Tumor Entities Research Articles

Use of surface tracking recordings to identify pitfalls during surface-guided radiotherapy.

The precise daily positioning of patients during radiation therapy determines the quality of the entire treatment. To avoid additional radiation exposure from regular cone-beam CT (CBCT) scans, surface-guided radiotherapy systems (SGRT) are increasingly used. The aim of this prospective clinical study was to evaluate the advantages, feasibility, and pitfalls of SGRT using the surface tracking recorder prototype of the camera component of ExacTrac Dynamic (Brainlab AG, Munich, Germany). This system combines both surface-based imaging technology and athermographic camera that records patients via thermal imaging to accurately measure patient geometry. The surfaces of patients with various tumor entities and therefore different regions of interest (ROIs) were recorded with the surface camera during positioning and throughout treatment. Subsequently, these surface camera datasets were analyzed to compare the accuracy of patient positioning with the current treatment standard (X-ray-based IGRT). The camera components were used only as an imaging tool and not to correct any deviations. For evaluation of typical pitfalls, errors > 5 mm for extracranial indications and > 2 mm for cranial indications were analyzed using parameters extracted from the surface recordings and the corresponding CBCT shifts. In total, 162 displacement vector datasets for 130 patients were generated and evaluated. The smallest deviations were found in the head and neck regions (mean deviation 1.9 mm/0.8°). The largest mean translational deviation (4.8 mm) and mean rotational deviation (1.1°) were found in the pelvic area. In all regions, most datasets showed clinically acceptable deviations; however, large outliers were observed in some measurements, particularly longitudinally. These outliers are of special interest because they may indicate mistakes in the use of SGRT, and they were therefore analyzed separately in detail. Several reasons for the outliers were identified, and potential solutions to avoid these pitfalls are presented. This observational study demonstrated the advantages and pitfalls of SGRT by using the surface tracking recorder prototype of the camera component of ExacTrac Dynamic. These pitfalls can be avoided through thorough application of SGRT. This study may serve as apractical guide for clinicians already using or introducing SGRT for patient positioning.

Functional screening reveals genetic dependencies and diverging cell cycle control in atypical teratoid rhabdoid tumors

BackgroundAtypical teratoid rhabdoid tumors (ATRT) are incurable high-grade pediatric brain tumors. Despite intensive research efforts, the prognosis for ATRT patients under currently established treatment protocols is poor. While novel therapeutic strategies are urgently needed, the generation of molecular-driven treatment concepts is a challenge mainly due to the absence of actionable genetic alterations.ResultsWe here use a functional genomics approach to identify genetic dependencies in ATRT, validate selected hits using a functionally instructed small molecule drug library, and observe preferential activity in ATRT cells without subgroup-specific selectivity. CDK4/6 inhibitors are among the most potent drugs and display anti-tumor efficacy due to mutual exclusive dependency on CDK4 or CDK6. Chemogenetic interactor screens reveal a broad spectrum of G1 phase cell cycle regulators that differentially enable cell cycle progression and modulate response to CDK4/6 inhibition in ATRT cells. In this regard, we find that the ubiquitin ligase substrate receptor AMBRA1 acts as a context-specific inhibitor of cell cycle progression by regulating key components of mitosis including aurora kinases.ConclusionsOur data provide a comprehensive resource of genetic and chemical dependencies in ATRTs, which will inform further preclinical evaluation of novel targeted therapies for this tumor entity. Furthermore, this study reveals a unique mechanism of cell cycle inhibition as the basis for tumor suppressive functions of AMBRA1.

Intraoperative label-free tissue diagnostics using a stimulated Raman histology imaging system with artificial intelligence: An initial experience.

Accurate intraoperative tissue diagnostics could impact on decision making regarding the extent of resection (EOR) during brain tumor surgery. Stimulated Raman histology (SRH) is a label-free optical imaging method that uses different biochemical properties of tissue to generate a hematoxylin-eosin-like image and, in combination with an artificial intelligence-based image classifier, offers the opportunity to obtain rapid intraoperative tissue diagnoses. The goal of this study was to report on our initial experience with SRH to evaluate its accuracy in comparison to final tissue diagnosis. We evaluated 70 consecutive adult cases with brain tumors. We compared results of the three different SRH classifier (diagnostic, molecular and tumor/non-tumor) to the respective final histopathological result. Similarly, we evaluated the isocitrate dehydrogenase (IDH) mutations in 18 patients using SRH. Lastly, we compared SRH results of samples taken from the tumor margins with early postoperative MRI. Prediction accuracy was evaluated by logistic regression and Receiver Operator Curve (ROC) analysis. We included 19 gliomas, 9 metastases, 22 meningiomas and 14 other tumor entities. Regarding accuracy of intraoperative SRH predictions, regression analysis showed an Area Under the Curve (AUC) of 0.77 (95 % C.I. 0.64-0.89, p = 0.0008), suggesting agreement of predictions with final diagnosis. For specific tumor entities, variable accuracies were observed: The highest accuracy was obtained for meningiomas followed by high-grade glioma. IDH mutations were predicted with an AUC of 0.93 (95 % C.I. 0.88-0.98; p < 0.0001). The SRH examination of tissue samples from tumor margins corresponded with postoperative MRI in 4 out of 5 cases. Our initial experience with SRH shows that this novel imaging technique is a promising approach to obtain rapid intraoperative tissue diagnosis to guide surgical decision making based on histology and cell-density. With further refinement of AI-based automated image classification and a better integration into the surgical workflow, prediction accuracy and reliability could be improved.

Multimodal imaging diagnosis of pancreatic Castleman disease with abdominal and retroperitoneal lymphadenopathy: a case report and literature review

IntroductionCastleman’s disease (CD) represents a rare polyclonal lymphoproliferative disorder characterized by atypical lymph node hyperplasia, the precise etiology of which remains undefined. Pancreatic involvement of CD is particularly uncommon and often misdiagnosed due to its nonspecific clinical features, making it difficult to distinguish from tumors with abundant blood supply such as solid pseudopapillary tumors and neuroendocrine tumors. Multimodal imaging plays a crucial role in diagnosing pancreatic CD and determining the extent of lymph node involvement. Surgical resection is the preferred treatment for unicentric CD (UCD). Regular follow-up and monitoring are essential for optimal patient management and treatment outcomes.Case PresentationA 26-year-old female presented to our hospital with a pancreatic mass detected during a routine health examination. Physical and laboratory examinations were unremarkable. Conventional ultrasound revealed a hypoechoic, oval-shaped mass measuring approximately 34×31 mm in the pancreatic head, with clear boundaries and heterogeneous internal echoes, but no significant blood flow signals. Contrast-enhanced ultrasound showed hyperenhancement of the pancreatic head mass, raising suspicion for a solid pseudopapillary tumor or other entities. To clarify the diagnosis, Contrast enhanced CT, MRI, and FDG PET-CT were performed. Both Contrast enhanced CT and MRI demonstrated hyperenhancement of the lesion, and PET-CT showed hypermetabolism in the pancreatic head mass, along with multiple enlarged lymph nodes in the abdominal and retroperitoneal regions. These findings suggested a lymph node origin for the pancreatic head mass. Surgical resection was performed, and pathological examination confirmed UCD. The patient has been followed for 44 months without recurrence.ConclusionThis case illustrates the utility of multimodal imaging in diagnosing pancreatic CD. In cases of benign pancreatic lesions with enlarged abdominal and retroperitoneal lymph nodes, CD should be considered.

Influence of postoperative D-dimer evaluation and intraoperative use of intermittent pneumatic vein compression (IPC) on detection and development of perioperative venous thromboembolism in brain tumor surgery

Background ObjectiveVenous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common complication in craniotomy patients and is associated with increased morbidity and mortality. The duration of surgery is a known risk factor. Other factors such as positioning and tumor entity have hardly been investigated or are controversial.In two pilot studies, the determination of plasma D-dimer concentration led to a high detection rate of DVT, while the use of intermittent pneumatic venous compression (IPC) drastically reduced the incidence of VTE. In the present study we investigated the efficacy of the two approaches, either alone or in combination, in a large patient cohort.Methods1759 patients who underwent elective craniotomy between 2009 and 2023 were retrospectively analyzed. The staggered use of D-dimer determination and intraoperative use of IPC resulted in 3 groups: Group 1: no procedure; Group 2: D-dimer evaluation; Group 3: IPC and D-dimer evaluation. If the D-dimer level was ≥ 2 mg/l (Fibrinogen equivalent units; FEU), venous ultrasound was performed. Age, gender, tumor entity, duration and extent of surgery, patient positioning, type of VTE were also recorded and analyzed.ResultsThe introduction of postoperative D-dimer evaluation increased the rate of detection of thrombosis from 1.7% in group 1 to 22.6% in group 2. The addition of IPC reduced the rate of thrombosis to 4.4%. Age, gender and patient positioning did not affect the rate of VTE. We were able to confirm the duration of surgery as an individual risk factor and showed that WHO grade 4 tumors and metastasis have an increased VTE risk.ConclusionsIf D-Dimer levels are not analyzed routinely about 20% of craniotomy patients suffer from a clinically silent thrombosis. Each with the risk of fate PE. Intraoperative use of IPC during craniotomy dramatically reduces the risk of VTE.

Bone Tumors of the Jaw - the "Blind Spot" for Radiologists Experienced with Tumors? - Part II.

Primary bone tumours of the jaw are rare tumoral entities and do substantially differ from other bone tumours of the human body with respect of their frequently encountered unusual radiological appearances. The reason for that may be confined to the co-existence of two closely neighbored but different anatomical structures (i.e., tooth-forming apparatus and jaw bones with adjacent gingiva) and some tumour pathologies which are nearly excusively encountered in the jaw bones only (e.g., ameloblastoma, ossifying fibroma, ghost cell carcinoma).This paper would like to highlight some basic principles of the diagnostic approach and possibilities of radiological differentiation of such tumour-suspicious changes within the gnathic system are elucidated and discussed.The paper presented here is substantially based on the most recent classification of odontogenic and maxillofacial tumours (5th edition, 2022) which serves as a scaffold for the selection of typical tumour entities. Due to the educational character of this paper, only important jaw tumours worth mentioning and their characteristics are subject to be extracted from the literature and further discussed.The main focus was put onto both the description of radiological tumoral appearance and the rational selection of a radiological diagnostic work-up. In order to better visualize this difficult field of tumour entities, much attention has been paid on a comprehensive pictorial essay.For radiologists, it is their foremast task to detect, describe, and to classify bone tumours of the jaw when they are found intentionally or accidentally, resp. A close co-operation with their clinical partners is of upmost importance to gain information about patient´s history and clinical presentation. It is readily reasonable that radiologists are mostly able to provide only a suggestion of the presented tumour entity but this expert opinion would be very helpful to further narrow down the list of potential differential diagnoses (e.g., differentiation of a cyst vs. solid tumour osteolysis, identification of jaw osteomyelitis vs. tumoral infiltration, recognizing of secondary tumour involvement of the jaw). · primary bone tumours of the jaw are very rare, moreover difficult to differentiate radiologically, and do need therefore histological proof;. · profound knowledge about tumour characteristics (location within the jaw, relationship to the tooth, bony destructive pattern) may allow a rough orientation and classification;. · matrix-forming tumours and dysplasias of the jaw facilitates their radiological differentiation and classification;. · in contrary, osteolyses should be thoroughly scrutinized for the more frequent gnathic cysts in differentiation of rather rare solid primary tumours;. · an interdisciplinary round-table discussion amongst well-experienced maxillofacial surgeons and specialized radiologists may be appropriate to avoid severe misinterpretations.. · Grieser T, Hirsch E, Tödtmann N. Tumours of the jaw bones - Part II. Fortschr Röntgenstr 2024; DOI 10.1055/a-2416-1282.

Bone Tumors of the Jaw - the "Blind Spot" for Radiologists Experienced with Tumors? - Part I.

Primary bone tumours of the jaw are rare tumoral entities and do substantially differ from other bone tumours of the human body with respect of their frequently encountered unusual radiological appearances. The reason for that may be confined to the co-existence of two closely neighbored but different anatomical structures (i.e., tooth-forming apparatus and jaw bones with adjacent gingiva) and some tumour pathologies which are nearly excusively encountered in the jaw bones only (e.g., ameloblastoma, ossifying fibroma, ghost cell carcinoma).This paper would like to highlight some basic principles of the diagnostic approach and possibilities of radiological differentiation of such tumour-suspicious changes within the gnathic system are elucidated and discussed.The paper presented here is substantially based on the most recent classification of odontogenic and maxillofacial tumours (5th edition, 2022) which serves as a scaffold for the selection of typical tumour entities. Due to the educational character of this paper, only important jaw tumours worth mentioning and their characteristics are subject to be extracted from the literature and further discussed.The main focus was put onto both the description of radiological tumoral appearance and the rational selection of a radiological diagnostic work-up. In order to better visualize this difficult field of tumour entities, much attention has been paid on a comprehensive pictorial essay.For radiologists, it is their foremast task to detect, describe, and to classify bone tumours of the jaw when they are found intentionally or accidentally, resp. A close co-operation with their clinical partners is of upmost importance to gain information about patient's history and clinical presentation. It is readily reasonable that radiologists are mostly able to provide only a suggestion of the presented tumour entity but this expert opinion would be very helpful to further narrow down the list of potential differential diagnoses (e.g., differentiation of a cyst vs. solid tumour osteolysis, identification of jaw osteomyelitis vs. tumoral infiltration, recognizing of secondary tumour involvement of the jaw). · primary bone tumours of the jaw are very rare, moreover difficult to differentiate radiologically, and do need therefore histological proof;. · profound knowledge about tumour characteristics (location within the jaw, relationship to the tooth, bony destructive pattern) may allow a rough orientation and classification;. · matrix-forming tumours and dysplasias of the jaw facilitates their radiological differentiation and classification;. · in contrary, osteolyses should be thoroughly scrutinized for the more frequent gnathic cysts in differentiation of rather rare solid primary tumours;. · an interdisciplinary round-table discussion amongst well-experienced maxillofacial surgeons and specialized radiologists may be appropriate to avoid severe misinterpretations.. · Grieser T, Hirsch E, Tödtmann N. Bone Tumors of the Jaw - the "Blind Spot" for Radiologists Experienced with Tumors? - Part I. Fortschr Röntgenstr 2024; DOI 10.1055/a-2415-8880.

CT-defined muscle density as a prognostic factor in multiple myeloma undergoing autologous stem cell therapy: a retrospective single center study.

Skeletal muscle quality assessment can be performed by cross-sectional imaging. Skeletal muscle density (SMD) identified to be of prognostic relevance of several clinically outcomes in patients with hematological diseases. The purpose of the present study was to establish the effect of SMD on overall survival (OS) and progression-free survival (PFS) in patients with multiple myeloma (MM). All patients with MM were retrospectively analyzed between 2009 and 2019. 127 patients were included into the analysis. Whole-body computed tomography (CT) was used to calculate skeletal muscle index (SMI), SMD, albumin-gauge score and intramuscular adipose tissue content (IMAC). Overall, 28 patients (22.0%) of the patient sample died. In the discrimination analysis muscle density was higher in non-survivors compared to survivors (mean 30.8 ± 12.5 versus 24.1 ± 15.8, p = 0.03) and IMAC was lower in non-survivors (-0.66 ± 1.8 versus -0.25 ± 0.21, p = 0.01). These differences, however, were not demonstrated in the logistic regression analysis, which could not show prognostic relevance for the investigated muscle density parameters on PFS or OS. CT-defined muscle density parameters have no prognostic relevance on survival in patients with MM undergoing autologous stem cell therapy, which was demonstrated in a comprehensive analysis. These results corroborate previous smaller studies that body composition might have a limited role in this tumor entity.

Enhancing patient activation: a controlled implementation study of an interprofessional evidence-based counseling program for complementary and integrative healthcare in cancer patients ('CCC-Integrativ').

Complementary and integrative healthcare (CIH) is increasingly recognized as a valuable approach to empowering and activating cancer patients. Studies have shown that higher patient activation is positively associated with improved health outcomes and reduced healthcare costs. The CCC-Integrativ study aimed to assess the implementation of an evidence-based counseling service on CIH at four Comprehensive Cancer Centers (CCC) in Germany. In this controlled implementation study, the patient-level intervention included three CIH consultations within a 3-month period delivered by interprofessional teams of physicians and nurses. The primary endpoint was patient activation using the PAM-13 at baseline (T1) and post-intervention (T2), and compared between control (CO, receiving routine care) and the intervention group (IG) using an analysis of covariance. Missing data were handled with multiple imputations. Maintenance effects at 6-month follow-up (T3) were investigated using a linear mixed model. A total of n = 1128 oncology patients (CO = 443, IG = 685) with diverse tumor entities and cancer stages were included in the study. The overall mean baseline PAM-13 score was 69.74 (SD = 14.24) (n = 959 (85.0%)). A statistically significant between-group difference in post-intervention PAM-13 scores was observed (Fgroup(1, 1866.82) = 8.634, P = 0.003), with an adjusted mean difference of 2.22 PAM-points. Age, gender, tumor entity, disease stage, or CCC study site did not significantly predict post-treatment PAM-13 scores. The maintenance effect of the intervention was not statistically significant (FtimeXgroup(1, 3316.04) = 2.337, P = 0.096). Individually tailored counseling on CIH, offered by specifically trained, interprofessional teams, significantly improved patient activation. Given the established positive effects of higher patient activation, the implementation of such a program at cancer centers may yield beneficial outcomes for both patients and the healthcare system.

Assessing the expression of Nectin-4 in solid tumors by immunohistochemistry - what do we know?

Antibody-Drug Conjugates (ADCs) represent a promising class of anti-cancer substances that combine the specificity of monoclonal antibodies with the potency of cytotoxic drugs, hence they enable a new approach of targeted therapy. The use of the ADC Entfortumab Vedotin (EV), which targets the viral receptor Nectin-4, showed an impressive clinical response in metastatic urothelial carcinoma. In this review, we present what is known about the expression of Nectin-4 in various tumor entities, focusing on immunohistochemistry as a diagnostic venue to detect positive expression, as this inexpensive technique is readily available in pathology laboratories. Various studies demonstrated expression of Nectin-4 in many solid tumor entities with the highest expression rates in urothelial carcinomas and breast cancer. To date, the relevance of the subcellular compartment of immunoreactivity (membranous vs. cytoplasmic) is still unclear in respect of its predictive value for EV therapy, which ought to be clarified in further studies.

Abstract B012: M-PACT: Methylation-based predictive algorithm for CNS tumor liquid biopsies

Abstract Background: DNA methylation-based classification has been transformative in the molecular diagnostics of pediatric central nervous system (CNS) tumors. Current diagnostic pipelines integrate histopathology and molecular tools in accordance with the WHO classification of CNS tumors which rely on the availability of tissue specimens. However, some tumors are not amenable to neurosurgical resection due to their high-risk locations and tissue collection is not routinely performed at relapse. In addition, molecular biomarkers are largely lacking for longitudinal disease monitoring in pediatric neuro-oncology. Liquid biopsies (LBs) have emerged as a minimally invasive, longitudinal source of tumor-derived cell-free DNA (cfDNA) ideally suited for detecting minimal residual disease (MRD). In addition, LBs provide a sensitive means of studying tumor evolution at high temporal resolution. Success rates of LB analyses in neuro-oncology have varied drastically between studies, warranting the deployment of more robust and reproducible assays. Methods: We applied a novel cfDNA methylation-based workflow to a large cohort of cerebrospinal fluid (CSF) samples collected from pediatric brain tumor patients (n&amp;gt;200 patients). Enzymatic methylation sequencing (EM-seq) was adapted for CSF-derived cfDNA inputs in the picogram range, enabling the acquisition of genome-wide cfDNA methylation profiles across the cohort. Utilizing non-oncological cfDNA profiles and CNS tumor DNA methylation datasets as a reference, we developed an innovative computational pipeline that incorporates DNA methylation imputation and deep learning of a neural network. In addition, deconvolution of cfDNA profiles facilitated classification of low tumor burden samples, including those with balanced genomes that would have been missed using previous generation assays. Results: Our CSF-based classifier, M-PACT (Methylation-based Predictive Algorithm for CNS Tumors), yielded accurate tumor detection and entity prediction (AUC=0.9) in our benchmarking cohort (n&amp;gt;100 CSF samples). Proof-of-concept studies showed the potential of this methodology to track tumor evolution in serial CSF samples at both the genetic and epigenetic level, illuminating potential mechanisms driving treatment resistance and recurrence. Conclusions: Collectively, this study provides the framework for robust methylation- based tumor detection and classification of CSF LBs. M-PACT can be applied to aid in tumor diagnostics and to detect MRD during follow-up, warranting prospective validation of its broad applicability and clinical utility in future trials. Citation Format: Tom T. Fischer, Kyle S. Smith, Katie Han, Anna Kostecka, Hong Lin, Daniel Senfter, Tatjana Wedig, Nathalie Schwarz, Natalia Stepien, Sibylle Madlener, Christine Haberler, Esther Hulleman, Sandeep K. Dhanda, Stefan M. Pfister, Santhosh Upadhyaya, Amar Gajjar, Giles W. Robinson, Joonas Haapasalo, Hannu Haapasalo, Kristiina Nordfors, Johannes Gojo, Kendra K. Maass, Kristian W. Pajtler, Paul A. Northcott. M-PACT: Methylation-based predictive algorithm for CNS tumor liquid biopsies [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B012.

Abstract PR014: Robust disease monitoring using CSF liquid biopsies collected from children undergoing cellular therapy for malignant central nervous system tumors

Abstract Background: Central nervous system (CNS) tumors remain the leading cause of cancer-related mortality in children, necessitating more effective treatment options. Chimeric Antigen Receptor T-cells (CAR-T) have emerged as a promising strategy to treat CNS tumors, with B7H3 (CD276) representing an attractive target due to its high expression across a broad range of entities. B7H3-CAR-T therapy is currently being evaluated in a St. Jude Children’s Research Hospital Phase I clinical trial (NCT05835687) for the treatment of relapse/refractory pediatric CNS tumors. Monitoring disease progression after CAR-T infusion by magnetic resonance imaging (MRI) remains challenging, emphasizing the need for more sensitive biomarkers of treatment response. Detection of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) liquid biopsies holds tremendous potential for minimal residual disease (MRD) monitoring in the clinical setting. Here, we leverage CSF liquid biopsies for longitudinal disease profiling in pediatric CNS tumor patients receiving B7H3-CAR-T immunotherapy. Methods: CSF samples were collected from Ommaya reservoirs of 9 pediatric patients with relapse/refractory CNS tumors undergoing B7H3-CAR-T therapy. CSF was sampled at study enrollment, and weekly intervals pre- and post-infusion. Cell-free DNA (cfDNA) was extracted from 115 longitudinally collected CSF samples and subjected to enzymatic methylation sequencing (EM-seq). Implementation of a custom computational workflow enabled detection of tumor-derived copy number variations (CNVs), estimation of malignant vs. non-malignant fractions, and molecular classification of tumor entity. Results: Tumor-derived CNVs were detected in 7/9 (78%) CSF samples collected at enrollment, prior to immunotherapy. Liquid biopsy-inferred CNV profiles and entity classifications were highly concordant with matched tumor tissue profiles. Chromosomal alterations that were restricted to CSF profiles indicated clonal evolution. Increased ctDNA burden was repeatedly observed after B7H3-CAR-T infusions, suggesting subclinical antitumor activity. Transient subclonal alterations emerging in response to treatment were also identified in a subset of patients. Conclusions: EM-seq is a feasible method for serial tracking of ctDNA burden in patients receiving cellular immunotherapy. CSF liquid biopsies capture the global landscape of tumor heterogeneity and genetic alterations that arise during therapy, providing a sensitive platform for detecting clinical response and disclosing potential mechanisms of treatment resistance. Citation Format: Anna Kostecka, Kyle S Smith, Katie Han, Hong Lin, Deanna Langfitt, Tara Walhart, Stephen Gottschalk, Giedre Krenciute, Christopher DeRenzo, Kelsey Bertrand, Paul A Northcott. Robust disease monitoring using CSF liquid biopsies collected from children undergoing cellular therapy for malignant central nervous system tumors [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr PR014.

Type I Interferon Drives a Cellular State Inert to TCR-Stimulation and Could Impede Effective T-Cell Differentiation in Cancer.

Head and neck squamous cell carcinoma (HNSCC) is linked to human papillomavirus (HPV) infection. HPV-positive and HPV-negative HNSCC exhibit distinct molecular and clinical characteristics. Although checkpoint inhibitors have shown efficiency in recurrent/metastatic HNSCC, response variability persists regardless of HPV status. This study aimed to explore the CD8+ T-cell landscape in HPV-negative HNSCC. We performed simultaneous single-cell RNA and TCR sequencing of CD8+ tumor-infiltrating lymphocytes (TILs) from treatment-naïve HPV-negative HNSCC patients. Additionally, cells were stimulated ex vivo, which allowed for the tracking of clonal transcriptomic responses. Our analysis identified a subset of CD8+ TILs highly enriched for interferon-stimulated genes (ISG). TCR analysis revealed ISG cells are clonally related to a population of granzyme K (GZMK)-expressing cells. However, unlike GZMK cells, which exhibited rapid effector-like phenotypes following stimulation, ISG cells were transcriptionally inert. Additionally, ISG cells showed specific enrichment within tumor and were found across multiple tumor entities. ISG-enriched CD8+ TILs are a consistent feature of various tumor entities. These cells are poorly understood but possess characteristics that may impact antitumor immunity. Understanding the unique properties and functionality of ISG cells could offer innovative treatment approaches to improve patient outcomes in HPV-negative HNSCC and other cancer types.

Beyond the blood: expanding CAR T cell therapy to solid tumors.

Chimeric antigen receptor (CAR) T cell therapy stands as a transformative advancement in immunotherapy, triumphing against hematological malignancies and, increasingly, autoimmune disorders. After a decade of relatively modest results for solid tumors, recent clinical trials and patient reports have also started to yield promising outcomes in glioblastoma and other challenging solid tumor entities. This Perspective seeks to explore the reasons behind these latest achievements and discusses how they can be sustained and expanded through different strategies involving CAR engineering and synthetic biology. Furthermore, we critically analyze how these breakthroughs can be leveraged to maintain momentum and broaden the therapeutic impact of CAR T cells across a variety of solid tumor landscapes.

CNSC-58. BIOPROCESSING OF VIABLE SURGICAL PEDIATRIC BRAIN TUMOR SPECIMENS FOR GENOME-GUIDED PERSONALIZED DRUG TESTING

Abstract Novel treatment approaches are urgently needed for pediatric central nervous system (CNS) tumors as they are the leading cause of cancer-related deaths in children. A lack of research materials impedes progress towards developing such therapies. Although various brain cancer biobanks exist, these rarely store viable patient-derived tissue and cells for live cell analyses, including cell fate assays and testing for drug sensitivities. We propose that a biorepository of viable cell dissociates and tissue broadly representing CNS tumor entities overcomes these limitations. From a combination of molecular diagnoses and histopathologic assessment of over 120 samples collected, we generated a biorepository of roughly 35 distinct entities of pediatric CNS tumors in our Stanford neuro-bioprocessing cohort. Based on the Central Brain Tumor Registry of the United States, the proportion of subtypes represented in our cohort match that of the general population with exceptions. We established a standardized bioprocessing pipeline that can be used as a template for tissue collection and model development in the broader disease context and for multiple downstream applications. Our emphasis on cryostorage of viable cells and tissue facilitates ad hoc live cell analyses. In addition to gaining a better understanding of tumor pathophysiology, we attempted a rapid bed-to-bench-to-bedside approach using comparative RNA expression profile analyses in an individual patient’s pilocytic astrocytoma. Novel drug targets were identified by analyzing RNA transcripts that are highly expressed (outliers) compared with a compendium of 12,747 brain and non-brain tumor samples. We validated outliers as drug targets using acute cell isolates, and identified a novel target in recurrent low-grade glioma. These studies illustrate that biobanking of viable patient-derived material enables developing personalized therapies with the goal of improving patient outcomes. As demonstrated here, patient-derived acute cell isolates facilitate identifying drug vulnerability, creating an opportunity for more personalized treatment of patients with CNS tumors.

Comparison of different histomorphological grading systems in vulvar squamous cell carcinoma.

Histopathological biomarkers of carcinomas and their prognostic relevance, such as Broder's grading system (based on the total number of undifferentiated cells) or Bryne's grading system (rating morphological features at the tumor invasive front), have been repeatedly and successfully put to test. Since most studies focus on head and neck cancers or oral carcinomas, for squamous cell carcinoma of the vulva, no standardized and agreed on pathological tumor grading system, yielding prognostic significance, could be determined so far. To determine prognostic associations of different grading systems with regard to groin lymph node metastasis, 73 cases of vulvar carcinomas (VC) were re-examined within our study and Broder's and Bryne's grading system individually performed. To sub-classify between HPV-associated or HPV-independent VC, immunohistochemical p16 stainings were performed. Statistical relationships were evaluated using Spearman correlation and logistic regression analysis, validation was achieved by employment of the likelihood ratio test (LRT) and assessment of ROC curves/AUC values. Within our cohort, Broder's grade I (40≈55%) and Bryne's grade II (48≈66%) were the most frequently assigned histological gradings. We determined a positive correlation of Bryne's grading with the extent of lymph node involvement in HPV-associated tumors and demonstrated the feasibility of Bryne's grading to predict the presence of carcinoma cells within groin lymph nodes (LRT p = 0.0066; AUC value≈0.91) in this cohort. On the other hand, our data suggest that especially HPV-independent tumors may not sufficiently be characterized by current standardly performed grading approaches. Since only Bryne's grading system correlated positively with lymph node involvement in HPV-associated squamous cell carcinoma of the vulva, we propose to include it by name next to the distinct tumor entity on the histopathological report, allowing not only the interpretation of its prognostic relevance but also future research attempts.

Standardizing Nutritional Care for Cancer Patients: Implementation and Evaluation of a Malnutrition Risk Screening.

Introduction Cancer-related malnutrition is a highly prevalent, yet often overlooked concern in clinical practice. Although cancer-related management guidelines recommend standardized nutritional care, its implementation is scarce. The aim of this study was to investigate the prevalence of malnutrition and the medical need for nutrition counseling in cancer patients employing a novel standardized nutritional management program (containing malnutrition risk screening, nutritional assessment and counseling). Furthermore, differences of malnutrition parameters in different cancer patient cohorts were examined. Methods Cancer patients were screened for malnutrition using the Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF) on the first day of their inpatient admission to the internal oncology or hematology wards. PG-SGA total score and classification into the three PG-SGA nutrition stages (A, B, C) were used to determine nutritional status. In case of a positive screening, nutritional assessment and individualized counseling by a nutritionist followed. For group comparisons, patients were divided into different groups (e.g., age, gender, tumor entity) and were evaluated accordingly. Results A total of 1,100 inpatients were included. 56.8 % of the patients had suspected or already existing malnutrition. The most common nutrition impact symptom was loss of appetite (26.7 %), followed by fatigue (16.5 %) and pain (16.0 %). Female (p < 0.001), elderly (p < 0.001) and patients with upper gastrointestinal tract tumors (p < 0.001) showed an unfavorable nutritional status and higher need for counseling. Despite suffering from malnutrition, patients had Body Mass Indices within the upper end of the normal range. Conclusion This study shows a high prevalence of malnutrition in hospitalized cancer patients and highlights the need for a standardized nutritional management in the clinical setting. Therefore, it is recommended to provide a malnutrition risk screening for all cancer patients and a following adequate assessment and personalized nutritional care if needed.

Unravelling switch/sucrose non-fermentable (SWI-SNF) complex-deficient thoracic tumours: a clinicopathological comparative on undifferentiated tumours and non-small cell lung carcinomas with BRG1 and BRM deficiency

AimsThis study was undertaken to compare and expand the clinicopathological characteristics of SMARCA4-deficient thoracic undifferentiated tumour (SMARCA4-dUT) and switch/sucrose non-fermentable-deficient non-small cell lung carcinomas (SWI/SNF-dNSCLC) and to address cases with...

Prevalence and Significance of AGR2 Expression in Human Cancer.

Anterior gradient 2 (AGR2) is a resident endoplasmic reticulum (ER) protein with a vital role in embryonal development, mucus maturation, tissue regeneration, and wound healing. To determine the prevalence and clinical significance of AGR2 expression in cancer, a tissue microarray containing 14,966 tumors from 134 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry (IHC). AGR2 positivity was found in 103 of 134 tumor categories, and 83 tumor categories contained at least one strongly positive case. AGR2 expression was most frequently seen in tumors of the female genital tract, particularly adenocarcinomas (up to 100%), various breast cancer subtypes (57.1%-100%), urothelial carcinoma (74.6%-100%), adenocarcinomas of the upper and lower gastrointestinal tract (93.6%-99.6%), and pancreaticobiliary cancers (65.2%-98.2%). AGR2 positivity was slightly less common in squamous cell carcinomas (46.4%-77.3%) and mainly absent in mesenchymal and lymphoid tumors. While AGR2 expression was only weak or absent in the normal thyroid, it was moderate to strong in 46.0% of adenomas, 52.8% of follicular carcinomas, and 81.8% of papillary carcinomas of the thyroid. High AGR2 expression was strongly linked to poor ISUP (p < 0.0001), Fuhrman (p < 0.0001), and Thoenes (p < 0.0001) grades as well as advanced pT stage (p = 0.0035) in clear cell renal cell carcinoma (ccRCC). Low AGR2 expression was associated with high BRE grade in breast cancer (p = 0.0049), nodal metastasis (p = 0.0275) and RAS mutation (p = 0.0136) in colorectal cancer, nodal metastasis (p = 0.0482) in endometrioid endometrial carcinoma, high grade in noninvasive urothelial carcinoma (p = 0.0003), and invasive tumor growth in urothelial carcinoma (p < 0.0001). It is concluded that AGR2 expression occurs in a broad range of different tumor entities and that AGR2 assessment may serve as a diagnostic aid for the distinction of thyroidal neoplasms and as a prognostic marker in various cancer types.

Investigating determinants of surgical success in excising basal cell and cutaneous squamous cell carcinomas of the head and neck: A single-center retrospective analysis

This study aimed to identify factors influencing the completeness of primary and re-excision of basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (SCC), and cutaneous carcinoma in situ (CIS) of the head and neck. A retrospective single-center analysis was conducted, encompassing 1513 instances of cutaneous tumors recorded between 2015 and 2022. This dataset comprised 1108 primary excisions and 405 re-excisions, all of which were histologically verified cases of BCC, SCC, and CIS located within the head and neck region. Correlation analyses were performed, considering variables such as patients' gender and age, tumor localization, preoperative suspicion or histological confirmation of skin tumor diagnosis, surgeons’ levels of training, and the utilization of magnifying glasses. The primary objective was to assess the impact of these factors on the completeness of both primary and re-excisions of skin tumors. The analysis revealed a significant correlation between the localization of BCC and the completeness of primary excision. Specifically, the nose and ear exhibited a significantly higher rate of incomplete excisions (R1), whereas the cheek demonstrated a substantial reduction in the R1 rate. The utilization of magnifying glasses exhibited a positive correlation with the completeness of primary BCC excision. However, no discernible influencing factors were identified for BCC re-excisions and the combined group of primarily and re-excised cutaneous squamous cell carcinoma (SCC) and carcinoma in situ (CIS). Tumor entity and localization emerged as crucial factors influencing the completeness of skin tumor excisions, with specific anatomical sites exhibiting varying rates of incomplete procedures. Notably, the use of magnifying glasses demonstrated a significant positive correlation with reduced rates of incomplete excisions, re-excisions, and subsequent procedures, suggesting its potential as a valuable tool in enhancing surgical precision and optimizing outcomes.