Dilara Akbulut

Somatostatin receptor 2 is expressed in nasopharyngeal carcinoma (NPC). We report genomic and transcriptomic analysis results of 163 NPC cases, demonstrating that somatostatin receptor 2 ( SSTR2 ) gene expression in EBV‐positive and in EBV‐negative NPC correlated with genomic alterations and an inflamed microenvironment. Median SSTR2 expression was 6.52 transcripts per million (TPM), ranging from 0.59 TPM (Quartile 1 [Q1], 18.2% EBV‐positive) to 35.79 TPM (Q4, 82.9% EBV‐positive). PIK3CA (20.51%) and CYLD (10.53%)/ NFKBIA (12.82%) mutations were enriched in SSTR2 ‐Q1 versus ‐Q4. Tumor mutation burden was negatively correlated ( R = −0.27, p < 0.001) with SSTR2 , while PD‐L1 tumor proportion score (2% vs. 92.5% [ SSTR2 :Q1 vs. Q4], p < 0.001) and T‐cell inflamed score correlated with SSTR2 expression ( R = 0.53, p < 0.001). B‐cells, M1 macrophages, CD8+ T‐cells, Treg cells, and dendritic cells were enriched in SSTR2 ‐Q4, while neutrophils were prominent in SSTR2 ‐Q1. These results demonstrate a significant positive correlation between SSTR2 expression and an inflamed tumor microenvironment in NPC. This suggests that SSTR2 expression in NPC may be a clinically useful biomarker, correlating with the tumor microenvironment (including, potentially, sensitivity to immunotherapy) and its genetic profile.

Gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) are a rare subset of cancers with increasing incidence. Due to their slow growth and lack of targetable mutations, the identification of effective treatments remains limited. One reason behind this stagnation is the lack of applicable, accurate study models. One solution is patient tumor organoids (PTOs) that maintain tumor characteristics and can scale for high throughput assays. In this study, PTOs were generated from 35 tumors of pancreatic, small intestinal, and gastric origin, obtained from 17 patients. Important subtypes including hormone functional and MEN1 / VHL mutant GEP-NETs are represented, with each demonstrating growth in culture while maintaining GEP-NET immunohistochemistry and genomic characteristics. Half of G2/G3 tumors (10 of 20) could be cultured past passage 6, whereas G1 tumors ( n = 15) were capable of growth until passage 4. Therapeutic targeting of the PTOs displayed both tissue-origin and grade-based response to standard of care and investigational therapies while maintaining patient tumor sensitivity and resistance. Last, a successful PTO xenograft model was developed from one PTO line. This study describes GEP-NET organoid development that demonstrates feasibility for expansion, enabling their use for translational investigations.

Small cell carcinoma is the most frequently encountered neuroendocrine tumour (NET) of the urinary bladder, and it may present as either pure or in combination with urothelial carcinoma or other histological subtypes. Large cell neuroendocrine carcinoma is increasingly recognized in this location, but it is not yet fully characterized. Well‐differentiated NET and paraganglioma of the bladder are rare neuroendocrine neoplasms. Advances in the molecular characterization of these tumours have enhanced our understanding of their biology and can provide better classification and more accurate risk stratification for clinical decision‐making.

Primary central nervous system large B-cell lymphoma (PCNS-LBCL) is a rare, aggressive lymphoma that affects immune-privileged sites. Immune checkpoint molecules have been implicated in its aggressive biology, and promising results have emerged from immune checkpoint inhibitor therapy in relapsed/refractory cases. This study evaluates the tumor microenvironment (TME), immune checkpoint molecule expression, and the relationship with 9p24.1 gene region alterations in a large cohort of PCNS-LBCL, with detailed quantitative analyses. Tissue microarrays were constructed with 57 PCNS-LBCL cases and 45 systemic non-germinal center diffuse large B-cell lymphoma (DLBCL) controls. Immunostaining for CD3, CD8, CD68, CD163, PD-1, PD-L1, PD-L2, EBER in situ hybridization (ISH), and FISH for PD-L1/PD-L2 copy number alterations and translocations were performed. Digital image analysis was used for quantitative evaluations, which were compared with clinical and pathologic parameters. PCNS-LBCL showed significantly lower T-cell and histiocyte presence in the TME compared with nodal DLBCL (PP<0.001). PD-1, PD-L1, and PD-L2 expressions in the TME of PCNS-LBCL were 89%, 96%, and 90%, respectively, and were positively correlated with TME density. Tumor cell expressions of PD-L1 and PD-L2 were 31% and 34%, respectively. FISH alterations in the 9p24.1 region were infrequent and did not consistently correlate with protein expression in either PCNS-LBCL or DLBCL. Higher CD8+ T-cell and CD68+ histiocyte counts were associated with better survival in PCNS-LBCL. Lower TME density and high expression of PD-1/PD-L1/PD-L2 in PCNS-LBCL reflect the unique CNS microanatomy and may contribute to poorer prognosis. These findings support the potential benefit of immune checkpoint inhibitors in treating PCNS-LBCL, aligning with ongoing clinical trials and current literature.

Olfactory neuroblastoma (ONB), sinonasal undifferentiated carcinoma (SNUC), and sinonasal neuroendocrine carcinoma (SNEC) are rare malignancies arising from the sinonasal tract with limited therapeutic options. The expression of the somatostatin receptor 2 gene (SSTR2), which is expressed in other neuroendocrine neoplasms and is therapeutically actionable, has been reported in these tumors. Here, we analyzed SSTR2 gene expression and its associations with genomic features, established biomarkers predicting of immune response, and the tumor immune microenvironment in a cohort of ONB, SNUC, and SNEC tumor samples (26, 13, and 8 samples, respectively) from a real-world database. SSTR2 gene expression was high in neural-type ONB and low in basal-type ONB and in most of the SNUC and SNEC cases; there was no difference in expression between primary and metastatic tumors. The T cell-inflamed (TCI) score analysis classified 38.5% of SNUC cases as T cell-inflamed compared to only 3.9% of ONB and 0% of SNEC cases; 26.9% of ONB cases were classified as intermediate TCI; and SNEC had the lowest relative immune cell infiltration by deconvolution. In high SSTR2-expressing ONB, there was a higher proportion of infiltrating of Natural Killer cells and dendritic cells by deconvolution. Additionally, high SSTR2-expressing ONB was enriched for proliferation pathways, including E2F and Myc targets and G2M checkpoints. In conclusion, our findings delineate significant differences between these three types of sinonasal malignancies that were examined. In ONB, relative to SNUC and SNEC, the SSTR2 expression profile, combined with its immune profiles, indicates potential novel therapeutic strategies and combinations for this unmet clinical need. Conversely, the inflammatory microenvironment of SNUC may be targetable using immuno-oncologic therapies.

Prostate cancer has substantial heterogeneity in clinical outcomes and therapeutic responses, posing challenges in predicting disease progression and tailoring treatment strategies. Recent studies have highlighted the potential prognostic value of evaluating the tumor microenvironment, including the presence of a histologically overt stromal response (HOST-response) characterized by peri-glandular stromal changes and architectural distortions. This retrospective study examined patient records from The Cancer Genome Atlas database to identify genomic alterations associated with the HOST-response in prostate cancer. Among 348 patients who underwent radical prostatectomy, 160 (45.98%) were identified as having a HOST-response. A gene expression analysis revealed 1263 genes with significantly higher expression in patients with a HOST-response. A protein–protein interaction network analysis identified seven hub genes (KIF2C, CENPA, CDC20, UBE2C, ESPL1, KIF23, and PLK1) highly interconnected in the network. A functional enrichment analysis revealed alterations in the cell division, cytoskeletal organization, cytokinesis, and interleukin-16 signaling pathways in patients with a HOST-response, suggesting dysregulated proliferation and inflammation. The distinct molecular signature associated with the HOST-response provides insights into the tumor–stroma interactions driving adverse outcomes and potential targets for tailored therapeutic interventions in this subset of patients with prostate cancer.

Purpose: Given the variable clinical course of prostate cancer and the limitations of current prognostic factors, this study was conducted to investigate the impact of a histologically overt stromal response (HOST-response) to prostate cancer on clinical outcomes after radical prostatectomy. Methods: This retrospective analysis utilized The Cancer Genome Atlas (TCGA) to evaluate data from individuals with a confirmed diagnosis of prostate cancer who underwent radical prostatectomy and had available pathology slides. These slides were assessed for the presence of a HOST-response, similar to desmoplasia. The primary endpoint was progression-free survival (PFS). A multivariable competing risk regression analysis was used to assess whether a significant association existed between HOST-response and PFS, adjusting for known prostate cancer prognostic factors. Results: Among the 348 patients analyzed, 166 (47.70%) demonstrated a HOST-response. After a median follow-up of 37.87 months (IQR: 21.20, 65.50), the presence of a HOST-response was significantly associated with a shorter PFS (SDHR, 2.10; 95% CI, 1.26 to 3.50; p = 0.004), after adjusting for covariates. Conclusions: HOST-response in prostate cancer patients treated with radical prostatectomy is significantly associated with reduced PFS, suggesting a potential benefit from adjuvant therapy and highlighting the need for further investigation in a prospective randomized clinical trial.

Purpose: Given the diverse clinical progression of prostate cancer (PC) and the evolving significance of histopathological factors in its management, this study aimed to explore the impact of cribriform pattern 4 (CP4) on clinical outcomes in PC patients and examine its molecular characteristics. Methods: This retrospective study analyzed data from The Cancer Genome Atlas (TCGA) database and included PC patients who underwent radical prostatectomy (RP) and had pathology slides available for the assessment of CP4. A multivariable competing risk regression analysis was used to assess the association between CP4 and progression-free survival (PFS) while adjusting for established PC prognostic factors. The frequency of genomic alterations was compared between patients with and without CP4 using the Fisher’s exact test. Results: Among the 394 patients analyzed, 129 (32.74%) had CP4. After a median follow-up of 40.50 months (IQR: 23.90, 65.60), the presence of CP4 was significantly associated with lower PFS (AHR, 1.84; 95% CI, 1.08 to 3.114; p = 0.023) after adjusting for covariates. Seven hub genes—KRT13, KRT5, KRT15, COL17A1, KRT14, KRT16, and TP63—had significantly lower mRNA expression levels in patients with CP4 compared to those without. Conclusions: PC patients with CP4 have distinct genomic alterations and are at a high risk of disease progression following RP. Therefore, these patients may benefit from additional post-RP treatments and should be the subject of a prospective randomized clinical trial.

Kordomalar, notokordun embriyolojik artıklarından kaynaklanan nadir primer kemik tümörleridir. Servikal bölge yerleşimli kordomalar oldukça nadir görülmektedir. Tüm kordomaların %5 kadarını oluşturan servikal kordomalar, komşu oldukları parafarengeal bölge, orofarenks gibi anatomik boşluklara uzanım gösterip; boyunda şişlik, orofarenkste kitle, yutma güçlüğü, nefes darlığı benzeri klinik bulgular verebilirler. Bu olgu sunumunda yutma güçlüğü şikayeti ile başvuran ve orofarenkste kitle olarak bulgu veren servikal kordoma olgusunun klinik özellikleri sunulmuş, tanıda yaşanan güçlükler ve cerrahi bulgular tartışılmıştır.