Rapid Recurrence Research Articles

Single cell-spatial transcriptomics and bulk multi-omics analysis of heterogeneity and ecosystems in hepatocellular carcinoma.

This study profiled global single cell-spatial-bulk transcriptome landscapes of hepatocellular carcinoma (HCC) ecosystem from six HCC cases and a non-carcinoma liver control donor. We discovered that intratumoral heterogeneity mainly derived from HCC cells diversity and pervaded the genome-transcriptome-proteome-metabolome network. HCC cells are the core driving force of taming tumor-associated macrophages (TAMs) with pro-tumorigenic phenotypes for favor its dominant growth. Remarkably, M1-types TAMs had been characterized by disturbance of metabolism, poor antigen-presentation and immune-killing abilities. Besides, we found simultaneous cirrhotic and HCC lesions in an individual patient shared common origin and displayed parallel clone evolution via driving disparate immune reprograms for better environmental adaptation. Moreover, endothelial cells exhibited phenotypically conserved but executed differential functions in a space-dependent manner. Further, the spatiotemporal traits of rapid recurrence niche genes were identified and validated by immunohistochemistry. Our data unravels the great significance of HCC cells in shaping vibrant tumor ecosystems corresponding to clinical scenarios.

Abstract 4120743: MEK inhibition for recurring pulmonary valve stenosis in RASopathy patients

Backgound: The RASopathies are developmental syndromes resulting from variants in the RAS/mitogen-activated protein (MAPK) cascade. The vast majority of RASopathy-causing variants lead to a gain of function in RAS-MAPK signaling. This has motivated compassionate use of MEK inhibition (MEKi) for rare, but potentially lethal complications such as hypertrophic cardiomyopathy and lymphatic disease. However, the most recurrent cardiac complication in RASopathies is pulmonary valve stenosis (PVS). PVS may require balloon valvuloplasty (BV) and can recur over time. Research question: Can MEKi be successfully used for recurrent PVS in RASopathy-patients? Aim: To report compassionate use of MEKi (trametinib) in recurring RASopathy-associated PVS. Method: Retrospective, single-center study at CHU Sainte Justine, Montreal, from 2021 to 2024. Results: After informed parental consent for off-label compassionate use of trametinib, four patients with recurrence of severe PVS after balloon valvuloplasty (>= 80 mmHg) had a total of 5 treatment episodes. Three patients were female, and one patient was male. The following genotypes were represented: Case 1, RIT1 A77V; case 2, PTPN11 N308D; case 3, RIT1 F82V, del22q11dist; case 4, PTPN11 Q110G, dup Xp22.13 (VUS), dup 16p11.2. Initial BV was carried out between three weeks and 10 months of age. Recurrence of PVS was noted between 4 days and 6 months after BV. Peak gradients at recurrence measured 72 -96 mmHg, and decreased to 40 – 64 mmHg (Dp -10 to -40 mmHg) at one to three months after treatment. Treatment had to be stopped in three cases for cutaneous side effects, with a rapid second recurrence in one case, which again responded to MEKi. PVS residual gradients at latest follow-up ranged from 30 – 69 mmHg. In all four patients, repeat catheter intervention or surgery could be avoided. In three out of four RASopathy patients with severe recurrent PVS after initial BV, we observe mild or moderate residual PVS. The patient with residual severe PS also carries a del22q11.2dist, which renders her haploinsufficient for LZTR1, a potential disease/treatment modifier within the RAS-MAPK cascade. Conclusion: Our results potentially expand the indications for MEKi in selected cases of RASopathy-associated recurrence of PVS and suggest an alternative to surgery or repeat catheterization. However, this case series is limited by the lack of an adequate contemporaneous, genotyped control cohort and its retrospective nature.

INNV-22. CEREBELLOPONTINE EPIDERMOID CYST TO SQUAMOUS CELL CARCINOMA: MALIGNANT TRANSFORMATION, LEPTOMENINGEAL CARCINOMATOSIS, AND MANAGEMENT

Abstract BACKGROUND Intracranial epidermoid cysts (EDC) are rare, slow-growing, congenital tumors, that generally follow a benign course. EDCs have a rare potential for transformation to squamous cell carcinoma (SCC). We present a case of a malignant EDC transformation to SCC with leptomeningeal (LM) dissemination. METHODS Case report and review of literature. CASE PRESENTATION A 44-year-old female presented for evaluation of left-sided tinnitus and sensorineural hearing loss, which revealed a left cerebellopontine angle (CPA) tumor. She underwent a subtotal resection at age 47. One year later, she had rapid symptomatic recurrence of the cyst, as well as LM deposits of the right internal acoustic canal bundle, the left trigeminal nerve, and along the lumbar and sacral spine. She underwent repeat resection of the CPA lesion, with pathology now consistent with SCC, with CDKN2A loss. She received focal radiation therapy at the posterior fossa and the lumbar spine. SCC-directed chemotherapy with pembrolizumab and carboplatin followed by 5 cycles of pembrolizumab monotherapy was given as adjuvant therapy, prior to her developing symptomatic LM disease. CONCLUSION Malignant transformation of intracranial EDC is a rare occurrence in these typically benign tumours. Prognosis is especially poor when there is associated LM involvement, with median survival noted to be 10 months. Awareness of this phenomenon amongst clinicians is needed to ensure appropriate surveillance and aggressive treatment if it remains within patient wishes, though there is no consensus on recommendations for treatment. The patient presented has maintained disease stability with LM dissemination for over 10 months and ongoing, with a regimen of chemoradiotherapy informed by therapeutic approach to systemic SCC. To our knowledge, this is the first reported case of EDC to SCC transformation and LM dissemination stabilized with chemoradiotherapy using an immune-checkpoint inhibitor.

Circulating Neoplastic-Immune Hybrid Cells Are Biomarkers of Occult Metastasis and Treatment Response in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) presents significant diagnostic and prognostic challenges, as current biomarkers frequently fail to accurately stage disease, predict rapid metastatic recurrence (rPDAC), or assess response to neoadjuvant therapy (NAT). We investigated the potential for circulating neoplastic-immune hybrid cells (CHCs) as a non-invasive, multifunctional biomarker for PDAC. Peripheral blood specimens were obtained from patients diagnosed with PDAC. CHCs were detected by co-expression of pan-cytokeratin and CD45, normalized to 50,000 peripheral blood mononuclear cells. rPDAC was defined as metastatic recurrence within six months of margin-negative pancreatectomy. Cyclic immunofluorescence (CyCIF) analyses compared hybrid phenotypes in blood and tumors. Blood samples were collected from 42 patients with PDAC prior to resection. Those with radiographically occult metastatic disease and rPDAC had higher preoperative CHC numbers compared to patients who did not (65.0 and 74.4, vs. 11.52 CHCs; p < 0.001). Patients with complete or near-complete pathologic responses to NAT had lower preoperative CHC numbers than partial and/or non-responders (1.7 vs. 13.1 CHCs; p = 0.008). When assessed longitudinally, those with partial pathologic response saw CHC levels become undetectable while on treatment but increase in the interval between NAT completion and resection. In contrast, patients with poor responses or development of metastatic disease experienced persistent CHC detection during therapy or rising levels prior to radiographic evidence of metastases. Further, in metastatic PDAC patients, treatment-induced phenotypic changes in hybrid cells mirrored those in paired metastatic tumor samples. CHC enumeration and phenotyping display promise as a real-time indicator of disease burden, recurrence risk, and treatment response in PDAC. CHCs have great potential as tumor-derived biomarkers to optimize therapeutic strategies and improve survival in patients with PDAC.

Rapid diagnosis and recurrence prediction of choledocholithiasis disease using raw bile with machine learning assisted SERS

Surface-enhanced Raman spectroscopy (SERS) analysis based on body fluids has been widely applied in disease diagnose. Choledocholithiasis is a widespread and often recurrent digestive system disease, with limited data on factors predicting its formation and reappearance. Bile contains many components that could provide valuable diagnostic information; however, the current diagnosis of biliary disease by SERS focuses on detecting specific component in the bile, overlooking the complex interplay and correlations among multiple factors that could be crucial for accurate diagnosis. This work directly obtained multi-component SERS spectral information of raw bile from 46 patients. Characteristic information was extracted from bile SERS spectra using Principal Component Analysis (PCA), revealing variations in the content of characteristic components associated with different choledocholithiasis types and their recurrence frequency. Pearson correlation analysis was also introduced to reveal the interactions of primary active substances pertinent to choledocholithiasis diagnosis. The efficacy of PCA and Support Vector Machine (SVM) models in classifying stone types, presented an accuracy of 99.2 %. Furthermore, the interaction patterns among SERS characteristic components in choledocholithiasis recurrence frequency were revealed, and with the support of SVM, the prediction for different recurrence rates reached an accuracy of 95.2 %. Overall, this work demonstrates that integrating SERS with machine learning can support disease diagnosis and the interpretation of correlations among multiple components, facilitating elucidating the disease mechanisms.

12490 Management Of Autoimmune Hepatitis Under Mitotane Therapy: Reintroduction Of Mitotane Under High Dose Corticosteroids For Targeted Mitotane Therapeutic Levels In A Patient With Recurrent Myxoid Adrenocortical Carcinoma

Abstract Disclosure: T. Hristova: None. D. Fenyves: None. C. Cloutier: None. M. Latour: None. Z. El-haffaf: None. P. Karakiewicz: None. H.J. Olney: None. I. Bourdeau: None. Histologically rare variants of adrenocortical carcinoma (ACC) include myxoid, oncocytic and sarcomatoid subtypes. There are about 50 reported cases of myxoid variants up to now that are described as more aggressive than classical ACC with poorer overall survival. Surgical resection offers the best chance of survival, with mitotane being the first line of treatment after surgery. Mitotane is currently the only approved adrenolytic drug for ACC. Among mitotane adverse effects, auto-immune hepatitis (AIH) is reported in monography, yet barely anything is reported in the literature about it. The precise mechanism of AIH has not been reported yet, but the mainstem therapy of AIH is corticosteroids alone or in combination with azathioprine. We report the case of a 43-year-old male who was diagnosed with non-secreting myxoid ACC subtype stage 2 (7x6x5,5 cm, ki67 18%, Weiss score 6/9). Multigene panel testing revealed a germline pathogenic variant in the ATM gene. Post adrenalectomy, mitotane was initiated within 2 months and increased to 2,5g daily within 6 weeks. 11 weeks after starting mitotane, liver enzymes were as follows: ALT 127 U/L (N: 10-39), AST 54 U/L (N: 13-39), ALP 165 U/L (N: 36-110), GGT 489 U/L (N: 9-47), while pre-mitotane levels were normal. Although mitotane was stopped, ALT increased to 255 U/L and remained high for 10 weeks after its cessation. Liver biopsy showed chronic hepatitis with moderate inflammation which was compatible with toxic hepatitis vs AIH. As kinetic liver enzyme tests increased after mitotane cessation, AIH was the retained diagnosis. Treatment with 40mg prednisone daily was then initiated. Pre-prednisone liver enzymes were ALT 202 U/L, AST 64 U/L, ALP 154 U/L, GGT 216 U/L, whereas 8 weeks later values had decreased to ALT 74 U/L, AST 20 U/L, ALP 108 U/L, GGT 84 U/L, and prednisone was lowered to 15mg daily. ACC recurred 3 months later, about one year after the initial adrenalectomy. After surgical resection, mitotane was restarted at 500mg daily with prednisone 40mg daily. As liver enzymes were within normal ranges, mitotane was slowly increased to 2.5g daily, with mitotane plasma levels of 11.3mg/L, whereas prednisone was decreased gradually to 12.5mg daily. Second ACC recurrence occurred one year later and mitotane was further increased to 3g daily under prednisone 12.5mg reaching mitotane levels up to 21.2 mg/L with surgical debulking. Further therapeutic avenues are being considered for a rapid recent ACC recurrence, such as PARP inhibitors for targeted therapy in the context of ATM gene mutation, but further considerations are required due to previous AIH. To the best of our knowledge this is the first reported case of AIH due to mitotane in a rare ACC subtype in a patient carrying a germline ATM gene mutation. We also report restart of mitotane therapy with concomitant high dose prednisone in the context of ACC recurrence that allowed to reach targeted therapeutic levels. Presentation: 6/1/2024

Thoracic epithelioid inflammatory myofibroblastic sarcoma: a rare and aggressive disease with case report and literature review

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a rare subtype of inflammatory myofibroblastic tumor, characterized to be an aggressive disease with high frequency of ALK rearrangement, rapid recurrence, and poor prognosis. Primary EIMS of thoracic origin is rarely observed. Herein, we described a case of 28-year-old female developed primary EIMS in the anterior mediastinum with hepatic metastasis. The EIMS displayed sheet-like growth of epithelioid and spindle cells with enlarged nuclei, abundant and eosinophilic cytoplasm, and infiltration of inflammatory cells. Immunohistochemical staining revealed positive expression of ALK in the nuclear membrane, and ALK rearrangement was identified by polymerase chain reaction assay. Alectinib showed partial response, and achieved a meaningful survival benefit for four months. Based on this case report and literature review, ALK inhibitor reveals promising activity on the rare but aggressive EIMS. Awareness of EIMS in thoracic disease and its clinicopathological features is essential to avoid erroneous diagnosis.

Polydopamine-functionalized calcium-deficient hydroxyapatite 3D-printed scaffold with sustained doxorubicin release for synergistic chemo-photothermal therapy of osteosarcoma and accelerated bone regeneration

Interior bone-tissue regeneration and rapid tumor recurrence post-resection are critical challenges in osteosarcoma and other bone cancers. Conventional bone tissue engineering scaffolds lack inhibitory effects on bone tumor recurrence. Herein, multifunctional scaffolds (named DOX/PDA@CDHA) were designed through the spontaneous polymerization of Dopamine (PDA) on the surface of Calcium Deficient Hydroxyapatite (CDHA) scaffolds, followed by in situ loading of the chemotherapeutic drug Doxorubicin (DOX). The PDA coating endowed the scaffolds with significant photothermal properties, while the gradual release of DOX provided an effective chemotherapeutic effect. The on-demand release of DOX at tumor sites, triggered by dual stimulation (near-infrared (NIR) light and the acidic pH typical of tumor microenvironments), specifically targets cancer cells, thereby mitigating systemic side effects. These unique characteristics facilitated effective osteosarcoma eradication both in vitro and in vivo. Moreover, the scaffold's composition, which mimics the mineral phase of natural bone and is enhanced by PDA's biocompatibility, promotes critical osteogenic and angiogenic processes. This facilitates not only tumor eradication but also the regeneration of healthy bone tissue. Collectively, this study presents a potent candidate for the regeneration of bone defects induced by osteosarcoma.

Longitudinal cardiac magnetic resonance imaging following clinical response to rilonacept and prior to recurrence upon treatment suspension: a RHAPSODY subgroup analysis.

In the phase 3 trial, RHAPSODY, rilonacept effectively resolved active pericarditis recurrences, and long-term treatment led to sustained pericarditis recurrence risk reduction. Prior analysis suggested association between higher late gadolinium enhancement (LGE) at baseline and more rapid recurrence upon rilonacept suspension after 12 weeks of treatment. This subgroup analysis assessed the utility of longitudinal serial cardiac magnetic resonance (CMR) imaging for tracking clinical improvement and predicting post-treatment-cessation outcomes to help guide clinical decision making. At an 18-month decision milestone (18MDM) in the RHAPSODY long-term extension, investigators decided if patients would continue rilonacept, suspend rilonacept for off-treatment observation, or discontinue the study. Pericardial thickness, pericardial edema (T2-STIR), and LGE were determined at baseline and 18MDM by an imaging core lab blinded to clinical data, and pericarditis recurrence was investigator-assessed. CMR results in patients with data at both baseline and 18MDM (n=13) showed that pericardial thickness, T2-STIR, and LGE were reduced during rilonacept treatment. Among patients with CMR data who suspended rilonacept at the 18MDM (n=7), 5 (71%) had a pericarditis recurrence within 1-4 months of rilonacept suspension, despite all having had none/trace LGE (n=7) and negative T2-STIR (n=7) at the 18MDM and 2 having received prophylactic colchicine. Continued clinical improvement during prolonged rilonacept treatment corresponded with improvement on CMR, including reduced pericardial thickness, resolution of pericardial edema, and resolution of LGE. However, none/trace LGE at 18MDM while on treatment did not predict absence of pericarditis recurrence upon subsequent rilonacept suspension in this size-limited subgroup.

Rapid metastatic recurrence after pancreatic cancer resection: a multi-center, regional analysis of trends in surgical failure over two decades

BackgroundPancreatic ductal adenocarcinoma (PDAc) is a lethal malignancy, attributed in part to high rates of rapid recurrence (rrPDAc) following resection. We sought to characterize recurrence rates over time and investigate factors predictive of rrPDAc. MethodsA regional multi-institutional cancer registry, augmented with data from the National Surgical Quality Improvement Program database, was queried for patients with PDAc from 1996 to 2020. rrPDAc was defined as recurrence within 6 months following curative-intent resection. ResultsWe identified 924 patients who underwent resection for PDAc; rrPDAc occurred in 236 (26%) patients. Median incidence of rrPDAc was 25.3% (IQR 22–30.2%) per year. Median survival in rrPDAc, non-rapid recurrence, and no recurrence was 10.3, 25.2, and 56.1 months respectively (p < 0.001). Variables independently associated with greater odds of rrPDAc included surgical site infection (SSI) (OR 2.06) and nodal positivity (OR 2.05); adjuvant therapy was associated with lower odds (OR 0.38). Neoadjuvant chemotherapy did not alter risk of rrPDAc. Three-year post-recurrence survival was no different in rrPDAc versus those without. ConclusionDespite therapeutic advances, incidence of rrPDAc remains unchanged. SSIs and nodal positivity are independently associated with increased risk of rrPDAc, while adjuvant chemotherapy is associated with lower risk. Strategies focused on preventing rapid recurrence may improve survival.

Clinical Features of 17 Patients With Primary Angiitis of the Central Nervous System Confirmed by Brain Biopsy

Objective To analyze the clinical features of 17 patients with primary angiitis of the central nervous system (PACNS) and thus facilitate the early diagnosis and treatment,reduce the recurrence and mortality,and improve the prognoses of this disease. Methods We collected the data of patients with PACNS diagnosed by brain biopsy from January 2009 to June 2023 and analyzed their clinical presentations,laboratory and imaging manifestations,electrophysiological and pathological changes,and treatment regimens and prognosis. Results The 17 patients diagnosed with PACNS via brain biopsy included one child and 16 adults.The subtyping results showed that 10,2,3,2,1,and 1 patients had tumorous,spinal cord-involved,angiography-positive,rapidly progressive,hemorrhagic,and amyloid β-related PACNS,respectively.Eleven (64.7%) of the patients were complicated with secondary epilepsy.All the patients exhibited abnormal manifestations in head MRI,with 94.1% showing lesions with uneven enhancement around the lesions or in the leptomeninges. Magnetic resonance angiography revealed large vessel abnormalities in 3 patients,and spinal cord involvement was observed in 2 patients.Histopathological typing revealed 7 (43.7%) patients with lymphocytic vasculitis and 5 (31.2%) patients with necrotizing vasculitis.Eleven patients were treated with glucocorticoids and cyclophosphamide,which resulted in partial lesion disappearance and symptom amelioration in 6 patients upon reevaluation with head MRI after 3 months of maintenance therapy.Two,1,and 3 patients experienced rapid disease progression,death,and recurrence within 1 year,respectively.Three patients showed insensitivity to hormonotherapy and residual disabilities.Two patients received rituximab after relapse and remained clinically stable during a follow-up period of 0.5-1 year. Conclusion Tumorous PACNS was more prone to epilepsy,mainly occurring in males.The most common histopathological type was necrotizing vasculitis,which responded to hormonotherapy and had favorable outcomes.Therefore,for the young patients with epilepsy and intracranial tumorous lesions,the possibility of PACNS should be considered.Spinal cord involvement in PACNS was often located in the thoracic and cervical cords,suggesting a poorer prognosis.Electromyography commonly revealed neural conduction abnormalities in the anterior horn or roots,providing clues for differential diagnosis.For suspected spinal cord involvement,comprehensive electromyography is recommended.Rapidly progressive PACNS often presented infratentorial lesions,such as lesions in the pons and medulla,with a higher mortality rate.Hemorrhagic PACNS was rare,and a multifocal hemorrhagic lesion with enhancement in the intracranial region,particularly in young patients,should raise suspicion.For the patients with recurrent or progressive disease,rituximab is a recommended therapeutic option.

MDB-93. A TRANSCRIPTOME-BASED APPROACH TO DRUG REPURPOSING FOR AGGRESSIVE GROUP 3 MEDULLOBLASTOMAS

Abstract BACKGROUND Medulloblastoma (MB) is the most common malignant brain tumor in children, representing 20% of pediatric brain tumors. International consensus has identified molecular subgroups: WNT, SHH, group 3 (G3), and group 4 (G4). Current treatments, guided by histologic tumor grade and stage, do not fully harness these subgroups, resulting in varying prognoses. G3MB particularly faces challenges with rapid recurrence and aggressive disease, necessitating focused intervention. METHODS We conducted differential expression analysis on MB patient datasets (GSE148389, GSE164677) to generate a G3MB gene expression signature. This gene expression signature was analyzed against the LINCS database, yielding candidate antineoplastic compounds. Candidates were filtered for blood-brain barrier permeability and FDA approval. Functional assays evaluated drug effects on cytotoxicity, clonogenicity, wound healing, cell cycle, and apoptosis in G3MB cell lines (HDMB03 and D425). RNA sequencing of treated cells identified differentially regulated pathways to infer mechanism, followed by in vitro validation. Mitochondrial function and membrane potential were measured by Seahorse and TMRM assays, respectively. RESULTS Eighty-one candidates passed filtering. The leading drug class identified was antidepressants. Based on MTT assays, the top four candidates were nortriptyline, simvastatin, fluoxetine, and sertraline. Nortriptyline (NT) emerged as the lead compound, with IC50 values of ~7uM (HDMB03) and ~11uM (D425). Amongst the four drugs, NT induced consistent anti-neoplastic effects on wound healing, colony formation, medullosphere generation, and apoptosis. Mechanistically, NT induced mitochondrial stress, escalated mitochondrial superoxide, and decreased mitochondrial membrane potential. CHRM3, a receptor antagonized by NT and upregulated in G3MB samples was downregulated by NT treatment. Western blotting confirmed the inhibition of CHRM3 downstream effectors. CONCLUSIONS Our pipeline identified cytotoxic compounds against G3MB, including NT, which we hypothesize induces mitochondrial stress via CHRM3 modulation. This approach offers repurposable FDA-approved candidates for high-risk G3MB, potentially reducing current treatment toxicity and improving outcomes.

Radiation-Induced Breast Angiosarcoma Associated with Homolateral Axillary Recurrence: A Case Report

Breast angiosarcoma is a rare aggressive tumor that develops from connective tissue of vascular origin with a tendency towards rapid recurrence and the appearance of visceral metastases. It occurs either as a primary tumor in young women or as a secondary tumor following breast irradiation. We report a case of breast angiosarcoma associated with homolateral axillary recurrence in a 45-year-old woman treated for bilateral breast cancer.

Dual-Responsive and Aggregation-Induced-Emission Probe for Selective Imaging of Infectious Urolithiasis.

Identifying infected stones is crucial due to their rapid growth and high recurrence rate. Our study presents the calcium-magnesium dual-responsive aggregation-induced emission (AIE)-active probe TCM-5COOH, distinctively engineered to distinguish high-threat infection calculi from metabolic stones. Upon incorporation of flexible alkyl carboxyl group, TCM-5COOH featuring five carboxyl moieties demonstrates excellent water solubility and enhanced penetration into porous infectious stones. The robust chelation of TCM-5COOH with stone surface-abundant Ca2+ and Mg2+inhibits vibrational relaxation, thus triggering intense AIE signals. Remarkably, the resulting complex exhibits high insolubility, effectively anchoring within the porous structure of the infection calculi and offering prolonged illumination. Jobs' plot method revealed similar responses characteristics for Ca2+ and Mg2+, with a 1:2 coordination number for both ions. Isothermal titration calorimetry (ITC) results demonstrated higher enthalpy change (ΔH) and lower entropy change (ΔS) for the reaction, indicating enhanced selectivity compared to TCM-4COOH lacking the alkyl carboxyl group. Synchrotron X-ray absorption fine spectroscopy (XAFS) validated TCM-5COOH's interaction with Ca2+ and Mg2+ at the micro level. This dual-responsive probe excels in identifying infectious and metabolic calculi, compatible with endoscopic modalities and laser excitation, thereby prompting clinical visualization and diagnostic assessment. This article is protected by copyright. All rights reserved.

The Clinical and Economic Implications of Different Treatment Pathways for Patients With Rapidly Recurrent Malignant Pleural Effusion

BackgroundMalignant pleural effusion (MPE) is a common cancer complication. Clinical and economic implications of different recurrent MPE treatment pathways have not been fully evaluated. Research QuestionWhat clinical outcomes, complications, healthcare resource use, and costs are associated with various rapidly recurrent MPE treatment pathways? Study Design and MethodsThis retrospective cohort study using Surveillance, Epidemiology and End Results Medicare data (2011-2015) included patients aged 66-90 with rapidly recurrent MPE. Rapid recurrence was defined as receipt of a second pleural procedure within 14 days of the first thoracentesis including non-definitive repeated thoracentesis, or a definitive treatment option including chest tube, indwelling pleural catheter (IPC), or thoracoscopy. ResultsAmong 8,378 patients with MPE, 3,090 (36.9%) had rapidly recurrent MPE (mean [SD] age 75.9 [6.6], 45.6% male, primary cancer 62.9% lung and 37.1% other). Second pleural procedures were non-definitive thoracentesis (62.3%), chest tube (17.1%), IPC (13.2%), or thoracoscopy (7.4%). A third pleural procedure was more frequently required if the second pleural procedure was non-definitive thoracentesis vs. chest tube, IPC, or thoracoscopy (70.3% vs. 44.1% vs. 17.9% vs. 14.4%, respectively). The mean number of subsequent pleural procedures over the patient’s lifetime varied significantly among the procedures (1.74, 0.82, 0.31, and 0.22 for patients receiving thoracentesis, chest tube, IPC, and thoracoscopy, respectively; P < .05). Average total costs following the second pleural procedure to death adjusted for age at primary cancer diagnosis, race, year of second pleural procedure, Charlson Comorbidity Index, cancer stage at primary diagnosis, and time from primary cancer diagnosis to diagnostic thoracentesis were lower with IPC ($37,443; P < .0001) or chest tube ($40,627; P = .004) vs. thoracentesis ($47,711). Patients receiving thoracoscopy ($45,386; P = .5) had similar costs to patients receiving thoracentesis. InterpretationEarly definitive treatment was associated with fewer subsequent procedures and lower costs in rapidly recurrent MPE.

Modeling Extraordinary Response Through Targeting Secondary Alterations in Fusion-Associated Sarcoma.

Targeted therapy in translocation-associated sarcomas has been limited to oncogenic activation of tyrosine kinases or ligands while gene fusions resulting in aberrant expression of transcription factors have been notoriously difficult to target. Moreover, secondary genetic alterations in sarcomas driven by translocations are uncommon, comprising mostly alterations in tumor suppressor genes (TP53, CDKN2A/B). Our study was triggered by an index patient showing a dramatic clinical response by targeting the secondary BRAF V600E mutation in a metastatic angiomatoid fibrous histiocytoma (AFH) harboring the typical EWSR1::CREB1 fusion. The patient, a 28-year-old female, was diagnosed with an AFH of the thigh and followed a highly aggressive clinical course, with rapid multifocal local recurrence within a year and widespread distant metastases (adrenal, bone, liver, lung). The tumor showed characteristic morphologic features, with histiocytoid cells intermixed with hemorrhagic cystic spaces and lymphoid aggregates. In addition to the pathognomonic EWSR1::CREB1 fusion, targeted DNA sequencing revealed in both primary and adrenal metastatic sites a hot spot BRAF V600E mutation and a CDKN2A/B deletion. Accordingly, the patient was treated with a BRAF-MEK inhibitor combination (encorafenib/binimetinib) showing an excellent but short-lived response. Using a CRISPR-Cas9 approach, we introduced the BRAF c.1799 T>A point mutation in human embryonic stem (hES) cells harboring a conditional EWSR1 (exon7)::CREB1 (exon7) translocation and further differentiated to mesenchymal progenitors (hES-MP) before fusion expression. The cells maintained the fusion transcript expression and the AFH core gene signature while responding to treatment with encorafenib and binimetinib. These results highlight that additional targeted DNA NGS in chemotherapy-resistant translocation-associated sarcomas may reveal actionable oncogenic drivers occurring as secondary genetic events during disease progression.

Concurrent hyperthermic intraperitoneal chemotherapy and intraoperative radiotherapy with cytoreductive surgery in patients with rectal cancer with peritoneal carcinomatosis.

e15571 Background: Rectal cancer (RC) is often associated with peritoneal carcinomatosis (PC). Hyperthermic intraperitoneal chemotherapy (HIPEC) and intraoperative radiotherapy (IORT) have been shows to reduce recurrence and effectively treat PC across several cancers. However, little evidence is available regarding the concurrent use of HIPEC and IORT alongside cytoreductive surgery (CRS) in the literature. Methods: We retrospectively reviewed the medical records of RC patients with PC who received HIPEC plus IORT during CRS at the King Faisal Specialist Hospital and Research Centre. Demographic data, PC index (PCI), completeness of cytoreduction (CC), and tumor staging were collected. Overall survival (OS) was calculated from the time of surgery until death or last follow-up. Recurrence-free survival (RFS) was calculated from the time of surgery until recurrence or last follow-up. Unadjusted hazard ratios (HR) were used to determine the impact of parameters on OS or RFS. Results: 17 patients were included in our analysis. Basic demographic data can be found in Table 1. The most common operation performed was rectosigmoid resection in 7 (41.2%) patients, followed by low anterior resection in 6 (35.3%). The pT stage was T0 in 1 (5.9%), T4a in 7 (41.2%), and T4b in 9 (52.9%). The pN stage was N0 in 11 (64.7%), N1a in 1 (5.9%), N1b in 2 (11.8%), N1c in 2 (11.8%), and N2b in 1 (5.9%). There was positive resection margin in 2 patients. The PCI was ≤6 in 15 (88.2%), and the CC score was 0-1 in all patients. No patients had intraoperative complications. 12 (70.6%) received mitomycin C, 4 (23.5%) received cisplatin and mitomycin C, and one patient received a reduced dose of mitomycin C due to old age. 2 (11.8%) patients received two doses of IORT. 11 (64.7%) patients had postoperative complications, of which all were Clavein-Dindo grades 1-3b. Recurrence occurred in 11 (64.7%). The median OS was not reached, and the median RFS was 12 months. There were no parameters associated with OS. Male gender (HR: 7.7, 95% CI: 1.4-57.3), pM1 (HR: 4.5, 95% CI; 1.2-18.1), and perineural invasion (HR: 6.5, 95% CI: 1.2-49.3) were associated with poor RFS in univariate analysis. Conclusions: Incorporating HIPEC and IORT into CRS may be an effective treatment strategy for RC patients. Presence of distant metastasis and perineural invasion can be predictors of rapid recurrence. [Table: see text]

Dermatofibrosarcoma of Darrier and Ferrand: Recurrency Character: A Case-Report (Experience of the University Hospital Tangier-Tetouan-Al Hoceima)

Introduction: Dermatofibrosarcoma of Darier and Ferrand (DFSP) is a rare skin tumor characterized by its local aggressiveness and high potential. Its prognosis depends essentially on the quality of its management. Observation and Results: In this article, we report the case of a young patient treated at the Department of Plastic, Reconstructive and Aesthetic Surgery, Tangier, for a Darier and Ferrand dermatofibrosarcoma that recurred five times after surgical excision, with a 5-cm margin on the surface and a healthy anatomical barrier at depth. Coverage of the loss of substance (LOS) was performed after anatomopathological confirmation of the carcinological nature of the excision, and essentially involved skin grafting. Despite a course of radiotherapy prescribed at the 4th recurrence, a 5th rapid recurrence was noted. Discussion: The great clinical, histological and evolutionary polymorphism of this type of sarcoma results in an underestimated incidence and explains the delay in diagnosis. Recurrences are frequent, and usually local. Initial wide surgical excision is the reference treatment, and directly conditions the prognosis of DFSP. According to several studies, recurrence may depend on the quality of surgical excision, but could also be attributed to genetic or environmental factors, or to variations in the histological subtype of the sarcoma. Conclusion: Darier Ferrand is an uncommon tumor with local malignancy, whose evolutionary risk depends mainly on the quality of the initial excision. The chances of cure in the case of well performed primary surgery are significantly higher than in the case of salvage surgery. Tumor excision must the refore be wide and deep, with sacrifice of a healthy barrier at depth.

Resf1 is a compound G4 quadruplex-associated tumor suppressor for triple negative breast cancer.

Patients with ER-negative breast cancer have the worst prognosis of all breast cancer subtypes, often experiencing rapid recurrence or progression to metastatic disease shortly after diagnosis. Given that metastasis is the primary cause of mortality in most solid tumors, understanding metastatic biology is crucial for effective intervention. Using a mouse systems genetics approach, we previously identified 12 genes associated with metastatic susceptibility. Here, we extend those studies to identify Resf1, a poorly characterized gene, as a novel metastasis susceptibility gene in ER- breast cancer. Resf1 is a large, unstructured protein with an evolutionarily conserved intron-exon structure, but with poor amino acid conservation. CRISPR or gene trap mouse models crossed to the Polyoma Middle-T antigen genetically engineered mouse model (MMTV-PyMT) demonstrated that reduction of Resf1 resulted in a significant increase in tumor growth, a shortened overall survival time, and increased incidence and number of lung metastases, consistent with patient data. Furthermore, an analysis of matched tail and primary tissues revealed loss of the wildtype copy in tumor tissue, consistent with Resf1 being a tumor suppressor. Mechanistic analysis revealed a potential role of Resf1 in transcriptional control through association with compound G4 quadruplexes in expressed sequences, particularly those associated with ribosomal biogenesis. These results suggest that loss of Resf1 enhances tumor progression in ER- breast cancer through multiple alterations in both transcriptional and translational control.

Abstract PO2-18-08: Identification of novel genetic/therapeutic vulnerabilities in breast cancer

Abstract Background: Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death among women worldwide. Triple negative breast cancer (TNBC) is an aggressive subtype that is defined by the lack of expression of estrogen and progesterone receptors in the absence of HER2 amplification or overexpression. TNBC represents 15-20% of all breast cancers and occurs more frequently in young premenopausal women. TNBC often ends with a poor clinical outcome due to high histological grade, rapid recurrence in many patients combined with few treatment options. These realities highlight the urgent need to identify novel therapeutics vulnerabilities that can be leveraged to improve TNBC patient outcomes. Methods: We utilized the publicly available DepMap and Kaplan Meier datasets to identify essential genes that were unique to TNBC cells and whose expression levels were associated with worse patient outcomes. siRNA based approaches were used to confirm the relevance of top hits in mediating cancer cell phenotypes including viability, cell-cycle profiles and induction of apoptosis among others. A novel drug currently being developed was identified for the top hit in these studies and was subsequently employed in multiple in vitro approaches to characterize the mechanisms of action in TNBC as well as initial efficacy studies using clinically relevant ex vivo patient derived models. Results: Using the DepMap database, we interrogated genome-wide sgRNA knockout screens conducted in over 40 breast cancer cell lines to identify specific genes whose expression was required for cell viability in TNBC cells, but not other breast cancer cell lines. This endeavor identified 6 genes (CTPS1, HUS1, PRKRA, RAD1, RAD9A and RHOA) that were preferentially essential in TNBC cells. Further profiling of these genes revealed that CTPS1 expression is higher in cancer relative to normal tissue and that its expression is further upregulated in chemotherapy- and PARPi-resistant models. Knockdown of CTPS1 in TNBC cells was shown to decrease cell proliferation and viability with no effects observed in estrogen receptor+ cell lines. Using a first-in-class, highly selective and orally bioavailable CTPS1 inhibitor (STP938) developed by Step-Pharma, we identified IC50s in the low nM range for many TNBC cell lines, including cell models that are resistant to existing standard-of-care therapies. Inhibition of CTPS1 was shown to arrest cells in S phase. Conclusions: Our studies have identified CTPS1 as an essential gene in TNBC. CTPS1 encodes an enzyme responsible for the catalytic conversion of UTP (uridine triphosphate) to CTP (cytidine triphosphate), an essential step in the biosynthesis of nucleic acids. These findings are timely in light of the recent and ongoing development of the first-in-class CTPS1 inhibitor, STP938, for which first-in-human studies are underway for refractory B- and T-cell lymphomas. Based on our initial studies using this drug, we provide pre-clinical evidence of its efficacy in multiple models of primary and advanced TNBC. Efforts are currently underway to move this work toward a clinical trial for TNBC patients. Citation Format: Xiyin Wang, Michael Emch, Lauren Voll, Rebecca Russell, Esther Rodman, Philip Beer, John Hawse. Identification of novel genetic/therapeutic vulnerabilities in breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-18-08.