Case Of Metastasis Research Articles

The Immune Landscape of Pheochromocytoma and Paraganglioma: Current Advances and Perspectives.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors derived from neural crest cells from adrenal medullary chromaffin tissues and extra-adrenal paraganglia, respectively. Although the current treatment for PPGLs is surgery, optimal treatment options for advanced and metastatic cases have been limited. Hence, understanding the role of the immune system in PPGL tumorigenesis can provide essential knowledge for the development of better therapeutic and tumor management strategies, especially for those with advanced and metastatic PPGLs. The first part of this review outlines the fundamental principles of the immune system and tumor microenvironment, and their role in cancer immunoediting, particularly emphasizing PPGLs. We focus on how the unique pathophysiology of PPGLs, such as their high molecular, biochemical, and imaging heterogeneity and production of several oncometabolites, creates a tumor-specific microenvironment and immunologically "cold" tumors. Thereafter, we discuss recently published studies related to the reclustering of PPGLs based on their immune signature. The second part of this review discusses future perspectives in PPGL management, including immunodiagnostic and promising immunotherapeutic approaches for converting "cold" tumors into immunologically active or "hot" tumors known for their better immunotherapy response and patient outcomes. Special emphasis is placed on potent immune-related imaging strategies and immune signatures that could be used for the reclassification, prognostication, and management of these tumors to improve patient care and prognosis. Furthermore, we introduce currently available immunotherapies and their possible combinations with other available therapies as an emerging treatment for PPGLs that targets hostile tumor environments.

A160 A CASE OF BREAST CANCER METASTASIS MASQUERADING AS SIGNET RING CELL ADENOCARCINOMA OF THE STOMACH

Abstract Background Gastric cancer has a poor prognosis, particularly at advanced stages. Endoscopic submucosal dissection (ESD) can be used to treat selected early-stage gastric cancers. This case study explores the challenge of diagnosing and managing patients when metastatic lesions mimic primary gastric cancer, as seen in this case of breast cancer metastasis resembling signet ring cell adenocarcinoma of the stomach. Aims The aim of this case report is to describe an unusual case of breast cancer metastasis to the stomach identified unexpectedly on random gastric biopsies, initially diagnosed as a primary gastric signet ring cell adenocarcinoma. Methods Clinical and pathological records of the described patient were reviewed retrospectively. Furthermore, a review of the relevant literature was also performed. Results A 68 year-old-woman underwent gastroscopy for nausea and vomiting. Her past medical history was remarkable for bilateral mastectomies ten years ago for invasive lobular carcinoma, with metastatic bone disease diagnosed by imaging five years prior. She had been well controlled on letrozole taken intermittently due to side effects. At endoscopy, while the stomach appeared grossly normal, random biopsies done for Helicobacter pylori identified a single focus of signet ring cell adenocarcinoma. Subsequent chromoendoscopy identified an area of subtle mucosal abnormality for which the patient declined surgery and was instead managed by ESD which surprisingly yielded no dysplasia. A follow up gastroscopy with random biopsies also failed to identify any areas of dysplasia, but random biopsies on a subsequent gastroscopy again identified a minute focus of adenocarcinoma with signet ring cell morphology. Given the unusual presentation of apparent signet ring cell adenocarcinoma in two distinct areas in the stomach without any visible endoscopic abnormality an in-depth pathological analysis was conducted. By immunohistochemistry the tumor cells stained positive for Estrogen Receptor, GATA3, and CK7 and negative for antibodies targeting CK20 and CDX2, which supported an interpretation of minute multifocal breast cancer metastases to the stomach from hematogenous spread. Conclusions In this case, repeated endoscopic investigations and immunohistochemical staining revealed minute multifocal breast cancer metastases to the stomach. Conventional tumor staging methods often cannot identify microscopic metastases, potentially impacting disease progression and patient care. A high level of suspicion for metastatic breast cancer and a detailed pathological analysis allowed for the correct diagnosis in this patient. Funding Agencies None

Melanoma biology and treatment: a review of novel regulated cell death-based approaches

AbstractThe incidence of melanoma, the most lethal form of skin cancer, has increased due to ultraviolet exposure. The treatment of advanced melanoma, particularly metastatic cases, remains challenging with poor outcomes. Targeted therapies involving BRAF/MEK inhibitors and immunotherapy based on anti-PD1/anti-CTLA4 antibodies have achieved long-term survival rates of approximately 50% for patients with advanced melanoma. However, therapy resistance and inadequate treatment response continue to hinder further breakthroughs in treatments that increase survival rates. This review provides an introduction to the molecular-level pathogenesis of melanoma and offers an overview of current treatment options and their limitations. Cells can die by either accidental or regulated cell death (RCD). RCD is an orderly cell death controlled by a variety of macromolecules to maintain the stability of the internal environment. Since the uncontrolled proliferation of tumor cells requires evasion of RCD programs, inducing the RCD of melanoma cells may be a treatment strategy. This review summarizes studies on various types of nonapoptotic RCDs, such as autophagy-dependent cell death, necroptosis, ferroptosis, pyroptosis, and the recently discovered cuproptosis, in the context of melanoma. The relationships between these RCDs and melanoma are examined, and the interplay between these RCDs and immunotherapy or targeted therapy in patients with melanoma is discussed. Given the findings demonstrating melanoma cell death in response to different stimuli associated with these RCDs, the induction of RCD shows promise as an integral component of treatment strategies for melanoma.

An Unusual Case of Oligometastases in a Patient with Renal Cell Carcinoma: Insights from 18F-FDG PET/CT.

Renal cell carcinoma (RCC) is a significant cause of mortality worldwide. To date, many atypical metastatic sites have been observed and reported in patients with RCC. However, to the best of our knowledge, there have been no reported cases of thyroid cartilage metastasis in the context of RCC metastasis. Herein, we present the case of a 68-year-old man who developed left arm pain that led to an RCC diagnosis. First, evaluation by pan-computed tomography (CT) denoted right kidney RCC and identified left humeral metastasis. Subsequently, 18F-fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) was performed after right nephrectomy and left humeral lesion excision and fixation. Interestingly, few intramedullary hypermetabolic lesions were observed in addition to a single intensely hypermetabolic thyroid cartilage lesion indicative of oligometastases. This case underscores the importance of 18F-FDG PET/CT in the evaluation of RCC disease for baseline staging and beyond.

Cutaneous Metastasis Revealing Breast Cancer: A Case Report

Cutaneous metastases are phenomena typically more frequently observed in advanced stages of the disease. However, some cancers can remain clinically silent until the discovery of a cutaneous metastasis, often complicating the diagnosis of the primary tumor, especially if it's a rare tumor like breast cancer in men. It is in this context that we report a case of localized cutaneous metastasis on the scalp, without the presence of other associated clinical signs. Investigations revealed a metastatic breast carcinoma requiring extensive surgical intervention, complemented by adjuvant treatments.

NDRG1 is a prognostic biomarker in breast cancer and breast cancer brain metastasis

AbstractBrain metastases are secondary brain tumours characterised by their aggressive nature and poor prognosis. Breast cancer is one of the most common primary tumours in women to spread to the brain. A lack of biomarkers predicting likely spread to the brain and limited therapeutic interventions represents major areas of clinical unmet need. We investigated N‐myc downregulated gene‐1 (NDRG1) as a clinically relevant biomarker in breast cancer brain metastasis patients. NDRG1 expression was investigated using immunohistochemistry on tissue microarrays of two clinical cohorts: (i) brain metastatic breast cancers (n = 48) and brain metastases (n = 64; including a subset of 39 patient‐matched breast and brain metastasis cases) and (ii) unselected primary breast cancers (n = 336). NDRG1 was highly expressed in breast‐to‐brain metastases, as well as in high‐grade primary breast cancers. High NDRG1 expression and also an absence of expression were associated with worse survival outcomes in both breast cancer and breast cancer brain metastasis patients. This establishes NDRG1 as a ‘Goldilocks’ protein, where too much or too little has a negative effect on survival. We pose that this accounts for its previous categorisation as both tumour suppressor and oncoprotein. Additionally, a shift in NDRG1 localisation with a gain of nuclear expression was seen at the brain metastasis stage. Significant survival benefit in cases expressing cytoplasmic NDRG1 was observed, whereas NDRG1 localisation in the nucleus showed a clear association with poorer survival. In vitro analyses revealed that hypoxic stress significantly elevated NDRG1 expression and resulted in its nuclear localisation. Our findings suggest NDRG1 expression and subcellular localisation are clinically relevant biomarkers for poor prognosis in breast cancer and breast cancer brain metastasis.

(283) Evaluating The Impact of Prior Prostate Cancer Hormonal Therapy on Satisfaction Rates in Post Implantation of Inflatable Penile Prosthesis

Abstract Introduction Androgen deprivation therapy (ADT), a vital treatment modality for prostate cancer, effectively reduces androgens (testosterone & dihydrotestosterone) through inhibiting its production or blocking its action, thereby impeding the growth and even causing shrinkage of prostate cancer cells. It has been utilized in the treatment of early-stage, recurrent, and metastatic cases of prostate cancer. Common side effects were hot flashes, fatigue, decreased bone density, mood changes, decrease libido and sexual dysfunction. Inflatable penile prosthesis (IPP) implantation has already emerged as a highly successful treatment option, garnering significant satisfaction rates among the general population with erectile dysfunction (ED) and specifically in prostate cancer patients who underwent radical prostatectomy (RP) or radiation therapy (XRT). Nevertheless, there remains a dearth of literature examining satisfaction rates specifically in patients with hormonal therapy history post-IPP implantation Objective Our study aims to comprehensively evaluate patient satisfaction rates post IPP implantation for ED, in relation to their ADT status for prostate cancer. Methods A retrospective chart review from our institutional database was conducted to identify 529 patients who underwent IPP at our institution by a single surgeon from 2017 to 2022. Eligible patients for inclusion included those with histological confirmation of prostate cancer treated by RP or XRT with or without hormonal therapy, followed by IPP implantation for ED, and had completed the 11-item Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) validated questionnaire with data available for review. All EDITS questionnaires were administered at least 6 months from operative date or later. Eligible patients were screened for placement into one of two groups depending on their ADT status. To prevent crossover confounding; patients with history of other types of hormonal therapy for non prostate cancer patients were excluded. Results A total of 96 patients were included and categorized into group 1 (ADT, n=30) and group 2 (No ADT, n=66). All patients' demographics were summarised in Table 1. The study revealed notable results regarding the impact of ADT on post IPP satisfaction rates which exhibited a significantly lower EDITS score compared to group 2 (P= 0.034) (Figure 1). Furthermore, group 1 showed no significant changes in post IPP satisfaction with relation to type of prostate cancer treatment offered. While group 2 demonstrated a significantly higher EDITS score post IPP in RP patients compared to XRT, which aligns with the reported literature. Conclusions Our initial findings suggest that despite IPP implantation for managing erectile dysfunction, which is expected to yield high satisfaction rates compared to other available treatment options, Yet the previous or ongoing history of androgen deprivation therapy continues to influence such patients' satisfaction. These observations provide valuable insights; however, further investigation on a larger scale is essential to validate these trends. Additionally, it is crucial to offer proper counseling to these patients regarding the expected outcomes to assist them in making informed decisions regarding the management of their ED. Lastly, the routine use of validated questionnaires has demonstrated significant value in quantifying device and sexual satisfaction following IPP implantation and should be considered as an integral evaluation tool. Disclosure No.

Intratumoral metastasis of sigmoid colon cancer to chromophobe renal cell carcinoma: a case report

We herein report an extremely rare case of intratumoral metastasis of colon cancer to chromophobe renal cell carcinoma. A 71-year-old woman was diagnosed with lung metastasis of sigmoid colon cancer and underwent sigmoid colon resection with D3 lymph node dissection. Preoperative contrast-enhanced computed tomography (CT) revealed a left renal tumor; however, colon resection was prioritized, and the renal tumor was placed under observation. Two years later, CT revealed enlargement of the left renal tumor, and laparoscopic partial left nephrectomy was performed 1 month later. Histopathologic examination showed that the resected renal tumor was a chromophobe renal cell carcinoma with intratumoral metastasis of colon cancer to the renal tumor center, and adjuvant chemotherapy with bevacizumab plus SOX (L-OHP + S-1) was initiated. Because of severe chemotherapy-induced fatigue and nausea, the patient was switched to bevacizumab + S-1. However, the patient’s nausea did not improve after this change, and postoperative adjuvant chemotherapy was discontinued at the patient’s request 4 months after the partial nephrectomy. Two months after discontinuation of chemotherapy, CT showed no renal recurrence; however, increased lung metastases and a new bone metastasis in the left sciatic bone were observed. Palliative treatment was then initiated because of severe adverse events that made it difficult to continue treatment. In patients who have multiple cancers and an increase in renal tumor size, the possibility of intratumoral metastasis to the renal tumor should be considered.

Metastasis infiltrating tumor to meningioma: a case report

BackgroundThere have been many reports of tumor-to-tumor metastasis, in which cancer metastasizes directly into meningiomas. However, metastasis infiltrating tumors in which cancer metastasizes around meningiomas are rare. Therefore, we report a case of metastasis originating from lung cancer that infiltrated meningioma.Case presentationA 79-year-old Japanese woman underwent head magnetic resonance imaging for brain metastasis screening before lung cancer surgery. At that time, asymptomatic meningioma of the left frontal region was accidentally found. Magnetic resonance imaging 6 months later revealed a lesion suspected to be a metastatic brain tumor close to the meningioma. Brain tumor resection was performed, and histopathological diagnosis was meningioma and metastatic brain tumor. Metastatic cancer had invaded the meningioma at the boundary between the brain tumor and metastasis.ConclusionsA sudden change in imaging findings on routine examination of meningiomas in patients with lung carcinoma may indicate a metastatic brain tumor. The form of cancer metastasis to meningioma is not limited to tumor-to-tumor metastasis, but also includes metastasis infiltrating tumors near the meningioma.

Abstract A076: The role of PARP-1-mediated FoxA1 ADP-ribosylation in breast cancer biology

Abstract Breast cancer is the most common cancer diagnosed in women. At the time of diagnosis, approximately 70% of breast cancers express Estrogen Receptor alpha (ERα), a key signature of luminal subtype tumors. Equally important in these cases is the expression of FoxA1, a subtype-specific transcription factor (TF) essential for ERα-mediated cell proliferation. FoxA1 is a key pioneer TF that assists ERα with the assembly of enhancers and the transcription of estrogen (E2)-regulated target genes. Together, the FoxA1-ERα axis is a major driver of cancer cell growth. Our recently published work implicates poly(ADP-ribose) polymerase 1 (PARP-1) and ADP-ribosylation (ADPRylation) in the regulation of E2-dependent transcriptional responses in ERα+ breast cancer cells. To determine the underlying mechanisms, we identified FoxA1 as a substrate of PARP-1-mediated ADPRylation. We hypothesize that (1) PARP-1 elicits its effects on E2 signaling and ERα enhancer function, in part, by ADPRylating FoxA1 at specific residues and (2) Loss of these regulatory ADPRylation events alters FoxA1 activity, which in turn can alter the assembly of ERα enhancers and transform the breast cancer cell transcriptome. Indeed, the sites of FoxA1 ADPRylation are recurrently mutated in breast cancers and are highly enriched in metastatic cases. Using an integrated set of biochemical, molecular, cell based, genomic and proteomic approaches, we have validated the ADPRylation of FoxA1 by PARP-1 in vitro and in vivo. We selected two FoxA1 ADPRylation sites, D226 and E255, for further analysis due to their positions in a mutation ‘hot spot’ region corresponding to the C-terminal forkhead DNA-binding domain. Mutation of these sites blocks FoxA1 ADPRylation and enhances cell proliferation in MCF-7 human breast cancer cells. Additionally, preliminary ChIP-seq analysis indicates that the binding of both ERα and FoxA1 are globally reduced at ERα enhancers in MCF-7 cells expressing the FoxA1 ADPRylation site mutants compared to wild-type but may also increase both at selected enhancers. While there is a global reduction in mutant FoxA1 binding near the canonical estrogen-regulated genes, interestingly, we observe an overall enhanced binding of FoxA1 D226N compared to wild-type outside of this canonical program. Collectively, these studies will (1) reveal new molecular endpoints modulated by PARP-1, providing new insights about the use of PARPi to treat ERα+ breast cancers, and (2) suggest new therapeutic strategies to disrupt the aberrant signaling pathways associated with mutant FoxA1 luminal breast cancers, and more importantly metastatic cases, which is of utmost clinical significance. Citation Format: Cristel V. Camacho, Aishwarya Sundaresan, Tulip Nandu, W. Lee Kraus. The role of PARP-1-mediated FoxA1 ADP-ribosylation in breast cancer biology [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A076.

Short-term outcomes of the TRIANGLE operation after neoadjuvant chemotherapy in locally advanced pancreatic cancer

Objective: To investigate the safety and efficacy of the TRIANGLE operation after neoadjuvant chemotherapy in locally advanced pancreatic cancer(LAPC). Methods: This study is a retrospective case series analysis. Between January 2020 and December 2022, a total of 103 patients were diagnosed as LAPC who underwent neoadjuvant chemotherapy at the Pancreas Center, the First Affiliated Hospital of Nanjing Medical University. Among them, 26 patients (25.2%) underwent the TRIANGLE operation. There were 15 males and 11 females,with a age of (59±7) years (range: 49 to 74 years). The pre-treatment serum CA19-9(M(IQR)) was 248.8(391.6)U/ml (range: 0 to 1 428 U/ml),and the serum carcinoembryonic antigen was 4.1(3.8)μg/L(range: 1.4 to 13.4 μg/L). The neoadjuvant chemotherapy regimens included: mFOLFIRINOX regimen in 6 cases(23.1%), GnP regimen in 14 cases(53.8%), and mFOLFIRINOX+GnP regimen in 6 cases(23.1%). The follow-up duration extended until June 2023 or until the occurrence of the patient's death or loss to follow-up. The Kaplan-Meier method was employed to estimate the 1-year and 3-year overall survival rates. Results: After neoadjuvant chemotherapy,CA19-9 levels decreased by 92.3(40.1)%(range:2.1% to 97.7%). Evaluation of the response to treatment revealed 13 cases(50.0%) of stable disease,11 cases(42.3%) of partial response,and 2 cases(7.7%) of complete response. The surgical operation consisted of 12 cases(46.2%) of pancreaticoduodenectomy,12 cases(46.2%) of distal pancreatectomy,and 2 cases(7.7%) of total pancreatectomy. Margin determination was based on the "standardised pathology protocol" and the "1 mm" principle. No R2 and R1(direct) resections were observed,while the R0 resection rate was 61.5%(16/26), and the R1(1 mm) resection rate was 38.5%(10/26).The R1(1 mm) resection rates for the anterior margin,posterior margin,transected margin,portal vein groove margin,and uncinate margin were 23.1%(6/26),19.2%(5/26),12.5%(3/24),2/14, and 1/12, respectively. The overall postoperative complication rate was 57.8%(15/26),with major complications including grade B/C pancreatic fistula 25.0%(6/24,excluding 2 cases of total pancreatectomy),delayed gastric emptying in 23.1%(6/26),wound complications 11.5%(3/26),postoperative hemorrhage 7.7%(2/26), chylous fistula 7.7%(2/26) and bile fistula 3.8%(1/26). No reoperation was performed during the perioperative period(<90 days). One patient died on the 32nd day postoperatively due to a ruptured pseudoaneurysm. A total of 25 patients were followed up,with a follow-up time of 21(24)months(range: 8 to 42 months). During the follow-up period,8 cases(32.0%) died due to tumor recurrence and metastasis,while 17 patients(68.0%) remained alive,including 11 cases of disease-free survival,5 cases of distant metastasis,and 1 case of local recurrence. The overall survival rates at 1- and 3-year after the initiation of neoadjuvant chemotherapy were 95.8% and 58.9%, respectively. The overall survival rates at 1- and 3-year after surgery were 77.7% and 57.8%, respectively. Conclusion: Performing pancreatoduodenectomy according to the Heidelberg triangle protocol in LAPC patients after neoadjuvant chemotherapy might increase the R0 resection rate without increasing perioperative mortality or the incidence of major postoperative complications.

An unusual case of solitary metachronous calf metastasis from gastric carcinoma after curative surgery

Gastric carcinoma is the fifth most common cancer worldwide and a significant cause of cancer-related mortality. It commonly metastasizes to the liver, peritoneum, lungs, and bones. We highlight a rare case with solitary metachronous metastasis to the soleus muscle. A 70-year-old man was evaluated for complaints of dysphagia and diagnosed with locally advanced gastric carcinoma. He underwent radical gastrectomy followed by adjuvant chemotherapy and remained disease free for 2.5 years. Subsequently, he developed a painless swelling in the right calf. Radiological and functional imaging showed an intramuscular lesion within the right soleus muscle with no evidence of disease elsewhere. Histopathological examination of the swelling revealed metastatic adenocarcinoma, consistent with gastric primary. He was started on palliative chemotherapy. Solitary skeletal muscle metastasis with a well-controlled primary is challenging to diagnose and requires histopathology and immunohistochemistry to differentiate it from other soft-tissue neoplasms. The prognosis is poor and the intent of treatment remains palliative.

Interleukin-3 production by basal-like breast cancer cells is associated with poor prognosis

ABSTRACT: Breast cancer represents a collection of pathologies with different molecular subtypes, histopathology, risk factors, clinical behavior, and responses to treatment. “Basal-like” breast cancers predominantly lack the receptors for estrogen and progesterone (ER/PR), lack amplification of human epidermal growth factor receptor 2 (HER2) but account for 10–15% of all breast cancers, are largely insensitive to targeted treatment and represent a disproportionate number of metastatic cases and deaths. Analysis of interleukin (IL)-3 and the IL-3 receptor subunits (IL-3RA + CSF2RB) reveals elevated expression in predominantly the basal-like group. Further analysis suggests that IL-3 itself, but not the IL-3 receptor subunits, associates with poor patient outcome. Histology on patient-derived xenografts supports the notion that breast cancer cells are a significant source of IL-3 that may promote disease progression. Taken together, these observations suggest that IL-3 may be a useful marker in solid tumors, particularly triple negative breast cancer, and warrants further investigation into its contribution to disease pathogenesis.

Chemokine profiling of melanoma-macrophage crosstalk identifies CCL8 and CCL15 as prognostic factors in cutaneous melanoma.

During cancer evolution, tumor cells attract and dynamically interact with monocytes/macrophages. To find biomarkers of disease progression in human melanoma, we used unbiased RNA sequencing and secretome analyses of tumor-macrophage co-cultures. Pathway analysis of genes differentially modulated in human macrophages exposed to melanoma cells revealed a general upregulation of inflammatory hallmark gene sets, particularly chemokines. A selective group of chemokines, including CCL8, CCL15, and CCL20, was actively secreted upon melanoma-macrophage co-culture. Because we previously described the role of CCL20 in melanoma, we focused our study on CCL8 and CCL15 and confirmed that in vitro both chemokines contributed to melanoma survival, proliferation, and 3D invasion through CCR1 signaling. In vivo, both chemokines enhanced primary tumor growth, spontaneous lung metastasis, and circulating tumor cell survival and lung colonization in mouse xenograft models. Finally, we explored the clinical significance of CCL8 and CCL15 expression in human skin melanoma, screening a collection of 67 primary melanoma samples, using multicolor fluorescence and quantitative image analysis of chemokine-chemokine receptor content at the single-cell level. Primary skin melanomas displayed high CCR1 expression, but there was no difference in its level of expression between metastatic and nonmetastatic cases. By contrast, comparative analysis of these two clinically divergent groups showed a highly significant difference in the cancer cell content of CCL8 (p = 0.025) and CCL15 (p < 0.0001). Kaplan-Meier curves showed that a high content of CCL8 or CCL15 in cancer cells correlated with shorter disease-free and overall survival (log-rank test, p < 0.001). Our results highlight the role of CCL8 and CCL15, which are highly induced by melanoma-macrophage interactions in biologically aggressive primary melanomas and could be clinically applicable biomarkers for patient profiling. © 2024 The Pathological Society of Great Britain and Ireland.

Evaluation 172 patients of submandibular gland swelling with a case of adenocarcinoma, not otherwise specified: a needle in a haystack

Background: Aim of the study was to assess the patients of submandibular gland pathology and to describe a case of adenocarcinoma, not otherwise specified (ANOS) of the submandibular gland in terms of clinical presentation, diagnosis, line of management and prognosis. Methods: The study was conducted as a retrospective review of all the patients who underwent submandibular gland excision in the last 6 years at the department of otorhinolaryngology, M.D.M. hospital, Dr. S.N. Medical college, Jodhpur. The records were assessed and statistically evaluated. Results: Out of 172 cases of submandibular gland excision, only 1 case of ANOS was seen. The rest included 134 cases were of chronic non-inflammatory process, 24 cases of sialolithiasis, 10 cases of metastasis from oral cavity cancer and 3 cases of primary squamous cell carcinoma. Fine needle aspiration cytology (FNAC) was not diagnostic in ANOS. Excision of the gland with primary closure was done. Adjuvant radiotherapy was given. Conclusions: ANOS has a rare occurrence in submandibular gland swelling and it is also very tricky to diagnose it. The nature of this malignancy is invasive and nodal metastasis is present. Surgical excision and post-op evaluation can be life-saving.

OTUB1 Targets CHK1 for Deubiquitination and Stabilization to Facilitate Lung Cancer Progression and Radioresistance

PurposeRadioresistance of lung cancer poses a significant challenge when it comes to the treatment of advanced, recurrent, and metastatic cases. OTUB1, known as Ovarian tumor domain ubiquitin aldehyde binding 1, is a key member of the deubiquitinase OTU superfamily. This protein is involved in various cellular functions, including cell proliferation, iron death, lipid metabolism and cytokine secretion, as well as immune response processes. However, its specific role and molecular mechanism in lung cancer radioresistance remain to be clarified. Methods and MaterialsThe expression levels of OTUB1 in paired lung cancer tissues were determined by immunohistochemistry (IHC). In vitro and in vivo experiments were conducted to investigate the impact of OTUB1 on the growth and proliferation of lung cancer. Coimmunoprecipitation and Western blotting techniques were performed to examine the interaction between OTUB1 and CHK1. The DNA damage response was measured by comet tailing and immunofluorescence staining. KEGG pathways and GO terms were analyzed based on RNA-seq. ResultsOur findings reveal a high frequency of OTUB1 overexpression, which is associated with an unfavorable prognosis in patients diagnosed with lung cancer. Through comprehensive investigations, we demonstrate that OTUB1 depletion impairs the process of DNA damage repair and overcomes radioresistance. In terms of the underlying mechanism, our study uncovers that OTUB1 deubiquitinates and stabilizes CHK1, which enhances CHK1 stability, thereby regulating DNA damage and repair. Additionally, we identify CHK1 as the primary downstream effector responsible for mediating the functional effects exerted by OTUB1 specifically in lung cancer. Importantly, OTUB1 has the potential to be a valuable marker for improving the efficacy of radiotherapy for lung adenocarcinoma. ConclusionsThese findings unveil a novel role for OTUB1 in enhancing radioresistance by deubiquitination and stabilizing the expression of CHK1 in lung cancer and indicate that targeting OTUB1 holds great potential as an effective therapeutic approach for enhancing the efficacy of radiotherapy in lung cancer.

Characterizing the genomic landscape of locally advanced pancreatic cancer.

697 Background: Locally advanced pancreatic cancer (LAPC) accounts for approximately 30% of pancreatic ductal adenocarcinomas (PDAC). Optimal management for LAPC is controversial and combination treatments are extrapolated from treatment guidelines for metastatic disease. The biological underpinnings of LAPC remain unclear, although the loss of tumor suppressor SMAD4 has been associated with metastatic disease. Here we characterize the genomic landscape of LAPC in a large series of prospectively sequenced PDAC. Methods: Clinical, genomic and survival data were obtained from the COMPASS trial (NCT02750657), a prospective multi-institutional study that included patients with treatment-naïve advanced PDAC, with predominantly metastatic cases due to ease of biopsy. Fresh tumor tissue was acquired by percutaneous core biopsy for real-time whole genome sequencing (WGS) and RNA sequencing (RNAseq). Laser capture micro-dissection was performed for all cases. Response to therapy was assessed every 8 weeks, and patients were followed prospectively. Results: Of 268 patients (268 with available WGS and 253 with RNAseq), 37 (14%) had LAPC. Baseline epidemiological variables were similar, with no differences between sex, age, smoking status, or history of diabetes. Patients with LAPC had a lower BMI (median 22 vs 24, p=0.005) and lower baseline CA19-9 (median 488 vs 2551, p=0.002) than metastatic cases. All patients with LAPC had a low (&lt;2 points) Gustave Roussy Immune Score, previously shown to be prognostic in our dataset. Driver alternations were similar in LAPC and metastatic cases with no differences in SMAD4 loss between the two groups; however, major imbalances in mutant KRAS were absent in the LAPC group. The burden of SNVs, indels and SVs was significantly lower in LAPC (Table). All LAPC cases demonstrated a classical RNA subtype, compared to 23% in metastatic cases ( p=0.0008). Median OS measured 12.5 and 8.3 months for LAPC and metastatic cases, respectively (HR 0.65, 95% CI 0.48-0.89, p=0.003). In addition, when measuring CD8+ T cell infiltration by IHC using median cut-off values, primary site biopsies had a higher CD8+ T cell infiltrate compared to metastatic sites (77% vs 56% CD8-high, respectively, p=0.01). Conclusions: These integrated genomic, RNA subtyping and early immunophenotyping results suggest that LAPC demonstrate less genomic instability and classical programming. Further study will delineate how these genomic differences, along with better clinical features, may influence treatment decision-making and design of future clinical trials. Clinical trial information: NCT02750657 . [Table: see text]

Incorporating stereotactic body radiation therapy for inoperable pancreatic cancer.

656 Background: The management of inoperable pancreatic cancer (PC) is controversial. We sought to compare local progression (LP) for inoperable PC managed with chemotherapy (CHT) and/or stereotactic body radiation therapy (SBRT). Methods: This single-institution retrospective review analyzed 94 patients diagnosed with locally advanced (LA), medically inoperable, or metastatic PC between 2014 and 2022. Patients received CHT alone, sequential (seq) CHT + SBRT, or SBRT alone. The primary endpoints were LP and intervention due to local progression (ILP) from start of treatment. Obstructive symptoms needing intervention, percutaneous endoscopic gastrostomy tube, gastrojejunostomy, or bleeding needing transfusion were considered ILP. Primary tumor growth on imaging or ILP were defined as LP. Fine-Gray regression models with treatment received considered a time-varying covariate were used to compare ILP and LP between treatment groups where death without LP was treated as a competing risk adjusting for ECOG, stage, age and year of diagnosis. In the subgroup of patients who received SBRT, patients were stratified at the median time between diagnosis and receipt of SBRT, and risk of ILP and LP was compared between the groups using cause-specific cumulative incidence functions. Results: Of 94 patients, 51 had CHT alone, 21 received seq CHT + SBRT, and 22 had SBRT alone. The median year of diagnosis was 2019 (range, 2014 - 2022). The median ECOG was 1 with worse ECOG in SBRT alone and seq CHT + SBRT groups (p = 0.012). There were more LA or metastatic cases in the CHT (78%) and seq CHT + SBRT groups (67%) compared to the SBRT group (23%) [p &lt; 0.001]. The median SBRT dose was 36Gy (range, 25 – 40Gy) in 5 fractions. Rates of LP and ILP were higher for CHT alone (68.6%, 39.2%) compared to seq CHT + SBRT (42.9%, 38.1%) or SBRT alone (18.2%, 4.5%) [p &lt; 0.001; p = 0.004]. Higher rate of ILP associated with an increasing year of diagnosis (HR = 2.03, p &lt; 0.005) and younger age of diagnosis (HR = 0.922, p = 0.011). The median time to SBRT was 116 days. Early (&lt; 116 days) vs late SBRT LP rates differed (ILP: 4.8% vs 30%, LP: 14.3% vs 40%). Cause-specific cumulative incidence functions showed that death without LP favored early vs late SBRT (p = 0.009). Additionally, death without ILP favored early vs late SBRT (p=0.011). Conclusions: LP rates are high among patients with inoperable PC. SBRT for inoperable PC provides reasonable local control. Early SBRT reduces the need for ILP before death compared with late SBRT. Further investigation into the role of SBRT for inoperable PC is necessary. [Table: see text]

Esophageal cancer in Hispanics: A propensity score matched analysis of the National Cancer Database.

258 Background: Hispanics are the fastest-growing minority and largest ethnic group accounting for 19.1% of the US population. The American Cancer Society estimated 21,560 new cases of esophageal cancer (EC) in the US in 2023. Hispanics are reported to be at high risks for EC. We sought to interrogate the demographic patterns of esophageal cancer in Hispanics. Additionally, we sought to examine evidence of socioeconomic disparities and differential therapy. Methods: We identified Hispanic vs Non-Hispanic (NH) patients in the National Cancer Database with esophageal cancer between 2005–2018. Variables compared were age, sex, tumor data, surgical intervention, type of treatment, insurance status, income, residence area, and Charlson/Deyo score. Pearson’s Chi-square test was used to compare categorical variables. Groups were statically equated with propensity score-matched analysis (PSM). Survival analysis was estimated by the Kaplan-Meier method and associated log-rank test. Significance was considered at p-value ≤0.05. Results: We identified 66,335 patients with a median age of 63 years (18-90). Hispanics represented 4.2% (2,786) of the entire patient cohort. In this US population we identified significant disparities between Hispanic and NH groups. Differences among Hispanics included higher prevalence of squamous EC (22% vs 19%) p&lt;0.001, higher likelihood of stage IV disease (40.7% vs. 34.8%) p&lt;0.001, younger age p&lt;0.001, higher uninsured status (10.3% vs 3.3%) with income &lt; $40,227 (27.5% vs 16.9%) p&lt;0.001 when compared to NH. However, Hispanics were less likely to have surgical intervention (20.5% vs 27.5%) p&lt;0.001, receive neoadjuvant therapy (61.8% vs 72%) and overall, less likely to receive any type of treatment (30.1% vs 26.1%) when compared to NH p&lt;0.001. Time to treatment was delayed in those Hispanics who were uninsured 37 weeks (22-55) compared to those with private insurance 31 weeks (20-47) p&lt;0.001. Multivariate analysis revealed that any treatment, insurance status, and lower income were all predictors of survival. Treated Hispanics demonstrated no difference in survival then their treated non-Hispanic counterparts (median survival 18.5 vs 18.7 months) with overall 5 year survival at 24% and 25% respectively (p=0.66). Conclusions: Despite lower prevalence, there is a disproportionately higher number of metastatic and untreated cases of esophageal cancer among Hispanics. This disparity may be explained by Hispanics' limited access to medical care exacerbated by their socioeconomic and insurance status. Our findings warrant further clinical and epidemiologic research to reveal other factors impacting these health and health care disparities.

Real-world data of TAS-102 therapy in refractory metastatic colorectal cancer (mCRC): The experience of the University Hospital of Montreal (CHUM).

137 Background: Colorectal cancer poses a substantial healthcare burden due to its elevated rates of diagnosis and mortality. Managing refractory metastatic cases remains a challenge in our practice due to the paucity of therapeutic options. Treatment with Trifluridine-Tipiracil (TAS-102) prolonged overall survival among patients (pts) with mCRC. This study investigates the efficacy of TAS-102 therapy in this patient population and explores various prognostic factors influencing clinical outcomes. Methods: We retrospectively reviewed the data of 53 patients with refractory mCRC treated with at least 1 cycle of TAS-102 at CHUM between March 2018 and January 2023. Multivariate and univariate analyses were employed to evaluate the impact of age, number of prior treatments, presence of KRAS mutation, gender, tumor origin, and Eastern Cooperative Oncology Group (ECOG) performance status on progression-free survival (PFS) and overall survival (OS). Survival analysis was conducted using the Kaplan-Meier method, and Cox regression analysis assessed prognostic factors. Results: The median age was 61 years (23-82), and 27 pts (50.9%) were females. Twenty-two pts (41.5%) had their primary tumor located in the left colon, 17 pts (32.1%) had right-sided tumors, and 14 pts (26.4%) with rectal tumors. 52% of pts received TAS-102 after 2 lines of therapy and 43% beyond third line. The performance status was: ECOG 0/1 in 46 pts (86.8%), and ECOG 2 in 7 pts (13.2%). In our refractory mCRC pts, median PFS was 3 months and median OS 7 months. Univariate analysis demonstrated no significant differences in PFS or OS based on patient sex, KRAS mutation status, tumor sidedness, or the number of prior treatments. In univariate and multivariate analysis ECOG 0/1 pts compared to ECOG 2 pts had a significant improvement in both PFS (HR = 0.33; p = 0.0511) and OS (HR = 0.21; p = 0.0086). Conclusions: In our real-world experience, clinical outcomes were comparable to the findings from the RECOURSE trial, suggesting improved PFS and OS with TAS-102 in heavily pre-treated mCRC patients. ECOG performance status remains a significant prognostic factor and underscores its importance in treatment decisions for this patient population.