Unfavorable Disease Research Articles

Is Confirmatory Biopsy Still Necessary for Active Surveillance of Men With Grade Group 1 Prostate Cancer in the Era of Multiparametric Magnetic Resonance Imaging?

Men diagnosed with prostate cancer (PCa) considering active surveillance (AS) are recommended confirmatory biopsy (CBx). Whether this is necessary in the era of MRI-informed biopsies is questionable. We studied men with Grade Group [GG] 1 PCa at diagnostic biopsy (DBx) considering AS who underwent MRI and CBx (systematic + targeted) within 18 months. Outcomes were grade reclassification to GG ≥ 2, GG ≥ 3, and reclassification to unfavorable intermediate risk disease (UIR). Subset analyses were performed for men with (1) MRI prior to DBx and (2) MRI after DBx. Five hundred twenty-two men had GG1 PCa at DBx. At CBx, 20% reclassified to GG ≥ 2, 12% to UIR, and 5.6% to GG ≥ 3. Of the 306 with positive MRI (PI-RADS > 3), 27% reclassified to GG ≥ 2 and 16% to UIR disease; men with negative MRI experienced these outcomes at rates of 9.2% and 5.5%. There were no differences in reclassification outcomes based on MRI timing (group A vs B), and neither PSA density nor prostate volume added to MRI information. In men with MRI targets, approximately 1/3 of GG > 2 reclassification events were only captured by systematic biopsy core(s). Reclassification rates at CBx were high in men with positive MRI, but < 10% for all reclassification outcomes in men with negative MRI (95% CI 5.8%-14% for GG > 2, 2.9%-10% for UIR, 0.8%-5.3% for GG > 3). Our data support systematic + targeted CBx for men with positive MRI considering AS, while men with GG1 cancer and negative MRI should be able to defer CBx.

Mitogen-activated protein kinase kinase kinase 1 facilitates the temozolomide resistance and migration of GBM via the MEK/ERK signalling.

Mitogen-Activated Protein Kinase Kinase Kinase 1 (MAP3K1) is overexpressed in gliomas; however, its clinical significance, biological functions, and underlying molecular mechanisms remain unclear. Abnormal overexpression of MAP3K1 in glioma is strongly associated with unfavourable clinicopathological characteristics and disease progression. MAP3K1 could potentially serve as a reliable diagnostic and prognostic biomarker for glioma. MAP3K1 silencing suppressed the migration but had no effect on the proliferation and cell death of Glioblastoma Multiforme (GBM) cells. MAP3K1 knockdown exacerbated the temozolomide (TMZ) induced inhibition of glioma cell proliferation and death of GBM cells. In addition, MAP3K1 knockdown combined with TMZ treatment significantly inhibited the growth and increased cell death in organoids derived from GBM patients. MAP3K1 knockdown reversed TMZ resistance of GBM in intracranial glioma model. In terms of molecular mechanisms, the phosphorylation level of ERK was significantly decreased by MAP3K1 silencing. No significant change in the JNK pathway was found in MAP3K1-silenced GBM cells. Inhibition of ERK phosphorylation suppressed the migration and enhanced the TMZ sensibility of GBM cells. MAP3K1 was correlated with the immune infiltration in glioma. MAP3K1 could facilitate the migration and TMZ resistance of GBM cells through MEK/ERK signalling.

Primary Biliary Cholangitis in Men: A Case Report

Primary biliary cholangitis (PBC) is a rare chronic autoimmune liver disease, especially in men, that causes progressive inflammation and destruction of the intrahepatic bile ducts. This leads to hepatic fibrosis that can progress to cirrhosis. PBC diagnosis is suggested by cholestatic jaundice in the absence of abnormalities in intrahepatic and extrahepatic bile ducts, with alkaline phosphatases (ALP) &gt; 1.5 times the upper limit of normal and gamma-glutamyl transferase (GGT) &gt; 3 times the upper limit of normal, with or without elevated bilirubin levels. Confirmation is made through immunological tests, and liver biopsy (PBH) is necessary if tests are negative. The disease is often diagnosed at an advanced stage. Poor prognostic factors include early diagnosis, male gender, severe symptoms, and biological abnormalities such as elevated bilirubin levels. Specific autoantibodies, such as anti-gp210 and anti-sp100, also predict unfavorable disease progression. The first-line treatment is ursodeoxycholic acid (UDCA), which helps slow disease progression and improve symptoms. If UDCA is ineffective, other options include obeticholic acid (OCA) or fibrates like bezafibrate, often used in combination with UDCA. Liver transplantation is the only curative treatment for severe cases. Research is ongoing for new treatments, including PPAR agonists and bile acid transporter inhibitors.

Years of potential life lost due to hepatitis B with or without Delta agent in the Kyrgyz Republic

Recent studies indicate that a marked percentage of chronic viral hepatitis B patients is coinfected with hepatitis D virus known to accelerate the progression of liver disease and contribute to unfavourable disease outcome. Data on premature mortality assessed by the Lost Years of Potential Life (LYPL) indicator, provide the most accurate social burden estimate for such coinfection able to contribute to strengthening viral hepatitis control measures. The aim of the study was to conducting comparative LYPL analyses due to acute and chronic hepatitis B infection without and with delta agent in the Kyrgyz Republic in the years 2014–2018. Materials and methods. LYPL magnitude was calculated using the number of recorded deaths in the reporting form of the 2014–2018 National Statistics Committee «C51-Distribution of deaths by sex, age groups and causes of death». Results. In 2014–2018, 145 cases of death of patients with viral hepatitis B without (HB) and with a delta agent (D) were registered in the Kyrgyz Republic. Of these, 66% (96/145) of patients died from hepatitis B, of which a third (32/96) had an acute disease course. And among those who died from hepatitis D (19/49), acute course was registered in 39%. LYPL for the 145 deceased patients totaled 3766 years, of which 63% (2365 years) were due to HB. Despite that only 35% of patients (51/145) died from acute forms of such hepatitides, their LYPL accounted for 52% (1968) of total years lost that decreased by 4.5-fold for 2014–2018 due to AHB (6.3‰ and 1.41‰, 2014 and 2018, respectively) but increased by 1.1-fold due to AHD (2.7‰ and 3.1‰, 2014 and 2018, respectively). Chronic hepatitis B vs CHD resulted in 1.6 times higher LYPL magnitude (1108 and 691, respectively). At the same time, LYPL due to CHB dynamically increased by 2.6 times, whereas due to CHD — by 6.3 times. Сonclusion. The high LYPL level due to hepatitis B and D infection related to pediatric cases evidence about a heavy burden of such diseases in the Kyrgyz Republic. The data obtained prove that it is necessary to increase adherence of adult population to hepatitis B vaccination and examine children at the site of infection, regardless of vaccination history. Abruptly increased LYPL due to chronic hepatitis cases requires strengthening secondary prevention measures and ensuring timely access to specialized care at infection sites. It is also necessary to evaluate epidemiological surveillance after fatal viral hepatitis.

Electrocardiographic criteria for occlusive and prognostically unfavorable coronary artery disease

Since patients with occlusive coronary artery thrombosis benefit more from emergency reperfusion, after the widespread introduction of thrombolytic therapy, the concept of Q-wave and non-Q-wave myocardial infarction was replaced by the concept of ST-segment elevation (STE) and non-STE (NSTE) acute coronary syndrome (ACS). But at present, due to the spread of mechanical reperfusion, this concept does not seem to be fully perfect. The electrocardiographic (ECG) diagnostic method allows, among patients with NSTE-ACS, to identify a group of patients with occlusive and/or prognostically unfavorable hemodynamically significant coronary lesions, as well as to provide them with timely percutaneous coronary intervention as early as possible and to improve outcomes. This article rationales changing approaches to the management of patients with NSTE-ACS and analyzes in detail the currently known ECG criteria for occlusive and/or prognostically unfavorable coronary lesions.

Candidate prognostic biomarkers and prediction models for high-grade serous ovarian cancer from urinary proteomics

High-grade serous ovarian cancer (HGSOC) is one of the most common histologic types of ovarian cancer. The purpose of this study was to identify potential prognostic biomarkers in urine specimens from patients with HGSOC. First, 56 urine samples with information on relapse-free survival (RFS) months were collected and classified into good prognosis (RFS ≥ 12 months) and poor prognosis (RFS < 12 months) groups. Next, data-independent acquisition (DIA)-based mass spectrometry (MS) analysis was combined with MSFragger-DIA workflow to identify potential prognostic biomarkers in a discovery set (n = 31). With the aid of parallel reaction monitoring (PRM) analysis, four candidate biomarkers (ANXA1, G6PI, SPB3, and SPRR3) were finally validated in both the discovery set and an independent validation set (n = 25). Subsequent RFS and Cox regression analyses confirmed the utility of these candidate biomarkers as independent prognostic factors affecting RFS in patients with HGSOC. Regression models were constructed to predict the 12-month RFS rate, with area under the receiver operating characteristic curve (AUC) values ranging from 0.847 to 0.905. Overall, candidate prognostic biomarkers were identified in urine specimens from patients with HGSOC and prediction models for the 12-month RFS rate constructed. SignificanceOC is one of the leading causes of death due to gynecological malignancies. HGSOC constitutes one of the most common histologic types of OC with aggressive characteristics, accounting for the majority of advanced cases. In cases where patients with advanced HGSOC potentially face high risk of unfavorable prognosis or disease advancement within a 12-month period, intensive medical monitoring is necessary. In the era of precision cancer medicine, accurate prediction of prognosis or 12-month RFS rate is critical for distinguishing patient groups requiring heightened surveillance. Patients could significantly benefit from timely modifications to treatment regimens based on the outcomes of clinical monitoring. Urine is an ideal resource for disease surveillance purposes due to its easy accessibility. Furthermore, molecules excreted in urine are less complex and more stable than those in other liquid samples. In the current study, we identified candidate prognostic biomarkers in urine specimens from patients with HGSOC and constructed prediction models for the 12-month RFS rate.

ETMR-13. MARROW-ABLATIVE CONSOLIDATION CHEMOTHERAPY WITH AUTOLOGOUS HEMATOPOIETIC PROGENITOR CELL RESCUE (HDCT) DECREASES THE DEVELOPMENT OF CHOROID PLEXUS CARCINOMA (CPC)-SPECIFIC RELAPSE IN HIGH-RISK TP53-MUTATED (GERMLINE OR SOMATIC) YOUNG CHILDREN WITH NEWLY DIAGNOSED CPC

Abstract BACKGROUND CPC are childhood cancers in which the loss of TP53 function defines unfavorable disease. CPC-free survival rates have remained poor in patients with TP53 mutations and recent data revealed CPC-free survival of 29% with a non-marrow-ablative chemotherapy strategy. Previously reported results of the “Head Start” (HS) HDCT approach were limited by small patient numbers and incomplete TP53 mutation data. Consequently, the role of HDCT in TP53-mutated CPC remains unclear. METHODS We have analyzed data on TP53 status, CPC-free survival and second cancers from the largest cohort of patients who received initial therapy with the intent of undergoing HDCT. RESULTS Twenty-seven children with CPC received HS-like induction chemotherapy and 23 completed HDCT consolidation. Somatic or germline TP53 mutations were identified in 17 patients, 4 exhibited TP53 wild type (TP53wt); TP53 status remained untested in 6. Five-year CPC-free survival was 66% for patients with TP53 germline mutations (n=12), 40% for those with somatic tumor TP53 mutations (n=5) and 50% with confirmed TP53wt (n=4). Among patients with germline TP53 mutations, only 4/12 experienced CPC recurrences, 4 died from secondary cancers and 4 are currently alive. The 5-year CPC-free survival for 23 patients who underwent HDCT was 52%. All six survivors with TP53 mutations had undergone HDCT, and 5/6 avoided irradiation. Eight/12 patients with TP53 germline mutations and Li-Fraumeni Syndrome (LFS) developed second malignancies, including 6 patients in HDCT group and the remaining 2 patients who did not undergo consolidative HDCT. CONCLUSIONS Our data indicate that HDCT consolidation is associated with improved CPC-free survival compared with historical reports in children with TP53 mutated CPC. The ultimate development of second cancers affects outcomes for those with LFS, irrespective of HDCT treatment. These data justify the inclusion of HDCT in the prospective international trial under development for young children with newly diagnosed TP53 mutated CPC.

Эволюция транспупиллярной лазерной коагуляции сетчатки в лечении активной ретинопатии недоношенных: от режима одиночного импульса до навигационного сопровождения

Abstract Evolution of transpupillary laser coagulation of the retina in the treatment of active retinopathy of prematurity: from single pulse mode to navigational support A.V. Tereshchenko, I.G. Trifanenkova, Yu.A. Sidorova, V.V. Firsova, V.V. Shaulov S. Fyodorov Eye Microsurgery Federal State Institution, Kaluga branch, Kaluga, Russian Federation K.E. Tsiolkovski Kaluga State University, Kaluga, Russian Federation Purpose. To present the development stages and results of 18 years of experience in laser technologies application for the treatment of premature infants with active ROP in the Kaluga branch of S. Fyodorov Eye Microsurgery Federal State Institution. Material and methods. Transpupillary laser coagulation of the retina (LCR) was performed in 1583 children (2537 eyes) with active ROP for the period from 2004 to 2021. LCR was carried out with various stationary laser ophthalmocoagulators. Stages 2 and 3 of active ROP with an unfavorable disease course, stage of early clinical manifestations, manifestation of aggressive posterior ROP were indications for laser treatment. Results. Transpupillary LCR began to be performed for children with active ROP with a stationary ophthalmic coagulator for the first time in Kaluga branch of the S. Fyodorov Eye Microsurgery in 2004. The technology of patterned LCR in active ROP was applied for the first time at domestic and international clinical practice, in the Kaluga branch of Eye Microsurgery in 2009. Pattern LCR began to be performed on the Integre Pro Scan device in 2016. Pattern with the most dense and uniform arrangement of laser applications – hexagonal – was identified. In 2021 transpupillary LCR of the avascular zone of the retina was performed in automatic mode with navigation support on the Navilas 577s laser system. It was possible to perform LCR of the avascular zone of the retina up to the dentate line in all cases. Regression of disease was achieved in 100% of cases. Conclusion. Evolution of laser technologies and the experience of their use demonstrate the high efficacy, safety and predictability of the results of laser treatment of active ROP. Modern pattern laser techniques are highly effective, safe, dosed and tissue-saving, which can serve as the basis for standardization of retinal laser coagulation technology in the treatment of active ROP. Key words: retinopathy of prematurity, unfavorable type of course, laser coagulation of the retina, hexagonal pattern, navigation system

Fecal miRNA profiles in colorectal cancers with mucinous morphology

Abstract The diagnostic performance of molecular markers in surrogate tissues like stool may be affected by colorectal cancer (CRC) morphological heterogeneity. The mucinous histotype represents a subgroup of CRC with a peculiar molecular program and unfavorable disease progression. However, the percentage of mucinous morphology necessary to define this subtype is still a matter of debate. In this study, we investigated whether stool miRNA profiles of CRC patients differ in patients with mucinous histopathological subtypes compared to non-mucinous cancers. In this respect, we also explored how the stool miRNA signature reported in our previous multicentric study behaves in this histotype. Small-RNA sequencing was performed in fecal and tissue samples of an Italian cohort (n = 172), including 27 CRC with mucinous morphology (mucinous cancers with ≥ 50% mucinous morphology and those with mucinous component ≥ 5% but &amp;lt; 50%), 58 non-mucinous CRC, and 87 colonoscopy-negative controls. Results were compared with fecal miRNA profiles of a cohort from the Czech Republic (n = 98). Most of the differentially expressed (DE) stool miRNAs (n = 324) were in common between CRC with mucinous morphology and non-mucinous histopathological subtypes in comparison with healthy controls. Interestingly, the altered levels of 25 fecal miRNAs previously identified distinguishing CRC cases from controls in both cohorts were also confirmed after stratification for mucinous morphology. Forty-nine miRNAs were DE exclusively in CRC with mucinous morphology and 61 in non-mucinous CRC. Mucinous cancers and those with mucinous component showed fairly similar profiles that were comparable in the Czech cohort. Among the stool DE miRNAs observed in CRC with mucinous morphology, 20 were also altered in the comparison between tumor and adjacent mucosa tissue. This study highlights miRNAs specifically altered in CRC with mucinous morphology. Nevertheless, the performance of our stool miRNA signature in accurately distinguishing CRC cases from controls was not significantly affected by this histological subtype. This aspect further supports the use of stool miRNAs for noninvasive diagnosis and screening strategies.

The impact of self-reported social determinants of health (SDOH) on patient engagement and symptom burden across a remote patient monitoring (RPM) pathway in 42 European hospitals.

1506 Background: SDOH are a significant driver of cancer care disparities impacting access to care, adherence to treatment plans, treatment-related toxicities and quality of life (QoL) across the cancer care continuum. RPM based on electronic patient-reported outcomes (ePROs) is a powerful tool to facilitate communication between pts and providers, thereby improving symptom management, QoL and disease outcomes. Equitable participation in RPM pathways must be ensured to avoid increase existing disparities. In this study we report the prevalence of unfavorable SDOH and their impact on engagement with RPM and symptom burden in an RPM pathway deployed in routine care across 42 hospitals in FR and BE. Methods: Patient-level SDOH data provided by consented pts enrolled in the RPM pathway between 08-2023 and 12-2023 was used. Single-item questions were dichotomized from validated ePROs covering educational level, health literacy (3 subdomains health status, treatment and disease understanding), digital literacy, employment status, financial and food security, caregiver support, and access to care. SDOH profiles were defined as unfavorable (impairment at moderate/elevated level) vs. favorable (absence or impairment at a low level). RPM engagement and symptom burden were defined respectively as weekly ePRO reporting and number of alerts due to severe or worsening symptoms. Multivariable backward stepwise regression models (including age, gender, stage, health behaviors) assessed associations between SDOH profile and RPM engagement and symptom burden. Results: 896 (40%) pts provided SDOH data, of which 622 (69%) females with median age of 60 (P25-75 50-70). Most common primary tumor were breast (436, 49%) and gastrointestinal (171, 19%), 488 (55%) were non-metastatic. 653 (73%) pts reported at least 1 unfavorable SDOH, specifically: 199 (22.2%) on educational level, 134 (15.0%) on health status understanding, 27 (3.0%) on treatment understanding, 84 (9.4%) on disease understanding, 218 (24.3%) on digital literacy, 63 (7.0%) on employment status, 104 (11.6%) on financial security, 89 (9.9%) on food security, 348 (38.8%) on caregiver support and 56 (6.3%) on access to care. Lower RPM engagement was associated with unfavorable digital literacy (β -0.05, p&lt;0.001) and treatment understanding (β -0.1, p=0.004). Higher symptom burden was associated with unfavorable financial security (β 0.066, p=0.020) and disease understanding (β -0.1077, p=0.001), but favorable employment status (β 0.0497, p=0.025). Conclusions: RPM with ePROs offers an opportunity to screen for SDOH in routine care. The vast majority of pts enrolled had at least 1 unfavorable SDOH. Specific actionable unfavorable SDOH were associated with lower engagement and higher symptom burden. Personalizing RPM pathways according to SDOH may foster equitable care.

Marrow-ablative consolidation chemotherapy (HDCT) to decrease the development of choroid plexus carcinoma (CPC) specific relapse in high-risk TP53-mutated (germline or somatic) young children with newly diagnosed CPC.

2088 Background: Choroid plexus carcinomas (CPC) are highly malignant, early childhood cancers in which the loss of TP53 function is a central element of their development and defines unfavorable disease. To date, CPC-free survival rates have remained poor; recent data from St. Jude including complete TP53 mutation status, yielded CPC-free survival of only 29% with a non-marrow-ablative chemotherapy strategy. The rarity of CPC has constrained the ability to explore the role of HDCT with autologous hematopoietic progenitor cell rescue (AuHPCR). Previously reported results of the "Head Start" (HS) HDCT approach showed some promise of cure, but were limited by small patient numbers, short follow-up and incomplete TP53 mutation data. Consequently, the role of HDCT and AuHPCR in TP53-mutated CPC remains unclear. Methods: We have analyzed data on TP53 status, therapy, treatment responses, CPC-free and overall survivals (OS) and second cancers from the largest cohort of such patients, all who received initial therapy with the intent/consideration of undergoing consolidative HDCT. Results: Twenty-seven children with CPC (median age, 16 months) received HS-like induction chemotherapy regimens or ICE with the intent of utilizing consolidative HDCT. Twenty-three of 27 completed HDCT consolidation; the remaining 4 patients did not proceed with HDCT due to parental choice. Somatic or germline TP53 mutations were identified in 17 patients, while 4 patients exhibited TP53 wild type (TP53wt); TP53 status remains untested or unavailable in 6 patients. Five-year CPC-free survival and OS for the entire cohort were 47.8% and 44.4%. CPC-free survival for those with TP53 germline mutations (n=12) was 66%, for those with somatic tumor TP53 mutations (n=5) was 40% and for those with confirmed TP53wt (n=4) was 50%. The 5-year CPC-free survival for all 23 patients who underwent HDCT and AuHPCR was 52%, comprising 3/4 TP53wt patients, 10/12 TP53 germline mutated patients and all 5 TP53 somatic tumor mutated patients. Notably, all six survivors with TP53 mutations had undergone HDCT with AuHPCR, and all but one avoided irradiation. Eight out of 12 patients with documented genotypic (TP53 germline mutated) Li-Fraumeni Cancer Predisposition Syndrome (LFS) developed second malignancies. Conclusions: Our data indicate that HDCT with AuHPCR consolidation is associated with improved CPC-free survival compared with historical reports in young children with high-risk TP53 mutated CPC. However, the ultimate development of second cancers substantially affects outcomes for those with LFS, irrespective of HDCT treatment. These data justify the inclusion of HDCT and AuHPCR in the prospective international trial under development for young children with newly diagnosed TP53 mutated CPC.

Breast Cancer With HER2 Immunohistochemical Score 2 and Average HER2 Signals/Cell 6 or More and HER2/CEP17 Ratio Less Than 2 ('ISH Group 3'): A Multi-Institutional Cohort Analysis Emphasizing Outcome and Molecular Subtype

Breast cancer (BC) with average human epidermal growth factor receptor 2 (HER2) signals/cell ≥6 and HER2/chromosome enumeration probe 17 (CEP17) ratio <2 (in situ hybridization [ISH] group 3) is very rare, accounting for 0.4% to 3.0% of cases sent for the dual-probe ISH assay. Although such patients are currently eligible for treatment with HER2-targeted therapy, their characteristics and outcomes remain poorly understood. Sixty-two BCs with equivocal HER2 immunohistochemical score (2+) and reflex ISH group 3 results were identified across 4 institutions. Available clinicopathologic characteristics, MammaPrint and BluePrint molecular results, and follow-up information were retrospectively analyzed. Most BCs with HER2 equivocal immunohistochemical and ISH group 3 results were histologic grade 2 or 3 (100%), estrogen receptor (ER) positive (90.3%), with an average HER2 signals/cell of 7.3. Molecular profiles revealed that 80% (16/20) of tumors were luminal subtypes, and HER2 molecular subtype was identified in 10% of tumors (2/20). Twelve (19.4%) out of 62 patients developed local recurrence and/or distant metastasis with a median follow-up of 50 months. One (10%) of 10 patients achieved pathologic complete response after neoadjuvant chemotherapy. Forty-nine (79%) out of 62 patients completed anti-HER2 agents, and exploratory analysis showed no statistically significant difference in disease outcomes between patients who completed anti-HER2 treatment and those who did not. Univariate analysis revealed advanced clinical stage, and ER/progesterone receptor negativity was associated with unfavorable disease outcomes, and exploratory multivariate analysis demonstrated that clinical stage was the most significant factor associated with disease outcomes in the studied population. These findings increase our understanding of this rare, but clinically important HER2 category. Large-scale prospective randomized studies are needed to further evaluate the role of perioperative HER2-targeted therapy in this patient population.

Self-assembled gel microneedle formed by MS deep eutectic solvent as a transdermal delivery system for hyperpigmentation treatment

Hyperpigmentation (HP) is an unfavorable skin disease that typically caused by injury, inflammation, or photoaging and leads to numerous physical and psychological issues in patients. Recently, development and application of natural whitening substances, particularly compound curcumin (CUR), is one of the most prevalent treatments for HP. However, it is still a formidable challenge to improve the percutaneous delivery of CUR due to its inadequate solubility in water and excellent barrier function of skin. To overcome the limitations of conventional delivery and increase the percutaneous absorption of CUR, the efficient delivery of CUR is urgently required. Herein, we developed a new malic acid-sorbitol deep eutectic solvent (MS/DES) gel microneedle loaded with CUR as a transdermal delivery system for HP treatment. The MS/DES gel produces three-dimensional (3D) network structure by self-assembly of hydrogen bond interactions, which conferred the CUR-MS/DES-GMN with sufficient mechanical properties to successfully penetrate skin tissue while also helping to enhance the drug's release rate. The CUR-MS/DES-GMN exhibit high biocompatibility and mechanical property in vivo of mice. The zebrafish experiments also show that CUR-MS/DES gel has significant effect of anti-pigmentation. Therefore, the designed CUR-MS/DES-GMN system provides a novel strategy for HP treatment based on self-assembly of naturally molecules.

OA22 Pregnancy in connective tissue diseases: a 30 year follow-up study of 465 pregnancies from a Spanish monocentric registry

Abstract Background/Aims Pregnancy in patients with connective tissue diseases (CTDs) are known to be at high risk for the occurrence of adverse pregnancy outcomes. We aimed to evaluate pregnancy outcomes in patients with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), primary Sjögren’s syndrome (pSS) and undifferentiated connective tissue disease (UCTD). Methods A retrospective and descriptive study was conducted from 1990 to 2020. All data were collected from the medical records of women of childbearing age with SLE, SSc, SS and UTCD enrolled in our clinic at the time of their pregnancy and childbirth. The obstetric, maternal and fetal outcomes were collected and compared regarding diagnosis and adverse outcomes. Results The study group included 295 patients: 125 patients (42%) with SLE; 50 patients (17%) with SSc; 80 patients (27%) with pSS; 40 patients (14%) with UCTD. A total of 465 pregnancies were registered. The mean age at delivery was 31.5±8.5 years and the mean duration of disease was 7.2±5.6 years. Pregnancy loss occurred in 21% of patients, live births in 66% of pregnancies, preterm delivery in 8%, postpartum haemorrhage in 6%, preeclampsia in 5%, placental abnormalities in 4%, ectopic pregnancy in 3%, and premature rupture of membranes in 2%. Treatment with hydroxychloroquine (HCQ) was received in 115 pregnancies in SLE (59%), 21 pregnancies in SSc (24%) 62 pregnancies in pSS (52%) and 32 pregnancies in UCTD (49%). Exposure to corticosteroids and biologics during pregnancy was 23 (18.4%), 6 (12%), 15 (19%) and 3 (7.5%), respectively. Patients with SLE had a higher risk of fetal morbidity, including abortion (p = 0.03), mean abortion rate (p = 0.03), preeclampsia (p = 0.04), ectopic pregnancy (p = 0.03), preterm delivery (p = 0.02) and postpartum haemorrhage (p = 0.01) than patients without SLE. The multivariate model found an association between unfavourable pregnancy outcomes and disease activity (OR 2.4; 95% CI 1.3-7.2; p 0.003), whilst HCQ during pregnancy (OR 0.23; 95% CI 0.03-0.82) had a protective effect. Conclusion 66% of pregnancies in patients with autoimmune diseases resulted in live births. Patients with SLE had higher rates of fetal and maternal morbidity than SSc, pSS and UCTD. Disease activity was associated with unfavourable pregnancy outcomes. Exposure to HCQ had a protective effect during pregnancy. Disclosure C. Sieiro Santos: None. P. Pérez García: None. J. Ordas Martínez: None. C. Álvarez Castro: None. E. Díez Álvarez: None.

Nieuwe aanbevelingen voor de behandeling van acute otitis media in de eerste lijn

New recommendations for the management of acute otitis media in primary care This article is a summary of the recent clinical guideline update of acute otitis media with recommendations for its diagnosis, treatment and prevention, including complicated acute otitis media or acute otitis media at risk of complications in children and adults in general practice. The clinical practice guideline came about with the participation of all relevant disciplines and according to an internationally recognized methodology for guideline development (Adapte procedure). The elements of the medical history and clinical examination have limited diagnostic value. Moreover, symptoms alone are not enough to make the diagnosis of acute otitis media. The diagnostic hypothesis is based on the combination of these elements. The doctor pays attention to the patient’s experience and provides the necessary information to enable the patient to manage his/her disease properly (e.g. pain management). Shared decision-making is a key point. Antibiotics are justified in case of an unfavorable disease course and in the presence of major risk factors for complications. However, certain subgroups may benefit from antibiotic therapy. Effective pain or fever treatment (with paracetamol or ibuprofen) has become the cornerstone of acute otitis media management. More targeted antibiotic therapy is reserved for specific indications.

TSPAN8+ myofibroblastic cancer-associated fibroblasts promote chemoresistance in patients with breast cancer.

Cancer-associated fibroblasts (CAFs) are abundant stromal cells in the tumor microenvironment that promote cancer progression and relapse. However, the heterogeneity and regulatory roles of CAFs underlying chemoresistance remain largely unclear. Here, we performed a single-cell analysis using high-dimensional flow cytometry analysis and identified a distinct senescence-like tetraspanin-8 (TSPAN8)+ myofibroblastic CAF (myCAF) subset, which is correlated with therapeutic resistance and poor survival in multiple cohorts of patients with breast cancer (BC). TSPAN8+ myCAFs potentiate the stemness of the surrounding BC cells through secretion of senescence-associated secretory phenotype (SASP)-related factors IL-6 and IL-8 to counteract chemotherapy. NAD-dependent protein deacetylase sirtuin 6 (SIRT6) reduction was responsible for the senescence-like phenotype and tumor-promoting role of TSPAN8+ myCAFs. Mechanistically, TSPAN8 promoted the phosphorylation of ubiquitin E3 ligase retinoblastoma binding protein 6 (RBBP6) at Ser772 by recruiting MAPK11, thereby inducing SIRT6 protein destruction. In turn, SIRT6 down-regulation up-regulated GLS1 and PYCR1, which caused TSPAN8+ myCAFs to secrete aspartate and proline, and therefore proved a nutritional niche to support BC outgrowth. By demonstrating that TSPAN8+SIRT6low myCAFs were tightly associated with unfavorable disease outcomes, we proposed that the combined regimen of anti-TSPAN8 antibody and SIRT6 activator MDL-800 is a promising approach to overcome chemoresistance. These findings highlight that senescence contributes to CAF heterogeneity and chemoresistance and suggest that targeting TSPAN8+ myCAFs is a promising approach to circumvent chemoresistance.

Deficiency in DNA Damage Repair Proteins Promotes Prostate Cancer Cell Migration through Oxidative Stress

Introduction: DNA damage repair gene deficiency defines a subgroup of prostate cancer patients with early metastatic progression and unfavorable disease outcome. Whether deficiency in DNA damage repair genes directly promotes metastatic dissemination is not completely understood. Methods: The migratory behavior of prostate cancer cells was analyzed after siRNA-mediated knockdown of DNA damage repair and checkpoint proteins, including BRCA2, ATM, and others, using transwell migration assays, scratch assays and staining for F-actin to ascertain cell circularity. Cells deficient in BRCA2 or ATM were tested for oxidative stress by measuring reactive oxygen species (ROS). The effects of ROS inhibition on cell migration were analyzed using the antioxidant N-acetylcysteine (NAC). The correlation between BRCA2 deficiency and oxidative stress was ascertained via immunohistochemistry for methylglyoxal (MG)-modified proteins in 15 genetically defined primary prostate cancers. Results: Prostate cancer cells showed a significantly increased migratory activity after the knockdown of BRCA2 or ATM. There was a significant increase in ROS production in LNCaP cells after BRCA2 knockdown and in PC-3 cells after BRCA2 or ATM knockdown. Remarkably, the ROS scavenger NAC abolished the enhanced motility of prostate cancer cells after the knockdown of BRCA2 or ATM. Primary prostate cancers harboring genetic alterations in BRCA2 showed a significant increase in MG-modified proteins, indicating enhanced oxidative stress in vivo. Conclusions: Our results indicate that DNA damage repair gene deficiency may contribute to the metastatic dissemination of prostate cancer through enhanced tumor cell migration involving oxidative stress.

Abstract 4565: Reckless mitotic entry as a chemosensitization approach for alkylating agents

Abstract The cell cycle is tightly regulated by checkpoints, playing a vital role in controlling its progression and timing. Cancer cells exploit the G2/M checkpoint, which serves as a resistance mechanism against genotoxic anti-cancer treatments, allowing for DNA repair prior to cell division. Therefore, manipulating cell cycle timing has emerged as a potential strategy to augment the effectiveness of DNA damage-based therapies such as alkylating agents and radiation. In this study, we conducted a forward genome scale CRISPR/Cas9 chemogenomic screening with repeated exposure to the alkylating agent temozolomide (TMZ) to investigate the mechanisms underlying tumor cell survival under genotoxic stress. Our findings revealed that canonical DNA repair pathways, including ATM/Fanconi and mismatch repair, determine cell fate under genotoxic stress. Notably, we identified the critical role of the membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase, known as Myt1 (encoded by PKMYT1), in ensuring cell survival. Analysis on patient cohort demonstrated that PKMYT1 is not only highly presented in malignancy, but also predisposes an unfavorable disease outcome. Genetic depletion of PKMYT1 led to overwhelming TMZ-induced cytotoxicity in cancer cells. Isobologram analysis demonstrated potent drug synergy between TMZ and other clinically used alkylating agents, such as carmustine, busulfan, and dacarbazine, when combined with a novel Myt1 kinase inhibitor, RP-6306. Mechanistically, inhibiting Myt1 forced G2/M-arrested cells into an unscheduled transition to the mitotic phase without complete resolution of DNA damage, as indicated by a substantial increase in γH2AX-positive cells in mitosis. Moreover, RP-6306 dramatically altered cell cycle timing, reducing the threshold time for mitotic entry. This forced entry into mitosis, along with persistent DNA damage, resulted in severe mitotic abnormalities, including unaligned and partially condensed chromosomes, lagging chromosomes, chromosome bridges, and multipolar spindles. Ultimately, these aberrations led to mitotic exit with substantial apoptosis. Importantly, preclinical animal studies demonstrated that the combination regimen involving TMZ and RP-6306 prolonged the overall survival of glioma-bearing mice. Collectively, our findings highlight the potential of targeting cell cycle timing through Myt1 inhibition as an effective strategy to enhance the efficacy of current standard cancer therapies, potentially leading to improved disease outcomes. Citation Format: Fengchao Lang, James A. Cornwell, Karambir Kaur, Mirit I. Aladjem, Michael Aregger, Steven D. Cappell, Chunzhang Yang. Reckless mitotic entry as a chemosensitization approach for alkylating agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4565.

Genetically Distinct Oligosarcoma Arising from Oligodendroglioma: Systematic Review & Illustrative Case Example

BackgroundOligosarcoma is a rare central nervous system (CNS) neoplasm that may arise following oligodendroglioma resection, which demonstrates a unique genetic profile and aggressive clinical phenotype. We present a systematic review and illustrative case example emphasizing the clinical and prognostic features of this unusual and unfavorable neuro-oncologic disease. MethodsSystematic literature review and illustrative case report. ResultsA 41-year-old man who had undergone two neurosurgical resections for a WHO grade II oligodendroglioma (Ki-67=5-10%, 1p/19q co-deleted, IDH2 mutated), without adjuvant chemoradiation, presented with seizures seven years after resection. An extra-axial mass was identified adjacent to the resection cavity, in which gross total resection was achieved. Pathology confirmed WHO grade IV oligosarcoma (Ki-67=20%). Adjuvant chemoradiation was initiated, with disease control observed over 6 months of follow-up.7 publications met inclusion criteria. Oligosarcoma has been confirmed in 36 lesions, arising in 35 patients; 5 were primary oligosarcoma, while 31 occurred in the setting of prior resected oligodendroglioma or oligoastrocytoma. Features shared by these lesions include re–gain of H3K27me3 expression, 1p/19q codeletion, homozygous deletion of CDKN2A/B, loss of 6q, loss of NF1 and YAP1, and attenuation of CpG island methylator (G-CIMP). Median survival after oligosarcoma diagnosis was 1.3 years (range, 0-5.2; n=35). ConclusionOligosarcoma is a prognostically unfavorable CNS neoplasm with characteristic imaging and pathologic features, and a strong association with previously resected oligodendroglioma. Aggressive treatment is recommended, including gross total resection and adjuvant chemoradiation. Further study is required to define optimal treatment protocol for this CNS malignancy.

High-volume prostate biopsy core involvement is not associated with an increased risk of cancer recurrence following 5-fraction stereotactic body radiation therapy monotherapy

PurposePercentage of positive cores involved on a systemic prostate biopsy has been established as a risk factor for adverse oncologic outcomes and is a National Comprehensive Cancer Network (NCCN) independent parameter for unfavorable intermediate-risk disease. Most data from a radiation standpoint was published in an era of conventional fractionation. We explore whether the higher biological dose delivered with SBRT can mitigate this risk factor.MethodsA large single institutional database was interrogated to identify all patients diagnosed with localized prostate cancer (PCa) treated with 5-fraction SBRT without ADT. Pathology results were reviewed to determine detailed core involvement as well as Gleason score (GS). High-volume biopsy core involvement was defined as ≥ 50%. Weighted Gleason core involvement was reviewed, giving higher weight to higher-grade cancer. The PSA kinetics and oncologic outcomes were analyzed for association with core involvement.ResultsFrom 2009 to 2018, 1590 patients were identified who underwent SBRT for localized PCa. High-volume core involvement was a relatively rare event observed in 19% of our cohort, which was observed more in patients with small prostates (p < 0.0001) and/or intermediate-risk disease (p = 0.005). Higher PSA nadir was observed in those patients with low-volume core involvement within the intermediate-risk cohort (p = 0.004), which was confirmed when core involvement was analyzed as a continuous variable weighted by Gleason score (p = 0.049). High-volume core involvement was not associated with biochemical progression (p = 0.234).ConclusionsWith a median follow-up of over 4 years, biochemical progression was not associated with pretreatment high-volume core involvement for patients treated with 5-fraction SBRT alone. In the era of prostate SBRT and MRI-directed prostate biopsies, the use of high-volume core involvement as an independent predictor of unfavorable intermediate risk disease should be revisited.