Odontogenic carcinosarcoma (OCS) is a rare neoplasm defined by the World Health Organization as a mixed odontogenic tumor containing both malignant epithelial and mesenchymal components. The diagnosis of OCS requires meticulous histopathologic evaluation, as sarcomatoid change in an odontogenic carcinoma raises the possibility of a spindle cell odontogenic carcinoma. Herein, we describe a 70-year-old male who presented with an aggressive tumor of the left posterior maxilla. Computed tomography revealed a lytic, destructive lesion obliterating the left maxillary sinus, extending into the inferior orbit, and advancing medially toward the cranial base. The patient was asymptomatic, and the lesion was identified incidentally during a routine dental exam. An incisional biopsy was performed, and a diagnosis of odontogenic carcinosarcoma was rendered. The patient was referred to Baylor University Medical Center for surgical resection. Intraoperatively, extensive growth of the lesion into the sinus and masticator space was noted, and the surgery was halted. The patient was rescheduled for a larger resection with complex reconstruction. Histologic examination of the resection specimen revealed a biphasic tumor composed of islands of atypical odontogenic epithelium surrounded by malignant mesenchymal cells showing areas of chondroid matrix production. The tumor was frankly invasive, perforating bone and infiltrating into the subjacent connective tissue and muscle. Immunohistochemical studies revealed SOX9 positivity and a Ki-67 proliferation index of approximately 30% in both the epithelial and mesenchymal components, supporting the diagnosis of high-grade OCS. OCS remains an extremely rare odontogenic malignancy, with only twenty cases previously reported in the literature. Cartilage and chondroid production are unusual findings and have rarely been reported.

Squamous odontogenic tumor (SOT) is an exceedingly rare, benign epithelial odontogenic tumor showing squamous differentiation. It is composed of variably sized and shaped islands of cytologically bland, mature squamous epithelium within a fibrous stroma. In this report, we present a rare transformation of a squamous odontogenic tumor (SOT) of the maxilla into a well-differentiated squamous cell carcinoma (SCC) with involvement of the pterygoid plates. To the best of our knowledge, only two cases of malignant transformation of SOT has been reported in the literature. Herein, we seek to report this extremely rare occurrence to raise awareness of oral and maxillofacial surgeons and pathologists of this unusual, but serious event and perform a literature review of squamous odontogenic tumors.

A 60-year-old male patient was referred for evaluation of a well-circumscribed, asymptomatic lesion located on the right ventral tongue of unknown duration. His medical history was non-contributory other than clinically diagnosed psoriasis on his right lower extremity and face. The patient was edentulous and denied use of any removable prostheses. Intraoral examination revealed a circinate lesion with a slightly elevated pink and well-defined margin measuring 5.0 × 4.0 mm in the anterior right ventral tongue. The mucosa in the central portion of the lesion appeared normal (Figure 1). The patient did not report any pain, difficulty chewing or speaking and no history of trauma or surgery in the area. An excisional biopsy was performed under local anesthesia, and the specimen was sent for histopathological analysis. The correct diagnosis is C, porokeratosis. Histopathological analysis revealed parakeratinized squamous epithelium with two cornoid lamellae composed of parakeratotic columns present at either end of the specimen (Figure 2a). Dyskeratotic and vacuolated keratinocytes were present at the base of the cornoid lamellae (Figure 2b). Porokeratosis is an uncommon dermatologic disorder characterized by a clonal abherration of keratinocytes in the skin and/or oral mucosa which produces a well-defined, annular, elevated, hyperkeratotic marginal ridge (Errichetti, 2019). It usually presents on the skin of individuals in their fifth decade of life in equal distribution between sexes (Williams & Fillman, 2023). It is commonly seen as a genodermatosis, however, sporadic cases that arise due to somatic mutations have been reported (Williams & Fillman, 2023). There are multiple clinical variants of porokeratosis; porokeratosis of Mibelli, as shown in this case, is the second most common type (Williams & Fillman, 2023). Oral manifestations of porokeratosis are exceedingly rare, with less than 20 cases reported in the literature to date. Oral porokeratosis most commonly affects the labial and buccal mucosa of patients in the fourth decade of life, with a slight female predominance (Bhatia et al., 2017; Roson et al., 2001). Lesions in the oral cavity usually present as small asymptomatic annular plaques, similar to their dermatologic counterpart, and may or may not be associated with skin lesions. Histologically, porokeratosis shows one or multiple cornoid lamellae composed of a column of perakeratin. In sites that are usually orthokeratinized, the underlying granular cell layer is diminished or absent. Dyskeratotic and vacuolated keratinocytes can be seen in the spinus layer directly beneath the cornoid lamella (Patterson, 2016). The clinical relevance of this condition is highlighted by its increased risk for malignant transformation. Retrospective analyses have characterized the malignant transformation rate of porokeratosis within the range of 6.4%–16.4% (Novice et al., 2021; Sasson & Krain, 1996). Squamous cell carcinoma and basal cell carcinoma have been repeatedly shown to be the first and second most common types of skin cancer to arise within lesions of porokeratosis, respectively (Inci et al., 2023; Novice et al., 2021; Sasson & Krain, 1996). While the clinical course of the condition is more widely understood, much of our understanding of the pathogenesis remains unresolved. Keratinocytes in porokeratosis have been shown to overexpress p16 and p53, which have been hypothesized to be related to the disease's pro-oncogenic qualities (Magee et al., 1994; Uryu & Furue, 2017). None of the reported cases in the oral cavity have undergone malignant transformation to date. The patient healed after the excisional biopsy with no complications. He will return for a three-month follow-up appointment and will continue to be monitored at future visits. Maxwell E. Perelgut: Conceptualization; writing – original draft; writing – review and editing. Allison M. Lee: Conceptualization; writing – original draft; writing – review and editing. Ana Luiza O. C. Roza: Conceptualization; writing – original draft; writing – review and editing. Joshua C. Allen: Conceptualization; writing – original draft; writing – review and editing. John M. Wright: Supervision; conceptualization; writing – original draft; writing – review and editing. The authors have nothing to report. All authors have no conflicts of interest to disclose. The patient reported in this manuscript provided written informed consent for the publication of the case details. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

PURPOSE Despite fibroblast growth factor receptor ( FGFR) inhibitors being approved in tumor types with select FGFR rearrangements or gene mutations, amplifications of FGFR represent the most common FGFR alteration across malignancies. Subprotocol K1 (EAY131-K1) of the National Cancer Institute-MATCH platform trial was designed to evaluate the antitumor efficacy of the oral FGFR1-4 inhibitor, erdafitinib, in patients with tumors harboring FGFR1-4 amplification. METHODS EAY131-K1 was an open-label, single-arm, phase II study with central confirmation of presence of FGFR1-4 amplification in tumors. Patients with urothelial carcinoma were excluded. Enrolled patients received oral erdafitinib at a starting dose of 8 mg once daily continuously with escalation to 9 mg once daily continuously, on the basis of predefined time point assessments of phosphate levels, until disease progression or intolerable toxicity. The primary end point was centrally assessed objective response rate (ORR), with key secondary end points being 6-month progression-free survival (PFS6), PFS, overall survival (OS), and safety. RESULTS Thirty-five patients were enrolled into this study with 18 included in the prespecified primary efficacy analysis. The median age of the 18 patients was 60 years, and 78% had received ≥3 previous lines of therapy. There were no confirmed responses to erdafitinib; however, five patients experienced stable disease (SD) as best response. One patient with an FGFR1-amplified breast cancer had a prolonged PFS >168 days (5.5 months). The median PFS was 1.7 months (90% CI, 1.1 to 1.8 months) and the median OS was 4.2 months (90% CI, 2.3 to 9.3 months). The estimated PFS6 rate was 13.8% (90% CI, 3.3 to 31.6). The majority of toxicities were grade 1 to 2 in nature, although there was one grade 5 treatment-related adverse event. CONCLUSION Erdafitinib did not meet its primary end point of efficacy as determined by ORR in treatment-refractory solid tumors harboring FGFR1-4 amplifications. Our findings support that rearrangements and gene mutations, but not amplifications, of FGFR remain the established FGFR alterations with approved indications for FGFR inhibition.

Supplementary Tables S1-S3.

PDF file - 39K, Response by schedule and diagnosis.

PDF file - 41K, Pharmacokinetic parameters of vorinostat and its major metabolites.

PDF file - 42K, Alvocidib pharmacokinetic parameters.

TPS4660 Background: Radiolabeled somatostatin analogues provide a means of delivering targeted radiation with a high therapeutic index to NETs that express somatostatin receptors (SSTRs). Radiolabeled somatostatin analogue Lutetium Lu 177 Dotatate (Lutathera) is a beta-emitting radionuclide, recently FDA approved for use in SSTR positive gastroenteropancreatic neuroendocrine tumors (GEPNETS) in the US based on the NETTER-1 Phase III trial. Despite favorable PFS and safety profile, the drug has limited cytoreductive capability with a 17% ORR. We hypothesize that addition of an effective radiation sensitizer could help improve antitumor activity of Lutathera. Ribonucleotide reductase (RNR) is the only enzyme responsible for conversion of ribonucleoside diphosphate to deoxyribonucleotide diphosphate (dNDP), the key building blocks for DNA synthesis. Radiation is a potent inducer of DNA double-strand breaks (DSBs), and RNR is the rate-limiting enzyme in the repair of DNA in this setting. Triapine is an inhibitor of RNR. This study will test the hypothesis that radiation sensitizer triapine can be safely combined with peptide receptor radionuclide therapy and ultimately may improve antitumor activity of Lutetium Lu 177 Dotatate. Methods: This study is an investigator initiated, NCI sponsored, multicenter phase 1 trial of triapine and Lutetium Lu 177 Dotatate in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumor (GEP-NETs) after the failure of at least one line of prior systemic cancer treatment. A total of 29 patients will be enrolled in the dose escalation with help of Bayesian optimal interval design (BOIN) and dose expansion cohorts. The study will be open through the NCI ETCTN (National Cancer Institute Experimental Therapeutics Clinical Trials Network) program. Patients will be treated with 177 lutetium dotatate in combination with triapine. Triapine will be administered orally (100 mg once a day starting dose) from D1-14 with each dose of PRRT [200 mCi]. Primary endpoint is to evaluate recommended phase II dose (RP2D). Secondary endpoints are to evaluate safety, pharmacokinetics, and clinical activity (ORR and PFS). We are also evaluating NETEST, a novel blood based test that evaluates levels of 51 neuroendocrine tumor gene transcripts. In addition, the study will correlate clinical outcome with baseline somatostatin receptor density, somatic tumor mutations and germline mutations. Clinical trial information: 04234568 .

Deep learning approaches for medical image analysis are limited by small data set size due to factors such as patient privacy and difficulties in obtaining expert labelling for each image. In medical imaging system development pipelines, phases for system development and classification algorithms often overlap with data collection, creating small disjoint data sets collected at numerous locations with differing protocols. In this setting, merging data from different data collection centers increases the amount of training data. However, a direct combination of datasets will likely fail due to domain shifts between imaging centers. In contrast to previous approaches that focus on a single data set, we add a domain adaptation module to a neural network and train using multiple data sets. Our approach encourages domain invariance between two multispectral autofluorescence imaging (maFLIM) data sets of in vivo oral lesions collected with an imaging system currently in development. The two data sets have differences in the sub-populations imaged and in the calibration procedures used during data collection. We mitigate these differences using a gradient reversal layer and domain classifier. Our final model trained with two data sets substantially increases performance, including a significant increase in specificity. We also achieve a significant increase in average performance over the best baseline model train with two domains (p = 0.0341). Our approach lays the foundation for faster development of computer-aided diagnostic systems and presents a feasible approach for creating a robust classifier that aligns images from multiple data centers in the presence of domain shifts.

This file contains Supplementary Tables S1 and S2 (pharmacokinetic data) and Supplementary Figures S1 (chemical structures of the four MET kinase inhibitors examined in this study), S2 (pharmacokinetic and pharmacodynamic data for ARQ197), S3 (body weight data for pharmacodynamics-guided dosage regimens), S4 (total full-length MET levels in the single-dose, dose-response time course experiment), S5 (total full-length MET levels in single- and multi-dose experiments using the pharmacodynamics-guided dosage regimens), and S6 (mouse tolerability information for XL880, XL184, and EMD1214063).

PDF file - 39K, Response by schedule and diagnosis.

Clear cell Odontogenic Carcinoma (CCOC) is an uncommon malignant odontogenic tumor (MOT). It is the fifth most common MOT. A systematic review is presented of reported cases, case series and retrospective studies of CCOC, to determine trends in presentation, diagnostic features, treatment, and patient outcome. Searches of detailed databases were carried out to identify papers reporting CCOC. The variables were demographics, patient symptoms, tumor location, histopathological findings, immunohistochemical studies, treatment, follow-up, and recurrence. 117 cases were identified; CCOC was most frequently seen in mature females 65% (n = 76). The total average age was 55.4 with a range from 17 to 89 years, for females 56.4 and males 53.6 years. The mean size was 3.41 cm. The most common location was in the mandibular body 36.2% (n = 42), followed by the anterior mandible 23.3% (n = 27). The most common clinical presentation was a swelling 80.4% (n = 74), and the main symptom was pain 41.3% (n = 31), followed by painless lesion 24% (n = 18). The most common Immunohistochemistry positive expression was CK19, EMA, and CEA, and for special staining periodic acid Shiff (PAS); 97% of cases were treated surgically. The average follow-up was 30.3 months, and recurrence was reported in 52.4% of the cases. Conclusion: CCOC shows a strong predilection for the body and anterior mandible, and females are more frequently affected. CCOCs can be painful and the principle clinical sign is swelling, CCOCs can metastasize, and the prognosis is fair.

Abstract Background: The NCI-MATCH precision medicine trial assigns patients (pts) with solid tumors, lymphoma, or multiple myeloma whose cancers have progressed on prior treatment to a targeted therapy based on genetic alterations identified in pre-treatment biopsies. Arm K2 (EAY131-K2) evaluated the pan-FGFR inhibitor erdafitinib (E) in pts with FGFR mutations or fusions. Patients and methods: Pts with bladder or urothelial cancers were excluded. Pts received E 8 mg PO daily (28-day cycle) until disease progression or unacceptable toxicity; dose reduction for toxicities was allowed; imaging was performed every 2 cycles. The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS). Results: A total of 35 pts were enrolled to this arm from 07/2018-07/2019; one was ineligible and one did not receive treatment. Nine distinct tumor histologies were represented, most common being pancreatobiliary (11), CNS (7) and gynecological tumors (5). 73% of pts were female, with median age of 59y (range 26-83y), 70% were Caucasian, and 61% of pts had received at least 3 prior therapies (range 0-22). Alterations in FGFR1, FGFR2 and FGFR3 were recorded in 6, 18, and 9 evaluable pts, respectively. 18 pt tumors had fusions and 15 had mutations in an FGFR gene. The confirmed ORR was 12% (90% CI 4%, 26%), with a median duration of response (DoR) of 7.3 months (mo), range 4.2-11.7 mo. Responses were seen in cholangiocarcinoma (2 pts), Brenner ovarian tumor and adenoid cystic carcinoma (1 pt each). Two (50%) of these 4 tumors harbored FGFR fusions and 2 FGFR mutations. 13 pts had stable disease (SD). Median PFS was 3.9 mo, and 6-mo PFS was 32.8% (90% CI 21.2%, 50.6%). Median OS was 11.0 mo. Of the 6 pts with intrahepatic cholangiocarcinoma, 2 had PR and 2 SD. The most frequent grade 3 treatment-related AEs were oral mucositis/pain (5 pts), paronychia, electrolyte disorders, and anemia/lymphopenia (2 pts each). There were no treatment-related grade 4-5 toxicities. Toxicities were reversible and manageable with E dose interruptions and/or dose reduction. Conclusions: In this pre-treated, mixed histology cohort with tumors harboring FGFR somatic alterations, E showed activity with durable responses and disease stabilizations outside of currently approved FDA indications, although the pre-specified criterion that the primary endpoint, ORR, be significantly greater than 16% was not reached. Toxicities were consistent with E safety profile. Responses were observed in tumors harboring FGFR fusions as well as in those with mutations of FGFR; further correlative analyses are planned. Citation Format: Alain C Mita, Zihan Wei, Ingrid A Mayer, Heather Cheng, Edith P Mitchell, John J Wright, Percy Ivy, Robert J Gray, Victoria Wang, Lisa M McShane, Larry V Rubinstein, David R Patton, Mickey Williams, Stanley R Hamilton, Barbara A Conley, Carlos L Arteaga, Lyndsay N Harris, Peter J O'Dwyer, Alice P Chen, Keith T Flaherty. Erdafitinib in patients with tumors harboring FGFR gene mutations or fusions: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Sub-protocol K2 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA003.

BACKGROUND:MET (also known as hepatocyte growth factor receptor) signalling is a key driver of papillary renal cell carcinoma (PRCC). Given that no optimal therapy for metastatic PRCC exists, we aimed to compare an existing standard of care, sunitinib, with the MET kinase inhibitors cabozantinib, crizotinib, and savolitinib for treatment of patients with PRCC. METHODS:We did a randomised, open-label, phase 2 trial done in 65 centres in the USA and Canada. Eligible patients were aged 18 years or older with metastatic PRCC who had received up to one previous therapy (excluding vascular endothelial growth factor-directed and MET-directed agents). Patients were randomly assigned to receive sunitinib, cabozantinib, crizotinib, or savolitinib, with stratification by receipt of previous therapy and PRCC subtype. All drug doses were administered orally: sunitinib 50 mg, 4 weeks on and 2 weeks off (dose reductions to 37·5 mg and 25 mg allowed); cabozantinib 60 mg daily (reductions to 40 mg and 20 mg allowed); crizotinib 250 mg twice daily (reductions to 200 mg twice daily and 250 mg once daily allowed); and savolitinib 600 mg daily (reductions to 400 mg and 200 mg allowed). Progression-free survival (PFS) was the primary endpoint. Analyses were done in an intention-to-treat population, with patients who did not receive protocol therapy excluded from safety analyses. This trial is registered with ClinicalTrials.gov, NCT02761057. FINDINGS:Between April 5, 2016, and Dec 15, 2019, 152 patients were randomly assigned to one of four study groups. Five patients were identified as ineligible post-randomisation and were excluded from these analyses, resulting in 147 eligible patients. Assignment to the savolitinib (29 patients) and crizotinib (28 patients) groups was halted after a prespecified futility analysis; planned accrual was completed for both sunitinib (46 patients) and cabozantinib (44 patients) groups. PFS was longer in patients in the cabozantinib group (median 9·0 months, 95% CI 6-12) than in the sunitinib group (5·6 months, 3-7; hazard ratio for progression or death 0·60, 0·37-0·97, one-sided p=0·019). Response rate for cabozantinib was 23% versus 4% for sunitinib (two-sided p=0·010). Savolitinib and crizotinib did not improve PFS compared with sunitinib. Grade 3 or 4 adverse events occurred in 31 (69%) of 45 patients receiving sunitinib, 32 (74%) of 43 receiving cabozantinib, ten (37%) of 27 receiving crizotinib, and 11 (39%) of 28 receiving savolitinib; one grade 5 thromboembolic event was recorded in the cabozantinib group. INTERPRETATION:Cabozantinib treatment resulted in significantly longer PFS compared with sunitinib in patients with metastatic PRCC. FUNDING:National Institutes of Health and National Cancer Institute.

5039 Background: We investigated challenging/re-challenging pts with ipilimumab (ipi) after progression on CaboNivo or CaboNivoIpi. Methods: In a phase I expansion study, patients with mUC post-platinum chemotherapy and other GU tumors patients who progressed on Cabo 40 mg daily plus nivolumab, 3 mg/kg every 21 days (CaboNivo) alone or with ipi, 1 mg/kg every 21 days for 4 cycles (CaboNivoIpi)-and achieved a PR or SD≥6 mo, were challenged/re-challenged with ipi, 1 mg/kg every 21 days for up to 4 cycles. Restaging scans were done every 6 wks for the first 12 wks, then every 8 wks and evaluated by RECIST 1.1. Results: In total, 24 patients were evaluated: 18 pts (8 UC (5 bladder and 3 upper tract), 4 clear cell renal cell carcinoma (RCC), 3 urachal adenocarcinoma (adeno), 2 bladder adeno, and 1 sarcomatoid clear cell RCC) who progressed on CaboNivo were challenged with ipi. In the challenge group, median (m) follow-up was 21.2 months. One pt achieved a PR in the LNs, but was found to have brain metastases before the next restaging, 13 had SD and 4 had PD. Median duration of PR or SD was 3.6 months (95% CI: 1.4 – 7.8 months). The mOS from start of ipi challenge was 13.9 months (95% CI: 5.8 months- not estimable); mPFS was 4.6 months (95% CI: 1.9 – 8.7 months). Grade 1/2 treatment related adverse events (AEs) occurred in all 18 pts (100%) and ≥Grade 3 (G≥3) AEs occurred in 11 pts (61%). The most common G≥3 AEs were hypophosphatemia (22%), hypertension (6%), adrenal insufficiency (6%), increased AST (6%), and ALT (6%). Six patients (3 bladder UC, 1 penile squamous cell (SCC) carcinoma, 1 urethral SCC, and 1 clear cell RCC with sarcomatoid features) who progressed on CaboNivoIpi were re-challenged with Ipi. On re-challenge, mfollow-up was 20.9 months. There were no PRs, 3 SDs and 3 PDs. mOS from start of re-challenge was 4.0 months (95% CI: 2.2 – 23.3 months) and mPFS was 1.9 months (95% CI: 1.1 – 2.6 months). Grade 1/2 treatment related AEs occurred in all 6 pts (100%) and ≥Grade 3 (G≥3) AEs occurred in 2pts (33%). G≥3 AEs included 1 hypertension (17%) and 1 hyperphosphatemia (17%). Conclusions: Ipi challenge/re-challenge showed low response rates in pts previously treated with CaboNivo or CaboNivoIpi. However, pts treated with CaboNivo who were challenged with ipi had a better OS than patients who had progressed on CaboNivoIpi and were re-challenged with ipi. Larger trials are warranted testing the ipi challenge in pts progressing on CaboNivo. Clinical trial information: NCT02496208 .

TPS270 Background: MET amplification (amp) is a well-described driver of acquired EGFR antibody (Ab) resistance and is found in 10-20% of pts with KRAS and NRAS wild-type mCRC treated with anti-EGFR Abs. Blood-based genomic profiling of cfDNA is a non-invasive and efficient means of identifying acquired MET amp in mCRC. Although the activity of anti-MET tyrosine kinase inhibitors (TKIs) in EGFR Ab refractory mCRC has been shown in preclinical and clinical studies, the clinical efficacy of anti-MET TKIs in pts with MET amplified mCRC is not well established. Savolitinib is a potent and highly selective oral small molecule anti-MET TKI that is currently under clinical development for MET-driven papillary renal cell carcinoma, NSCLC and gastric cancer. Methods: This single-arm phase II study will evaluate the clinical efficacy and tolerability of savolitinib in pts with MET amplified mCRC. Eligible pts include those with RAS wild-type mCRC who have been previously treated with 5-FU, oxaliplatin, irinotecan, an anti-VEGF Ab and an anti-EGFR Ab. Pts must have MET amp detected by Guardant360 (G360) cfDNA screening assay. Up to 150 patients will be screened to identify at least 15 pts for study accrual. Prior treatment with an anti-MET TKI or monoclonal Ab against c-MET or HGF is excluded. The primary objective is to estimate the objective response rate (ORR) for savolitinib. In this heavily pre-treated cohort an observed ORR of 20% is considered clinically meaningful and worthy of further study. Secondary objectives are to evaluate the efficacy (progression-free survival, duration of response), safety and tolerability. Correlation between tissue and blood-based biomarkers and clinical outcomes will be explored. Blood will be collected at baseline and each restaging to determine if savolitinib eliminates MET amp in cfDNA. Subjects will receive savolitinib at a dose of 600mg by mouth daily on 28-day cycles. Response will be assessed every 2 cycles (8 weeks) per RECIST version 1.1. This study was initiated on 1/30/2019. Recruitment is ongoing in the NCI Experimental Therapeutics Clinical Trials Network (ETCTN). Clinical trial information: NCT03592641.