Advanced-stage Cancer Research Articles

Clinical value of comprehensive genomic profiling on clinical trial enrollment for patients with advanced solid tumors

Abstract The use of biomarker testing to inform treatment decisions has emerged as a standard of care in multiple cancer types. However, the rates of patients with genomic testing results in hand to inform treatment decision-making remain variable. Here, we studied the impact of comprehensive genomic profiling (CGP) on clinical trial enrollment rates in patients with advanced-stage non-small cell lung, colorectal, breast, and prostate cancer using a real-world clinicogenomic database. On average, clinical trial enrollment in the therapy line immediately after CGP report receipt was 5.4%, which represents a 3.0 percentage point increase compared to therapy lines preceding CGP report receipt, supporting a meaningful association between CGP report availability and increased clinical trial enrollment.

Hematologic Predictors of Chemotherapy-Induced Neutropenia in Breast Cancer Patients Receiving Anthracycline- or Taxane-Based Chemotherapy

Background: Chemotherapy-induced neutropenia (CIN) is a common and serious complication of chemotherapy in breast cancer patients, leading to increased morbidity, mortality, and treatment disruptions. This study aimed to investigate the association between hematologic profiles and the occurrence of CIN in breast cancer patients receiving anthracycline-based or taxane-based chemotherapy. Methods: A retrospective observational analytic study with a cross-sectional design was conducted using medical records of breast cancer patients treated at the Oncology Surgery Clinic between 2022 and 2023. Sixty patients were included in the study. Hematologic profiles, including hemoglobin and leukocyte counts, were analyzed to assess their association with CIN in both anthracycline- and taxane-based chemotherapy groups. Results: The majority of patients were aged 15-64 years (86.67%), normoweight (65%), had luminal B subtype (63.3%), and were in the locally advanced breast cancer (LABC) stage (45%). Most patients were non-anemic (Hb ≥12 mg/dL) and leukopenic (71.7% and 80%, respectively). No significant association was found between age, nutritional status, or breast cancer stage and CIN (p > 0.05). However, hemoglobin and leukocyte profiles were significantly associated with CIN in both chemotherapy groups (p < 0.05). No association was found between the type of chemotherapy (anthracycline- or taxane-based) and CIN occurrence. Conclusion: Anemia (Hb <12 g/dL) and leukopenia are significant predictors of CIN in breast cancer patients, regardless of the chemotherapy regimen. These findings highlight the importance of monitoring hematologic profiles in these patients to identify those at higher risk of CIN and implement appropriate preventive and management strategies.

Articulation in postoperative patients treated for early- and advanced-stage tongue cancer

Tongue cancer is among the most prevalent head and neck cancers and is most commonly treated via surgery. We assessed the articulation differences in patients with early and advanced tongue cancer. The study included 26 postoperative tongue cancer patients. We evaluated articulation based on bilabial, labiodental, apical, posterior, laminal, apical front, and apical back speech sounds. The 26 postoperative tongue cancer patients (24 males, two females) had an average age of 54.3 (range 37–89 old) years. Twelve patients were classified as early T stage (T1/T2), while 14 were classified as advanced T stage (T3/T4). The total articulation score was not significantly related to the T stage but apical sounds were so associated. The total articulation score did not significantly differ between postoperative patients with early and advanced tongue cancer. In subgroup analysis, the apical sound was significantly impaired in postoperative patients with advanced tongue cancer.

Targeting Tumor Hypoxia with Nanoparticle-Based Therapies: Challenges, Opportunities, and Clinical Implications.

Hypoxia is a crucial factor in tumor biology, affecting various solid tumors to different extents. Its influence spans both early and advanced stages of cancer, altering cellular functions and promoting resistance to therapy. Hypoxia reduces the effectiveness of radiotherapy, chemotherapy, and immunotherapy, making it a target for improving therapeutic outcomes. Despite extensive research, gaps persist, necessitating the exploration of new chemical and pharmacological interventions to modulate hypoxia-related pathways. This review discusses the complex pathways involved in hypoxia and the associated pharmacotherapies, highlighting the limitations of current treatments. It emphasizes the potential of nanoparticle-based platforms for delivering anti-hypoxic agents, particularly oxygen (O2), to the tumor microenvironment. Combining anti-hypoxic drugs with conventional cancer therapies shows promise in enhancing remission rates. The intricate relationship between hypoxia and tumor progression necessitates novel therapeutic strategies. Nanoparticle-based delivery systems can significantly improve cancer treatment efficacy by targeting hypoxia-associated pathways. The synergistic effects of combined therapies underscore the importance of multimodal approaches in overcoming hypoxia-mediated resistance. Continued research and innovation in this area hold great potential for advancing cancer therapy and improving patient outcomes.

SERPINH1 as a Novel Biomarker for Colon Cancer Bone Metastasis with Machine Learning and Immunohistochemistry Validation.

Background: Bone metastasis (BM) is a serious clinical symptom of advanced colorectal cancer. However, there is a lack of effective biomarkers for early diagnosis and treatment. Method: RNA-seq data from public databases (GSE49355, GSE101607) were collected and normalized and batch effects were removed using the combat package. Differential expression analysis was performed to identify significant genes. Robust Rank Aggregation and machine learning algorithms were used to pinpoint candidate biomarkers. These biomarkers were validated using immunohistochemistry and further analyzed for survival rates. Enrichment analysis was conducted to explore biological mechanisms. Additionally, drug sensitivity and immune infiltration analyses were performed to provide insights into potential therapeutic targets. Results: Analysis results revealed 386 genes elevated in primary versus normal tissues and 26 genes varying between primary and BM. Serpin Protease Inhibitor Clade H1 (SERPINH1) as a novel biomarker for colon cancer metastasis. High SERPINH1 expression correlates with poor survival outcomes and is linked to high lymphatic invasion and advanced cancer stages. Additionally, SERPINH1 expression influences immune infiltration and is not predictive of chemotherapy response, but potential new drugs are suggested for high-expression cases. The gene also enriches classical cancer pathways such as Hedgehog and transforming growth factor-β. Conclusions: We identified novel colon cancer BM markers, including SERPINH1, using machine learning algorithms combined with traditional transcriptomic data and validated their expression through immunohistochemistry. This biomarker could significantly assist clinicians in making more precise treatment decisions.

Association between tumour-infiltrating lymphocyte-T CD8+ and programmed death-ligand 1 protein with the occurrence of metastasis in colorectal cancer patients: An observational study

Background: Tumour-infiltrating lymphocytes CD8+ (TILs CD8+) as an anticancer immune response and Programmed Death-Ligand 1 (PD-L1) as an immune checkpoint molecule expression are important in colorectal cancer (CRC) as their expression correlates with the immune status and the progression of cancer. The primary objective of this study is to examine the relationship between TILs CD8+ and PD-L1 expression levels and CRC metastasis to provide insights into the immune microenvironment’s role in CRC progression and metastasis, potentially improving patient outcomes and treatment response. Methods: This study was an observational study involving colorectal cancer patients who were treated at a tertiary hospital in Bandung, West Java, Indonesia. There were 40 patients included in the study. Tumour tissue samples were collected from patients, and immunohistochemical staining was performed to evaluate TILs CD8+ infiltration and PD-L1 expression levels. Clinical data, including metastasis occurrences, were collected from the cancer registry. Results: Analysis of TILs CD8+ and PD-L1 expression levels in CRC patients revealed significant findings regarding metastasis occurrence and cancer staging. There was a notable positive correlation between PD-L1 expression and TILs-CD8+ infiltration in the presence of distant metastasis and advanced cancer stage (p < 0.05). However, no significant association was observed between TILs CD8 and PD-L1 expression levels and lymphatic metastasis. Conclusion: This study highlights the potential prognostic value of TILs CD8+ and PD-L1 expression levels in predicting CRC progression and metastasis. However, the lack of a significant correlation with lymphatic metastasis suggests the need for further investigation into the underlying mechanisms. Understanding the roles of PD-L1 and TILs-CD8+ expression in CRC metastasis may facilitate the development of targeted therapeutic strategies to improve patient outcomes.

Utilization of Primary Cytoreductive Surgery for Advanced-Stage Ovarian Cancer

This cohort study examines changes in surgical approach for patients with stage III and IV epithelial ovarian cancer from 2010 to 2021.

Prediction of 90-day mortality risk after unplanned emergency department visits of advanced stage cancer patients

PurposeCancer represents the leading cause of mortality in high-income countries. In the last years, the rate of emergency department (ED) visits by cancer patients has increased 5.5-fold. These ED visits impose a significant economic burden and may indicate the progression of the oncologic disease. The goal of this retrospective study was to identify patient-derived risk factors, especially focusing on serum albumin and body mass index (BMI) for 90-day mortality following unplanned ED visits by cancer patients.MethodsA retrospective chart review of all patients with an ICD-10 diagnosis for cancer undergoing palliative treatment presenting at the ED between 2016 and 2018 at the General Hospital of Vienna was performed. Laboratory values, emergency severity index (ESI), and BMI were collected at the ED presentation. 90-day mortality (90MM) was calculated from the ED presentation.ResultsA total of 448 cancer patients were included. Lung cancer (19.2%) and pancreaticobiliary cancer (15.6%) were the most frequent diagnoses. The main reasons for ED visits were pain (20.5%) and fever (17.4%). Sixty-nine percent of patients had to be admitted and 17.5% of patients died during hospitalization. 90MM was highest for patients with low albumin (< 35 g/L vs. > 35 g/L: 60.4% vs. 31.4%; p < .0001). When incorporating albumin levels and BMI, patients with both values below the cutoff had the highest risk for death (HR 4.01, 95% CI 2.30–7.02).ConclusionCancer patients face a high risk for hospitalization when presenting at the ED. The 90MM rate is highest in patients with low BMI and albumin levels. This highlights an especially vulnerable cohort of cancer patients for whom supportive care and palliative care have to be optimized.

Predictive Value of Multi-Phase CT Radiomics in Delineating Early and Advanced T Staging of Colon Cancer

This study leveraged the power of multi-phase CT radiomics, which extracts detailed features from multi-phase images, to explore the distinction between early (T1-T2) and advanced (T3-T4) colon cancer stages in each of multiple phases, providing valuable insights to healthcare professionals and enhancing their decision-making capabilities. A total of 191 patients with surgically confirmed primary colon cancer were retrospectively included, and multi-phase CT scans (non-enhanced contrast phase, arterial phase, portal venous phase, and delayed phase) were conducted within one week before surgery. Three-dimensional segmentation of colonic tumors was performed on the images of the four phases, and radiomics features of each colonic tumor were automatically extracted. Minimum redundancy maximum relevance (mRMR) was applied to features selection in each of the four phases. The least absolute shrinkage and selection operator logistic regression was conducted to determine the association between radiomics features and early (T1-T2) and advanced (T3-T4) stages of colon cancer. Additionally, diagnostic performance comparison was carried out in four phases. The mean (±SD) age of the 191 individuals was 61.87±13.137 years, with females comprising 43.5% of the cohort. The selected features for the non-enhanced, arterial, portal venous, and delayed phases numbered 7, 11, 6, and 10, respectively. In the test set, the AUC values for the on-enhanced, arterial, portal venous, and delayed phases were 0.86 (0.76-0.96), 0.84 (0.73-0.94), 0.82 (0.71-0.93), and 0.86 (0.75-0.97), with corresponding accuracies of 0.84, 0.80, 0.75, and 0.88, sensitivities of 0.73, 0.64, 0.86, and 0.68, and specificities of 0.91, 0.91, 0.68, and 1.00, respectively. DeLong's test revealed no statistically significant differences in the AUC values between the four phases within the test sets (P = 0.3233~ 0.9912). Multi-phase CT radiomics demonstrated substantial value in differentiating between early (T1-T2) and advanced (T3-T4) stages of patients with colon cancer.

Histopathological Characteristics and Distinction of Immune Checkpoint Inhibitor-Related Colitis

Abstract Introduction/Objective Immune checkpoint inhibitors (ICPIs) represent a groundbreaking class of cancer immunotherapy for patients with various advanced-stage solid cancers. ICPIs have been associated with immune- related adverse events, with ICPI-related colitis being a prominent concern due to its potential for life-threatening clinical complications. Recognizing the histopathologic characteristics specific to ICPI-related colitis is crucial for pathologists to provide an accurate diagnosis. Here we have collected and analyzed colon biopsies from patients with ICPI-related colitis following treatment of ICPIs to identify its distinctive histopathologic features and differentiate it from other colitis. Methods/Case Report Colon biopsies are collected from patients with ICPI-related colitis after receiving CTLA-4 and PD-L1 inhibitors as treatment for advanced melanoma. Histopathological features, including epithelial mucin depletion, enterocyte apoptosis, basal lymphoplasmacytosis, cryptitis, glandular architectural distortion, and granuloma, are compared with those in other colitis including ulcerative colitis, Crohn’s disease, microscopic colitis, ischemic and infectious colitis. Immunohistochemistry is employed to analyze inflammatory cell populations and specific enterocyte subtypes. Results (if a Case Study enter NA) ICPI-related colitis, following treatment with Ipilimumab and Nivolumab, commonly presents as active colitis, either with or without chronic colitis. Less frequently, it manifests as microscopic colitis, infectious or ischemic colitis. The acute active form of ICPI-related colitis resembles acute colitis in infectious or ischemic colitis; however, prominent enterocyte apoptosis and intraluminal apoptotic debris are relatively unique features to ICPI-related colitis. The chronic active form of ICPI-related colitis resembles inflammatory bowel diseases, particularly Crohn’s disease, but ICPI-related colitis exhibits an inflammatory injury more affecting surface mucosa and less basal lymphoplasmacytosis. Notably, the most distinctive feature of ICPI-related colitis is the depletion of specific mucinous epithelium observed in our cohort. Conclusion Recognizing specific histopathologic features of ICPI-related colitis, such as mucinous epithelial depletion, enterocyte apoptosis, and surface-dominant inflammation, are essential for pathologists in accurately diagnosing and distinguishing this disease to ensure proper clinical management for patients receiving ICPI treatment.

Psychological Well-Being and Quality of Life in Laryngeal Cancer Patients across Tumor.

Background/Objectives: Laryngeal cancer significantly impacts patients' psychological well-being and quality of life (QoL). This study aims to evaluate the psychological impact and QoL in patients with laryngeal cancer, focusing on differences based on tumor stage and treatment. Methods: This longitudinal study included 75 patients diagnosed with laryngeal cancer. Participants were assessed at diagnosis and 3 months post-treatment using validated tools such as the Hospital Anxiety and Depression Scale (HADS) and the EORTC QLQ-H&N35 questionnaire. This study analyzed the impact of tumor stage, treatment type, and demographic factors on psychological well-being and QoL. Results: Patients with early-stage tumors (Stage I) reported significantly better psychological well-being and QoL compared to those with more advanced tumors (Stages III and IV) both before and after treatment. The non-significant p-values in advanced stages suggest a uniformity of severe distress and poor QoL among these patients. Treatment led to significant reductions in anxiety and depression in early-stage patients, while those with advanced-stage disease showed less improvement. Conclusions: The findings highlight the critical need for early psychological intervention, particularly in advanced-stage laryngeal cancer patients who continue to experience substantial psychological distress and poor QoL despite treatment. Integrating comprehensive psychological support into standard care is essential to improve overall outcomes for these patients.

PER3 promoter hypermethylation correlates to the progression of pan-cancer

BackgroundMalignant cells exhibit reduced period circadian regulator 3 (PER3) expression. However, the underlying mechanisms of variations in PER3 expression in cancers and the specific function of PER3 in tumor progression remain poorly understood.ResultsWe explored multiple public databases, conducted bioinformatics analyses, and performed in vitro and in vivo experiments for validation. We found PER3 expression was decreased in most types of cancers, and PER3 downregulation was associated with a poor prognosis in 8 types of cancer. PER3 promoter methylation levels were increased in 11 types of cancer. Promoter hypermethylation (CpG islands [CGIs] cg12258811 and cg14204433) correlated with decreased PER3 expression in six cancers (breast invasive carcinoma, colon adenocarcinoma, head and neck squamous cell carcinoma, kidney renal papillary cell carcinoma [KIRP], lung adenocarcinoma [LUAD], and uterine corpus endometrial carcinoma). CGI cg12258811 hypermethylation was associated with reduced survival time and advanced cancer stages. Moreover, the bisulfite pyrosequencing assay confirmed CGI cg12258811 hypermethylation and its negative correlation with PER3 expression. In vitro and in vivo experiments demonstrated that PER3 inhibited KIRP and LUAD progression. Decitabine enhanced PER3 expression and inhibited KIRP cell functions by reducing promoter (cg12258811) methylation level.ConclusionsOur findings advanced the mechanistic understanding of variations in PER3 expression in cancers and confirmed the tumor-associated function of PER3 hypermethylation and downregulation.

Humanized Recombinant Immunotoxin Targeting hCG Demonstrates Therapeutic Potential for Advanced Stage Difficult to Treat Cancers

We report the development of an immunotherapeutic molecule, a humanized immunotoxin, for treating hCG-expressing advanced-stage cancers. PiPP, a high-affinity anti-hCG monoclonal antibody, is used in the immunotoxin for ‘homing’ hCG-positive cancer cells. The deimmunized (DI) form of α-Sarcin, a fungal-origin toxin that lacks functional T-cell epitopes, is used in the design to ensure minimal immunogenicity of the immunotoxin for repetitive use in humans. A single-chain variable fragment (scFv) of PiPP was constructed by linking the humanized VH and VL regions of the antibody. The scFv part of the antibody was further linked to the toxin α-Sarcin (DI) at the gene level and expressed as a recombinant protein in E. coli. The immunotoxin was purified from the bacterial cell lysate and analyzed for binding and cytotoxicity to hCG-secreting colorectal and pancreatic cancer cells. The results showed that the scFv(PiPP)-Sarcin immunotoxin was able to bind to colorectal and pancreatic cancer cells and killed approximately 85% of the cells. In vivo testing of the immunotoxin produced results similar to those of in vitro testing against colorectal adenocarcinoma-induced tumors. This immunotoxin could be a promising immunotherapeutic agent for treating colorectal, pancreatic and other terminal-stage hCG-expressing cancers.

Prevalence, treatment patterns, and survival of patients with brain metastases from small cell lung cancer: A retrospective study using the TriNetX Oncology Database

Abstract Background Brain metastases (BM) portend increased morbidity and mortality in patients with small cell lung cancer (SCLC). We aimed to characterize the prevalence, timing, treatment patterns, and survival outcomes of BM associated with SCLC over the past decade. Methods Data from 4014 patients with histologically confirmed SCLC were extracted from the TriNetX Oncology database. Clinical and demographic variables were compared between patients with and without BM using Chi-squared and t-tests. Kaplan–Meier and Cox regression analyses were used to evaluate overall survival (OS), after propensity score matching cohorts for age at diagnosis, sex, cancer stage at diagnosis, extracranial metastases, and cancer-directed therapy. Results Among 4014 patients with SCLC, 35.0% had BM (9.9% synchronous, 21.2% metachronous, 3.9% precocious). Patients who developed BM were younger (P &amp;lt; .001) at SCLC diagnosis, more likely Black/African American (P = .0068), and presented with more advanced cancer stages (P &amp;lt; .001) than patients who did not develop BM. The median BM-free survival from the time of SCLC diagnosis was 27.9 months. Patients with BM received higher rates of cancer-directed therapies than those without BM. Synchronous BM was associated with lower OS than metachronous BM after the diagnosis of SCLC (HR[95% CI] = 1.56[1.32–1.83]), but there was no difference in OS after the BM diagnosis. OS did not differ between patients with BM and patients with extracranial metastases only, following the diagnosis of metastatic disease. Conclusions Our findings support that independently of the chronicity of BM diagnosis, patients with SCLC have poor survival once the diagnosis of BM is conferred.

Thyroid Cancer Incidence During 2020 to 2021 COVID-19 Variant Waves

How rates of thyroid cancer diagnosis were affected by the emergence of COVID-19 variants during the 2020 to 2021 era of the pandemic has not been described. To estimate the total number of undiagnosed cases of thyroid cancer, by histologic type, during the first 2 years of the COVID-19 pandemic (2020 and 2021) by comparing observed to expected incidence and to test for changes in size of cancer at incidence during the same period compared to prior years. This longitudinal study analyzed trends in thyroid cancer diagnoses from 2016 to 2021 among US adults using data from the Surveillance, Epidemiology, and End Results 22 (SEER-22) program database. Data analyses were performed in April to May 2024. Age-adjusted incidence rate per 100 000 US adults, changes in incidence, estimated number of undiagnosed cases, and mean cancer size. Absolute rates of overall thyroid cancer incidence in the first quarter of 2016 and of 2019 were 21.0 and 18.8 per 100 000, respectively. From 2020 through 2021, the quarterly rates were 17.3, 11.1, 17.2, 17.9, 17.4, 19.0, 17.1, and 17.3 per 100 000, respectively. The observed incidence of thyroid cancers decreased by 11% for papillary cancers 2 cm or smaller (risk ratio [RR], 0.89; 95% CI, 0.83-0.95), 14% for papillary cancers larger than 2 cm (RR, 0.86; 95% CI, 0.79-0.93), 8% for follicular cancers (RR, 0.92; 95% CI, 0.82-0.92), 10% for medullary cancers (RR, 0.90; 95% CI, 0.78-1.04), and 15% for anaplastic cancers (RR, 0.85; 95% CI, 0.68-1.07) from March 2020 to December 2021. Oncocytic cancers declined in incidence early in the pandemic, but rates returned to baseline or above through 2021 (RR, 1.15; 95% CI, 0.97-1.37). Extrapolated to the general US population, the total estimated number of thyroid cancer cases not diagnosed (expected minus observed) from March 2020 to December 2021 was approximately 10 200: 5400 papillary cancers 2 cm or smaller (95% CI, 2380-8530), 3700 papillary cancers larger than 2 cm (95% CI, 1660-5810), 600 follicular cancers (95% CI, -260 to 1550), 300 medullary cancers (95% CI, -110 to 720), and 190 anaplastic cancers (95% CI, -75 to 530). Mean size at diagnosis did not change significantly between 2016 and 2021 for any histologic type. This longitudinal study found that by the end of 2021, many thyroid cancers remained undiagnosed. These were predominantly small papillary cancers but also affected all histologic types except oncocytic. These deficits in diagnosis could produce a temporary increase in the rate of patients presenting with larger or more advanced stage cancers in the future, and consequently, temporary increases in population morbidity and mortality.

Prognostic impact of diagnostic and therapeutic time delays in breast cancer: an exploratory data analysis for patients at Parirenyatwa Hospital, Zimbabwe

Objective: This paper seeks to investigate factors related to time delays for diagnosis and treatment in breast cancer patients at Parirenyatwa Hospital in Zimbabwe and subsequently evaluate the effects of presentation and diagnosis delays on cancer stage. Methods: The study was done for 379 patients with histologically diagnosed invasive breast cancer, from 2015 through to 2029. The study sought to identify factors associated with the time delays ( months)using parametric and non-parametric methods, depending on whether underlying assumptions of such tests are met. A multiple logistic regression model was also used to analyse the association between factors, primary delay, secondary delay variables and cancer stage. Results: The median of the primary, secondary and treatment delay were found to be 7.6, 1 and 0.4 months respectively. Rural residence, Karnofsky Performance Score below 70%, hypertension comorbidity, tumor size (&gt;5cm) and well differentiated tumors (grade 1) were significant factors for delayed presentation. Longer primary delay times and post-menopausal status were associated with secondary delay. Advanced cancer stage at diagnosis and those on medical aid were more likely to have a delay in treatment onset. Conclusion: Primary and secondary delay were predictive of advanced disease using logistic regression. Keywords: Breast cancer; primary delay; secondary delay; treatment delay; Zimbabwe.

7917 Bilateral Adrenal Hemorrhages As The Initial Presentation Of Poorly Differentiated Bronchogenic Carcinoma

Abstract Disclosure: B. Malapur: None. M.G. Jakoby: None. V. Williams: None. Introduction: Bilateral adrenal hemorrhage is rare, and most cases occur in the setting of bacterial sepsis, coagulopathies such as antiphospholipid antibody syndrome, treatment with anticoagulants, surgery, or trauma. We present a patient with asynchronous bilateral adrenal hemorrhages that resulted in an eventual diagnosis of poorly differentiated bronchogenic carcinoma. Case: A 65-year-old female smoker was found to have a large right adrenal hematoma on computed tomography (CT) obtained for evaluation of acute onset right flank pain. No hemorrhage or anatomic abnormalities of the left adrenal gland were apparent, and the patient was discharged home after her pain was controlled. Approximately one month later, she returned to hospital with bilateral flank pain, and bilateral adrenal hemorrhages were diagnosed on repeat CT imaging. An 8 cm left upper lobe lung mass was revealed on a chest CT scan, and cytology from a bronchoscopic biopsy confirmed poorly differentiated bronchogenic carcinoma. The patient had no recent surgeries, abdominal trauma, or treatment with anticoagulants, serologic evaluation for coagulopathies and disseminated intravascular coagulation was unremarkable, blood cultures failed to grow bacterial pathogens, and acid-fast staining of lung tissue was negative. The patient was discharged from her second hospital admission on hydrocortisone and fludrocortisone. Discussion: Adrenal hemorrhage in the setting of malignancy is usually a complication of adrenal metastases. The prevalence of adrenal metastases in advanced stage cancer is approximately 3%, with lung and breast cancers and melanoma showing the highest predilection for adrenal metastases. This case is unusual because the patient had no focal masses or disruption of left adrenal contour on CT to indicate adrenal metastases at the time of right adrenal hemorrhage, and she did not have other established risk factors for pathologic bleeding in the setting of malignancy such as thrombocytopenia or treatment with chemotherapy agents, anticoagulants, or nonsteroidal anti-inflammatory drugs. Adrenal hemorrhage is also a rare inciting event resulting in the diagnosis of lung cancer; to date, there are only 29 published cases of spontaneous adrenal hemorrhage as the initial presentation of lung cancer. This case illustrates the importance of careful evaluation for malignancy in patients with spontaneous adrenal hemorrhage and no clear etiology for adrenal bleeding. Presentation: 6/1/2024

6634 Dual-Mediated PTH And Osteolytic Hypercalcemia In Metastatic Endometrial Carcinoma

Abstract Disclosure: C.K. Persaud: None. D.J. Beckman: None. Background: Hypercalcemia of malignancy occurs in 20-30% of advanced stage cancer patients. Etiologies include parathyroid hormone-related peptides (PTHrP)-mediated, osteolytic metastases-mediated, overproduction of 1,25-dihydroxycholecalciferol, and rarely parathyroid hormone (PTH)-mediated. PTH-mediated hypercalcemia of malignancy is rare and occurs through ectopic PTH production or primary hyperparathyroidism. We report a rare case of both PTH-mediated and osteolytic-mediated hypercalcemia in the setting of malignancy. Clinical Case: A 57-year-old female with history of endometrial cancer and multiple solid organ metastasis, presented with two weeks of progressive poor oral intake, nausea, emesis, and right flank pain. On hospital admission, she had a serum calcium of &amp;gt;20.1 mg/dL (8.6-10.2), PTH of 203 pg/mL (15.0-65.0), and creatinine of 1.7 mg/dL (0.7-1.2, baseline 1.3). Non-contrasted CT chest/abdomen/pelvis noted increased size of known right adrenal metastasis, new left adrenal metastasis, periaortic lymphadenopathy, and scattered nodules in the subcutaneous tissues of the abdomen and chest, however bone metastasis were not noted. Patient’s hypercalcemia was treated with zoledronic acid, calcitonin, cinacalcet, and eventually denosumab due to difficulty controlling hypercalcemia. Additional labs obtained during evaluation included ionized calcium &amp;gt;2.5 nmol/L (1.12-1.32), PTHrP &amp;lt;2.0 pmol/L (&amp;lt;2.0), 1,25-dihydroxycholecalciferol &amp;lt;10 pg/mL (21-65). Patient’s right adrenal metastasis biopsy one month prior to admission was subsequently stained for PTH and was negative. Technetium-99m sestamibi scan was obtained for localization of parathyroid adenoma or carcinoma. The scan did not localize, however did show numerous new lytic lesions in the skull, spine, sternum, rib cage, and right humerus. Patient’s hospital course was complicated by progressively worsening renal function, anemia, and thrombocytopenia. Patient was discharged to a long-term acute rehab facility off hypercalcemia treatment with a corrected calcium of 10.0 mg/dL. Conclusion: PTH-mediated hypercalcemia is a rare cause of hypercalcemia of malignancy. PTH levels are typically low or low-normal in osteolytic mediated hypercalcemia. Generally, if PTH is elevated in hypercalcemia, an alternate etiology is not evaluated. This case highlights a rare dual-mediated hypercalcemia of malignancy. The patient’s PTH level elevation was discordant with her high degree of hypercalcemia and prolonged treatment course. She was subsequently found to have widespread bone metastases contributing to hypercalcemia. While multiple etiologies of hypercalcemia can be rare, it is important to evaluate for all contributing causes, especially with additional clinical conditions, such as malignancy. Presentation: 6/3/2024

SRSF6 modulates histone-chaperone HIRA splicing to orchestrate AR and E2F activity in prostate cancer.

Despite novel therapeutic strategies, advanced-stage prostate cancer (PCa) remains highly lethal, pointing out the urgent need for effective therapeutic strategies. While dysregulation of the splicing process is considered a cancer hallmark, the role of certain splicing factors remains unknown in PCa. This study focuses on characterizing the levels and role of SRSF6 in this disease. Comprehensive analyses of SRSF6 alterations (copy number/mRNA/protein) were conducted across eight well-characterized PCa cohorts and the Hi-MYC transgenic model. SRSF6 was up-regulated in PCa samples, correlating with adverse clinical parameters. Functional assays, both in vitro (cell proliferation, migration, colony, and tumorsphere formation) and in vivo (xenograft tumors), demonstrated the impact of SRSF6 modulation on critical cancer hallmarks. Mechanistically, SRSF6 regulates the splicing pattern of the histone-chaperone HIRA, consequently affecting the activity of H3.3 in PCa and breast cancer cell models and disrupting pivotal oncogenic pathways (AR and E2F) in PCa cells. These findings underscore SRSF6 as a promising therapeutic target for PCa/advanced-stage PCa.

Emerging Claudin18.2-targeting Therapy for Systemic Treatment of Gastric Cancer: Seeking Nobility Amidst Danger.

Gastric cancer in advanced stages lacked effective treatment options. claudin18.2 (CLDN18.2) is a membrane protein that is crucial for close junctions in the differentiated epithelial cells of the gastric mucosa, playing a vital role in barrier function, and can be hardly recognized by immune cells due to its polarity pattern. As the polarity of gastric tumor cells changes, claudin18.2 is exposed on the cell surface， resulting in immune system recognition, and making it an ideal target. In this review, we summarized the expression regulation mechanism of claudin18.2 both in normal cells and malignant tumor cells. Besides, we analyzed the available clinical results and potential areas for future research on claudin18.2-positive gastric cancer and claudin18.2-targeting therapy. In conclusion, claudin18.2 is an ideal target for gastric cancer treatment, and the claudin18.2-targeting therapy has changed the treatment pattern of gastric cancer.