epigenetic changes also play a fundamental role in tumorigenesis. The SET family of lysine methyltransferases (KMT) has been implicated in a number of cancers, and SETD4 is a member that is still poorly characterized. In the present study we used qPCR to analyze the expression pattern of SETD4 among 83 pediatric ALL patients and non-neoplastic bone marrow (BM) samples and investigated the correlation between SETD4 transcription changes with the leukemic burden in ALL patients during chemotherapy. We found that SETD4 transcription levels are significantly upregulated in BM samples derived from ALL patients compared to non-neoplastic BM (8,5-fold higher, p < 0,001) and its expression correlated with leukemic burden. Importantly, levels of SETD4 decreased in patients that responded to chemotherapy treatment. We further investigated whether SETD4 transcription levels associates with that of SMYD2, another KMT previously identified as a prognostic marker in ALL. Transcription levels of SETD4 and SMYD2 were examined on day 15th and 29th of chemotherapy. Surprisingly, a high level of correlation (Spearman r = 0.925, p < 0.01) between both genes was observed in both treatment time points. Finally, survival outcomes were worst in ALL patients with high levels of SETD4 transcription (log-rank test, p < 0,05), evidencing its dysregulated expression is associated with an unfavorable disease prognosis. Together, these results point to SETD4 as a useful prognostic marker, a possible tool to assess response to therapy and an attractive target for drug development. Citation Format: Luis Augusto Muniz Telles, Luis Henrique Sakamoto, Alan Jhones Assis, Doralina de Amaral Rabello, Andrea Barretto Motoyama, Fabio Pittella-Silva. SETD4 transcription levels correlates with leukemic burden and SMYD2 transcription in acute lymphoblastic leukemia. [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 4758.

Abstract 6722: RNAScope in situ hybridization as a novel approach for the spatiotemporal assessment of RD3 mRNA expression in neuroblastoma

Abstract Our recent investigations unveiled the transcriptional and translational loss of Retinal degeneration Protein 3 in neuroblastomas (NB) when compared to the healthy adult and fetal tissues. Further, our preclinical studies with patient derived cellular systems and mouse model of high-risk NB (HR-NB) demonstrated that RD3 loss orchestrates disease progression. More importantly, we defined the therapy pressure driven acquired loss of RD3 in neuroblastomas, its crucial function in the evolution of progressive disease (PD), and further defined the prognostic and predictive significance of RD3 loss in NB. In this study, we investigated the use of RNAScope as a sensitive and specific method for the evaluation of spatiotemporal RD3 transcriptional loss in NB. We investigated the expression of RD3 mRNA in FFPE NB (n = 100) tissues utilizing RNAScope with custom archived RD3 specific probes comparing it with the matched RD3 protein (IHC) expression patterns. With positive (PPIB) and negative (DapB) controls in place, our results displayed definite and specific RD3 mRNA expression in NB. We observed a statistically significant association of RD3 mRNA loss to the disease progression and poor clinical outcomes. Further, we observed significant correlation to the loss of RD3 transcription to the evolution of progressive disease. More importantly, the expression gradients of RD3 mRNA observed with RNAScope assay (compared in terms of no treatment vs progressive disease, primary vs metastatic disease, relapsed vs no relapse, favorable to unfavorable disease) illustrate the concordance with the RD3 IHC outcomes. Our results provide a reference basis for better RD3 mRNA readouts in NB, and more importantly identify the technically sound, adaptable (high throughput/single event, manual/automatic) RNAScope in situ hybridization assay as an alternate approach to detect spatiotemporal expression of RD3 mRNA. Together, the results provide a new, descriptive, and efficient platform, RNAScope for assessing spatiotemporal RD3 mRNA expression that could better inform disease prognosis and therapy response in children with NB. Funding: This work was partially or in full, funded by Department of Defense DoD-CA210339 and Oklahoma Center for the Advancement of Science and Technology, OCAST-HR19-045. Citation Format: Dinesh Babu Somasundaram, Sheeja Aravindan, Zhongxin Yu, Ashley Baker, Natarajan Aravindan. RNAScope in situ hybridization as a novel approach for the spatiotemporal assessment of RD3 mRNA expression in neuroblastoma. [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 6722.

MP38-01 PATIENT-LEVEL VALIDATION OF LIFE EXPECTANCY CUTOFFS FOR TRIAGE OF AGGRESSIVE TREATMENT BY TUMOR RISK USING TARGETED CROWDSOURCING

You have accessJournal of UrologyCME1 Apr 2023MP38-01 PATIENT-LEVEL VALIDATION OF LIFE EXPECTANCY CUTOFFS FOR TRIAGE OF AGGRESSIVE TREATMENT BY TUMOR RISK USING TARGETED CROWDSOURCING John M. Masterson, Michael Luu, Rebecca Gale, Brennan Spiegel, Stephen J. Freedland, and Timothy J. Daskivich John M. MastersonJohn M. Masterson More articles by this author , Michael LuuMichael Luu More articles by this author , Rebecca GaleRebecca Gale More articles by this author , Brennan SpiegelBrennan Spiegel More articles by this author , Stephen J. FreedlandStephen J. Freedland More articles by this author , and Timothy J. DaskivichTimothy J. Daskivich More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003276.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Life expectancy (LE) thresholds for triage of treatment vs conservative management (CM) in prostate cancer (PC) guidelines are based on expert opinion. However, patient opinion of when to defer treatment based on LE is lacking. We crowdsourced a conjoint analysis to define at which LE men are more likely to choose against treatment. METHODS: We used targeted crowdsourcing to query 2,046 men sociodemographically reflecting a US PC population based on SEER. We asked subjects to complete a conjoint analysis exercise in which they chose between treatment versus CM considering 4 tradeoffs: tumor risk, risk of erectile dysfunction, risk of urinary incontinence, risk of irritative urinary symptoms. Subjects were asked to consider LE throughout, which was calculated using the validated Prostate Cancer Comorbidity Index. Multinomial logistic regression defined the LE at which men were more likely to choose no treatment overall and in subgroups of tumor risk. RESULTS: We found an interaction between LE and treatment, indicating the odds of treatment vs CM choice is dependent on LE (p<0.001). The predicted probability of treatment decreased 15% with every 5 years of decreasing LE (OR 0.85, 95% CI .82-.89, p <0.001). Across all tumor risk levels, men were more likely to choose CM at a LE threshold <10 years (OR<1, p<0.05) (Figure 1). For low-, favorable intermediate-, unfavorable intermediate-, and high-risk cancers, men were more likely to choose CM at LE thresholds of <15, <10, <9, and <7 years, respectively. NCCN guidelines recommend CM overall at LE thresholds of £10 and <5–10 years for favorable and unfavorable intermediate-risk disease, and <5 years for high-risk disease (Figure 2). CONCLUSIONS: Patient preferences for LE cutoffs for when to consider CM align well with current guidelines recommendations, except for low-risk disease, for which patients are likely to consider conservative management even at LE <15 years, rather than <10. Guidelines should take patient preferences into account when recommending thresholds for CM. Source of Funding: none © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e523 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information John M. Masterson More articles by this author Michael Luu More articles by this author Rebecca Gale More articles by this author Brennan Spiegel More articles by this author Stephen J. Freedland More articles by this author Timothy J. Daskivich More articles by this author Expand All Advertisement PDF downloadLoading ...