Papillary Tumors Research Articles

TFE3 and TFEB-rearranged renal cell carcinomas: an immunohistochemical panel to differentiate from common renal cell neoplasms.

TFE3/TFEB-rearranged renal cell carcinomas are characterized by translocations involving TFE3 and TFEB genes. Despite the initial description of typical morphology, their histological spectrum is wide, mimicking common subtypes of renal cell tumors. Thus, the diagnosis is challenging requiring the demonstration of the gene rearrangement, usually by FISH. However, this technique is limited in most laboratories and immunohistochemical TFE3/TFEB analysis is inconsistent. We sought to identify a useful immunohistochemical panel using the most common available markers to recognize those tumors. We performed an immunohistochemical panel comparing 27 TFE3-rearranged and 10 TFEB-rearranged renal cell carcinomas to the most common renal cell tumors (150 clear cell, 100 papillary, 50 chromophobe renal cell carcinomas, 18 clear cell papillary renal cell tumors, and 50 oncocytomas). When dealing with neoplasms characterized by cells with clear cytoplasm, CA9 is a helpful marker to exclude clear cell renal cell carcinoma. GATA3, AMACR, and CK7 are useful to rule out clear cell papillary renal cell tumor. CK7 is negative in TFE3/TFEB-rearranged renal cell carcinoma and positive in papillary renal cell carcinoma, being therefore useful in this setting. Parvalbumin and CK7/S100A1 respectively are of paramount importance when TFE3/TFEB-rearranged renal cell carcinoma resembles oncocytoma and chromophobe renal cell carcinoma. Moreover, in TFEB-rearranged renal cell carcinoma, cathepsin K and melanogenesis markers are constantly positive, whereas TFE3-rearranged renal cell carcinoma stains for cathepsin K in roughly half of the cases, HMB45 in 8% and Melan-A in 22%. In conclusion, since TFE3/TFEB-rearranged renal cell carcinoma may mimic several histotypes, an immunohistochemical panel to differentiate them from common renal cell tumors should include cathepsin K, CA9, CK7, and parvalbumin.

SPTBN2 Promotes the Progression of Thyroid Cancer by Accelerating G1/S Transition and Inhibiting Apoptosis.

Background Thyroid carcinoma (TC) is an increasingly common malignancy of endocrine organs, and its most frequently encountered histotype is papillary thyroid cancer (PTC). Identifying new potential gene alterations is important for completely elucidating the mechanism of PTC initiation and progression. Thus, we performed whole transcriptome sequence analysis (RNA-seq) on 79 PTC tissue samples and paired adjacent nontumor tissue samples to study the molecular mechanism of TC tumorigenesis and progression further. The results of RNA-seq analysis showed that spectrin beta, nonerythrocytic 2 (SPTBN2), was markedly overexpressed in PTC tissues relative to that in the paired nontumor tissues. Additionally, the analysis results for 502 PTC samples and 58 nontumor thyroid samples from The Cancer Genome Atlas dataset were consistent with our RNA-seq results. However, the molecular mechanisms and function of SPTBN2 in TC progression remain unknown. Methods We examined SPTBN2 gene expression in 48 papillary thyroid tumor tissues and paired adjacent normal thyroid tissues by using qRT-PCR. SPTBN2 expression in the TC cell lines was silenced by small interfering RNA. Then, the transfected TC cells were used to investigate the in vitro function of SPTBN2. Result The expression of SPTBN2 was significantly upregulated in our RNA-seq cohort, our local validated cohort, and TCGA RNA-seq cohort. The results of the in vitro experiment revealed that in TC cell lines, SPTBN2 downregulation considerably suppressed tumor cell proliferation, the cell cycle, migration, colony formation, and invasion and induced cell apoptosis. Furthermore, the protein levels of CCNE2, CDK2, CDK4, and Bcl-2 were downregulated, and those of P21, Bax, cleaved caspase-8, and cleaved caspase-3 had increased in transfected TC cells relative to in control TC cells. Conclusion The downregulation of SPTBN2 caused apoptosis and retarded G1/S cell cycle transition in TC cells. Thus, SPTBN2 may be a good candidate gene for TC diagnosis and therapy.

Diagnosis and Treatment of Pineal Region Tumors in Adults: A EURACAN Overview.

Simple SummaryPineal region tumors are rare intracranial tumors. A deeper knowledge of these tumors’ molecular mechanisms has been gained in recent years, which has led to a new classification and new potential systemic treatments. Surgery remains the mainstay of treatment, while radiotherapy and systemic therapy depend on histological, molecular, and clinical characteristics. This paper highlights recent developments in the diagnosis and treatment of these tumors.Pineal region tumors are rare intracranial tumors, accounting for less than 1% of all adult intracranial tumor lesions. These lesions represent a histologically heterogeneous group of tumors. Among these tumors, pineal parenchymal tumors and germ cell tumors (GCT) represent the most frequent types of lesions. According to the new WHO 2021 classification, pineal parenchymal tumors include five distinct histotypes: pineocytoma (PC), pineal parenchymal tumors of intermediate differentiation (PPTID), papillary tumor of the pineal region (PTPR), pinealoblastoma (PB), and desmoplastic myxoid tumor of the pineal region, SMARCB1-mutant; GCTs include germinoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma, mixed GCTs. Neuroradiological assessment has a pivotal role in the diagnostic work-up, surgical planning, and follow-up of patients with pineal masses. Surgery can represent the mainstay of treatment, ranging from biopsy to gross total resection, yet pineal region tumors associated with obstructive hydrocephalus may be surgically managed via ventricular internal shunt or endoscopic third ventriculostomy. Radiotherapy remains an essential component of the multidisciplinary treatment approach for most pineal region tumors; however, treatment volumes depend on the histological subtypes, grading, extent of disease, and the combination with chemotherapy. For localized germinoma, the current standard of care is chemotherapy followed by reduced-dose whole ventricular irradiation plus a boost to the primary tumor. For pinealoblastoma patients, postoperative radiation has been associated with higher overall survival. For the other pineal tumors, the role of radiotherapy remains poorly studied and it is usually reserved for aggressive (grade 3) or recurrent tumors. The use of systemic treatments mainly depends on histology and prognostic factors such as residual disease and metastases. For pinealoblastoma patients, chemotherapy protocols are based on various alkylating or platinum-based agents, vincristine, etoposide, cyclophosphamide and are used in association with radiotherapy. About GCTs, their chemosensitivity is well known and is based on cisplatin or carboplatin and may include etoposide, cyclophosphamide, or ifosfamide prior to irradiation. Similar regimens containing platinum derivatives are also used for non-germinomatous GCTs with very encouraging results. However, due to a greater understanding of the biology of the disease’s various molecular subtypes, new agents based on targeted therapy are expected in the future. On behalf of the EURACAN domain 10 group, we reviewed the most important and recent developments in histopathological characteristics, neuro-radiological assessments, and treatments for pineal region tumors.

Multiparametric Classification of Non-Muscle Invasive Papillary Urothelial Neoplasms: Combining Morphological, Phenotypical, and Molecular Features for Improved Risk Stratification.

Diagnosis and grading of non-invasive papillary urothelial tumors according to the current WHO classification poses some challenges for pathologists. The diagnostic reproducibility of separating low-grade and high-grade lesions is low, which impacts their clinical management. Whereas papillary urothelial neoplasms with low malignant potential (PUN-LMP) and low-grade papillary non-invasive carcinoma (LG-PUC) are comparable and show frequent local recurrence but rarely metastasize, high-grade papillary non-invasive carcinoma (HG-PUC) has a poor prognosis. The main objective of this work is to develop a multiparametric classification to unambiguously distinguish low-grade and high-grade tumors, considering immunohistochemical stains for p53, FGFR3, CK20, MIB-1, p16, p21 and p-HH3, and pathogenic mutations in TP53, FGFR3, TP53, ERCC2, PIK3CA, PTEN and STAG2. We reviewed and analyzed the clinical and histological data of 45 patients with a consensus diagnosis of PUN-LMP (n = 8), non-invasive LG-PUC (n = 23), and HG-PUC (n = 14). The proliferation index and mitotic count assessed with MIB-1 and P-HH3 staining, respectively correlated with grading and clinical behavior. Targeted sequencing confirmed frequent FGFR3 mutations in non-invasive papillary tumors and identified mutations in TP53 as high-risk. Cluster analysis of the different immunohistochemical and molecular parameters allowed a clear separation in two different clusters: cluster 1 corresponding to PUN-LMP and LG-PUC (low MIB-1 and mitotic count/FGFR3 and STAG2 mutations) and cluster 2, HG-PUC (high MIB-1 and mitosis count/CK20 +++ expression, FGFR3 WT and TP53 mutation). Further analysis is required to validate and analyze the reproducibility of these clusters and their biological and clinical implication.

Encapsulated Follicular Variant of Papillary Thyroid Carcinoma: A review on Surgical Treatment.

Differentiated thyroid carcinoma is one of the commonest malignancies in head and neck region. Among differentiated thyroid carcinoma, papillary carcinoma is the commonest. Encapsulated follicular variant of papillary thyroid carcinoma tumors are very indolent tumors which behave like benign tumors. Many tumors have been over diagnosed and over treated in spite of their indolent nature. We aimed to find out if total thyroidectomy is really required for very low grade tumors like encapsulated FVPTC. We operated 672 patients of thyroid disease during 2012 to 2020 in SMS Medical College, Jaipur. Out of 256 patients, 199 patients (78%) had papillary carcinoma of thyroid. Classical variant was present in 40% and follicular variant was present in 35% (N-69). Out of 69 patients with follicular variant of PTC, 59 patients had well encapsulated type of follicular variant of PTC while 10 patients had invasive type of follicular variant of PTC. Encapsulated FVPTC are less aggressive and indolent tumors. They should be treated more conservatively. Hemithyroidectomy is sufficient treatment for its complete cure. Out of 69 patients with Follicular variant of PTC, 59 patients had encapsulated disease. Out of 59 patients, 14 (24%) had bilateral nodular disease. 45 (77%) patients had unilateral disease; multicentric in one lobe in 9 (15%) patients and unicentric in 36 (61%) patients. However, encapsulated FVPTC was only found in predominant lobe and the non dominant lobe had benign disease.

O036 Does Cxbladder accurately exclude bladder urothelial cell malignancy on diagnostic and surveillance cystoscopy? a prospective multi-centre study

Abstract Introduction and Objectives Health systems incur significant costs from bladder cancer. Diagnostic and surveillance protocols are intensive. Urine cytology and Computed tomography (CT) have low sensitivity as screening and surveillance tools. Cxbladder is a non-invasive urinary biomarker approved for use in Australia, with high reported sensitivity in bladder cancer detection. The purpose of this study was to determine the accuracy of Cxbladder as a screening and surveillance tool in patients with suspected and established bladder cancer, respectively. Methods A prospective trial (88 participants) was performed at Gosford and North Gosford Hospitals (New South Wales, Australia). Inclusion criteria were: patients undergoing investigation for macroscopic haematuria or bladder cancer surveillance. Patients were asked to perform a Cxbladder test prior to either flexible or rigid cystoscopy. Exclusion criteria were: patients aged < 18 years, or patients that had undergone transurethral resection of the bladder within five months. Testing kits were supplied at no cost by Pacific Edge Ltd. Cxbladder results were then compared with cystoscopic findings, the prevailing gold-standard for bladder cancer diagnosis. Results Sensitivity and specificity of Cxbladder for detection of bladder cancer were 76.5% and 45.1% respectively. Positive and negative predictive values (PPV/NPV) were 31.7% and 85% respectively. False negative cases comprised low-grade papillary tumours only. Cxbladder had 100% NPV in detection of high-risk bladder cancer. Conclusion There is evidence to support Cxbladder as a screening tool in the detection of high-risk bladder cancer. Further studies involving larger populations are required to validate its accuracy. Take-home message The purpose of this study was to determine the accuracy of Cxbladder as a screening and surveillance tool in patients with suspected and established bladder cancer, respectively. Sensitivity and specificity of Cxbladder for detection of bladder cancer were 76.5% and 45.1% respectively, whilst a 100% negative predictive value was obtained in detection of high-risk bladder cancer.

The landscape of common genetic drivers and DNA methylation in low-grade (epilepsy-associated) neuroepithelial tumors: A review.

Low-grade neuroepithelial tumors (LNETs) represent an important group of central nervous system neoplasms, some of which may be associated to epilepsy. The concept of long-term epilepsy-associated tumors (LEATs) includes a heterogenous group of low-grade, cortically based tumors, associated to drug-resistant epilepsy, often requiring surgical treatment. LEATs entities can sometimes be poorly discriminated by histological features, precluding a confident classification in the absence of additional diagnostic tools. This study aimed to provide an updated review on the genomic findings and DNA methylation profiling advances in LNETs, including histological entities of LEATs. A comprehensive search strategy was conducted on PubMed, Embase, and Web of Science Core Collection. High-quality peer-reviewed original manuscripts and review articles with full-text in English, published between 2003 and 2022, were included. Results were screened based on titles and abstracts to determine suitability for inclusion, and when addressed the topic of the review was screened by full-text reading. Data extraction was performed through a qualitative content analysis approach. Most LNETs appear to be driven mainly by a single genomic abnormality and respective affected signaling pathway, including BRAF p.V600E mutations in ganglioglioma, FGFR1 abnormalities in dysembryoplastic neuroepithelial tumor, MYB alterations in angiocentric glioma, BRAF fusions in pilocytic astrocytoma, PRKCA fusions in papillary glioneuronal tumor, between others. However, these molecular alterations are not exclusive, with some overlap amongst different tumor histologies. Also, clustering analysis of DNA methylation profiles allowed the identification of biologically similar molecular groups that sometimes transcend conventional histopathological classification. The exciting developments on the molecular basis of these tumors reinforce the importance of an integrative histopathological and (epi)genetic classification, which can be translated into precision medicine approaches.

Pediatric pineal region tumors: institutional experience of surgical managements with posterior interhemispheric transtentorial approach.

Resecting pineal region tumors in children is often challenging. Several approaches have been proposed and practiced. A personal series of pediatric pineal region tumors resected through craniotomy with posterior interhemispheric occipital transtentorial (OT) approach are reviewed. We present the surgical techniques, pitfalls, and their results. Eighty patients ranging in age from 3months to 21years old, and treated over 3 decades were reviewed. Hydrocephalus caused the main presenting symptoms and was noted in 74 patients. It was treated prior to the craniotomy for tumor resection with endoscopic third ventriculostomy (ETV) in 33, external ventricular drainage in 26, and precraniotomy shunt in 15. Nine patients had ETV together with endoscopic biopsy. All patients had a parieto-occipital craniotomy in a prone position. Through a tentorial section, a gross total resection of the tumor was attempted except for germinomas. The tumor pathology showed 32 germ cell tumors (GCT), 22 benign astrocytomas, 13 pineal parenchymal tumors, 5 ATRTs, 3 papillary tumors, and 5 others. Of GCTs, 18 were teratomas. The extent of resection consisted of 55 gross total resections, 13 subtotal resections, 10 partial, and 2 biopsies with one postoperative death. Hemiparesis in 2, cerebellar ataxia in another 2, and hemiballismus in 1 were transient and improved over time. One had permanent hemisensory loss and another patient had bilateral oculomotor palsy. Postoperative homonymous hemianopia occurred in 2 patients but subsided over a short period of time. Parinaud's sign was noted in 24 patients, of which 16 were transient. The posterior interhemispheric OT approach provides a safe route and comfortable access to the pineal region inchildren. A great majority of postoperative neurological complications are the results of direct manipulations of the midbrain at tumor resection. Identification and preservation of the tumor-brain interface are of paramount importance. GCTs other than teratomas are treated with neoadjuvant chemotherapy and may eliminate the need for craniotomy. Exophytic midbrain JPAs are amenable to resection.

A diagnostic approach to paratesticular lesions with tubulopapillary architecture: a series of 16 serous borderline tumors/low-grade serous carcinoma and 14 well-differentiated papillary mesothelial tumors and mesothelioma

As there is limited literature on paratesticular tumors of müllerian and mesothelial origin, we reviewed archived cases of serous borderline tumors (n=15), low-grade serous carcinoma (n=1), well-differentiated papillary mesothelial tumors (WDPMTs; n=2), and mesothelioma (n=12), for relevant clinicopathologic features. Molecular profiling data from the American Association for Cancer Research (AACR) GENIE registry was accessed for 8 additional patients with testicular mesothelioma. For tumors of mesothelial origin, the median age at surgical excision was 62 years, the median size was 4.5cm, and they consistently exhibited positivity for mesothelial markers (CK5/6, calretinin, WT1, and D2-40). Recurrent alterations of the NF2 gene were identified in 3 of 8patients (38%), and alterations of BAP1 and CDKN2A were relatively infrequent. While one patient with WDPMT had a recurrence, a second patient with WDPMT progressed to a biphasic mesothelioma 2 years after initial resection. For tumors of müllerian origin, the median age at surgical excision was 45 years, the median size was 2.5cm, and these exhibited consistent positivity for ER, WT1, and PAX8. Although no recurrences were documented in patients with serous borderline tumors, a single patient with a low-grade serous carcinoma developed widely metastatic disease and died of disease-related complications. Our study emphasizes the need for close clinical follow-up in patients with WDPMT and highlights the prognostic significance of documenting invasive behavior in tumors of müllerian origin as they can have an aggressive clinical course. Finally, our results suggest that NF2 alterations may play an important role in the pathogenesis of testicular mesothelioma.

An introduction to the WHO 5th edition 2022 classification of testicular tumours.

The 5th edition of the World Health Organisation Blue Book was published recently and includes a comprehensive update on testicular tumours. This builds upon the work of the 4th edition, retaining its structure and main nomenclature, including the use of the term ‘germ cell neoplasia in situ’ (GCNIS) for the pre‐invasive lesion of most germ cell tumours and division from those not derived from GCNIS. While there have been important developments in understanding the molecular underpinnings of testicular cancer, this updated classification paradigm and approach remains rooted in morphology. Nomenclature changes include replacement of the term ‘primitive neuroectodermal tumour’ by ‘embryonic neuroectodermal tumour’ based on the non‐specificity of the former term and to separate these tumours clearly from Ewing sarcoma. Seminoma is placed in a germinoma family of tumours emphasising relation to those tumours at other sites. Criteria for the diagnosis of ‘teratoma with somatic transformation’ have been modified to not include variable field size assessments. The word ‘carcinoid’ has been changed to ‘neuroendocrine tumour’, with most examples in the testis now classified as ‘prepubertal type testicular neuroendocrine tumour’. For sex cord‐stromal tumours, the use of mitotic counts per high‐power field has been changed to per mm2 for malignancy assessments, and the new entities, ‘signet ring stromal tumour’ and ‘myoid gonadal stromal tumour’, are defined. Well‐differentiated papillary mesothelial tumour has now been defined as tumour type with a favourable prognosis. Sertoliform cystadenoma has been removed as an entity from testicular adnexal tumours and placed with Sertoli cell tumours.

Новое в классификации эпителиальных опухолей поджелудочной железы (воз, 2019, 5-е издание)

Most of the classification of pancreatic epithelial tumors in the 5th edition remains unchanged from the previous edition. In the new classification, precancerous lesions are classified according to two levels of dysplasia. Intraductal papillary tumors and intraductal papillary tumors associated with invasive carcinoma are separated from the other subtypes. Some changes have occurred in the TNM classification.

Endoscopic management of tumors of minor ampulla: a multicenter study.

Background and study aims Papillary and duodenal carcinoma are aggressive cancers with poor 5-year survival rates. Papillectomy is a well-established treatment for early-stage carcinoma of the major papilla. Tumors arising in the minor papilla are relatively rare and there is little research available on the endoscopic management of these tumors. Patients and methods The purpose of this study was to establish the safety and efficacy of endoscopic papillectomy in the management of minor papillary tumors. A total of six patients undergoing ERCP for papillectomy for minor papillary tumor at four hospitals were included in this study over a period of 5 years. Results Papillectomy was technically successful in all six patients. Pathology revealed adenoma in three patients, adenoma with high-grade dysplasia in one patient, carcinoma in one patient, and carcinoid tumor in one patient. For follow-up, one patient had an additional tumor identified at 2 years which was found to be a recurrence of the original adenoma. This patient was treated with repeat papillectomy with no further evidence of recurrence. Conclusions In our pilot study, we demonstrate that endoscopic papillectomy appears safe and effective in the management of minor papillary tumors.

Genetic profile identification and clinicopathologic characteristics analysis of the thyroid-like low-grade nasopharyngeal papillary adenocarcinoma

Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma (TL-LGNPPA) is an extremely rare malignancy bearing histomorphological similarities to papillary thyroid carcinoma with good prognosis. It’s important to distinguish TL-LGNPPA from other papillary tumors including nasopharyngeal papillary adenocarcinoma (NPPA), metastatic and ectopic papillary thyroid cancer, and metastasized adenocarcinomas, etc. To date, only 48 cases of TL-LGNPPA have been reported in the English literatures. Here, we reported the genomic characteristics of additional 4 cases and reviewed other reports to clarify the clinicopathological features of this tumor. In this study, 41 mutations were detected by whole-exome sequencing, but no typical driver mutations were found. Two sample with Copy Number Variations (CNV) were found (7 q22. 17 q12), of which the segment spanned the regions of RASA4, POLR2J2, SPDYE2, CCL3, CCL4, etc. Additionally, no MSI and HLA LOH were found. To our knowledge, we are the first to reveal the genetic underpinnings of this rare tumor. The clinicopathological features of TL-LGNPPA were characterized, shedding more light on the essential difference between TL-LGNPPA with other papillary tumors.

Abstract 5130: Prognostic significance of loss of Cathepsin L expression in urinary bladder cancer progression

Abstract During 2021 there will be 83,730 new cases of urinary bladder cancer (UBC) in the US and 17,200 UBC deaths. Most UBC arise from the urothelial lining. UBC frequently recurs and is the most expensive cancer to treat due to the need for constant patient monitoring. New prognostic markers are needed to assist patient management. This study aims to determine if Cathepsin L is an independent prognostic factor after controlling for UBC Stage and Grade. We studied the interrelationship of Cathepsin L with Ki67, a prognostic marker in UBC. A clearer understanding of the biological mechanisms underlying UBC development and progression will lead to improved methods of UBC prognosis and suggest new therapies. Cathepsin L is a ubiquitously expressed cysteine endopeptidase capable of degrading enzymes, receptors, and transcription factors, and of activating enzymes, receptors, biologically active peptides, and pro-hormone processing by limited proteolysis. Subcellularly located in the endosomal lysosomal compartment, Cathepsin L is catalytically active at pH 3.0 - 6.5. This is a retrospective study of archived tissues and existing deidentified medical records and tumor registry information. Archived FFPE tissues were donated to Wood Hudson Cancer Research Laboratory by St. Elizabeth Healthcare (SEHC). The study was approved by the SEHC IRB. Tumors were from 41 women and 92 men. UBC were classified according to subtype, depth of invasion and grade by a Board Certified pathologist (LED). 36/62 (58.1%) of Stage 0 non-invasive UBC were Grade 1 or 2, and 26/62 (41.9%) were Grade 3 or 4. Similarly 39/90 papillary tumors (43.3%) were Grade 1 or 2 and 51/90 (36.7%) were Grade 3 or 4. In contrast 68/71 invasive UBC (Stages II, III and IV) were Grade 3 or 4. 39/90 papillary tumors were Grade 1 or 2. All non-papillary tumors were Grade 3 or 4. Ki 67 (clone MIB-1, Dako) and Cathepsin L (Abcam) expression were detected immunohistochemically. Cathepsin L was highly expressed in normal urothelium (p < 0.0001). In Stage 0, Cathepsin L expression in Grade 1,2,3 UBC was similar compared to expression in normal urothelium (p = 0.9070, 0.2560 and 0.0722). In Stage 0, Cathepsin L expression in Grade 4 UBC was significantly reduced compared to normal urothelium (p = 0.0011). Cathepsin L expression was significantly reduced in Grade 3 and 4 papillary tumors vs Grade 1 and 2 papillary tumors (p = 0.0002) and in Grade 3 and 4 non-papillary tumors vs Grade 3 and 4 papillary tumors (p = 0.0133). In each UBC subtype, grade or stage, when Cathepsin L expression was reduced cell proliferation as measured by Ki67 expression was increased and overall, this was significant (p < 0.0001). Significantly reduced Cathepsin L expression was associated with tumor recurrence and death from UBC (p = 0.03, p < 0.0001). These data suggest that when Cathepsin L is lost, intracellular levels of growth factor receptors such as EGFR may increase driving cell proliferation and UBC progression. Citation Format: Julia H. Carter, James A. Deddens, Michelle C. Robillard, Mariah K. Dooley, Daniel Stelzer, Zachary S. Taylor, Larry E. Douglass. Prognostic significance of loss of Cathepsin L expression in urinary bladder cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5130.

Abstract CT036: CORE1: Phase 2, single arm study of CG0070 combined with pembrolizumab in patients with non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG)

Abstract Introduction: CG0070, is an Ad5-based oncolytic vaccine engineered to express GM-CSF and replicate selectively in tumor cells with mutated or deficient RB. The CG0070 mechanism of action includes cell lysis and immunogenic cell death which is enhanced in the presence of GM-CSF. In an open label ph. 2 study, an overall CR rate of 62% and a CR at 12 months (m) of 29% have been observed in patients with high risk NMIBC previously treated with BCG. IV pembrolizumab, was recently approved by the FDA for patients with BCG-unresponsive CIS (with or without papillary tumors) with an overall complete RR of 41% and a 12 m CR rate of ~20%.This ph. 2 study will assess the potential synergy of the two agents in the treatment of BCG-unresponsive NMIBC. Methods:35 pts with BCG-unresponsive CIS with or without concurrent Ta or T1 disease will be treated with intravescical CG0070 (1x1012 vp) in combination with pembrolizumab at a dose of 400 mg IV q6 weeks. CG0070 will be administered weekly x 6 as induction followed by weekly x 3 maintenance instillations at months 3, 6, 9, 12, and 18. Pts with persistent CIS or HG Ta at 3 m may receive re-induction with weekly x 6 of CG0070. Pembrolizumab will be administered up to 24 m. Assessment of response will include q 3 m cystoscopy with biopsy of areas suspicious for disease, urine cytology, CTU/MRU, and mandatory bladder mapping biopsies at 12 m. Recurrence of HG disease will be enumerated as disease recurrence. The primary endpoint of the study is CR at 12 m. Secondary endpoints will include CR at any time, progression free survival, duration of response, cystectomy free survival and the safety of the combination. Correlate assessments will include changes in the tumor immune microenvironment, systemic immune induction, viral replication and transgene expression. Baseline expression of PD-L1, coxsackie adenovirus receptor, E2F transcription factor as well as anti-Ad5 Ab titer will be correlated with tumor response. Results: Thus far, 10 patients are evaluable at the 3 m timepoint for efficacy. Assessment of these 10 pts demonstrates 100% CR at 3 mos. Six of the 10 pts have also reached the 6 m hallmark in a CR as well as 2 at the 12 mos timepoint. Treatment related AE have been limited to transient grade 1-2 local-regional genitourinary adverse events with no grade 3 or 4 treatment related AE reported date. Conclusions: This initial data on the efficacy and safety of CG0070 plus pembrolizumab for the treatment of BCG unresponsive NMIBC is encouraging. An update on the study will be provided at the time of presentation. Citation Format: Roger Li, Gary Steinberg, Paras Shah, Ed Uchio, Donald Lamm, Trinity Bivalacqua, Vignesh Packiam, Ashish Kamat, Michael Chisamore, John McAdory, Paola Grandi, Jee-Hyun Kim, James Burke. CORE1: Phase 2, single arm study of CG0070 combined with pembrolizumab in patients with non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT036.

Abstract 913: Tert mutant promoter mouse model induces cancer progression in BrafV600E-driven thyroid tumors: A novel tool to understand the biology of telomerase-reactivated cancers

Abstract Hotspot mutations in the proximal promoter of the telomerase reverse transcriptase (TERT) gene are the first cross-cancer alterations lying in a gene regulatory region. TERT promoter mutations (TPMs) are enriched in advanced thyroid tumors and constitute markers of disease severity. TPMs enhance TERT transcription, which is otherwise silenced in adult tissues, thus reactivating a bone fide oncoprotein. To study TERT deregulation and its downstream consequences in a biologically accurate model, we generated a Tert-mutant promoter mouse model via CRISPR/Cas9 editing of the equivalent murine locus and crossed these animals with thyroid-specific BrafV600E-mutant mice. BrafV600E animals develop highly penetrant papillary thyroid tumors (PTC) by week 5, but do not progress. In contrast, BrafV600E+TertMUT animals showed an increased incidence of poorly differentiated thyroid cancers (PDTC) by 20 weeks (30% vs. 0% in BrafV600E; chi-squared P= 0.03), mimicking those exhibited by an alternative transgenic model of Tert overexpression (BrafV600E+K5-Tert; 36% PDTCs). Mouse Tert promoter mutation increased Tert transcription in vitro and in vivo, as reported in patients’ tumors carrying TPMs. Braf+Tert animals partially responded to MAPK pathway inhibition (dabrafenib plus trametinib), showing that MAPK signaling remains relevant in these specimens. Interestingly, RNA sequencing of Tert-reactivated murine thyroid tumors showed unique transcriptomic profiles (compared to BrafV600E alone), suggesting that downstream effects, other than the canonical Tert-mediated telomere maintenance, operate in cancers harboring TPMs. These cancer models of telomerase reactivation provide excellent pre-clinical settings to understand the regulatory mechanisms and biological underpinnings of TPM-induced progression of thyroid and other tumors, and to explore novel therapeutic strategies. Citation Format: Inigo Landa, Jingzhu Hao, Bin Xu, Joseph Giacalone, Zach Herbert, Maria A. Blasco, Jeffrey A. Knauf, Ronald Ghossein, James A. Fagin. Tert mutant promoter mouse model induces cancer progression in BrafV600E-driven thyroid tumors: A novel tool to understand the biology of telomerase-reactivated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 913.

Neoadjuvant B-RAF and MEK Inhibitor Targeted Therapy for Adult Papillary Craniopharyngiomas: A New Treatment Paradigm.

BackgroundSurgical and clinical management of craniopharyngiomas is associated with high long-term morbidity especially in the case of hypothalamic involvement. Improvements in knowledge of craniopharyngioma molecular biology may offer the possibility of safe and effective medical neoadjuvant treatments in a subset of patients harboring papillary subtype tumors with a BRAFV600E mutation.MethodWe report herein two cases of tubero-infundibular and ventricular Papillary Craniopharyngiomas in which BRAF/MEK inhibitor combined therapy was used as adjuvant (Case 1) or neoadjuvant (Case 2) treatment, with a 90% reduction in tumor volume observed after only 5 months. In Case 2 the only surgical procedure used was a minimal invasive biopsy by the trans-ventricular neuroendoscopic approach. As a consequence, targeted therapy was administered in purely neoadjuvant fashion. After shrinkage of the tumor, both patients underwent fractionated radiotherapy on the small tumor remnant to achieve long-term tumor control. A review of a previously reported case has also been performed.ResultThis approach led to tumor control with minimal long-term morbidity in both cases. No side effects or complications were reported after medical treatment and adjuvant radiotherapy.ConclusionOur experience and a review of the literature argue for a change in the current treatment paradigm for Craniopharyngiomas (CPs). In giant and invasive tumors, confirmation of BRAFV600E mutated PCPs by biopsy and BRAF/MEK inhibitor therapy before proposing other treatments may be useful to improve long term outcomes for patients.

OTHR-15. Papillary tumor of the pineal region: case series of this rare pediatric entity

BACKGROUND: The optimal management of pediatric papillary tumors of the pineal region (PTPR) is not yet established. We report three cases, as an addition to the existing literature. PATIENT 1: A 22-month-old female presented with progressive ataxia and incoordination, found to have an enhancing solid and cystic mass centered within the pineal region, with associated obstructive hydrocephalus. Tumor biopsy revealed PTPR, prompting a subsequent subtotal resection. No adjuvant therapy was recommended. Patient has remained without evidence of disease progression for 92 months, since resection. PATIENT 2: An 8-year-old female presented with progressive headaches and new-onset generalized seizures, found to have a heterogeneously enhancing pineal lesion, with associated obstructive hydrocephalus. Following a biopsy demonstrating PTPR, patient underwent subtotal resection of the tumor. A second resection was completed 6 months later followed by focal irradiation. Targeted next-generation sequencing (NGS) demonstrated two non-targetable genomic alterations (CREBBP and MLL2). The patient remains without tumor recurrence, now 37 months, since irradiation. PATIENT 3: A 7-year-old male with Autism spectrum disorder presented with new-onset focal complex seizures. A brain MRI showed a heterogeneously enhancing lesion in the region of the pineal gland, with associated obstructive hydrocephalus. A tumor biopsy revealed PTPR, prompting a subsequent gross total resection (GTR). NGS demonstrated no reportable genomic alterations. Methylome profiling classified the tumor as PTPR, group B. Post-operative imaging with no residual tumor and he has remained without tumor progression, now eight months, since resection. CONCLUSION: PTPR are extremely rare in the pediatric setting, and were initially introduced in the WHO 2007 classification as grade II-III pineal gland tumors with distinct morphologic and immunohistochemical features. GTR is the mainstay of treatment but post-surgical management remains controversial. The clinical course is characterized by frequent local recurrence, hence, adjuvant chemotherapy and/or irradiation may be necessary upon disease progression.

OTHR-01. Papillary tumor of pineal region rare pediatric CNS tumor: case series treated in King Fahad Medical City KFMC

Abstract Clinical behaviors, prognosis, and appropriate treatments of PTPR are not fully defined due to the rarity of these tumors. At diagnosis, PTPR may present with various clinical symptoms with obstructive hydrocephalus, as well as neurological signs including Parinaud’s syndrome. Radiological assessment of pineal region lesions is challenging with a wide range of potential differential diagnoses. PTPR typically presents as a heterogeneous, well circumscribed mass in the pineal region. we report 3 female pediatric cases of PTPR treated in our institution. Histological and immunohistochemical diagnosis was confirmed by analysis of genome-wide DNA methylation profiles. the first case presenting with spinal leptomeningeal dissemination with excellent tumor control with radiation therapy alone. The second patient had aggressive course with recurrent local tumor growth despite radiation therapy and 0repeated surgical resections and she responded well to Pineoblastoma like intensive chemotherapy6 repeats of alternating 4-week cycles A&B : Cycle A: Cisplatin 90 mg/m2/day, day 1 of a & oral Etoposide 35 mg/m2/day P.O. days 1-21 . Cycle B: Cyclophosphamide 1 g/m2/day, days 1 and 2, Vincristine 1.5 mg/m2, days 1, 8 . While the third patient after first near gross total surgical resection with no recurrence for 18 months without adjuvant therapy then she had local recurrence which was salvaged by second complete resection and focal radiation The proper therapeutic strategy for PTPR is not clearer and the clinical behavior of PTPRs can be compared to that of ependymoma with complete resection is the mainstay of treatment and we recommend that adjuvant therapies like radiation with or without or chemotherapy should be considered when complete surgical resection is not feasible. This case series expands on the available reports on the clinical presentations of PTPR and provides important information on the responses to different treatments modalities

CORE1: Phase 2, single-arm study of CG0070 combined with pembrolizumab in patients with nonmuscle-invasive bladder cancer (NMIBC) unresponsive to bacillus Calmette-Guerin (BCG).

4597 Background: CG0070, is an Ad5-based oncolytic vaccine engineered to express GM-CSF and replicate selectively in tumor cells with mutated or deficient RB. The CG0070 mechanism of action includes cell lysis and immunogenic cell death which is enhanced in the presence of GM-CSF. In an open label ph. 2 study, an overall CR rate of 62% and a CR at 12 months (m) of 29% have been observed in patients with high risk NMIBC previously treated with BCG. IV pembrolizumab, was recently approved by the FDA for patients with BCG-unresponsive CIS (with or without papillary tumors) with an overall complete RR of 41% and a 12 m CR rate of ̃20%. This ph. 2 study will assess the potential synergy of the two agents in the treatment of BCG-unresponsive NMIBC. Methods: 35 pts with BCG-unresponsive CIS with or without concurrent Ta or T1 disease will be treated with intravescical CG0070 (1x1012 vp) in combination with pembrolizumab at a dose of 400 mg IV q6 weeks. CG0070 will be administered weekly x 6 as induction followed by weekly x 3 maintenance instillations at months 3, 6, 9, 12, and 18. Pts with persistent CIS or HG Ta at 3 m may receive re-induction with weekly x 6 of CG0070. Pembrolizumab will be administered up to 24 m. Assessment of response will include q 3 m cystoscopy with biopsy of areas suspicious for disease, urine cytology, CTU/MRU, and mandatory bladder mapping biopsies at 12 m. Recurrence of HG disease will be enumerated as disease recurrence. The primary endpoint of the study is CR at 12 m. Secondary endpoints will include CR at any time, progression free survival, duration of response, cystectomy free survival and the safety. Correlate assessments will include changes in the tumor immune microenvironment, systemic immune induction,viral replication and transgene expression. Baseline expression of PD-L1, coxsackie adenovirus receptor, E2F transcription factor as well as anti-Ad5 Ab titer will be correlated with tumor response. Results: A CR rate of 87.5% (14/16) at the 3 m assessment timepoint has been observed thus far. All patients in CR at 3 m remain in CR at downstream timepoints including: 9/9 at 6 m, 6/6 at 9 m, and 3/3 at 12 m. Treatment related AE have been generally limited to transient grade 1-2 local-regional genitourinary adverse events with no reports of grade 3, 4 or SAE attributed to treatment with CG0070/Pembroluzimab. Conclusions: This initial data on the efficacy and safety of CG0070 plus pembrolizumab for the treatment of BCG unresponsive NMIBC is encouraging. Additional data on efficacy as well as safety and biomarker (CAR, E2F, and PDL1) assessment will be presented for at least 25 of the projected 35 patients at the time of the conference. Clinical trial information: NCT04387461.