System Malignancies Research Articles

TRLS-15. TARGETED THERAPY IN PEDIATRIC CNS TUMORS - A SINGLE INSTITUTION EXPERIENCE

Abstract Primary central nervous system malignancy treatment remains a difficult problem despite advancement in techniques. Personalized medicine is evolving in making treatment decisions and particular molecular characteristics allow new targeted therapies to be specific and effective. We retrospectively present patients with primary CNS tumors receiving targeted therapy from 2016 to the present date. Outcomes included length of therapy, time until progression of disease, and overall response. Our study includes 32 patients with malignancies such as Astrocytoma, Ganglioglioma, Glioblastoma, and Diffuse Intrinsic Pontine Glioma (DIPG), among others. Analysis was based on patients’ underlying malignancy and included variables such as identified mutations, targeted therapy, progression vs resolution of disease, and time to progression of disease after initiation of targeted therapy. Overall results show 23 patients with at least 1-year-survival. The most common targeted therapy was Trametinib, treating tumors of glial origin. 14 patients showed no progression after starting targeted therapy, the majority low grade Gliomas and Medulloblastomas. Multiple mutations were found with the most frequent being BRAF. Of our 11 patients with BRAF mutations, 8 had no progression of disease after starting Trametinib or Dabrafenib. Patients with Atypical Teratoid Rhabdoid Tumors (ATRT) were treated with either Alisertib or Alisertib/Tazemetostat and 2 out of 4, both treated with Alisertib maintenance therapy, had no disease progression after targeted therapy. Best outcomes with no disease progression were primarily Gliomas, treated with Trametinib, and Medulloblastomas, treated with Vismodegib. Of our patients with DIPG, treated with Ribociclib, average time to disease progression on targeted therapy was 4.7 months and survival rate was 33%. We have shown excellent use of targeted therapy and our analysis highlights the need for continued exploration of targeted therapy among patients with CNS tumors.

Malignancy in dermatomyositis: a mono-centric retrospective study of 134 patients in China and a potential predictive model.

To describe the demographics and phenotypes of malignancies-associated dermatomyositis (MADM) in east China and pinpoint potential factors indicative of malignancies in patients with dermatomyositis and establish a predictive model. We retrospectively analyzed clinical data from 134 patients with adult-onset dermatomyositis hospitalized between January 2019 and May 2022 in one comprehensive hospital. Clinical data including disease course, initial symptoms and signs, and demographic information were retrieved from the Electronic Medical Records System. Other parameters including myositis-specific autoantibodies profiles, ferritin, sedimentation, etc. were all referable. Multivariable multinomial logistic regression was employed to simulate a model to predict cancer risks. Receiver operating characteristic curve was adopted to evaluate the potency of the model. 134 patients with adult-onset dermatomyositis were aptly enrolled in this study based on inclusive and exclusive criteria: 12 (8.96%) with malignancies, 57 (42.53%) with aberrant tumor biomarkers but no malignancies, 65 (48.51%) with neither malignancies nor abnormal tumor biomarkers. Senior diagnostic age, higher LDH, higher ferritin, positive anti-TIF1γ and anti-Mi2 rather than anti-NXP2 autoantibodies were positive indicators of malignancies. Additionally, neither initial complaints nor signs were found to be correlated to a tendency towards malignancies. Digestive system, nasopharyngeal, and lung malignancies were mostly documented in east China. One multivariable multinomial logistic regression model was established to predict the phenotypes of dermatomyositis on the basis of potential malignancies and the overall sensitivity and specificity was satisfactory. Positivity of anti-TIF1γ and anti-Mi2 autoantibodies are highly indicative of malignancies while the role of anti-NXP2 autoantibody in MADM in the Chinese population remains unclear. The phenotypes of malignancies can be predicted through the model and the predictive power is sufficient. More attention should be paid to malignancies screening in patients with aberrant tumor biomarkers but no malignancies, particularly digestive system, nasopharyngeal, and lung malignancies in patients with dermatomyositis but without malignancies.

Prevalence of primary malignant tumours, rates of pathological fracture, and mortality in the setting of metastatic bone disease.

The modern prevalence of primary tumours causing metastatic bone disease is ill-defined in the oncological literature. Therefore, the purpose of this study is to identify the prevalence of primary tumours in the setting of metastatic bone disease, as well as reported rates of pathological fracture, postoperative complications, 90-day mortality, and 360-day mortality for each primary tumour subtype. The Premier Healthcare Database was queried to identify all patients who were diagnosed with metastatic bone disease from January 2015 to December 2020. The prevalence of all primary tumour subtypes was tabulated. Rates of long bone pathological fracture, 90-day mortality, and 360-day mortality following surgical treatment of pathological fracture were assessed for each primary tumour subtype. Patient characteristics and postoperative outcomes were analyzed based upon whether patients had impending fractures treated prophylactically versus treated completed fractures. In total, 407,893 unique patients with metastatic bone disease were identified. Of the 14 primary tumours assessed, metastatic bone disease most frequently originated from lung (24.8%), prostatic (19.4%), breast (19.3%), gastrointestinal (9.4%), and urological (6.5%) malignancies. The top five malignant tumours resulting in long bone pathological fracture were renal (5.8%), myeloma (3.4%), female reproductive (3.2%), lung (2.8%), and breast (2.7%). Following treatment of pathological fractures of long bones, 90-day mortality rates were greatest for lung (12.1%), central nervous system (10.5%), lymphoma (10.4%), gastrointestinal (10.1%), and non-renal urinary (10.0%) malignancies. Finally, our study demonstrates improved 90-day and 360-day survival in patients treated for impending pathological fracture compared to completed fracture, as well as significantly lower rates of deep vein thrombosis, pulmonary embolism, urinary tract infection, and blood transfusion. This study defines the contemporary characteristics of primary malignancies resulting in metastatic bone disease. These data should be considered by surgeons when prognosticating patient outcomes during treatment of their metastatic bone disease.

Secondary primary malignancy risk by ER, PR, and HER-2 status in post-menopausal women with breast cancer: A population-based analysis.

1050 Background: Breast cancer is the most commonly diagnosed cancer and second leading cause of death due to cancer in women in the United States. We aimed to determine site specific incidence of SPMs in post-menopausal women with primary BC using data from the US Surveillance, Epidemiology, and End Results (SEER-17) cancer registries. Methods: We retrospectively analyzed post-menopausal women aged 45 or older with a first primary breast cancer diagnosis between 2000 and 2019, excluding those aged 45 or younger or with non-breast cancers as their first malignancy. We defined SPMs as second malignancies occurring at least 6 months after the initial breast cancer diagnosis and calculated standardized incidence ratios (SIRs) and absolute excess risk (AER) using SEER*Stat. Statistical significance was determined using p-values <0.05 and a 95% CI assuming a Poisson distribution of SPM incidence. Results: Among 774,965 post-menopausal women ≥45 years old with primary breast cancer, 10.8% developed SPMs, with significantly increased risk compared to the general population (SIR=1.14, 95% CI=1.13-1.15, p<0.05), particularly for solid tumors (SIR=1.16, 95% CI=1.15-1.16, p<0.05) and certain malignancies including salivary gland (SIR=1.77), thyroid (SIR=1.56), endocrine system (SIR=1.56), and hematological malignancies such as ALL, ANLL, and AML (SIR>1.70). Women aged 45-59 and Black women had the highest risk for all malignancies. PR receptor-positive women had higher risk for thyroid SPMs, while PR-negative women had higher risk for SPMs in female genitalia, bones and joints, and hematological malignancies. HER-positive and triple-positive (HER ER PR) women had higher risk for thyroid and hematological SPMs, while triple-negative women had higher risk for ALL, ANLL, and AML. Conclusions: This study found that 11% of post-menopausal women with primary BC develop SPMs, with thyroid cancer being the most common. Black and older women (45-59 years) had a higher risk of developing SPMs. [Table: see text]

PIK3CB as a potential target to regulate chemosensitivity in glioblastoma.

e14051 Background: Glioblastoma (GBM) is the most common primary central nervous system malignancy but exhibits universally poor outcomes in part due to chemoresistance. Temozolomide (TMZ) can significantly improve overall survival, but resistance mechanisms limit its consistent efficacy. The phosphoinositide 3 kinase (PI3K) pathway is involved in multiple TMZ resistance mechanisms and is highly druggable; however, pan-inhibition of its four grossly homologous but functionally distinct catalytic subunits (PIK3CA/B/D/G encode p110α/β/δ/γ, respectively) was unsuccessful clinically. Therefore, by understanding how the individual PI3K subunits regulate TMZ sensitivity, a more selective treatment strategy can be developed to combat chemoresistance. Methods: Differential expression of PI3K subunit genes was assessed using RNA sequencing (RNAseq) results obtained from public databases (e.g., DepMap, The Cancer Tissue Genome Atlas) for GBM cell lines and patient tumors expressing high or low O6-methylguanine-DNA-methyltransferase (MGMT), a DNA repair enzyme highly implicated in TMZ resistance. PI3K protein levels were assessed using immunohistochemistry of gliomas available at The Human Protein Atlas (THPA). PI3K gene expression was correlated with PI3K pathway activation, quantified as protein kinase B phosphorylation (pAKT). PI3K mRNAs and pAKT were then correlated with the half maximal inhibitory concentrations (IC50s) of TMZ in GBM cell lines to evaluate for a relationship between PI3K gene expression, PI3K pathway activity, and TMZ sensitivity. Finally, hazard ratios were used to compare PI3K gene expression in patient tumors with survival and response to chemotherapy to determine if expression was predictive of prognosis and/or chemosensitivity. Results: PIK3CB was the only PI3K gene enriched in both GBM cell lines and tumors, demonstrating significantly higher expression than all other PI3K genes in GBM (P < 0.0001), independent of MGMT levels. PIK3CB expression remained the highest even after controlling for GBM risk factors such as tumor recurrence, isocitrate dehydrogenase (IDH) mutations, molecular subtypes, or patient gender/age differences. Levels of the p110β protein were also significantly higher than those of other PI3K catalytic subunits (P < 0.001). PIK3CB expression was positively correlated with pAKT levels (P < 0.05), but only in cell lines and tumors with low MGMT activity. Both PIK3CB expression and pAKT levels correlated positively with TMZ IC50s (P < 0.05) in MGMT-deficient GBMs, suggesting an inverse relationship between PIK3CB and TMZ sensitivity. Finally, better prognosis and significant survival benefit with chemotherapy were both associated with lower levels of PIK3CB in MGMT-deficient patients. Conclusions: PIK3CB may selectively regulate chemoresistance in GBM, suggesting a role for p110β selective inhibition to improve chemosensitivity.

Critical Appraisal of Proton Therapy for Patients with Central Nervous System (CNS) Malignancies.

As more hospital-based proton treatment centres become operational, the indications for proton beam therapy (PBT) are being evaluated. Recent advances in PBT technology are expanding the indications for the use of protons in the treatment of central nervous system (CNS) tumours. Prospective trials that assess the late toxicity of different radiation therapy (RT) techniques are needed to confirm any expected reduction in long-term side effects with PBT. The ASTRO Model Policy on proton beam therapy currently supports the reasonable use of protons in the treatment of specific CNS tumour types. Specifically, PBT plays a key role in the management of CNS tumours where anatomy, extent of disease or previous treatment cannot be satisfactorily addressed with conventional RT. As the availability of PBT rises around the world, the number of patients with CNS disease treated with PBT will continue to grow.

Difficulties of nasocutaneous fistula repair, following lacrimal outflow system malignancy resection

ABSTRACT Purpose To evaluate the incidence of nasocutaneous fistula (NCF) development, following en bloc resection of lacrimal outflow system malignancies (LOSM), and describe the methods of surgical repair. Methods Retrospective review of all patients who underwent resection of LOSM with reconstruction and post-treatment protocol at the University of Miami between 1997 and 2021. Results Of the 23 included patients, 10 (43%) developed postoperative NCF. All NCFs developed within one year of surgical resection or completion of radiation therapy. NCF was seen more frequently in patients who underwent adjuvant radiation therapy and those who had reconstruction of the orbital wall with titanium implants. All patients underwent at least one revisional surgery to close the NCF, including local flap transposition (9/10), paramedian forehead flap (5/10), pericranial flap (1/10), nasoseptal flap (2/10), and microvascular free flap (1/10). Local tissue transfer, pericranial, paramedian, and nasoseptal forehead flaps failed in most cases. Two patients had long-term closure; one patient who underwent a paramedian flap and a second who underwent a radial forearm free flap, suggesting that well-vascularized flaps may be the most viable option for repair. Conclusions NCF is a known complication, following en bloc resection of lacrimal outflow system malignancies. Risk factors for formation may include adjuvant radiation therapy and use of titanium implants for reconstruction. Surgeons should consider utilizing robust vascular-pedicled flaps or microvascular free flaps for repair of NCF in this clinical scenario.

The Diagnostic Value of Circulating miR-29 Family for Digestive System Malignancies: A Meta-Analysis.

To evaluate the diagnostic value of circulating microRNA-29 (miR-29) in digestive system malignant neoplasms by meta-analysis. We searched the PubMed, Embase, Cochrane Library, and Web of Science to collect studies, published through September 2022, on the diagnostic value of miR-29 in digestive system tumors. We included 7 studies in this meta-analysis, including colorectal cancer, esophageal squamous cell carcinomas, and cholangiocarcinoma. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 0.64 (95% CI, 0.53-0.74), 0.83 (0.60-0.94), 3.75 (1.42-9.91), 0.44 (0.31-0.61), and 8.63 (2.54-29.26), respectively. The area under the summary receiver operating characteristic curve was 0.75. The sensitivity of miR-29 derived from serum was higher than that of miR-29 derived from plasma for malignant digestive system tumors (0.71 vs 0.54; P = .04). This meta-analysis suggests that the circulating miR-29 family has good diagnostic performance for digestive system malignant tumors, with moderate sensitivity and good specificity.

New pro-inflammatory cytokine IL-40 is produced by activated neutrophils and plays a role in the early stages of seropositive rheumatoid arthritis

ObjectiveInterleukin (IL)-40 is a new cytokine related to immune system function and malignancies. Recently, an association of IL-40 with rheumatoid arthritis (RA) and externalisation of neutrophil extracellular traps (NETosis) was...

Elucidating the cellular mechanisms underlying adoptive cell transfer in models of glioma

Abstract Despite advances in solid tumor biology and oncology, pediatric and adult primary brain cancer and metastasis to the brain harbor dismal prognosis and poor outcomes. One avenue to overcome these clinical challenges is through developing robust immunotherapy to better target the tumor. Our group has previously shown that adoptive cellular therapy (ACT) provides therapeutic benefit against central nervous system (CNS) malignancies, namely medulloblastoma, brain stem glioma and glioblastoma. In this study, we characterized cell cycling differences of immune cellular sub-populations in peripheral lymphoid and tumor tissue compartments in vivo. ACT was conducted in orthotopic KR158 luciferase tumor-bearing mice, a syngeneic murine glioma model. Following completion of ACT, bromodeoxyuridine (BRDU) was administered to mice 12-hours prior to tissue collection and flow cytometry was utilized to measure the level of BRDU incorporation. 7-aminoactinomycin D was used in conjunction with BRDU to provide insight into all phases of the cell cycle. We observed significant differences in cycling populations of myeloid derived suppressor cells (MDSC) and T cells. In mice receiving ACT, MDSCs found in secondary lymphoid tissues were significantly more proliferative. In the tumor microenvironment (TME), proliferating MDSCs were significantly reduced compared to mice that did not receive treatment. Frequencies of proliferating CD4+ and CD8+ T-cells were significantly increased in cervical lymph node and TME, but reduced in spleen. These findings suggest that ACT changes immune cycling and migration dynamics in lymphoid tissue and TME to potentially promote antitumor T-cell responses and minimize tumor-mediated immunosuppression. 5R01NS112315-04

Hemophagocytic Lymphohistiocytosis as a Presenting Sign of Neuroblastoma

BackgroundMalignancy-associated hemophagocytic lymphohistiocytosis (M-HLH) is a syndrome of life-threatening inflammation that can arise in the context of cancer or cancer-directed therapy. While commonly associated with leukemias/lymphomas, M-HLH cases related to solid tumors, particularly neuroblastoma, a sympathetic nervous system malignancy, are rarely described. Five prior neuroblastoma-associated HLH cases are reported, wherein the HLH was primarily attributed to rapid lysis of the neuroblastoma initiating a massive systemic cytokine release (Table 1). Here we report a case of HLH as a presenting sign of neuroblastoma. Case DiscussionA 13-month-old male presented with fever, hypoxia and abdominal distention. Labs were notable for hemoglobin 5.8 (G/dL), platelets 13 (cells/µL), hypofibrinogenemia 63 (mg/dL), AST >6000 (U/L), ALT 2777 (U/L), ammonia 135 (uM/L), INR 4.8, LDH 33 000 (U/L), uric acid 14.4(mg/dL), ferritin 56,198(ng/mL), soluble IL2-receptor 10,1128(pg/mL). Imaging demonstrated numerous bulky abdominal masses. He was admitted to the PICU in the setting of multiple organ dysfunction requiring intubation, vasopressors and CRRT. Presumed M-HLH was diagnosed on the basis of bicytopenia, hypofibrinogenemia, fever, elevated ferritin and liver dysfunction.He was started on anakinra (2 mg/kg q6hrs), however his ferritin continued to escalate with no significant clinical improvement. On day 3 of hospitalization and prior to surgical biopsy results, emergent chemotherapy was initiated with dexamethasone (3 mg/m2 BID) and cyclophosphamide (300 mg/m2). Further workup with urine catecholamines and biopsy confirmed a diagnosis of neuroblastoma. On day 5, he transitioned from cyclophosphamide to cisplatin (19.5 mg or 40 mg/m2) due to concern cyclophosphamide was inadequately hepatically activated. On day 6, due to ongoing multiorgan failure, ruxolitinib (2.5 mg BID or 5 mg/m2) therapy was initiated. On day 9 of hospitalization ferritin improved to 22050 however due to worsening multiorgan failure he was also given a dose of alemtuzumab (10 mg or 20 mg/m2). He experienced neurological decline and died on day 9. Of note, he underwent genome-wide sequencing with no HLH-related variants identified. ConclusionThis case is a rare presentation of the M-HLH occurring pre-therapy as a presenting sign of neuroblastoma with auto-necrosis of the neuroblastoma likely precipitating the uncontrolled inflammatory cascade. Screening for neuroblastoma via urine catecholamines in children presenting with HLH should be strongly considered, particularly in those with abdominal, thoracic, or paravertebral masses.

Clinical characteristics and prognostic nomogram analysis of patients with dual primary cancers with first gastric cancer: a retrospective study in China.

With the improvement in diagnosis and treatment of gastric cancer (GC), the survival time of patients has been gradually prolonged. However, these survivors are at increased risk for other diseases, including second primary cancers (SPCs). Currently, there remain few central studies concerning double primary cancers with first gastric cancer (DPCFGC). Thus, this study aimed to investigate these patients' clinical characteristics and perform prognostic nomogram analysis. The clinical data of 78 DPCFGC patients were retrospectively collected and analyzed through the hospital electronic medical record system. Univariate and multivariate Cox regression analyses were performed to screen independent risk factors, based on which the prognostic nomogram was further constructed and validated using the R software package. Finally, Kaplan-Meier curves were plotted to explore the association of overall survival (OS) with prognostic factors and the model. The prevalence of DPCFGC was 0.86%, of which the proportions of synchronous and metachronous patients were 47.44% and 52.56% , respectively; 65.38% (51/78) and 34.62% (27/78) of patients were male and female, respectively. The median age at GC and SPC diagnosis was 63 and 65 years, respectively, and 52.57% of GC patients developed SPCs within 1 year. The top three SPCs were in the esophagus (19.24%), colon (16.67%), and rectum (15.39%). The most common features of GC and SPCs were adenocarcinoma, poorly and moderately differentiated histology, and pathological stages I and II. The radical resection rate of GC was significantly lower in synchronous patients than in metachronous patients (45.94% vs. 100.00%, P < 0.001), but no significant difference was noted in the radical resection rate of SPCs (35.13% vs. 46.34%, P = 0.315). The OS of DPCFGC patients was 31.03 ± 4.14 months. The pathological stage of GC and SPCs, whether to operate for GC, and diagnostic interval were independent risk factors. The predictive efficacy of the prognostic nomogram for 1-, 2- and 3-year OS in DPCFGC patients was 0.922, 0.935 and 0.796 , respectively, with good consistency and clinical applicability. The OS was significantly lower in the high-risk group than in the low-risk group. During follow-up, clinicians should attach great importance to the screening of GC survivors, especially at early stage in older men within 1 year after diagnosis, and be alert to the possibility of occurrent digestive system malignancies. The nomogram constructed in this study can provide a theoretical basis for the early clinical development of individualized treatment plans.

Outcome of Second Line Treatment of Recurrent High- Grade Glioma by re-Irradiation or Bevacizumab-based Chemotherapy: A Cross Sectional Study.

Currently, there is no standard of treatment for the management of the recurrent high-grade glioma. Re-resection, re-irradiation, and chemotherapy are among main treatment options without any proven efficacy. To compare the outcome of second line treatment of recurrent high-grade glioma by re-irradiation or bevacizumab-based chemotherapy. Retrospectively, patients with the recurrent high-grade glioma treated by re-irradiation (ReRT group) (34 patients) or bevacizumab-based chemotherapy (Bev group) (40 patients) as the first-file after the first recurrence were compared in term of first-line progression free survival (PFS), second-line PFS, and overall survival (OS). Both groups were similar in term of gender (p=0.859), age (=0.071), type of first-line treatment (p=0.227), and performance status (p=0.150). With a median follow-up of 31 months (m), mortality rate was 41.2% and 70% in the ReRT and Bev groups, respectively. In the Bev and ReRT groups, median OS was 27 m (95% confidence interval (CI) 20-33.9 m) vs. 132 m (95% CI 52.9-211 m) (p<0.0001), median first-line PFS was 11 m (95% CI 7.14-28.7 m) vs. 37 m (95% CI 8.42-65.75 m) (p<0.0001), and median second-line PFS was 7 m (95% CI 3.9-10 m) vs. 9 m (95% CI 5.5-12.4 m) (p=0.564), respectively. The PFS is similar after the second line treatment of recurrent primary central nervous system malignancies either by re-irradiation or bevacizumab-based chemotherapy.

Olaparib and advanced ovarian cancer: Summary of the past and looking into the future.

Ovarian cancer (OC) is women's eighth most common cancer, bearing the highest mortality rates of all female reproductive system malignancies. Poly (ADP-ribose) polymerase inhibitors (PARPis) have reshaped the treatment scenario of metastatic OC as a maintenance post platinum-based chemotherapy. Olaparib is the first PARPi developed for this disease. Results from Study 42, Study 19, SOLO2, OPINION, SOLO1, and PAOLA-1 clinical trials, led to the FDA and EMA approval of olaparib for the maintenance treatment of women with high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer without platinum progression: in the platinum-sensitive recurrent OC; in the newly diagnosed setting in case Breast Cancer (BRCA) mutations and, in combination with bevacizumab, in case of BRCA mutation or deficiency of homologous recombination genes. In this review, we synthetized olaparib's pharmacokinetic and pharmacodynamic properties and its use in special populations. We summarized the efficacy and safety of the studies leading to the current approvals and discussed the future developments of this agent.

Amasya ilinde 2013-2017 yılları arasında bildirimi yapılan kanser olgularının klinik ve epidemiyolojik özellikleri

Objective: In order to determine the region-specific risk factors of cancers, it is necessary to examine the distribution according to the characteristics of person, place and time. In the current study, it was aimed to determine the distribution of cancer diagnoses reported between 2013 and 2017 in Amasya province and these diagnoses in terms of clinical features and various sociodemographic variables.&#x0D; &#x0D; Methods: The population of this descriptive study was composed of the cases who were diagnosed with cancer, which the Middle East Cancer Consortium deems necessary to be reported, in various health institutions between 2013 and 2017 and were registered in the Cancer Registry Center. The codes in ICD-O-3 were used in the classification of cancer diagnoses. In order to eliminate the confounding effect of the age variable in the presentation of cancer rates, age-standardized rates were calculated using the World Standard Population. &#x0D; &#x0D; Results: The three most common cancers between 2013 and 2017 were trachea/bronchus/ lung, colorectal and stomach cancers. The three most common cancers in men were trachea/ bronchus/lung, prostate and stomach cancers. This was ranked as breast, colorectal and thyroid cancers in women. It was found that between 2013 and 2017, age-standardized rates of all cancers were found to increase from 151.3 to 184.1 per 100,000 population. &#x0D; &#x0D; Conclusion: The incidence rate of all cancers for both genders between 2013 and 2017 is below Turkey’s average. Gastrointestinal system malignancies, especially gastric cancer, have an incidence rate higher compared to Turkey for both genders. Intervention studies should be planned using the results of the current study.

Abstract CT172: A phase 1, open-label, dose-escalation study of PRT1419, a selective induced myeloid leukemia cell differentiation protein (MCL-1) inhibitor, in patients (pts) with advanced/metastatic solid tumors

Abstract Introduction: PRT1419, a selective inhibitor of MCL-1, has demonstrated preclinical activity in solid tumors and hematologic malignancies. We report the results of a phase 1, open-label, multicenter, dose-escalation study of PRT1419 in pts with advanced/metastatic solid tumors (NCT04837677). Methods: Adults with select advanced/metastatic solid tumors were enrolled. Key inclusion criteria were absolute neutrophil count &amp;gt;1.0, platelets &amp;gt;75, hemoglobin &amp;gt;9, and left ventricular ejection fraction ≥50%. Key exclusion criteria were active central nervous system malignancy, significant cardiac disease, and concurrent strong CYP2C8 inhibitors. The study employed a 3+3 dose escalation design. PRT1419 was administered as a once-weekly (QW) infusion. Primary outcome measures were to evaluate dose-limiting toxicities (DLT) and establish the maximum tolerated dose and recommended phase 2 dose (RP2D). Secondary outcome measures included safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity. Results: Pts with melanoma (n=8), sarcoma (n=5), esophageal (n=4), cervical (n=3), head and neck (n=3), non-small cell lung, small cell lung, and triple-negative breast cancer (all n=1) were enrolled. Median age was 59.5 (range, 32-78) years, 61.5% pts were female, and median prior lines of systemic therapy was 3 (range, 1-8). Overall, 26 pts received ≥1 dose of PRT1419 (20 mg/m2 [n=4], 40 mg/m2 [n=4], 80 mg/m2 [n=15], and 120 mg/m2 [n=3]). Most pts (84.6%) discontinued treatment (primary reason: progressive disease, 72.7%). No DLTs, adverse events (AEs) of increased troponin or heart failure, or grade 5 (fatal) AEs were observed. Any grade treatment-related AEs (TRAE) occurred in 80.8% pts; the most common were nausea (50.0%), diarrhea (46.2%), and vomiting (46.2%). Grade 3/4 TRAEs occurred in 11.5% pts; the most common was neutropenia (11.5%), which was dose related. Due to neutropenia observed at doses &amp;gt;80 mg/m2, further dose escalation was not investigated. BAX and caspase 3 activation in peripheral blood monocytes was observed at 80 mg/m2 and 120 mg/m2. Stable disease was the best response observed. Tumor shrinkage was seen in 1 pt with melanoma (10% reduction) and 1 pt with lung cancer (4% reduction) but did not meet the criteria for partial response. At Week 3, mean clearance was 12.6 L/hr and mean half-life was 2.5 hrs; no PRT1419 accumulation was seen with QW dosing. Conclusions: PRT1419 demonstrated acceptable safety and tolerability in pts with advanced/metastatic solid tumors, with primary TRAEs of neutropenia, nausea, diarrhea, and vomiting. No cardiac toxicity was observed. BAX and caspase 3 activation was observed, suggesting potentially successful MCL-1 inhibition. Investigation of PRT1419 in pts with hematologic malignancy in a separate study is ongoing (NCT05107856). Citation Format: Gerald Falchook, Manish Patel, Meredith McKean, Alexander Philipovskiy, Rachel Chiaverelli, William Sun, Michael Fossler, William Novotny, Michael Kurman, Sarah Rowe, Deborah Hunter, Mohammed Milhem. A phase 1, open-label, dose-escalation study of PRT1419, a selective induced myeloid leukemia cell differentiation protein (MCL-1) inhibitor, in patients (pts) with advanced/metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT172.

A Cell Type Selective YM155 Prodrug Targets Receptor-Interacting Protein Kinase 2 to Induce Brain Cancer Cell Death.

Glioblastoma (GBM) is the most prevalent and aggressive primary central nervous system (CNS) malignancy. YM155 is a highly potent broad-spectrum anti-cancer drug that was derived from a phenotypic screen for functional inhibitors of survivin expression, but for which the relevant biomolecular target remains unknown. Presumably as a result of its lack of cell-type selectivity, YM155 has suffered from tolerability issues in the clinic. Based on its structural similarity to the GBM-selective prodrug RIPGBM, here, we report the design, synthesis, and characterization of a prodrug form of YM155, termed aYM155. aYM155 displays potent cell killing activity against a broad panel of patient-derived GBM cancer stem-like cells (IC50 = 0.7-10 nM), as well as EGFR-amplified and EGFR variant III-expressing (EGFRvIII) cell lines (IC50 = 3.8-36 nM), and becomes activated in a cell-type-dependent manner. Mass spectrometry-based analysis indicates that enhanced cell-type selectivity results from relative rates of prodrug activation in transformed versus non-transformed cell types. The prodrug strategy also facilitates transport into the brain (brain-to-plasma ratio, aYM155 = 0.56; YM155 = BLQ). In addition, we determine that the survivin-suppressing and apoptosis-inducing activities of YM155 involve its interaction with receptor-interacting protein kinase 2 (RIPK2). In an orthotopic intracranial GBM xenograft model, aYM155 prodrug significantly inhibits brain tumor growth in vivo, which correlates with cell-type selective survivin-based pharmacodynamic effects.

890 Disparities in Supportive Care Utilization Among Neurosurgical Patients With Malignant Central Nervous System Tumors

INTRODUCTION: Patients with central nervous system (CNS) malignancies benefit from palliative care (PC) in addition to other supportive services, such as home health and social work. Guidelines also propose early PC for patients with advanced cancers. Racial disparities exist in healthcare access, and we introduce a novel construct, “provider patient racial diversity index” (provider pRDI), higher categories of which refer to higher proportions of non-white patients a provider sees as a measure of the provider’s exposure to racial diversity and cultural sensitivity. METHODS: Using Optum Clinformatics Datamart Database, all patients with at least one neurosurgery encounter, diagnosis of primary or secondary CNS malignancy, and no prior supportive services were included. Patient-level demographics were collated. Supportive services were defined based on provider categorization on individual claims. RESULTS: The cohort of 48,722 patients demonstrated significantly low rates of PC, home health, and social work services among racial minorities. However, patients who saw providers categorized into high provider pRDI categories were increasingly more likely to interface with supportive services and at an earlier point in their disease courses. Patient race did not impact supportive service spending, but higher provider pRDI was associated with monotonic increases in spending on PC. CONCLUSIONS: Neurosurgical patients with CNS malignancies from minority backgrounds are less likely to receive supportive services. Such effect is mitigated when they encounter at least one provider who scores highly in provider pRDI; patients receive supportive services earlier and demonstrate greater utilization. Our study highlights patient-level healthcare disparities and the need for provider-level intervention to address cultural sensitivity.

Time interval from diagnosis to treatment of brain metastases with stereotactic radiosurgery is not associated with radionecrosis or local failure.

Brain metastases are the most common intracranial tumor diagnosed in adults. In patients treated with stereotactic radiosurgery, the incidence of post-treatment radionecrosis appears to be rising, which has been attributed to improved patient survival as well as novel systemic treatments. The impacts of concomitant immunotherapy and the interval between diagnosis and treatment on patient outcomes are unclear. This single institution, retrospective study consisted of patients who received single or multi-fraction stereotactic radiosurgery for intact brain metastases. Exclusion criteria included neurosurgical resection prior to treatment and treatment of non-malignant histologies or primary central nervous system malignancies. A univariate screen was implemented to determine which factors were associated with radionecrosis. The chi-square test or Fisher's exact test was used to compare the two groups for categorical variables, and the two-sample t-test or Mann-Whitney test was used for continuous data. Those factors that appeared to be associated with radionecrosis on univariate analyses were included in a multivariable model. Univariable and multivariable Cox proportional hazards models were used to assess potential predictors of time to local failure and time to regional failure. A total of 107 evaluable patients with a total of 256 individual brain metastases were identified. The majority of metastases were non-small cell lung cancer (58.98%), followed by breast cancer (16.02%). Multivariable analyses demonstrated increased risk of radionecrosis with increasing MRI maximum axial dimension (OR 1.10, p=0.0123) and a history of previous whole brain radiation therapy (OR 3.48, p=0.0243). Receipt of stereotactic radiosurgery with concurrent immunotherapy was associated with a decreased risk of local failure (HR 0.31, p=0.0159). Time interval between diagnostic MRI and first treatment, time interval between CT simulation and first treatment, and concurrent immunotherapy had no impact on incidence of radionecrosis or regional failure. An optimal time interval between diagnosis and treatment for intact brain metastases that minimizes radionecrosis and maximizes local and regional control could not be identified. Concurrent immunotherapy does not appear to increase the risk of radionecrosis and may improve local control. These data further support the safety and synergistic efficacy of stereotactic radiosurgery with concurrent immunotherapy.

Characteristics of malignant tumors of digestive system and autoimmune diseases.

With the development of preoperative examination technology, endoscopic ultrasonography-guided fine-needle aspiration biopsy (EUS-FNA) has been widely used in preoperative pathological diagnosis. However, challenges remain in obtaining appropriate tissue samples and obtaining accurate pathological results to predict disease risk. Therefore, this study aimed to analyze the characteristics of digestive system malignancies and their autoimmune diseases, and to analyze the clinicopathological features, preoperative CT imaging features and pathological grades of pNENs of different pathological degrees of pNENs on the prognosis of pNENs. Experimental results showed that non-functioning pancreatic neuroendocrine tumors showed prominent surrounding hypervascular lesions on multiphase CT examination. Among them, arterial phase and portal venous phase were most clearly imaged at the end, and the degree of local vascular invasion could be used as an index to evaluate its resectability. The sensitivity of CT examination was 63% to 82%, and the specificity was 83% to 100%, depending on the size.