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S-methyl-5'-thioadenosine phosphorylase (MTAP) deficiency is an emerging biomarker in non-small cell lung cancer (NSCLC) and beyond. The MTAP gene is located in the chromosomal region 9p21.3, which shows one of the most common homozygous deletions across all human cancers (9p21 loss). Loss of 9p21 is found in the majority of pleural mesotheliomas, where it serves as an established diagnostic marker. Until recently, fluorescence in situ hybridization (FISH) was the gold standard for the detection of 9p21 losses, but loss of MTAP expression by immunohistochemistry (IHC) gains increasing importance as an easy to apply and cost-effective diagnostic surrogate marker. Besides, MTAP loss, which has been reported in 13% of NSCLC, is becoming an emerging predictive biomarker in two different scenarios in NSCLC and other cancer types: 1) MTAP loss seems to negatively predict the response to immune checkpoint inhibitor (ICI) treatment via silencing of the tumor microenvironment, and 2) MTAP loss serves as a predictive biomarker for novel targeted treatment strategies. MTAP deficiency leads to an impaired function of the protein arginine methyltransferase 5 (PRMT5) due to its partial inhibition by MTAP's accumulating substrate methylthioadenosine (MTA). This process leaves MTAP deficient tumor cells heavily dependent on the remaining function of PRMT5, making it a perfect target for synthetic lethality. Indeed, MTA-cooperative PRMT5-inhibitors are now tested in several clinical trials with promising early results in solid malignancies. With its emergence as a predictive biomarker, the implementation of MTAP IHC into diagnostic routine for NSCLC and other tumors is likely to take place soon. In this review article, we summarize the current literature on the role of MTAP in thoracic tumors and evaluate different testing methods, including IHC, FISH and next generation sequencing., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lukas Bubendorf reports a relationship with Astra Zeneca that includes: consulting or advisory and speaking and lecture fees. Lukas Bubendorf reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory. Lukas Bubendorf reports a relationship with Bayer AG that includes: consulting or advisory and speaking and lecture fees. Lukas Bubendorf reports a relationship with Eli Lilly and Company that includes: consulting or advisory. Lukas Bubendorf reports a relationship with Amgen Inc that includes: consulting or advisory. Lukas Bubendorf reports a relationship with Takeda Oncology that includes: consulting or advisory and speaking and lecture fees. Lukas Bubendorf reports a relationship with Thermo Fisher Scientific Inc that includes: funding grants and speaking and lecture fees. Lukas Bubendorf reports a relationship with Novartis that includes: funding grants. Lukas Bubendorf reports a relationship with Systems Oncology that includes: board membership and consulting or advisory. David Koenig reports a relationship with Astra Zeneca that includes:. David Koenig reports a relationship with MSD that includes: consulting or advisory. David Koenig reports a relationship with Novartis Pharmaceuticals Corporation that includes: consulting or advisory. David Koenig reports a relationship with Mirati Therapeutics Inc that includes: consulting or advisory. David Koenig reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory. David Koenig reports a relationship with PharmaMar SA that includes: consulting or advisory. David Koenig reports a relationship with Amgen Inc that includes: consulting or advisory. David Koenig reports a relationship with Sanofi that includes: consulting or advisory. Lukas Bubendorf reports a relationship with Janssen Pharmaceuticals Inc that includes: consulting or advisory and speaking and lecture fees. Spasenija Savic Prince reports a relationship with Merck & Co Inc that includes: consulting or advisory. Spasenija Savic Prince reports a relationship with Astra Zeneca that includes: consulting or advisory. Spasenija Savic Prince reports a relationship with Boehringer Ingelheim GmbH that includes: consulting or advisory. Spasenija Savic Prince reports a relationship with F Hoffmann-La Roche Ltd that includes: consulting or advisory. Spasenija Savic Prince reports a relationship with Pfizer that includes: consulting or advisory. Spasenija Savic Prince reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory. Spasenija Savic Prince reports a relationship with Thermo Fisher Scientific Inc that includes: consulting or advisory. Lukas Bubendorf reports a relationship with F Hoffmann-La Roche Ltd that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

As an internationally accepted diagnostic system, the Paris classification has achieved a global breakthrough in the standardization of diagnoses in urine cytology. Based on experience over the past few years since its first publication, the new edition of the Paris classification refines the diagnostic criteria and discusses diagnostic pitfalls. While the detection of high-grade urothelial carcinoma remains the main focus, other aspects of urine cytology, including cytology of the upper urinary tract and the associated challenges, have also been addressed. Low-grade urothelial neoplasia is no longer listed as a separate category but is now included in the category "negative for high-grade urothelial carcinoma" (NGHUC). Essentially, the Paris classification provides an important basis for estimating the risk of malignancy and further clinical management., (© 2024. The Author(s).)

Homozygous deletion of the chromosomal region 9p21.3 is common in urothelial carcinoma (UC) and leads to loss of several genes, including CDKN2A and MTAP, resulting in loss of MTAP protein expression. Here, we aimed to explore the diagnostic potential of MTAP immunohistochemistry (IHC) as a surrogate marker for homozygous 9p21.3 deletion (9p21 homozygous deletion [HD]) in UC. MTAP status was determined by IHC on 27 UC tissue specimens with known 9p21.3 status as defined by fluorescence in situ hybridization in matched cytological specimens, by IHC and fluorescence in situ hybridization on a tissue microarray (TMA) containing 359 UC at different stages, and by IHC on 729 consecutive UC from routine practice. Moreover, we analyzed a longitudinal series of matched specimens from 38 patients with MTAP-negative recurrent UC. MTAP loss by IHC was found in all 17 patients with 9p21 HD and in 2/8 cases without 9p21 HD. In the TMA, MTAP loss was more common in metastases (53%) than in muscle-invasive (33%) and non-muscle-invasive UC (29%) (P = .03). In the consecutive series, 164/729 (22%) cases showed loss of MTAP expression. In 41 of these 164 cases (25%), loss of MTAP expression was heterogenous. We also discovered loss of MTAP expression in flat urothelium adjacent to MTAP-negative low-grade UC, suggesting true flat low-grade neoplasia that could not be diagnosed by morphology alone. Longitudinal analysis of recurrences showed persistent negative MTAP status over time in 37/38 (97%) patients. MTAP IHC can serve as a surrogate marker for 9p21 HD in UC and as a diagnostic tool to differentiate reactive urothelium from urothelial neoplasia. It also provides a unique opportunity to study clinicopathological associations and the heterogeneity of 9p21 HD across the whole spectrum of UC manifestations., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Prostate cancer is morphologically and molecularly heterogeneous. Genomic heterogeneity might be mirrored by variability in DNA ploidy. Aneuploidy is a hallmark of genomic instability and associated with tumor aggressiveness. Little attention has been paid to the biological significance of the diploid tumor cell population that often coexists with aneuploid populations. Here, we investigated the role of DNA ploidy in tumor heterogeneity and clonal evolution., Methods: Three radical prostatectomy specimens with intratumoral heterogeneity based on nuclear features on H&E were selected. DNA content of each subpopulation was determined by DNA image cytometry and silver in situ hybridization (SISH). Genomic evolution was inferred from array comparative genomic hybridization (aCGH). Additionally, immunohistochemistry was used to examine the stemness-associated marker ALDH1A1., Results: Nuclear morphology reliably predicted DNA ploidy status in all three cases. In one case, aCGH analysis revealed several shared deletions and one amplification in both the diploid and the aneuploid population, suggesting that these populations could be related. In the other two cases, a statement about relatedness was not possible. Furthermore, ALDH1A1 was expressed in 2/3 cases and exclusively observed in their diploid populations., Conclusions: In this proof-of-concept study, we demonstrate the feasibility to predict the DNA ploidy status of distinct populations within one tumor by H&E morphology. Future studies are needed to further investigate the clonal relationship between the diploid and the aneuploid subpopulation and test the hypothesis that the aneuploid population is derived from the diploid one. Finally, our analyses pointed to an enrichment of the stemness-associated marker ALDH1A1 in diploid populations, which warrants further investigation in future studies., (© 2023 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Most men with prostate cancer (PCa), despite potentially curable localized disease at initial diagnosis, progress to metastatic disease. Despite numerous treatment options, choosing the optimal treatment for individual patients remains challenging. Biomarkers guiding treatment sequences in an advanced setting are lacking. To estimate the diagnostic potential of liquid biopsies in guiding personalized treatment of PCa, we evaluated the utility of a custom-targeted next-generation sequencing (NGS) panel based on the AmpliSeq HD Technology. Ultra-deep sequencing on plasma circulating free DNA (cfDNA) samples of 40 metastatic castration-resistant PCa (mCRPC) and 28 metastatic hormone-naive PCa (mCSPC) was performed. CfDNA somatic mutations were detected in 48/68 (71%) patients. Of those 68 patients, 42 had matched tumor and cfDNA samples. In 21/42 (50%) patients, mutations from the primary tumor tissue were detected in the plasma cfDNA. In 7/42 (17%) patients, mutations found in the primary tumor were not detected in the cfDNA. Mutations from primary tumors were detected in all tested mCRPC patients (17/17), but only in 4/11 with mCSPC. AR amplifications were detected in 12/39 (31%) mCRPC patients. These results indicate that our targeted NGS approach has high sensitivity and specificity for detecting clinically relevant mutations in PCa.

Sarcomatoid Urothelial Bladder Cancer (SARC) is a rare and aggressive histological subtype of bladder cancer for which therapeutic options are limited and experimental models are lacking. Here, we report the establishment of a long-term 3D organoid-like model derived from a SARC patient (SarBC-01). SarBC-01 emulates aggressive morphological, phenotypical, and transcriptional features of SARC and harbors somatic mutations in genes frequently altered in sarcomatoid tumors such as TP53 (p53) and RB1 (pRB). High-throughput drug screening, using a library comprising 1567 compounds in SarBC-01 and conventional urothelial carcinoma (UroCa) organoids, identified drug candidates active against SARC cells exclusively, or UroCa cells exclusively, or both. Among those, standard-of-care chemotherapeutic drugs inhibited both SARC and UroCa cells, while a subset of targeted drugs was specifically effective in SARC cells, including agents targeting the Glucocorticoid Receptor (GR) pathway. In two independent patient cohorts and in organoid models, GR and its encoding gene NR3C1 were found to be significantly more expressed in SARC as compared to UroCa, suggesting that high GR expression is a hallmark of SARC tumors. Further, glucocorticoid treatment impaired the mesenchymal morphology, abrogated the invasive ability of SARC cells, and led to transcriptomic changes associated with reversion of epithelial-to-mesenchymal transition, at single-cell level. Altogether, our study highlights the power of organoids for precision oncology and for providing key insights into factors driving rare tumor entities., (© 2023. The Author(s).)

The management of prostate cancer is undergoing rapid changes in all disease settings. Novel imaging tools for diagnosis have been introduced, and the treatment of high-risk localized, locally advanced and metastatic disease has changed considerably in recent years. From clinical and health-economic perspectives, a rational and optimal use of the available options is of the utmost importance. While international guidelines list relevant pivotal trials and give recommendations for a variety of clinical scenarios, there is much room for interpretation, and several important questions remain highly debated. The goal of developing a national consensus on the use of these novel diagnostic and therapeutic strategies in order to improve disease management and eventually patient outcomes has prompted a Swiss consensus meeting. Experts from several specialties, including urology, medical oncology, radiation oncology, pathology and nuclear medicine, discussed and voted on questions of the current most important areas of uncertainty, including the staging and treatment of high-risk localized disease, treatment of metastatic hormone-sensitive prostate cancer (mHSPC) and use of new options to treat metastatic castration-resistant prostate cancer (mCRPC).

Background: Cylindroma of the breast is a rare benign neoplasm. Since its first description in 2001, 20 cases have been reported in the literature., Methods and Results: We report another case of this rare tumor in a 60-year-old woman with demonstration of the underlying molecular alteration. Histologically, the tumor showed the typical "jigsaw" pattern of a dual population of cells with a triple-negative phenotype. The pathognomonic mutation of the CYLD gene mutation was detected by whole exome sequencing. Cylindromas show morphological overlap with the solid-basaloid variant of adenoid cystic carcinoma, which renders this differential diagnosis difficult. However, distinction of these two lesions is of outmost importance, since cylindromas, in contrast to solid-basaloid variant of adenoid cystic carcinoma, behave in an entirely benign fashion., Conclusions: Careful evaluation of morphological features such as mitotic figures and cellular atypia is crucial in the diagnostic work-up of triple-negative breast lesions. It is important to keep cylindroma in mind as a pitfall and possible differential diagnosis for the solid-basaloid variant of adenoid cystic carcinoma. Molecular detection of CYLD gene mutation is helpful in cases with ambiguous histology. With this case report, we aim to contribute to a better understanding of mammary cylindroma and facilitate the diagnosis of this rare entity., (© 2023. The Author(s).)

Purpose: All patients living with cancer, including those with metastatic cancer, are encouraged to be physically active. This paper examines the secondary endpoints of an aerobic exercise intervention for men with metastatic prostate cancer., Methods: ExPeCT (Exercise, Prostate Cancer and Circulating Tumour Cells), was a multi-centre randomised control trial with a 6-month aerobic exercise intervention arm or a standard care control arm. Exercise adherence data was collected via heart rate monitors. Quality of life (FACT-P) and physical activity (self-administered questionnaire) assessments were completed at baseline, at 3 months and at 6 months., Results: A total of 61 patients were included (69.4 ± 7.3 yr, body mass index 29.2 ± 5.8 kg/m 2 ). The median time since diagnosis was 34 months (IQR 7-54). A total of 35 (55%) of participants had > 1 region affected by metastatic disease. No adverse events were reported by participants. There was no effect of exercise on quality of life (Cohen's d =  - 0.082). Overall adherence to the supervised sessions was 83% (329 out of 396 possible sessions attended by participants). Overall adherence to the non-supervised home exercise sessions was 72% (months 1-3) and 67% (months 3-6). Modelling results for overall physical activity scores showed no significant main effect for the group (p-value = 0.25) or for time (p-value = 0.24)., Conclusion: In a group of patients with a high burden of metastatic prostate cancer, a 6-month aerobic exercise intervention did not lead to change in quality of life. Further exercise studies examining the role of exercise for people living with metastatic prostate cancer are needed., Trial Registration: The trial was registered at clinicaltrials.gov (NCT02453139) on May 25th 2015., (© 2023. The Author(s).)

Background: Assessment of programmed death protein-ligand 1 (PD-L1) in triple-negative breast cancer (TNBC) has entered daily practice to identify patients eligible for treatment with immune checkpoint inhibitors. However, different antibodies and different cut-offs for PD-L1 positivity are used, and the interchangeability of these methods is not clear. The aim of our study was to analyze whether different PD-L1 antibodies can be used interchangeably to identify TNBC patients as PD-L1 positive., Methods: A tissue microarray encompassing 147 TNBC cases was immunohistochemically analyzed using 3 different antibodies against PD-L1: SP142, SP263, and E1L3N. PD-L1 positivity was determined as ≥1% of positive tumor-associated immune cells. The staining patterns of the 3 antibodies were compared and correlated with clinicopathological data., Results: A total of 84 cases were evaluable for PD-L1 analysis with all 3 antibodies. PD-L1 was positive in 50/84 patients (59.5%) with SP263, in 44/84 (52.4%) with E1L3N, and in 29/84 (34.5%) with SP142. There was no statistical difference between the performance of SP263 and E1L3N, but both antibodies stained significantly more cases than the SP142 antibody., Conclusions: Our results show that the 3 PD-L1 antibodies identify different TNBC patient subgroups as PD-L1 positive and, therefore cannot be used interchangeably. Additional studies are needed to further investigate the use and impact of different PD-L1 antibody clones for predictive selection of TNBC patients for treatment with immune checkpoint inhibitors., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The molecular repertoire promoting cancer cell plasticity is not fully elucidated. Here, we propose that glycosphingolipids (GSLs), specifically the globo and ganglio series, correlate and promote the transition between epithelial and mesenchymal cells. The epithelial character of ovarian cancer remains stable throughout disease progression, and spatial glycosphingolipidomics reveals elevated globosides in the tumor compartment compared with the ganglioside-rich stroma. CRISPR-Cas9 knockin mediated truncation of endogenous E-cadherin induces epithelial-to-mesenchymal transition (EMT) and decreases globosides. The transcriptomics analysis identifies the ganglioside-synthesizing enzyme ST8SIA1 to be consistently elevated in mesenchymal-like samples, predicting poor outcome. Subsequent deletion of ST8SIA1 induces epithelial cell features through mTOR S2448 phosphorylation, whereas loss of globosides in ΔA4GALT cells, resulting in EMT, is accompanied by increased ERK Y202/T204 and AKT S124 . The GSL composition dynamics corroborate cancer cell plasticity, and further evidence suggests that mesenchymal cells are maintained through ganglioside-dependent, calcium-mediated mechanisms., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)