Tumors Of Origin Research Articles

Correlation of the treatment sensitivity of patient-derived organoids with treatment outcomes in patients with head and neck cancer (SOTO): protocol for a prospective observational study

IntroductionOrganoids have been successfully used in several areas of cancer research and large living biobanks of patient-derived organoids (PDOs) have been developed from various malignancies. The characteristics of the original...

Uveal melanoma: molecular-genetic mechanisms of arising and the therapeutic approaches

Uveal melanoma (UM) is a tumor of neuroectodermal origin, which results from malignant transformation of melanocytes of the eye vasculature: iris, ciliary body and chorioidea. UM represents up to 5% of all melanoma cases, but it is extremely aggressive, since half of patients with UM develop metastases within the first 1‒2 years after the tumor appearance. Molecular mechanisms of uveal melanoma carcinogenesis are poorly understood, and have already been shown to be different from those of skin melanoma. Activating mutations in the GNAQ and GNA11 genes, encoding the large G protein subunits Gq and G11, respectively, are found in 90% of UM patients. The main signaling cascade leading to the transformation of melanocytes of the uveal tract is the signaling pathway Gaq/PKC/MAPK, and the major regulators of this cascade are targets for the development of drugs. The development of the metastatic form of UM is most often associated with mutations in the genes BAP1, EIF1AX, GNA11, GNAQ, and SF3B1. A combination of a commercial expression test panel of 15 genes and a mutation panel of 7 genes, supplemented with data on the size of the primary tumor, has been shown to be highly effective prognostic signature in prediction the risk of metastases. The risk of metastases determines the choice of therapy and patient follow-up regimen. At the same time, no systemic therapy for the treatment of metastatic UM has been developed to date; new drugs undergoing clinical trials mostly refer to either targeted therapy aimed at inhibiting the protein products of mutant genes, or immunotherapy designed to stimulate an immune response against specific antigens. In addition to these approaches, the review also considers potential therapeutic targets of epigenetic regulation of UM development.

Induced tumor associated autoantibodies (iTAAs) by hapten plus drugs for targeting oncogenic nuclear antigens at sentinel lymph node of pancreatic cancer

Background: the abscopal is a hypothesis of effect on non-irradiated tumors after localized radiation therapy which associated with the products of tumor-associated gene as autoantibodies (aTAAs) in reaction to the tumor-associated antigens (TAAs). When TAAs interact with hapten within tumor after hapten plus chemotherapy drugs intratumoral injection to pancreatic cancer like tumor lysates vaccine, TAAs-hapten stimulates the immune system as a neu antigen and produces autologous tumor antibodies, it is called induced tumor-associated autoantibodies (iTAAs) which is lightly difference to aTAAs since epitope of antigen linked with hapten. Method: immunofluorescence (IF) was applied for detect the binding of the iTAAs in tumor cells at sentinel lymph node. Results: aTAAS naturally could not target and bind the TAAs in tumor since due to immune tolerance. The iTAAs can target and bind the TAAS, also the iTAAs targeted in the tumors of sentinel lymph node with complements C help, it was found Cmyc (P = 0.0017 at one week; P = 0.0001 at two weeks), p53 (P = 0.0373; 29.13 ± 6.91, and P = 0.0254), and Zeta (P = 0.1513, P = 0.0044) increased significantly in the tumor cells or perinuclear tumor cells in lymph node at one and two weeks after treatment. Conversely, IMP1 (P = 0.6154; P = 0.0138), Koc (P = 0.5684, P = 0.0103), Survivn (P = 0.1020; P = 0.0147) and Rala (P = 0.3226; P = 0.0249) increased significantly in the cell or perinuclear of tumor in lymph node at two weeks later following. Conclusions: it indicated all of iTAAs plays a function in the binding of original cellular tumor genes at sentinel lymph node while the aTAAs could not bind the cellular tumor genes at lymph node due to immune tolerance. We could make a hypothesis: TAAs inside the cancer cells’ nuclei can be targeted by the iTAAs which produced by hapten enhanced intratumoral chemotherapy. The iTAA may play a distinctive role in controlling tumor cell growth and resulting in an abscopal effect, which is one of hapten associated with TAA induced immune response.

Targeting Bcl-2 with Indole Scaffolds: Emerging Drug Design Strategies for Cancer Treatment.

The B-cell lymphoma-2 (Bcl-2) protein family plays a crucial role as a regulator in the process of apoptosis. There is a substantial body of evidence indicating that the upregulation of antiapoptotic Bcl-2 proteins is prevalent in several cancer cell lines and original tumour tissue samples. This phenomenon plays a crucial role in enabling tumour cells to avoid apoptosis, hence facilitating the development of resistant cells against chemotherapy. Therefore, the success rate of chemotherapy for cancer can be enhanced by the down-regulation of anti-apoptotic Bcl-2 proteins. Furthermore, the indole structural design is commonly found in a variety of natural substances and biologically active compounds, particularly those that possess anti-cancer properties. Due to its distinctive physicochemical and biological characteristics, it has been highly regarded as a fundamental framework in the development and production of anti-cancer drugs. As a result, a considerable range of indole derivatives, encompassing both naturally occurring and developed compounds, have been identified as potential candidates for the treatment of cancer. Several of these derivatives have advanced to clinical trials, while others are already being used in clinical settings. This emphasizes the significant role of indole in the field of research and development of anti-cancer therapeutics. This study provides an overview of apoptosis and the structural characteristics of Bcl-2 family proteins, and mainly examines the present stage and recent developments in Bcl-2 inhibitors with an indole scaffold embedded in their structure.

Early detection of cervical tumor cell of origin through Oncogene-induced senescent HPV-positive cells.

Human Papilloma Virus (HPV) is an oncogenic virus and is the most common cause of cervical cancer. HPV has been shown to induce senescence. Cellular senescence is involved in cancer progression and tumorigenesis. Identification and isolation of cells of tumor origin before tumorigeneses is an important step in cancer prevention and treatment. This study aimed to investigate the early cervical atypical senescent cytological preneoplastic change in non-menopausal women. Cervical smears of 121 patients were randomly selected and included in the study which cytopathologically diagnosed as atypical squamous cells of undetermined significance (AS-CUS) in correlation to HPV status, parakeratosis (PK), p16 immunostaining, enlarged Squamous cells nuclei (ES) and inflammatory cells infiltration (ICI). Results revealed that out of the total 121 patients, 32 cases (26%) were positive for high-risk HPV (HR-HPV), 26 cases (22%) were positive for low-risk HPV (LR-HPV) and 63 (52%) were negative for HPV. HPV infections were significantly associated with age groups (p<0.026), PK (p = 0.043), p16 (p = 0.001), ES (p = 0.002) and ICI (p = 0.049). The positive immunostaining expression of p16 was only noticed in two HR-HPV patients. ES cells were found in 9.5% of HPV-negative cases, 27% of LR-HPV cases and 40.5% of HR-HPV cases. High PK cell positivity was seen only in HR-HPV. High ICI scores were seen in 40.6% of HR-HPV patients, 26.9 % of LR-HPV and 17.4 % of negative HPV patients. It was concluded that high PK positivity, high ICI score, positive p16 immunostaining and ES were correlated with HR-HPV in non-menopausal women. These findings could provide potential diagnostic clues for HPV-harboring senescent cells as a strategy for reducing HPV risk of cervical cancer development and identifying the cell of tumor origin, which could be beneficial for improving the utility of senolytic agents and immunotherapy in clinical practice.

Signet ring cell carcinoma of the urinary bladder presenting with carcinocythemia and skeletal metastasis: A case report

Cancer of unknown primary accounts for approximately 3 &amp;ndash; 5% of all malignancies and is typically associated with a dismal prognosis. We describe a 65-year-old man who presented with skeletal metastasis and circulating tumor cells exhibiting signet ring (SR) morphology. The patient was diagnosed with SR cell carcinoma (SRCC) through a bone marrow biopsy. This case report aimed to emphasize the importance of clinicians&amp;rsquo; awareness of SRCC of the urinary bladder. The primary site of tumor origin was not identified as antemortem. The patient died 2 months after being admitted for pulmonary embolism. At autopsy, the urinary bladder was determined to be the primary site of the tumor. Primary SRCC of the urinary bladder is extremely rare. There are currently no established consensus guidelines for its management. Surgery continues to be the primary treatment option when the condition is localized.

Atypical Presentation and Postoperative Management of Vagal Nerve Tumors.

Tumors involving the vagus nerve are often clinically silent. We offer a case series with different clinical presentations and distinctive post-surgical sequelae that highlight some of the challenges associated with managing cervical vagal nerve tumors. Single-institution, retrospective review of patients with tumors involving the vagus nerve. We describe clinical presentations and postoperative sequelae of five patients who underwent surgical management of vagal nerve pathology with atypical presentation or subsequent clinical course. Here, we present five patients treated at our institution for vagal tumors. In four of the five patients, the presenting symptoms resolved after surgery. Two patients presented with intractable neurogenic cough, and another two presented with autonomic symptoms, one with syncope/palpitations and the other with intractable sweating. The final patient presented with a rapidly enlarging vagal paraganglioma and developed intractable cough after resection. We present two patients with novel approach to vagal paragangliomas that underwent ligation of feeding blood supply without removing the tumor, resulting in resolution of an intractable cough in one patient and resolution of severe nighttime sweating in the other. Management of tumors associated with the cervical vagus nerve that present with symptoms or rapid growth poses a clinical dilemma. Consideration of the tumor origin with either enucleation of schwannomas or ligation of feeding vessels may preserve function while addressing the presenting symptoms.

8203 A Solitary Fibrous Tumor Mimicking a Non-functional Pituitary Macroadenoma

Abstract Disclosure: L. Bernacet Rivera: None. S. Omay: None. A. Huttner: None. S.E. Inzucchi: None. Background: A solitary fibrous tumor (SFT), also known as hemangiopericytoma (HPC), is a rare subset of soft tissue tumors of mesenchymal origin. This type of tumor tends to have aggressive behavior and a high risk of recurrence. Approximately less than 1% of central nervous system (CNS) tumors have been identified as part of this subtype. Case Presentation: A 73-year-old female with medical history of primary hypothyroidism, myelodysplastic syndrome (MDS), and IgM kappa MGUS initially presented to her primary care physician for evaluation of progressive visual loss over several weeks, accompanied by worsening headaches. Ophthalmologic exam revealed bitemporal hemianopsia which prompted urgent imaging. Pituitary MRI with IV contrast revealed a solid sellar mass with suprasellar extension measuring 1.8 x 1.3 x 1.9 cm. The lesion was noted to superiorly displace the optic chiasm as well as to cause mild impingement of the anterior cerebral arteries. Patient was urgently referred to neurosurgery and endocrinology for further evaluation. Initial neuroendocrine laboratory assessment, performed at 8 am, revealed a cortisol 16.5 ug/dL, free T4 1.2 ng/dL, TSH 0.77 mIU/L, prolactin 9.9 ng/mL, IGF-1 17 ng/mL, the latter value consistent with adult growth hormone deficiency. Her LH and FSH were 4.3 mIU/mL and 12.6 mIU/mL, respectively, lower than expected for a post-menopausal woman. She underwent a transnasal transsphenoidal resection of the sellar lesion. Surgery was difficult due to the fibrous nature of the tumor, for which complete resection was not achieved. Post-operative course was complicated by thrombocytopenia due to MDS. Hormonal workup following surgery was consistent with central adrenal insufficiency, hypogonadotropic hypogonadism, and central hypothyroidism. Pathology showed densely cellular spindle cell neoplasm with a collagenous background consistent with hemangiopericytoma. She underwent fractionated radiotherapy and tumor has since remained stable in size. Her visual symptoms resolved quickly following surgery. Discussion: SFT is an aggressive mesenchymal tumor which rarely appears in the sellar region. There are no identified brain MRI findings that would suggest the nature of this tumor. As a result, endocrinologists should be aware of this rare condition while evaluating pituitary neoplasms. Presentation: 6/3/2024

9182 Metastatic Extra-Gastrointestinal Stromal Tumor Presenting As Hypoglycemia

Abstract Disclosure: O. faour: None. D. John: None. S.K. Suryanarayanan: None. A.A. Rizvi: None. Introduction: Non islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome seen in association with solid abdominal tumors of mesenchymal and epithelial origin. We report a case of metastatic extra-gastrointestinal stromal tumor (E-GIST) presenting with severe hypoglycemia as its initial manifestation. CASE DESCRIPTION: A 46-year-old patient was found to have a blood glucose of &amp;lt;45 mg/dl during a routine clinic visit with her primary care physician. Although she was asymptomatic, she was sent to the emergency room (ER) for further evaluation. She had a history of prediabetes managed by lifestyle modification. She has been experiencing multiple episodes of hypoglycemia previously which fulfilled the Whipple’s triad in the preceding months. These hypoglycemic episodes included loss of unconsciousness, falls in the shower with head injury, and several hospital visits. Serum glucose in the ER was 14 mg/dl and hypoglycemia persisted despite continuous dextrose solution. Physical examination was notable for a distended, non-tender abdomen and cervical lymphadenopathy. CT scan showed a 15 cm mass in the liver, multiple large masses in the mesentery, and a 11 cm lesion in the left pelvis. There were enlarged lymph nodes in the abdomen, chest, and neck. Serum chemistries drawn when the patient was hypoglycemic revealed potassium level of 2.7 mg/dl (3.5-5.5) an insulin level of &amp;lt;1.0 mIU/L (5-25), C-peptide &amp;lt;0.1 ng/mL (0.5-2), cortisol 13.8 mcg/dL (5-25), and insulin-like growth factor-2 (IGF-2) was 270 ng/mL (38-267). The IGF-2/IGF-1 molar ratio was 3.4 (normal &amp;lt;3:1). The sulfonylurea drug screen came back negative. Upper and lower endoscopies were unrevealing. Biopsy of the liver lesion showed cytology and immunohistochemical findings consistent with a epithelioid metastatic extra-gastrointestinal stromal tumor. A provisional diagnosis of NICTH was made. The patient responded well to intravenous glucose, oral carbohydrate intake and high-dose corticosteroids. She was subsequently started on therapy with the tyrosine kinase inhibitor (TKI) imatinib. Discussion: Paraneoplastic hypoglycemia is often seen in association with metastatic epithelial and mesenchymal tumors. IGF-2 and incompletely processed pro-IGF-2 activates autocrine, paracrine, and endocrine pathways that lead to tumor growth, fasting hypoglycemia, rarely of acromegalic features. Treatment with octreotide, diazoxide, and glucagon is generally ineffective, while glucocorticoid use and surgical intervention are helpful in ameliorating the hypoglycemia. Tumor-directed therapy with TKIs, primarily imatinib, appears promising in achieving remission. Our case is a clinical reminder that hypoglycemia secondary to NICTH can be the predominant presenting feature in patients with underlying E-GIST. Presentation: 6/3/2024

9337 Postprandial And “Fasting” Hypoglycemia In A Patient With A History Of Gastric Bypass Surgery And Carcinoid Syndrome

Abstract Disclosure: S. Ntelis: None. M. Pennant: None. Background: Hypoglycemia is an increasingly recognized complication of bariatric surgery that can occur years after the procedure. Episodes most commonly occur 1-3 hours after meals. Fasting hypoglycemia is not typical and raises concerns for other etiologies, including adrenal insufficiency and other causes of endogenous hyperinsulinism. Clinical Case: A 51-year-old woman with a history of carcinoid tumor of unknown origin with liver metastases, treated with monthly octreotide injections, and history of Roux-en-Y gastric bypass presented with multiple episodes of symptomatic hypoglycemia up to 24 mg/dl. Symptoms included tremor and diaphoresis and improved with juice. Morning cortisol was 22.7 mcg/dL (n &amp;gt; 19.4 mc/dL), ruling out adrenal insufficiency. A continuous glucose monitor (CGM) was placed, and she was advised to have frequent low-carbohydrate meals mixed with healthy fats and protein. She was also advised to add cornstarch to meals, until mixed-meal testing could be performed. She was hospitalized for a seizure provoked by hypoglycemia after a heavy high-carbohydrate meal, and treatment with acarbose 25 mg three times daily was started. Mixed-meal testing was consistent with post-prandial hyper-insulinemic hypoglycemia, with elevated insulin (58 mcIU/ml, n: 2.6-24.9 mcIU/ml) and c-peptide (11.2 ng/ml, n: 1.1-4.4 ng/ml) levels during an episode of symptomatic hypoglycemia (glucose 22 mg/dL) 2.5 hours after the patient’s meal. CGM showed hypoglycemia mostly occurring after meals and some episodes of hypoglycemia early in the morning, that occurred after late-night snacks. Clinical picture and laboratory testing were suggestive of post-bariatric surgery hypoglycemia. Poor hepatic glycogen reserve, secondary to the liver metastases, was considered a contributing factor. Interestingly, although hypoglycemia was mediated by hyperinsulinemia, treatment with a somatostatin analogue provided no benefit. The frequency of hypoglycemia decreased with adherence to a low-carbohydrate diet, and episodes mostly occurred when acarbose use was delayed. Octreotide was transitioned to lantreotide. Due to persistence of early-morning low glucose values on follow-up, further work-up was pursued to rule out etiologies of fasting hypoglycemia. Glucose values remained &amp;gt;70 mg/dl during 72 hours of fasting. IGF-I (115 ng/ml, n: 53-287 ng/ml) and IGF-II (608 ng/ml, n: 267-616 ng/ml) levels were normal, and insulin antibodies were undetectable. Post-bariatric surgery hypoglycemia was confirmed and acarbose dose was increased to 50 mg three times daily. Conclusion: Postprandial hypoglycemia is a late complication of bariatric surgery. Early-morning hypoglycemia can also be seen after bariatric surgery in patients who have late-night meals and snacks. Presentation: 6/1/2024

Oncolytic activity of a coxsackievirus B3 strain in patient-derived cervical squamous cell carcinoma organoids and synergistic effect with paclitaxel

BackgroundCervical squamous cell carcinoma (CSCC) is a prevalent gynecological malignancy worldwide. Current treatments for CSCC can impact fertility and cause long-term complications, underscoring the need for new therapeutic strategies. Oncolytic virotherapy has emerged as a promising option for cancer treatment. Previous research has demonstrated the oncolytic activity of the coxsackievirus B3 strain 2035 A (CVB3/2035A) against various tumor types. This study aims to evaluate the clinical viability of CVB3/2035A for CSCC treatment, focusing on its oncolytic effect in patient-derived CSCC organoids.MethodsThe oncolytic effects of CVB3/2035A were investigated using human CSCC cell lines in vitro and mouse xenograft models in vivo. Preliminary tests for tumor-selectivity were conducted on patient-derived CSCC tissue samples and compared to normal cervical tissues ex vivo. Three patient-derived CSCC organoid lines were developed and treated with CVB3/2035A alone and in combination with paclitaxel. Both cytotoxicity and virus replication were evaluated in vitro.ResultsCVB3/2035A exhibited significant cytotoxic effects in human CSCC cell lines and xenograft mouse models. The virus selectively induced oncolysis in patient-derived CSCC tissue samples while sparing normal cervical tissues ex vivo. In patient-derived CSCC organoids, which retained the immunohistological characteristics of the original tumors, CVB3/2035A also demonstrated significant cytotoxic effects and efficient replication, as evidenced by increased viral titers and presence of viral nucleic acids and proteins. Notably, the combination of CVB3/2035A and paclitaxel resulted in enhanced cytotoxicity and viral replication.ConclusionsCVB3/2035A showed oncolytic activity in CSCC cell lines, xenografts, and patient-derived tissue cultures and organoids. Furthermore, the virus exhibited synergistic anti-tumor effects with paclitaxel against CSCC. These results suggest CVB3/2035A could serve as an alternative or adjunct to current CSCC chemotherapy regimens.

7573 Cyclic Cushing’s Syndrome: Periodicity and Treatment Outcome in an International Multicenter Case Series

Abstract Disclosure: E. Nowak: None. M. Fleseriu: Consulting Fee; Self; Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals. Grant Recipient; Self; Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals. Q. Zhang: None. S. Zhang: None. K.C. Yuen: Grant Recipient; Self; Corcept, Sparrow. A. Gilis-Januszewska: None. F.A. Hanzu: None. N. Matikainen: None. M. Minasyan: None. R. Pichler: None. M. Araujo-Castro: None. E. Arvat: None. F. Bioletto: None. K. Isand: None. J.A. Wass: None. M. Reincke: Consulting Fee; Self; Recordati Rare Diseases, HRA Pharma, Crinetics, Lundbeck Pharmaceuticals. Grant Recipient; Self; Recordati Rare Diseases, HRA Pharma, Crinetics, Lundbeck Pharmaceuticals. Background: Cyclic Cushing’s syndrome (cCS) is characterised by variable cortisol secretion periodicity (peaks and throughs); it is marked by diagnostic errors, and possibly poorer overall outcome. Patients and Methods: We investigated cycle characteristics, diagnostic and treatment modalities in patients (pts) with CS from invited expert endocrine centers. cCS was defined as at least 2 clinical and biochemical hypercortisolaemic peaks (high) and 1 spontaneous eu-/or hypocortisolaemic (AI) trough (low) cortisol. Data was extracted from pts charts and transferred into a central database. Ethics approval was obtained centrally and locally. Statistical analysis was conducted with GraphPad Prism 10.1.1. Results: We included 37 pts (70% females) from 12 centers, 20 (54%) with pituitary (pit), 6 (16%) with ectopic, and 11 (30%) with occult tumour origin (suspected 10 ectopic, 1 pit). 24-h urine free cortisol (UFC) was the main diagnostic biomarker used to determine cyclicity; median 14.67 X ULN for peaks (IQR 3.58-45.92) and 0.29 X ULN for troughs (IQR 0.20-0.57). On average, pts experienced 3.11 peaks (± 1.34); 83% occurred at irregular intervals, separated by troughs lasting several months. Pts with suspected/proven ectopic cCS had significantly more peaks (mean 3.75 ± 1.57) vs pit cCS (mean 2.70 ± 0.92; p=0.023) and significantly higher levels of cortisol excess (p&amp;lt;0.05). Twenty-eight (76%) pts had symptoms worsening during peaks. Twelve (32%) pts had spontaneous AI phases. Only 69% of BIPSS were performed during hypercortisolism. In pts with suspected ectopic cCS, imaging was suggestive in 44%. Twenty-four (65%) pts had surgery (19 pit, 5 ectopic), four (11%) had radiation, and 2 (5%) bilateral adrenalectomy. Steroidogenesis inhibitors (SI) were used in 20 (54%) cases; 13 (65%) as titration regimen. After a median follow-up of 42.0 months (IQR 25.50-84.50), 17 (46%) pts achieved therapy-induced remission, 4 (11%) full spontaneous and five (14%) partial remission. Five pts were clinically and biochemically controlled by SI, 5 had persistent overt CS, and 1 (3%) died due to pneumonia pre-therapy. Median time to therapy-induced remission after referral to our centers was 34.0 months (IQR 4.25-58.50). A delayed diagnosis or therapy due to misleading findings was noted in 41% and 38% respectively. Conclusion: Cortisol secretion kinetics is highly variable in CS, with clearly defined cycles of hyper-, eu- and hypocortisolemia in some pts. Here, we show that cCS remains a challenging disease entity even in specialised centers, with less than half of the pts achieving remission at 3.5 years. Despite unpredictable cycle length and amplitude and risk of spontaneous AI, steroidogenesis inhibitors were frequently used in a titration rather than block and replace approach. Better understanding of cortisol secretion kinetics and periodicity may improve diagnostic accuracy and individualised care. Presentation: 6/1/2024

Deciphering resistance mechanisms in cancer: final report of MATCH-R study with a focus on molecular drivers and PDX development

BackgroundUnderstanding the resistance mechanisms of tumor is crucial for advancing cancer therapies. The prospective MATCH-R trial (NCT02517892), led by Gustave Roussy, aimed to characterize resistance mechanisms to cancer treatments through molecular analysis of fresh tumor biopsies. This report presents the genomic data analysis of the MATCH-R study conducted from 2015 to 2022 and focuses on targeted therapies.MethodsThe study included resistant metastatic patients (pts) who accepted an image-guided tumor biopsy. After evaluation of tumor content (TC) in frozen tissue biopsies, targeted NGS (10 < TC < 30%) or Whole Exome Sequencing and RNA sequencing (TC > 30%) were performed before and/or after the anticancer therapy.Patient-derived xenografts (PDX) were established by implanting tumor fragments into NOD scid gamma mice and amplified up to five passages.ResultsA total of 1,120 biopsies were collected from 857 pts with the most frequent tumor types being lung (38.8%), digestive (16.3%) and prostate (14.1%) cancer. Molecular targetable driver were identified in 30.9% (n = 265/857) of the patients, with EGFR (41.5%), FGFR2/3 (15.5%), ALK (11.7%), BRAF (6.8%), and KRAS (5.7%) being the most common altered genes. Furthermore, 66.0% (n = 175/265) had a biopsy at progression on targeted therapy. Among resistant cases, 41.1% (n = 72/175) had no identified molecular mechanism, 32.0% (n = 56/175) showed on-target resistance, and 25.1% (n = 44/175) exhibited a by-pass resistance mechanism. Molecular profiling of the 44 patients with by-pass resistance identified 51 variants, with KRAS (13.7%), PIK3CA (11.8%), PTEN (11.8%), NF2 (7.8%), AKT1 (5.9%), and NF1 (5.9%) being the most altered genes. Treatment was tailored for 45% of the patients with a resistance mechanism identified leading to an 11 months median extension of clinical benefit.A total of 341 biopsies were implanted in mice, successfully establishing 136 PDX models achieving a 39.9% success rate. PDX models are available for EGFR (n = 31), FGFR2/3 (n = 26), KRAS (n = 18), ALK (n = 16), BRAF (n = 6) and NTRK (n = 2) driven cancers. These models closely recapitulate the biology of the original tumors in term of molecular alterations and pharmacological status, and served as valuable models to validate overcoming treatment strategies.ConclusionThe MATCH-R study highlights the feasibility of on purpose image guided tumor biopsies and PDX establishment to characterize resistance mechanisms and guide personalized therapies to improve outcomes in pre-treated metastatic patients.Graphical

HLA-G neo-expression modifies genetic programs governing tumor cell lines

The development of immunotherapies has proved to be clinically encouraging to re-establish the immune function modified by the expression of immune inhibitory molecules in tumors. However, there are still patients with poor survival rates following treatment. The elucidation of molecular mechanisms triggered by the neo-expression of particular IC in tumors would constitute a major step toward better understanding tumor evolution and would help to design future clinical protocols. To this end, we investigate the modifications triggered by the neo-expression of the immune checkpoints HLA-G in ccRCC tumor cells. We demonstrate, for the first time, that HLA-G modifies key genes implicated mainly in tumor development, angiogenesis, calcium flow and mitochondria dynamics. The involvement of HLA-G on the expression of genes belonging to these pathways such as ADAM-12, NCAM1 and NRP1 was confirmed by the CRISPR/Cas9-mediated edition of HLA-G. The data reveal multifaceted roles of HLA-G in tumor cells which are far beyond the well-known function of HLA-G in the immune anti-tumor response. This warrants further investigation of HLA-G and these new partners in tumors of different origin so as to propose future new treatments to improve health patient’s outcome.

A combinatorial culture strategy to develop pseudomyxoma peritonei organoid models.

Few preclinical models of pseudomyxoma peritonei (PMP) have been developed, probably due to the tumor's low incidence and its peculiar characteristics of slow growth. Therefore, there is a need to develop more refined PMP models that better reflect its characteristics. The aim of the study is to develop a culture strategy to generate organoid models derived from PMP patient samples. We followed a strategy based on combinatorial culture conditions that include the different factors essential for PMP growth and that mimic the microenvironment present in the patients. We cultured PMP samples in the presence of the various factors produced by the niche environment of PMP. We obtained 12 PMP organoid models, each of which grows under specific culture conditions. PMP-derived organoids show long-term expansion capacity and reproduce the genetic landscape and histological phenotype of the tumor of origin. The organoids we developed faithfully reproduce the key features of PMP disease and will allow us to understand the biology of PMP. With them, we will be able to identify key regulatory networks that support PMP progression, providing a platform for multilevel preclinical testing, identify novel diagnostic biomarkers, and generate novel targets for patient treatments.

Pediatric soft tissue tumors : Tumors of uncertain origin

Soft tissue tumors of childhood are an extremely heterogeneous group of tumors that require precise diagnosis for therapy. In this article, selected tumors of uncertain origin that exhibit characteristic histological, immunophenotypical, and molecular features are addressed. Angiomatoid fibrous histiocytoma, alveolar soft part sarcoma, extrarenal rhabdoid tumor, synovial sarcoma, and desmoplastic small round cell tumor differ in their pathology, their clinical behavior, and prognosis.

PDOC-01 THERAPEUTIC DIFFICULTY IN THE MANAGEMENT OF A RECURRENT CRANIOPHARYNGIOMA IN A CHILD: REVIEW OF THE LITERATURE AND CASE REPORT

Abstract BACKGROUND Craniopharyngiomas are rare, benign epithelial tumors of embryonic origin in children that develop along the craniopharyngeal duct from Rathke’s pouch. The optimal treatment algorithm remains challenging. We report a child case of recurrent craniopharyngioma with therapeutic challenges. CASE PRESENTATION 12-year-old patient, followed for a multi-operated type 2 craniopharyngioma (December 2017, November 2018, and April 2022), stroke on left sylvian stenosis with right hemiplegia in 2020 during proton therapy (52 Gray), thrombolysed with good recovery after rehabilitation, sequellar panhypopituitarism. He was seen in consultation for visual field deterioration. Clinical examination showed a conscious, coherent, obese patient with a deteriorating visual field. Ophthalmological examination showed visual acuity 10/10 with slight temporal visual field amputation on the left and monocular blindness on the right due to probable optic atrophy sequelae of the craniopharyngioma. Magnetic resonance imaging revealed progression of the residual multicystic lesion in the sellar and left temporal regions, entering the sylvian valley and severely compressing the optic pathways. The tumor was removed under general anesthetic in a supine position, with release of the optic nerve, the carotid artery, and its division, and the left 3rd cranial nerve. The postoperative course is straightforward. CONCLUSION Morbidity and the assessment of sequelae are now at the forefront of the management of craniopharyngiomas. The current therapeutic approach should be reconsidered, in terms of the indications for surgery and the surgical protocol. This patient’s case is a typical example of the therapeutic difficulties involved in the management of craniopharyngiomas.

B-314 Utility of he4 in differential diagnosis of pleural effusions

Abstract Background The usefulness of tumor markers in the differential diagnosis of cancer in patients with pleural effusions (PE) remains controversial. Few studies have reported the measurement of human epididymal protein 4 (HE4) in pleural fluid. HE4 is a tumor marker associated with different types of cancer. An elevated serum concentration has been observed in ovarian and lung cancers. Other benign pathologies can increase HE4 levels, which can be detect with different laboratory tests identified with adenosine deaminase (ADA), C-reactive protein (CRP), % polynuclear cell count (%PMN) and glomerular filtration rate (GFR) can be used in order to detect possible false positives. The objective of this study was to assess the diagnostic usefulness of HE4 in malignant pleural effusions by comparing HE4 concentrations between benign and malignant samples, while considering the causes of HE4 false positives. Methods HE4, ADA, differential leukocyte count, CRP and GFR concentrations were determined in 238 pleural effusion samples. Diagnostic efficacy analysis using receiver operating curves (ROC) identified the ability of HE4 to detect malignancy, searching for cut-off points with 100% specificity. Results HE4 concentrations showed significant differences (P&amp;lt;0.01) between malignant (median 1065pmol/L) and benign (median 699pmol/L) pleural effusions. Significant differences (P&amp;lt;0.01) were found in HE4 concentrations for gynecological and lung cancer origin (median 7397 pmol/L and 5150 pmol/L respectively) and other malignant pleural effusions (median 1065 pmol/L). Patients with benign diseases with renal failure showed a higher HE4 concentration (median 964pmol/L) than in patients without these pathologies (median 696pmol/L) identified with GFR&amp;lt;30 mL/min. No differences were demonstrated in HE4 concentration levels using ADA, differential leukocyte count or CRP, so only glomerular filtration rate was considered cause of false positives. A sensitivity of 23% was obtained for HE4, with a cut-off point of 3050pmol/L and a specificity of 100% for the whole group. In the potential false positive group, the sensitivity of HE4 was 28% with a cutoff point of 3050 pmol/L with a specificity of 100%. In the group without potential false positives, we obtained a sensitivity of 30% with a specificity of 100% for a cutoff point of 1992pmol/L. When we used a specific cut-off point for each group, we obtained a sensitivity of 38% with a specificity of 100%. Conclusions HE4 levels are higher in malignant pleural effusions compared to other pathologies. HE4 levels allow the identification of malignant pleural effusions with moderate sensitivity and maximum specificity. HE4 levels can differentiate between tumors of gynecological or lung origin and others. Glomerular filtration rate (GFR&amp;lt;30 mL/min) was considered the main cause of false positives. If we identify possible false positives, we can use specific cut-offs and improve sensitivity up to 38% with maximum specificity compared to using a single cut-off for all effusions.

A deep-learning model for characterizing tumor heterogeneity using patient-derived organoids

Genotypic and phenotypic diversity, which generates heterogeneity during disease evolution, is common in cancer. The identification of features specific to each patient and tumor is central to the development of precision medicine and preclinical studies for cancer treatment. However, the complexity of the disease due to inter- and intratumor heterogeneity increases the difficulty of effective analysis. Here, we introduce a sequential deep learning model, preprocessing to organize the complexity due to heterogeneity, which contrasts with general approaches that apply a single model directly. We characterized morphological heterogeneity using microscopy images of patient-derived organoids (PDOs) and identified gene subsets relevant to distinguishing differences among original tumors. PDOs, which reflect the features of their origins, can be reproduced in large quantities and varieties, contributing to increasing the variation by enhancing their common characteristics, in contrast to those from different origins. This resulted in increased efficiency in the extraction of organoid morphological features sharing the same origin. Linking these tumor-specific morphological features to PDO gene expression data enables the extraction of genes strongly correlated with intertumor differences. The relevance of the selected genes was assessed, and the results suggest potential applications in preclinical studies and personalized clinical care.

A unique presentation of pericardial epithelioid angiosarcoma with multifaceted complications

Introduction and importance: Angiosarcomas are rare tumors of endothelial origin and may arise in any organ. Epithelioid angiosarcomas are a subtype of angiosarcoma that are rapidly progressive and typically fatal. Case presentation: The authors report a case of a 25-year-old previously healthy female who presented initially for dyspnea and palpitations, on further evaluation she was found to have large bilateral pleural effusions and cardiac tamponade. Clinical discussion: Pericardiocentesis and thoracentesis were performed alongside biopsies that revealed atypical cellular proliferation. Fluorodeoxyglucose-positron emission tomography (FDG-PET) showed avid uptake in the anterior mediastinum, perivascular, paratracheal, subcarinal and pleural lymph nodes with large FDG uptake in the bilateral pleural effusion. Mediastinoscopy was done and biopsies showed an overtly malignant, epithelioid neoplasm with foci of vaso-formation; Keeping with high-grade epithelioid angiosarcoma of the pericardium. She received six cycles of weekly paclitaxel, but imaging for abdominal pain incidentally showed evidence of metastasis to the liver and spine so she was switched to Adriamycin-Ifosfamide for which she received one cycle so far. Her hospital course was complicated by high-output pleural effusions, chylothorax, left atrial thrombus formation and an intensive care unit stay for septic shock. Conclusion: Pericardial epithelioid angiosarcoma has been reported rarely in the literature. The authors aim to report a case of extensive metastatic pericardial epithelioid angiosarcoma in a young patient; which we believe can be an addition to the literature of a malignancy associated with poor prognosis and no definitive proven treatment regimen.