Primary Tumor In Patients Research Articles

Role of 18FDG PET/CT in Detecting Primary Tumors in Patients with Carcinoma of Unknown Primary: Single-Center Cross-Sectional Study from 2017 to 2023 (Extension Study)

AbstractCarcinoma of unknown primary (CUP) is a diverse group of cancers in which the primary tumor site remains occult despite detailed investigations. This is an extension of a published parent study with a smaller cohort, to further validate the published facts of detection efficiency of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18FDG PET/CT) in patients with CUP over a larger sample from 2017 to 2023. Patients with CUP referred for 18FDG PET/CT scan for detection of primary sites during the study period were recruited. 18FDG PET/CT scan was acquired using a standardized protocol, and patients with suspected primary sites underwent biopsies. Scan findings and biopsy results were analyzed to find the detection rate, sensitivity, area under the curve (AUC), and positive predictive value (PPV). As no biopsy was performed in cases with negative scan, these cases were considered false negatives (FNs). Total 230 patients with CUP were included with similar demographic trend (mean age: 58 ± 14 years; 63% male and 37% female; mean body mass index: 26.82 ± 5.4 kg/m2); 138/230 (60 vs. 74% in parent study) patients were found to have a hypermetabolic focus suggestive of primary tumor sites and subjected to biopsy which turned out positive in 127/138 (true positive [TP]: 92 vs. 76% in parent study) and negative in 11/138 (true negative [TN]: 8 vs. 24% in parent study). Sensitivity and PPV of 18FDG PET/CT were 58 and 92%, respectively (68 and 76%, respectively, in parent study). The remaining 92/230 (40%) patients with negative 18FDG PET/CT for primary focus did not have biopsy. No significant demographic difference was seen in patients with TP and FN studies (p > 0.05). Receiver operating characteristics (ROC) curve revealed fair diagnostic strength of 18FDG PET/CT for detecting unknown primary (AUC 0.710; p ≤ 0.05; standard error = 0.0167; confidence interval: 0.647–0.768; vs. nonsignificant in parent study). We conclude that this extension study with a larger cohort compared with the parent study has found a similar detection efficiency of 18FDG PET/CT for identifying primary tumor in patients with CUP (58 vs. 57%) but with better PPV and sensitivity. Upfront use of 18FDG PET/CT in CUP could preclude the use of many futile diagnostic procedures. Furthermore, the use of tumor-specific PET tracers, higher resolution scanners, and acquiring delayed images in patients with negative 18FDG study could reduce FN results in patients with CUP.

EPCO-41. THE NUCLEOSOME REMODELING AND DEACETYLASE COMPLEX UNDERLIES SELECTIVE DEPENDENCY IN H3 G34-MUTANT DIFFUSE HEMISPHERIC GLIOMA

Abstract Pediatric-type diffuse high-grade gliomas are fatal central nervous system malignancies of childhood. Recurrent mutations in histone H3.3 at amino acid 34 (glycine to arginine/valine) are a defining molecular feature of diffuse hemispheric glioma, H3 G34-mutant (H3 G34-mutant DHG), which arises preferentially in adolescents and young adults. Single-nuclei sequencing of age and anatomically matched H3 wild-type and H3 G34-mutant primary patient tumors identified aberrant neuronal-like transcriptional programs enriched for signatures of cortical interneurons derived from the medial ganglionic eminence. The extent to which these molecular signatures reflect cancer dependencies in H3 G34-mutant DHG is poorly understood. To identify transcriptional vulnerabilities governing cellular state and underlying developmental lineage, we performed CRISPR screening targeting the DNA-binding domains of 1,427 proteins in H3 G34-mutant DHG (n=6) and H3 K27-altered diffuse midline glioma (DMG) (n=3). Through these efforts, we identified developmentally relevant transcription factor vulnerabilities corresponding to neuronal and oligodendrocyte precursor cell-like hierarchies comprising H3 G34-mutant DHG and H3 K27-altered DMG cellular states, respectively. Intriguingly, we also identified multiple members of the nucleosome remodeling and deacetylase (NuRD) complex as selective dependencies in H3 G34-DHG compared to H3 K27-altered DMG and 32 other cancer cell line models screened using the same DNA-binding domain library. Genetic perturbation of the holo-NuRD structural subunit MBD3 conferred an upregulation of genes involved in neuronal differentiation and synapse formation consistent with NuRD-mediated modulation of the aberrant neuronal-like cell hierarchy observed in H3 G34-mutant DHG. To therapeutically target NuRD-associated class I HDAC activity, patient-derived H3 G34-mutant DHG cell lines were treated with quisinostat, a highly potent class I and II HDAC inhibitor. Pharmacologic inhibition of HDAC activity was sufficient to impair cell growth in vitro. Ongoing experiments are evaluating dependencies in vivo. Our results may suggest a differential requirement for chromatin repressive complex dysregulation in the pathogenesis of oncohistone-mutant pediatric-type diffuse high-grade gliomas.

Unveiling the interplay of YAP1-driven pathways and miR-340-5P expression: insights into nasopharyngeal cancer metastasis.

Nasopharyngeal carcinoma (NPC) is a prevalent malignancy in Southeast Asia and Southern China, with a notable incidence in Indonesia. This study aimed to characterize the expression and correlation of Yes-associated protein (YAP1) and miR-340-5p in NPC metastasis tissues. This study utilized clinical samples from primary tumors of NPC patients to investigate the expression of YAP1 and miR-340-5p. The Cancer Genome Atlas (TCGA) Head and Neck Cancer dataset was analyzed to assess YAP1 and miR-340-5p expression in broader head and neck cancer samples. Protein-protein interaction (PPI) and functional enrichment analyses were performed to understand the putative regulatory mechanisms of YAP1 and miR-340-5p head and neck cancer. YAP1 mRNA and miR-340-5p level expression were measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and statistical analyses were performed to compare the expression of these markers in NPC samples. Analysis of clinical samples revealed lower expression levels of YAP1 and miR-340-5p in metastasis NPC cases compared to non-metastatic cases (p<0.0001). YAP1 and miR-340-5p revealed a negative correlation in metastasis and non-metastasis samples but were statistically insignificant. Additionally, both genes showed significantly lower expression in stage IVB compared to stage II, III, and IVA NPC tissues (p<0.0001). The TCGA dataset showed consistent decreases in YAP1 and miR-340-5p expression in head and neck cancer tumors as opposed to normal tissues. Functional enrichment and PPI analysis suggested the involvement of the Hippo signaling pathway and other cancer-related pathways in NPC progression. The study highlights the under-expressed YAP1 and miR-340-5p in metastasis tumor cases, suggesting their potential role as a tumor suppressor in NPC.

Added value of body MRI to detect primary abdominal malignancies in the diagnostic work-up of patients with adenocarcinoma of unknown primary

Abstract Purpose This study aimed to evaluate the added benefit of body MRI (covering the chest, abdomen, and pelvis) to detect the primary tumour in patients with adenocarcinoma of unknown primary (ACUP) and a suspected abdominal malignancy in whom previous diagnostic work-up with CT and/or FDG-PET/CT did not yield a primary tumour diagnosis. Methods Thirty ACUP patients with a suspected primary tumour in the abdomen/pelvis (based on pathology and/or pattern of disease) underwent MRI (T2-weighted, DWI, pre- and post-contrast T1-weighted) after completion of their initial diagnostic work-up with CT and/or PET/CT. Effects of MRI to establish a primary tumour diagnosis (and to detect additional metastatic sites) were documented. Integration of all available imaging data, additional diagnostic procedures (e.g., endoscopy), histopathology, and whole genome sequencing served as the composite standard of reference. Results MRI rendered a possible primary tumour diagnosis in 16/30 (53%) cases, which aligned with the final clinical diagnosis in 9/16 (56%) of these cases, thus resulting in a confirmed primary tumour diagnosis in 30% of our total patient cohort. These included four gastrointestinal, two hepatobiliary, one pancreatic, one ovarian and one breast cancer. MRI revealed extra metastatic sites in five patients (17%). Conclusion MRI can be of added value in the diagnostic work-up of ACUP patients with a suspected primary tumour originating from the abdomen or pelvis, in particular to detect gastrointestinal or hepatobiliary malignancies. Larger studies are needed to confirm these results and identify specific ACUP patients that are most likely to benefit from MRI. Key Points QuestionCan body MRI help identify the primary tumour in patients with adenocarcinoma of unknown primary (ACUP)? FindingsIn this pilot of n = 30 ACUP patients with clinically suspected abdominal malignancies, body MRI was able to establish the primary tumour in 30% of cases. Clinical relevanceBody MRI can be of added value (as an adjunct to CT and/or PET/CT) in the diagnostic work-up of ACUP patients with a suspected primary tumour originating from the abdomen or pelvis, especially to detect gastrointestinal or hepatobiliary malignancies.

Frequency and outcomes of new or suspicious MRI findings on breast MRI for patients on neoadjuvant therapy.

To assess the frequency and outcomes of indeterminate enhancing findings on breast MRI unrelated to the index primary tumor(s) in patients on neoadjuvant therapy (NAT). This retrospective review identified all diagnostic breast MRIs performed to evaluate response to NAT at our institution between 2017 and 2020. All exams with indeterminate enhancing findings (BI-RADS 3-5) unrelated to the index tumor(s) for which follow-up imaging or tissue diagnosis was recommended were included. Cases lacking a pre-treatment MRI or those with insufficient follow-up were excluded. Imaging of all post-NAT breast MRIs were re-reviewed. The electronic medical record was reviewed to evaluate patient and lesion characteristics and outcomes. Between 2017 and 2020, 614/4042 (15.2%) breast MRIs were performed to evaluate response to NAT. After exclusions, 38 of these exams (6.2%) identified 42 indeterminate enhancing findings unrelated to the index tumor for which follow-up imaging (15 exams) or tissue diagnosis (23 exams) was recommended. Fifteen of 42 (35.7%) of the findings were new compared to the pre-treatment baseline MRI, 8/42 (19.0%) increased and 19/42 (45.2%) were present on pre-treatment MRI. Most findings were contralateral to the index tumor (28, 66.7%). Findings were masses (17, 40.4%), focus (15, 35.7%), and non-mass enhancement (10, 23.8%). Of the 42 findings, 19 (45.2%) underwent percutaneous biopsy, 10 (23.8%) underwent surgical biopsy or mastectomy, and 13 (31%) were followed by imaging. Thirty-seven were benign, 4 were high-risk lesions without upgrade (atypical ductal hyperplasia, atypical lobular hyperplasia, and papillomatosis with atypical ductal hyperplasia), and one (2.4%) was malignant (invasive lobular carcinoma), which was non-mass enhancement present on the pre-treatment MRI. Indeterminate enhancing lesions unrelated to the index tumor(s) on breast MRIs performed to assess response to neoadjuvant chemotherapy are uncommon. When present, these lesions have an extremely low likelihood of malignancy, especially when new compared to the pre-treatment MRI. Because incidental indeterminate enhancing lesions on breast MRI at post-NAT follow-up are rarely malignant, radiologists should be judicious in recommending follow-up or tissue diagnosis for such lesions after NAT.

P-64830607-1086 - Second primary tumors in head and neck cancer patients. A literature review and case report

P-64830607-1086 - Second primary tumors in head and neck cancer patients. A literature review and case report

Establishing Patient-Derived Xenograft (PDX) Models of Lymphomas.

Patient-derived xenograft (PDX) models of lymphoma typically involve the injection of human tumor cells into an immunocompromised murine host. PDXs have the advantage that the tumor cells grow in a 3D environment within the mouse, meaning the selection pressure of in vitro establishment is avoided and the tumor cells better maintain their genetic heterogeneity. Here, we outline a method for producing and maintaining a PDX model of lymphoma. We describe three different methods to isolate a single cell suspension of the primary patient tumor, followed by either subcutaneous or intraperitoneal injection into an immunocompromised mouse. We then detail how to monitor tumor growth and how to harvest, passage, and store the tumors once they have grown. We highlight and discuss important protocol considerations including technical hints as well as the advantages and disadvantages of the methods described.

Clinical relationships between the intratumoral microbiome and risk factors for head and neck cancer

A bioinformatic analysis is a promising approach to understand the relationship between the vast tumor microbiome and cancer development. In the present study, we studied the relationships between the intratumoral microbiome and classical clinical risk factors using bioinformatics analysis of the Cancer Genome Atlas (TCGA) and the Cancer Microbiome Atlas (TCMA) datasets. We used TCMA database and investigated the abundance of microbes at the genus level in solid normal tissue (n = 22) and the primary tumors of patients with head and neck squamous cell carcinoma (HNSCC) (n = 154) and identified three major tumor microbiomes, Fusobacterium, Prevotella, and Streptococcus. The tissue level of Fusobacterium was higher in primary tumors than in solid normal tissue. However, univariate and multivariate analyses of these 3 microbes showed no significant effects on patient survival. We then extracted 43, 55, or 59 genes that were differentially expressed between the over and under the median groups for Fusobacterium, Prevotella, or Streptococcus using the criteria of >2.5, >1.5, or >2.0 fold and p < 0.05 in the Mann-Whitney U test. The results of a pathway analysis revealed the association of Fusobacterium- and Streptococcus-related genes with the IL-17 signaling pathway and Staphylococcus aureus infection, while Prevotella-associated pathways were not extracted. A protein-protein interaction analysis revealed a dense network in the order of Fusobacterium, Streptococcus, and Prevotella. An investigation of the relationships between the intratumoral microbiome and classical clinical risk factors showed that high levels of Fusobacterium were associated with a good prognosis in the absence of alcohol consumption and smoking, while high levels of Streptococcus were associated with a poor prognosis in the absence of alcohol consumption. In conclusion, intratumoral Fusobacterium and Streptococcus may affect the prognosis of patients with HNSCC, and their effects on HNSCC are modulated by the impact of drinking and smoking.

Tonsillectomy and tonsil biopsy in the search for primary oropharyngeal tumor in patients with CUP

The purpose of the study. To study the role of tonsillectomy and palatine tonsil biopsy in the identification of primary oropharyngeal tumor in patients with CUP. Material and methods. The study included the diagnostic findings of 69 patients with squamous cell cancer (SCC) metastases to the neck lymph nodes from an unknown primary site. Inclusion criteria for the study: the presence of morphologically verified SCC metastases in the cervical lymph nodes based on the FNA (fine needle aspiration biopsy) cytology findings, the pathology findings (cervical lymph node biopsy, core biopsy), no evidence of cervical lymph node metastases from another primary site, and no primary tumor detected upon the initial clinical examination. Thirteen (19%) patients out of 69 with no evidence of a primary tumor after clinical examination and instrumental investigations underwent transoral microsurgical palatine tonsillectomy using a Carl Zeiss operating microscope with cervical lymph node dissection. Biopsy of the tonsil was performed in 7 (10%) out of 69 patients. Results. According to the results of the study, the primary tumor localized in the palatine tonsil was detected in 11 cases (78%) of microsurgical palatine tonsillectomy, and in 2 cases (28%) of the palatine tonsil biopsy. Moreover, according to the IHC results, the verified tonsil cancer was associated with HPV in 62% of cases. Conclusion. Tonsillectomy is a valuable diagnostic option in the search for a primary oropharyngeal tumor in patients with CUP. It allows for targeted treatment (surgical treatment using minimally invasive microsurgical techniques, conformal radiation therapy), reducing the likelihood of developing adverse reactions that alter the patient’s quality of life. Цель исследования. Изучить роль тонзиллэктомии и биопсии небной миндалины в идентификации первичной опухоли ротоглотки у пациентов с CUP-синдромом. Материал и методы. В основу исследования положены результаты диагностики 69 пациентов с метастазами плоскоклеточного рака (ПКР) в лимфоузлы шеи из неизвестного первичного очага. Критерии включения в исследование: наличие морфологически верифицированных метастазов ПКР в лимфатические узлы шеи, полученным по результатам цитологического исследования ТАБ (тонкоигольная аспирационная биопсия), гистологического исследования (биопсии лимфоузлов шеи, трепан-биопсии), отсутствие данных за метастатическое поражение лимфоузлов шеи другой локализации, отсутствие первичной опухоли после первичного клинического обследования. Тринадцати (19%) пациентам из 69 с отсутствием данных о наличии первичной опухоли после клинического обследования, инструментальной диагностики была выполнена трансоральная микрохирургическая небная тонзиллэктомия с использованием операционного микроскопа Carl Zeiss, шейная лимфодиссекция. У 7 (10%) пациентов из 69 была выполнена биопсия небной миндалины. Результаты. По результатам проведенного исследования, первичный опухолевый очаг с локализацией в небной миндалине при микрохирургической небной тонзиллэктомии удалось выявить в 11 (78%) случаях, при биопсии небной миндалины – в 2 (28%) случаях. При этом в 62% случаев, по результатам иммуногистохимического исследования, верифицированный рак небной миндалины был ассоциирован с вирусом папилломы человека. Заключение. Выполнение небной тонзиллэктомии является ценной диагностической опцией в поиске первичной опухоли ротоглотки у пациентов с CUP-синдромом. Позволяет провести целенаправленное лечение (хирургическое лечение с использованием малоинвазивных микрохирургических методик, лучевую терапию в конформном режиме), снижая вероятность развития токсических реакций, ухудшающих качество жизни пациента.

Prognostic Value of PlGF Upregulation in Prostate Cancer.

Prostate cancer (PCa) is the second most commonly diagnosed cancer in men worldwide, with metastasis, particularly to bone, being the primary cause of mortality. Currently, prognostic markers like PSA levels and Gleason classification are limited in predicting metastasis, emphasizing the need for novel clinical biomarkers. New molecules predicting tumor progression have been identified over time. Some, such as the immune checkpoint inhibitors (ICIs) PD-1/PD-L1, have become valid markers as theranostic tools essential for prognosis and drug target therapy. However, despite the success of ICIs as an anti-cancer therapy for solid tumors, their efficacy in treating bone metastases has mainly proven ineffective, suggesting intrinsic resistance to this therapy in the bone microenvironment. This study explores the potential of immunological intratumoral biomarkers, focusing on placental growth factor (PlGF), Vascular Endothelial Growth Factor Receptor 1 (VEGFR1), and Programmed Cell Death Protein 1 (PD-1), in predicting bone metastasis formation. we analyzed PCa samples from patients with and without metastasis by immunohistochemical analysis. Results revealed that PlGF expression is significantly higher in primary tumors of patients that developed metastasis within five years from the histological diagnosis. Additionally, PlGF expression correlates with increased VEGFR1 and PD-1 levels, as well as the presence of intratumoral M2 macrophages. These findings suggest that PlGF contributes to an immunosuppressive environment, thus favoring tumor progression and metastatic process. Results here highlight the potential of integrating these molecular markers with existing prognostic tools to enhance the accuracy of metastasis prediction in PCa. By identifying patients at risk for metastasis, clinicians can tailor treatment strategies more effectively, potentially improving survival outcomes and quality of life. This study underscores the importance of further research into the role of intratumoral biomarkers in PCa management.

Establishment and characterization of a novel human gallbladder cancer cell line, GBC-X1

In this study, we successfully established a novel gallbladder cancer cell line, designated as GBC-X1, derived from a primary tumor of a gallbladder cancer patient. By comprehensively analyzing the cell line’s phenotype, molecular characteristics, biomarkers, and histological characteristics, we confirmed that GBC-X1 serves as a valuable model for investigating the pathogenesis of gallbladder cancer and developing therapeutic agents. GBC-X1 has been continuously cultured for one year, with over 60 stable passages. Morphologically, GBC-X1 exhibits typical features of epithelial tumors. The population doubling time of GBC-X1 is 32 h. STR analysis validated a high consistency between GBC-X1 and the patient’s primary tumor. Karyotype analysis revealed an abnormal hypertetraploid karyotype for GBC-X1, characterized by representative karyotypes of 98, XXXX del (4) p (12) del (5) p (21) der (10). Under suspension culture conditions, GBC-X1 efficiently forms tumor balls, while subcutaneous inoculation of GBC-X1 cells into NXG mice leads to xenograft formation with a rate of 80%. Drug sensitivity testing demonstrated that GBC-X1 is resistant to oxaliplatin and sensitive to 5-FU, gemcitabine, and paclitaxel. Immunohistochemistry revealed positive expression of CK7, CK19, E-cadherin, MMP-2, CD44, SOX2, and TP53 in GBC-X1 cells, weak positive expression of Vimentin, and a Ki67 positive rate of 35%. Our research highlights GBC-X1 as a novel gallbladder cancer cell line and emphasizes its potential as an effective experimental model for investigating the pathogenesis of gallbladder cancer and drug development.

Putative Dual Roles of Bone Morphogenetic Protein 8B (BMP8B) in Disease Progression of Gastric Cancer.

Increased expression of bone morphogenetic protein 8B (BMP8B) in bone marrow and primary tumors of patients with gastric cancer (GC) is associated with disease progression and poor prognosis. However, a reduced expression has also been seen in GCs due to histone acetylation. This study aimed to evaluate BMP8B transcript levels in a large GC cohort and its impact on cellular functions. BMP8B transcripts were determined in 319 gastric tumors and compared with 182 adjacent normal tissues using real time PCR, with a further analysis conducted in the TCGA database. Kaplan-Meier plotter analysis was performed to evaluate the correlation between BMP8B and prognosis of the disease. BMP8B knockdown model was employed to determine the effect of BMP8B on the function of GC cells (HGC27). BMP8B mRNA levels were significantly up-regulated in the GC tissues compared with adjacent normal tissues in both TCGA database and our own database from Beijing Cancer Hospital, and high BMP8B expression was associated with poor prognosis. BMP8B is most likely to be involved in the differentiation of GC. Poorly differentiated GC samples presented a significantly reduced BMP8B expression in relation to well-differentiated and moderately differentiated GC. BMP8B knockdown inhibited proliferation of GC cells, while promoted invasion and migration of cancer cells. BMP8B was reduced in GCs, whereas higher BMP8B expression was associated with poor prognosis. BMP8B knockdown inhibited proliferation of GC cells, and promoted invasion and migration. Our results suggest that BMP8B plays dual roles in GC.

Seeing the primary tumor because of all the trees: Cancer type prediction on low-dimensional data.

The Cancer of Unknown Primary (CUP) syndrome is characterized by identifiable metastases while the primary tumor remains hidden. In recent years, various data-driven approaches have been suggested to predict the location of the primary tumor (LOP) in CUP patients promising improved diagnosis and outcome. These LOP prediction approaches use high-dimensional input data like images or genetic data. However, leveraging such data is challenging, resource-intensive and therefore a potential translational barrier. Instead of using high-dimensional data, we analyzed the LOP prediction performance of low-dimensional data from routine medical care. With our findings, we show that such low-dimensional routine clinical information suffices as input data for tree-based LOP prediction models. The best model reached a mean Accuracy of 94% and a mean Matthews correlation coefficient (MCC) score of 0.92 in 10-fold nested cross-validation (NCV) when distinguishing four types of cancer. When considering eight types of cancer, this model achieved a mean Accuracy of 85% and a mean MCC score of 0.81. This is comparable to the performance achieved by approaches using high-dimensional input data. Additionally, the distribution pattern of metastases appears to be important information in predicting the LOP.

Stereotactic body radiation therapy for the primary tumor and oligometastases versus the primary tumor alone in patients with metastatic pancreatic cancer

BackgroundLocal therapies may benefit patients with oligometastatic cancer. However, there were limited data about pancreatic cancer. Here, we compared the efficacy and safety of stereotactic body radiation therapy (SBRT) to the primary tumor and all oligometastases with SBRT to the primary tumor alone in patients with metastatic pancreatic cancer.MethodsA retrospective review of patients with synchronous oligometastatic pancreatic cancer (up to 5 lesions) receiving SBRT to all lesions (including all oligometastases and the primary tumor) were performed. Another comparable group of patients with similar baseline characteristics, including metastatic burden, SBRT doses, and chemotherapy regimens, receiving SBRT to the primary tumor alone were identified. The primary endpoint was overall survival (OS). The secondary endpoints were progression frees survival (PFS), polyprogression free survival (PPFS) and adverse events.ResultsThere were 59 and 158 patients receiving SBRT to all lesions and to the primary tumor alone. The median OS of patients with SBRT to all lesions and the primary tumor alone was 10.9 months (95% CI 10.2–11.6 months) and 9.3 months (95% CI 8.8–9.8 months) (P < 0.001). The median PFS of two groups was 6.5 months (95% CI 5.6–7.4 months) and 4.1 months (95% CI 3.8–4.4 months) (P < 0.001). The median PPFS of two groups was 9.8 months (95% CI 8.9–10.7 months) and 7.8 months (95% CI 7.2–8.4 months) (P < 0.001). Additionally, 14 (23.7%) and 32 (20.2%) patients in two groups had grade 3 or 4 treatment-related toxicity.ConclusionsSBRT to all oligometastases and the primary tumor in patients with pancreatic cancer may improve survival, which needs prospective verification.

Glioblastoma Neurovascular Progenitor Orchestrates Tumor Cell Type Diversity.

Glioblastoma (GBM) is the deadliest form of primary brain tumor with limited treatment options. Recent studies have profiled GBM tumor heterogeneity, revealing numerous axes of variation that explain the molecular and spatial features of the tumor. Here, we seek to bridge descriptive characterization of GBM cell type heterogeneity with the functional role of individual populations within the tumor. Our lens leverages a gene program-centric meta-atlas of published transcriptomic studies to identify commonalities between diverse tumors and cell types in order to decipher the mechanisms that drive them. This approach led to the discovery of a tumor-derived stem cell population with mixed vascular and neural stem cell features, termed a neurovascular progenitor (NVP). Following in situ validation and molecular characterization of NVP cells in GBM patient samples, we characterized their function in vivo. Genetic depletion of NVP cells resulted in altered tumor cell composition, fewer cycling cells, and extended survival, underscoring their critical functional role. Clonal analysis of primary patient tumors in a human organoid tumor transplantation system demonstrated that the NVP has dual potency, generating both neuronal and vascular tumor cells. Although NVP cells comprise a small fraction of the tumor, these clonal analyses demonstrated that they strongly contribute to the total number of cycling cells in the tumor and generate a defined subset of the whole tumor. This study represents a paradigm by which cell type-specific interrogation of tumor populations can be used to study functional heterogeneity and therapeutically targetable vulnerabilities of GBM.

Stereotactic ablative radiotherapy for locally advanced non-small cell lung cancer: A systematic review and meta-analysis

IntroductionTo evaluate the feasibility, efficacy and safety of stereotactic ablative radiotherapy (SABR) to the primary tumor and lymph nodes in patients with locally advanced non-small cell lung cancer (LA-NSCLC) who are ineligible for or refused concomitant chemoradiation. Materials and MethodsIn accordance with the PRISMA and MOOSE guidelines, a systematic review with meta-analysis was conducted. The study included reports that assessed the outcomes of SABR treatment in patients with LA-NSCLC. Studies evaluating SBRT as a boost following primary radiotherapy were excluded. The primary outcomes measured were local control (LC) and overall survival (OS). The secondary endpoint was the incidence of severe toxicity (grades 3–5). A meta-regression analysis was performed to explore the relationship between LC, OS, and severe toxicity. The Biologically Effective Dose (BED) was analyzed as a continuous variable. Statistical significance was defined as a p-value < 0.05. ResultsA total of seven studies (3 prospective and 4 retrospective studies) involving 268 patients (SBRT to primary and lymph nodes) were included in the analysis. The pooled 1-year LC rate was 80 % (95 % CI: 63–94 %), and the factors significantly associated with LC were BEDGy10 (p = 0.005) and neoadjuvant chemotherapy (p = 0.005). The 1-year and 2-year OS rates were 74 % (95 % CI: 58–90 %) and 55 % (95 % CI: 34–76 %), respectively. Meta-regression analysis indicated a linear relationship between OS and LC, with a 0.7 % increase in OS for each 1 % improvement in LC (p = 0.005). The pooled rate of grade 3 acute toxicity was 5 % (95 % CI: 1–10 %), and the rate of grade 5 toxicity was 1.7 % (95 % CI: 0–3 %). ConclusionPromising results (LC and OS) with limited toxicity (feasibility) using SABR in LA-NSCLC warrant further research, emphasizing the need for larger, well-designed trials for further validation of the approach.

Suspected olfactory meningioma and synchronous pituitary microadenoma in a canine patient treated with radiation therapy

The authors report on the rare occurrence of dual synchronous primary brain tumors in a canine patient, successful treatment with radiation therapy, and medical therapy with patient stabilization for almost three years. A 12.5-year-old spayed mixed-breed female Labrador was referred to Purdue Veterinary Hospital to treat hyperadrenocorticism of suspected pituitary origin. During MRI imaging, the presence of two possible brain neoplasms was detected: a possible right olfactory bulb meningioma and a microadenoma of the pituitary gland. The patient was treated with a fractionated course of radiation in both tumors, 15 treatments of 3Gy, which limited the tumor growth. Mitotane therapy corrected the hormonal dysregulation. The dog had a normal life for nearly three years and recently passed. Cancer cells were not found at necropsy. No MEN1 germline mutations were identified in constitutional DNA (from blood) via high-coverage whole genome sequencing.

The impact of positive surgical margin parameters and pathological stage on biochemical recurrence after radical prostatectomy: A systematic review and meta-analysis.

To systematically review and perform a meta-analysis on the predictive value of the primary Gleason grade (PGG) at the positive surgical margin (PSM), length of PSM, number of PSMs, and pathological stage of the primary tumor on biochemical recurrence (BCR) in patients with prostate cancer (PCa) after radical prostatectomy (RP). A systematic literature search was performed using electronic databases, including PubMed, EMBASE, Cochrane Library, and Web of Science, from January 1, 2005, to October 1, 2023. The protocol was pre-registered in PROSPERO. Subgroup analyses were performed according to the different treatments and study outcomes. Pooled hazard ratios with 95% confidence intervals were extracted from multivariate analyses, and a fixed or random effect model was used to pool the estimates. Subgroup analyses were performed to explore the reasons for the heterogeneity. Thirty-one studies that included 50,028 patients with PCa were eligible for this meta-analysis. The results showed that, compared to PGG3, PGG4/5 was associated with a significantly increased risk of BCR. Compared with PSM ≤3 mm, PSM ≥3 mm was associated with a significantly increased risk of BCR. Compared with unifocal PSM, multifocal PSM (mF-PSM) was associated with a significantly increased risk of BCR. In addition, pT >2 was associated with a significantly increased risk of BCR compared to pT2. Notably, the findings were found to be reliable based on the sensitivity and subgroup analyses. PGG at the PSM, length of PSM, number of PSMs, and pathological stage of the primary tumor in patients with PCa were found to be associated with a significantly increased risk of BCR. Thus, patients with these factors should be treated differently in terms of receiving adjunct treatment and more frequent monitoring. Large-scale, well-designed prospective studies with longer follow-up periods are needed to validate the efficacy of these risk factors and their effects on patient responses to adjuvant and salvage therapies and other oncological outcomes.

Subpopulation composition of PD-L1-positive lymphocytes in the primary tumour in luminal breast cancer patients

The relationship between the tumour and the microenvironment is of great interest because it may determine the efficacy of new agents aimed at targeting the anti-tumour immune response, such as immune checkpoint inhibitors (ICI s), which have been used to treat breast cancer. PD -L1 status in immune cells should be examined when prescribing ICI s for breast cancer. This highlights the importance of studying the characteristics of the tumour microenvironment, the main approach being to uncover its heterogeneity. The aim of this study was to investigate the subpopulation composition of PD -L1-positive lymphocytes in the tumour microenvironment, separately in each luminal subtype of BC, and to compare it according to the PD -L1 status of the tumour. Material and Methods. Fifty-two primary tumour samples were obtained from patients with invasive luminal A, luminal B HER2- and luminal B HER2+ subtypes of breast cancer (T1–2N0–1M0). No drug therapy was administered prior to surgery to any patient in this study. Cytotoxic lymphocytes (CTL s), B lymphocytes, T helper lymphocytes, T regulatory lymphocytes and their PD -L1 expression in tumour tissue samples were assessed by flow cytometry, and tumour PD -L1 status was determined by Ventana SP 142 immunohistochemistry. Results. All of the key lymphocyte populations we identified were present in almost all patients. The number of PD -L1-positive Th2 lymphocytes was significantly higher in the luminal A and luminal B HER2- BC samples compared to the luminal B HER2+ cases (р=0.0240 and p=0.0092, respectively). When the proportion of PD -L1-positive cells was calculated, the proportion of PD -L1-positive Th2 lymphocytes and T regulatory lymphocytes was significantly lower in luminal B HER2-compared to luminal A BC. Cytotoxic lymphocytes, Th2 lymphocytes and T-regulatory lymphocytes represented the predominant PD -L1-positive immune cells in the breast cancer microenvironment and were present in higher numbers in PD -L1-positive luminal B HER2-. Conclusions. Different lymphocyte populations, including those expressing PD -L1, can be found in the breast cancer microenvironment and there are differences in their numbers between different luminal breast cancers. This may explain the discordant prognostic and predictive value of the microenvironment in luminal breast cancer when considered as a single molecular subtype.

Select gene mutations associated with survival outcomes in ER-positive ERBB2-negative early-stage invasive breast cancer: A single-institutional tissue bank study.

The prognostic capability of targeted sequencing of primary tumors in patients with estrogen receptor-positive, human epidermal growth factor receptor-2-negative early-stage invasive breast cancer (EBC) in a real-world setting is uncertain. Therefore, we aimed to determine the correlation between a 22-gene mutational profile and long-term survival outcomes in patients with ER+/ERBB2- EBC. A total of 73 women diagnosed with ER+/ERBB2- EBC between January 10, 2004, and June 2, 2008, were followed up until December 31, 2022. Univariate and multivariate Cox models were constructed to plot the relapse-free survival (RFS) and overall survival (OS). The log-rank test derived p-value was obtained. For external validation, we performed a survival analysis of 1163 comparable patients retrieved from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset. At follow-up, 16 (21.9%) patients had relapsed, while 21 (nearly 29%) harbored mutant genes. Thirty-three missense mutations were detected in 14 genes. The median ages were 51 and 46 years in patients with and without mutations, respectively. Patients with any mutation had a 1.85-fold higher risk of relapse (hazard ratio [HR]: 1.85, 95% confidence interval [CI]: 0.60-5.69) compared to those without any mutation. Patients who harbored any of the six genes (MAP2K4, FGFR3, APC, KIT, RB1, and PTEN) had a nearly 6-fold increase in the risk of relapse (HR: 5.82, 95% CI: 1.31-18.56; p = 0.0069). Multivariate Cox models revealed that the adjusted HR for RFS and OS were 6.67 (95% CI: 1.32-27.57) and 8.31 (p = 0.0443), respectively. METABRIC analysis also demonstrated a trend to significantly worse RFS (p = 0.0576) in the subcohort grouped by having a mutation in any of the six genes. Our single-institution tissue bank study of Taiwanese women with ER+/ERBB2- EBC suggests that a novel combination of six gene mutations might have prognostic capability for survival outcomes.