Brain metastases from renal cell carcinoma (RCC) remain a major cause of morbidity and mortality, yet the genomic features associated with metastatic dissemination remain poorly understood. Whole-exome sequencing was performed on 72 RCC brain metastasis samples with matched normal. To identify candidate genomic alterations associated with brain metastasis, the genomic alterations detected in the brain metastases were compared against alterations in extracranial metastases from the MSK-ECM cohort (n=137) and primary RCC tumors from TCGA (n=432) by case-control analyses. Candidate alterations were also identified through matched-pair analyses comparing brain metastases with matched primary tumors or extracranial metastases from the same patient (n=25). A random survival forest model incorporating the candidate CNA events was developed to predict overall survival. The candidate CNAs were further evaluated using functional experimental data from MetMap and DepMap. Survival analyses were conducted to assess the prognostic relevance of these alterations. We identified recurrent CNAs enriched in RCC brain metastases, including 4q loss, 7p gain, 7q gain, 8p loss, 8q gain, 9p21.3 deletion, 12q15 amplification, and 14q loss. These alterations were associated with significantly poorer patient survival among RCC patients. A random survival forest model based on these CNA events stratified TCGA-KIRC patients into prognostically distinct risk groups (C-index = 0.64). Among the recurrent CNAs, 8p loss, 8q gain, 9p21.3 deletion were associated with increased incidence of brain metastases across multiple primary cancer types in xenograft mouse models. These alterations were also strongly associated with metastatic progression and poor prognosis across RCC, lung adenocarcinoma, breast cancer, and melanoma. These findings indicate a shared genomic basis for brain tropism and highlight the potential utility of copy-number alterations as biomarkers for risk stratification and clinical decision-making.

AIM:To present a single-center experience, and to highlight the urgent need for multi-institutional collaboration in Türkiye and surrounding regions lacking access to methylation platforms, with the aim of enhancing diagnostic precision and neuropathological practice. MATERIAL AND METHODS:All pediatric patients who underwent methylation?based tumor classification (MBTC) between November 2023 and July 2025 were retrospectively identified. Clinical, histological, and molecular data were extracted and correlated with methylation results. Concordance between histopathology and MBTC was categorized as concordant, minor discordance, major discordance, novel classification, or un-classifiable. RESULTS:A total of 48 tumors were profiled (26 females [54%]; 22 males [46%]; median age, 6.5 years; range, 0?17). The most frequent localization was supratentorial (n=18, 36%). Of the entire cohort, concordance was 58%. Excluding unclassifiable cases, concordance among evaluable tumors was 67%. Discordance occurred in 11 cases (23%), including 6 (13%) with major discrepancies. Concordance was significantly associated with tumor localization (p=0.028) but not WHO grade (p=0.17) and classifier confidence (p=0.73). CONCLUSION:MBTC is a valuable complementary tool in the diagnostic workup of pediatric central nervous system (CNS) tumors, particularly in morphologically ambiguous and ultra-rare cases. It should be integrated with conventional histopathology rather than viewed as a replacement, as it may prevent prognostic misclassification and inappropriate treatment in selected patients.

The aim of this study was to evaluate histopathologically the conjunctival pigmentations occurring in post-enucleation anophthalmic sockets and to identify the common causes. Retrospective cohort study. This was a retrospective chart review of patients who presented with conjunctival pigmentation in the anophthalmic socket at a single tertiary care center and who underwent incisional conjunctival biopsy between 2018 and 2022. Demographic and clinicopathological data, and treatment outcomes were retrieved. A total of 14 consecutive patients aged between 17 and 70 years were enrolled. Indications for primary enucleations were: retinoblastoma in 5 (35.7

IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder that can affect multiple organs, yet neurological involvement has been considered rare and remains under-characterized. We retrospectively analyzed 77 adult patients with IgG4-RD registered in our database between 2014 and 2023. Clinical, laboratory, imaging, histopathological, and therapeutic data were reviewed, with particular focus on neurological manifestations. Neurological involvement was identified in 17 patients (22

Background:Desmoplastic infantile ganglioglioma/astrocytoma (DIG/DIA) is a rare, low-grade tumor of infants. They are usually composed of a mixed astrocytic and neuronal component with desmoplastic stroma and embryonal-looking areas. Despite some recent reports, clinical, morphological and molecular features of DIG/DIAs are still not well characterized. Here, we present a series of 8 DIG/DIA cases. Methods:Hacettepe University and Koc University Hospital, Departments of Pathology, databases were screened for DIG/DIA. Eight patients were identified. All the slides were reevaluated, and patients' clinical data were obtained. All cases were tested for BRAF V600 mutation and 3 BRAF V600 wild-type cases were sequenced. Results:Median age at the diagnosis was 5.5 months (4-30 months). The female to male ratio was 6:2. Two cases recurred. Four cases showed BRAF p. V600 mutation. Of those BRAF p. V600 wild-type cases, one harbored TMEM106B::BRAF fusion, described for the first time in a DIG/DIA case. Conclusions:DIG/DIA is a low-grade tumor seen in early childhood and characterized by an indolent clinical course. The most common molecular signature of these tumors is BRAF alterations, including rearrangements. The primary differential diagnosis is infant-type hemispheric glioma and given the similarities, pathologists must remain careful to ensure accurate diagnosis.

AIM:To evaluate the oncological outcomes and the prognostic factors for children with ependymoma who receive radiotherapy (RT) ± chemotherapy after surgery. MATERIAL AND METHODS:The medical records of 71 children with ependymoma who received RT between 2001 and 2022 were retrospectively evaluated. Survival outcomes and prognostic factors were analyzed using log-rank and cox-regression tests. SPSS v24.0 was utilized for statistical analyses. RESULTS:Gross total resection (GTR) was achieved in 37 (52%) patients. Craniospinal fluid (CSF) seeding was observed in 8 (11%) patients at the time of diagnosis. The median RT dose was 54 Gy (42-60 Gy). The median time from surgery to the first RT was 2.4 months (1-109 months). The median follow-up time was 65.9 months (2.5-242.8 months), and 5-y overall survival, progression-free survival (PFS), and local recurrence-free survival (LRFS) were 74%, 39%, and 46%, respectively. Recurrence was observed in 41 (58%) patients. Among patients who initiated treatment with chemotherapy, 5-y PFS and LRFS were higher in patients who received RT at the time of diagnosis than those who received RT at the progression (23% vs. 0%, p < 0.001 and 39% vs 0%, p < 0.001). In multivariate analysis, increased time from surgery to radiotherapy was found to be a poor prognostic factor for PFS. CONCLUSION:Young age, less than GTR, large residual tumor volume, initiation of treatment with chemotherapy after surgery, and increased time from surgery to radiotherapy may deteriorate survival. RT should not be delayed until progression, even in young patients receiving chemotherapy.

AIM: To investigate the efficacy of immunohistochemical methods to determine molecular subgroups and prognostic predictions of medulloblastomas (MBs). MATERIAL and METHODS: B-catenin, GAB1, YAP1, filamin A and p53 were immunohistochemically stained, and MYC and MYCN fluorescent in situ hybridization (FISH) procedures were applied to 218 cases in our series. RESULTS: Based on the histomorphological characteristics of the cases, 67.9% were deemed classic MB; 15.6% as desmoplastic/ nodular medulloblastoma (DNMB); 12.8% as large cell/anaplastic (LC/A) MB; 3.7% as medulloblastoma with extensive nodularity (MBEN). Molecular characteristics revealed that 50.5% had non-WNT/non-SHH; 33.9% had SHH-activated and TP53-wildtype: 8.7% had WNT-activated; 6.9% had SHH-activated and TP53-mutant. According to the survival curves, LC/A MBs or non-WNT/ non-SHH tumors showed the worst prognosis, whereas DNMBs and WNT-activated tumors showed the best prognosis. Classic MBs or SHH-activated tumors showed a moderate course. MYCN amplification was found to act as an independent poor prognostic factor in the study. CONCLUSION: The distribution of histological subtypes and molecular subgroups, amplification rates, and prognostic data obtained through immunohistochemical methods in our study were consistent with those reported in the literature. It was therefore hypothesized that the determination of molecular subgroups by immunohistochemical methods can be useful in daily diagnostic practice, especially in centers with limited access to molecular techniques.

This study aimed to investigate the immunogenicity of the hepatitis B virus (HBV) vaccine by applying a normal and high-dose hepatitis B virus vaccination program in the mice modeling of non-alcoholic fatty liver disease (NAFLD). NAFLD was induced in mouse livers via diet. At the 10-week mark, both groups were divided into 3 subgroups. While the standard dose vaccination program was applied on days 0, 7, and 21, two high-dose programs were applied: one was applied on days 0 and 7, and the other was applied on days 0, 7, and 21. All mice were euthanized. Blood samples from anti-HB titers; T follicular helper, T follicular regulatory, CD27+, and CD38+ cells; and the liver, spleen, and thymus were taken for histopathologic evaluation. NAFLD subgroups receiving high doses showed higher hepatocyte ballooning scores than normal-dose subgroup. There were differences in CD27+ and CD27+CD38+ cells in animals fed on different diets, without any differences or interactions in terms of vaccine protocols. In the NAFLD group, a negative correlation was observed between anti-HB titers and T helper and CD27+ cells, while a positive correlation was observed with CD38+ cells. NAFLD induced changes in immune parameters in mice, but there was no difference in vaccine efficacy among the applied vaccine protocols. Based on this study’s results, high-dose vaccination protocols are not recommended in cases of NAFLD, as they do not enhance efficacy and may lead to increased liver damage.

Background: FOLFIRINOX and gemcitabine-nabpaclitaxel (GnP) are standard first-line treatment regimens for advanced pancreatic ductal adenocarcinoma (PDAC). However, currently, there is a lack of predictive biomarkers to aid in the treatment selection. We aimed to explore the prognostic and predictive value of class III beta-Tubulin (TUBB3) and human equilibrative nucleoside transporter 1 (hENT1) expression, which have previously been shown to be associated with taxane and gemcitabine resistance in advanced PDAC. Methods: We conducted a retrospective analysis of 106 patients with advanced PDAC treated with GnP and/or FOLFIRINOX at our institution. TUBB3 and hENT1 immunohistochemical staining was performed on tumor specimens and subsequently evaluated based on the intensity and percentage of expression. Results: In patients who received the GnP regimen, a high combined score (TUBB3(low)/hENT1(high)) was associated with a higher DCR and longer PFS compared to those with intermediate (TUBB3(high)/hENT1(high) or TUBB3(low)/hENT1(low)) and low score (TUBB3(high)/hENT1(low)). In the multivariate analysis, a high combined score was an independent predictor of higher DCR (OR:11.96; 95 % CI:2.61-54.82; p = 0.001) and longer PFS (HR:0.33; 95%CI:0.18-0.60; p < 0.001). However, there was no difference in response rates or PFS based on TUBB3 and hENT1 expression among patients receiving the FOLFIRINOX regimen. Conclusion: Our findings indicate that tumor TUBB3 and hENT1 expression may predict the efficacy of the GnP regimen, and low TUBB3 and high hENT1 expression (TUBB3(low)/hENT1(high)) are associated with a higher DCR and longer PFS in patients treated with GnP. Evaluating TUBB3 and hENT1 jointly can identify the patients most (as well as least) likely to benefit from GnP chemotherapy.

PM&REarly View CASE IMAGE Unveiling a common peroneal nerve schwannoma: An ultrasonographic approach to a posterolateral knee mass Berkay Yalçınkaya MD, Corresponding Author Berkay Yalçınkaya MD [email protected] orcid.org/0000-0001-6069-4575 Department of Physical Medicine and Rehabilitation, Hacettepe University Medical School, Ankara, Turkey Correspondence Berkay Yalçınkaya, Hacettepe Üniversitesi Tıp Fakültesi Hastaneleri, Zemin Kat, FTR AD, Sıhhıye Ankara, 06230, Turkey. Email: [email protected]Search for more papers by this authorAhmet Furkan Çolak MD, Ahmet Furkan Çolak MD orcid.org/0000-0003-4034-1558 Department of Physical Medicine and Rehabilitation, Hacettepe University Medical School, Ankara, TurkeySearch for more papers by this authorTolga Hancı MD, Tolga Hancı MD Department of Neurosurgery, Hacettepe University Medical School, Ankara, TurkeySearch for more papers by this authorİlkay Işıkay MD, İlkay Işıkay MD Department of Neurosurgery, Hacettepe University Medical School, Ankara, TurkeySearch for more papers by this authorDeniz Pınar Baran MD, Deniz Pınar Baran MD Department of Pathology, Hacettepe University Medical School, Ankara, TurkeySearch for more papers by this authorBerrin Babaoğlu MD, Berrin Babaoğlu MD Department of Pathology, Hacettepe University Medical School, Ankara, TurkeySearch for more papers by this authorAlp Çetin MD, Alp Çetin MD Department of Physical Medicine and Rehabilitation, Hacettepe University Medical School, Ankara, TurkeySearch for more papers by this author Berkay Yalçınkaya MD, Corresponding Author Berkay Yalçınkaya MD [email protected] orcid.org/0000-0001-6069-4575 Department of Physical Medicine and Rehabilitation, Hacettepe University Medical School, Ankara, Turkey Correspondence Berkay Yalçınkaya, Hacettepe Üniversitesi Tıp Fakültesi Hastaneleri, Zemin Kat, FTR AD, Sıhhıye Ankara, 06230, Turkey. Email: [email protected]Search for more papers by this authorAhmet Furkan Çolak MD, Ahmet Furkan Çolak MD orcid.org/0000-0003-4034-1558 Department of Physical Medicine and Rehabilitation, Hacettepe University Medical School, Ankara, TurkeySearch for more papers by this authorTolga Hancı MD, Tolga Hancı MD Department of Neurosurgery, Hacettepe University Medical School, Ankara, TurkeySearch for more papers by this authorİlkay Işıkay MD, İlkay Işıkay MD Department of Neurosurgery, Hacettepe University Medical School, Ankara, TurkeySearch for more papers by this authorDeniz Pınar Baran MD, Deniz Pınar Baran MD Department of Pathology, Hacettepe University Medical School, Ankara, TurkeySearch for more papers by this authorBerrin Babaoğlu MD, Berrin Babaoğlu MD Department of Pathology, Hacettepe University Medical School, Ankara, TurkeySearch for more papers by this authorAlp Çetin MD, Alp Çetin MD Department of Physical Medicine and Rehabilitation, Hacettepe University Medical School, Ankara, TurkeySearch for more papers by this author First published: 06 July 2024 https://doi.org/10.1002/pmrj.13238Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. REFERENCES 1Erdogan B, Yuksel MO, Taner E, Cakir A. Large schwannoma of the deep peroneal nerve: a case report. Turk Neurosurg. 2021; 31(6): 992-995. PubMedWeb of Science®Google Scholar 2Abebe MW, Weldemicheal HA. Superficial peroneal nerve schwannoma. Plast Reconstr Surg Glob Open. 2023; 11(4):e4950. 10.1097/GOX.0000000000004950 PubMedWeb of Science®Google Scholar 3Özçakar L, Ricci V, Chang KV, Mezian K, Kara M. Musculoskeletal ultrasonography: ninety-nine reasons for physiatrists. Med Ultrason. 2022; 24(2): 137-139. 10.11152/mu-3759 PubMedWeb of Science®Google Scholar 4Lee SJ, Yoon ST. Ultrasonographic and clinical characteristics of schwannoma of the hand. Clin Orthop Surg. 2017; 9(1): 91-95. 10.4055/cios.2017.9.1.91 PubMedGoogle Scholar Early ViewOnline Version of Record before inclusion in an issue ReferencesRelatedInformation

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare, highly aggressive central nervous system tumor of childhood with variable morphologic features, which is characterized by alterations in SWI/SNF complex, such as SMARCB1/INI1 or SMARCA4/BRG1 loss. Poorly differentiated chordoma is the differential diagnosis, particularly in the infratentorial region of older children and the use of brachyury in such conditions is under debate. We investigated the brachyury expression in 44 samples of AT/RT from 40 patients. All AT/RTs except 2 infratentorial tumors were negative for brachyury (2 clones: A-4 and EPR18113). Both brachyury-positive tumors (one diffuse and one patchy expression) involved the clivus of children younger than 2 years old. The DNA methylation profile of one of these tumors showed epigenetic similarity to reference examples of chordoma in 2 public unsupervised and one supervised analysis systems. The second tumor exhibited a classical epigenetic microarray pattern found in samples with degraded DNA. We revised 2 initial AT/RT diagnoses as poorly differentiated chordoma based on the morphology, brachyury expression, topographical features, and methylation profile. Differentiating poorly differentiated chordoma from AT/RT could be challenging; brachyury expression can be useful in diagnosing poorly differentiated chordoma over AT/RT in suitable clinical and radiological settings.

According to the 2021 World Health Organization classification of brain tumors, astrocytomas containing a CDKN2A/B homozygous deletion (HD) are designated as grade 4 even when no microvascular proliferation and/or necrosis is present. In this study, we aimed to investigate the relationship between CDKN2A HD and loss of methylthioadenosine phosphorylase (MTAP) expression in adult-type IDH-mutant gliomas and to assess the sensitivity and specificity of MTAP immunohistochemistry (IHC) along with interobserver agreement as a surrogate biomarker for CDKN2A HD. Eighty-eight astrocytomas and 71 oligodendrogliomas cases that were diagnosed between 2014 and 2021 at Hacettepe University were selected and tissue microarrays were conducted to perform CDKN2A fluorescence in situ hybridization and MTAP IHC. Twenty-five (15.7%) cases harbored CDKN2A HD. MTAP loss was detected in 28 (15.7%) cases by the first observer and 27 (17%) cases by the second observer. The sensitivity and specificity of MTAP were calculated as 88% and 95.52%-96.27% for 2 observers. A very good/perfect agreement was noted between the observers (Cohen kappa coefficient = 0.938). Intratumoral heterogeneity was observed in 4 cases. MTAP IHC was found to be a reliable surrogate biomarker as a possible alternative to CDKN2A HD identification with a high sensitivity and specificity along with high interobserver agreement.

Anastomosing hemangioma of the liver (AHL) is a very rare condition and limited to a few cases. It is often confused with well-differentiated angiosarcomas and causes overtreatment. In this report, we present a 53-year-old female patient diagnosed with AHL. Since the tumor is rarely seen, it is important to define well the imaging and pathological features for preventing unnecessary surgeries and related morbidities.

Introduction: The discovery of immune checkpoint inhibitors has revolutionized metastatic renal cell carcinoma (RCC) treatment. However, in patients with RCC brain metastases, response rates are low and survival outcomes poor. To understand the tumor microenvironmental differences between primary kidney tumors, extracranial metastases, and brain metastases, we developed a detailed single-cell atlas of RCC brain metastases along with their matched extracranial and primary tumors. Methods: We performed single-nucleus RNA-seq on 27 samples (nearly 200,000 cells) from RCC patients; samples included 14 brain metastases, 8 matched primary kidney tumors, and 5 matched extracranial metastases. We performed multiplex IHC to validate selected transcriptomic findings. We used Nanostring CosMx 960-plex RNA spatial molecular imaging technique on selected samples to validate cellular interactions in a spatial context. Results: We established a multi-tissue single-cell atlas of RCC brain metastases by identifying 9 major and 37 minor malignant, immune, and stromal cell clusters. Brain metastases had higher neuronal and glial cells interacting with immune and tumor cells. Brain metastasis tumor cells were also transcriptomically reprogrammed to adapt to the brain microenvironment through enrichment of MYC targets, MTORC1 signaling, epithelial-mesenchymal transition, fatty-acid metabolism, oxidative phosphorylation, and reactive oxygen species pathways. Moreover, cell-to-cell communication and downstream target gene expression analyses showed that brain metastasis tumor cells expressed ligands and receptors that induce tumor cell proliferation in both autocrine and paracrine fashions. Among T-cell populations, we found fewer proliferating cytotoxic T lymphocytes in the brain than in other sites. Moreover, T cells in brain metastases expressed higher levels of several targetable inhibitory checkpoints than did extracranial metastases. In addition, we found that naïve/memory T cells in brain metastases were a favorable prognostic marker for overall survival after craniotomy. Our characterization of myeloid cell populations across the 3 disease sites found fewer dendritic cells and monocytes in the brain compared to other sites. Macrophages in brain metastases more highly expressed an M2 immunosuppressive gene signature than did those in primary RCC tumors. Conclusion: Our findings from the largest single-cell atlas of RCC brain metastases with matched primary and extracranial metastases suggest several unique targetable, immunosuppressive biological mechanisms in the brain microenvironment. These results provide a foundation for a deeper understanding of RCC brain metastasis biology and can serve as a resource for the scientific community to further explore therapeutically targetable tumor and immune-related mechanisms. Citation Format: Elshad Hasanov, Truong Nguyen Anh Lam, Jerome Lin, Patrick K. Reville, Merve Hasanov, Anna K. Casasent, David Shih, Sahin Hanalioglu, Mehmet Asim Bilen, Omar Alhalabi, Berrin Babaoglu, Baylar Baylarov, Adeboye O. Osunkoya, Lisa M. Norberg, Joy Gumin, Tuan M. Tran, Jianzhuo Li, Anh G. Hoang, Haidee D. Chancoco, Brittany C. Parker Kerrigan, Erika J. Thompson, Betty YS Kim, Dima Suki, Melike Mut, Figen Soylemezoglu, Giannicola Genovese, Kadir C. Akdemir, Hussain A. Tawbi, Nizar M. Tannir, Florencia McAllister, Michael A. Davies, Padmanee Sharma, Jason Huse, Frederick Lang, Nicholas Navin, Eric Jonasch. Single-cell and spatial transcriptomic mapping of human renal cell carcinoma brain metastases uncovers actionable immune-resistance targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5788.

OBJECTIVE:Our understanding of IgG4-RD and pachymeningitis has grown substantially, but the optimal approach for diagnosis, management, and long-term outcomes is still an area of uncertainty.METHODS:HUVAC is a database for IgG4-RD patients, this database was retrospectively evaluated for pachymeningeal disease. Demographic, clinical, serological, imaging, histopathological data, and treatment details were re-interpreted in patients with pachymeningitis.RESULTS:Among 97 patients with IgG4-RD, 6 (6.2%) had pachymeningitis. None of these patients had extracranial features, and also, in most of the patients, serum IgG4 levels were normal. Tentorium cerebelli and transverse sinus dura were the most commonly involved in the posterior fossa. During 18 months of median follow-up on steroid+-rituximab, none of them relapsed as pachymeningitis.CONCLUSION:Our patients were mainly older males with sole neurological involvement. Non-specific headache was the most common manifestation, and serum IgG4 levels were not useful for diagnosis. Typical radiology and tentorial thickening should suggest IgG4-RD and prompt an early biopsy. Moreover, accompanying hypophysitis could also be a clue. With steroids+ rituximab treatment, no relapse related to meningeal involvement was seen in long-term follow-up.