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Distinct molecular subtypes of muscle-invasive bladder cancer (MIBC) may show different platinum sensitivities. Currently available data were mostly generated at transcriptome level and have limited comparability to each other. We aimed to determine the platinum sensitivity of molecular subtypes by using the protein expression-based Lund Taxonomy. In addition, we assessed the tumor heterogeneity within the primary tumor and between the primary and lymph node (LN) metastatic sites. Thirteen immunohistochemical markers were stained in a tissue microarray with an overall number of 1,508 cores. Statistical evaluation was performed in 199 patients divided into three chemo-naïve MIBC cohorts: (1) pT3/4 and/or LN+ patients who received radical cystectomy without platinum treatment, (2) patients who received adjuvant chemotherapy (AC), and (3) patients who underwent palliative platinum treatment for metastatic disease or postoperative progression. Overall survival (OS) was used as the primary endpoint. Patients with the genomically unstable (GU) subtype had significantly better OS in the AC group compared to the radical cystectomy group (HR: 0.395, 95% CI: 0.205-0.795, p = 0.005). In contrast, no such association was observed for the basal/squamous (Ba/Sq) subtype. Intratumor heterogeneity was present in 19% of cases, with the lowest level in the Ba/Sq and GU tumors (14% each) and the highest level of 43% in small-cell/neuroendocrine-like tumors. There was greater subtype heterogeneity between primary tumors and LN metastases. In conclusion, immunohistochemistry-based Lund Taxonomy subtypes remain stable within the same primary tumor, with the GU subtype deriving the greatest OS benefit from AC. However, high tumor heterogeneity between the primary tumor and metastatic sites can impact the effectiveness of therapies., (© 2025 The Author(s). The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.)

Objective:  Neonatology quality improvement (QI) projects can improve the safety and value of health care, but the scholarly impact of published QI projects is unclear. We measured scholarly citation and media attention garnered by published neonatology QI projects and analyzed project or publication characteristics associated with increased impact metrics., Study Design:  We identified publications between 2016 and 2019 using mapping review methodology. We correlated project characteristics with measures of scholarly citation in Scopus and Google Scholar, and media attention as measured by Altmetrics. We collected Citation and Altmetric data in 2023., Results:  The search identified 148 eligible articles, with a median citation count of 7 based on Scopus (or 12, based on Google Scholar) and a median Altmetric score of 2. Notably, 66% of articles published in a journal with an Impact Factor (IF) had more citations per year than would be expected from the IF value. Higher scientific citations were associated with articles reporting process and cost outcomes; implementing interventions that addressed family education or organizational change; and using regression analysis. Higher media attention was associated with multicenter projects, longer intervention periods, and projects scoring higher on the Quality Improvement Minimum Quality Criteria Set (QI-MQCS) rubric., Conclusion:  Published neonatology QI projects are well cited in subsequent scientific publications, with the choice of project outcome, interventions, and analytic strategy influencing citation metrics. Adherence to QI-MQCS guidelines was favorably associated with media attention, but not with scholarly citations., Key Points: · Neonatology QI publications are frequently cited.. · Projects with cost data receive more citations.. · Citation and media mention predictors differ.., Competing Interests: D.T. discloses funding from the Kate B. Reynolds Charitable Foundation and Lilly Grant Office for unrelated research and QI projects. A.H. discloses funding from the North Carolina Digital Equity and Inclusion Collaborative for an unrelated QI project. All other authors have no conflict of interest to disclose., (Thieme. All rights reserved.)

Objective: To investigate alterations of homologous recombination repair (HRR) and especially BReast CAncer 1/2 (BRCA1/2) gene on overall survival (OS). Moreover, to explore the effect of inhibition of poly(ADP-ribose)-polymerase (PARPi) as systemic therapy for metastatic castration-resistant prostate cancer (mCRPC)., Patients and Methods: Of all HRR-screened patients with metastatic prostate cancer, baseline characteristics were sampled. Kaplan-Meier estimates and multivariable Cox regression models predicted the effect of HRR/BRCA1/2 alterations on OS., Results: Of 196 eligible patients, 61 (31%) harboured any HRR and 40 (20%) BRCA1/2 alterations. Of HRR alterations, 40 (66%) vs six (10%) vs five (8.2%) vs four (6.6%) vs two (3.3%) vs four (6.6%) were BRCA1/2 vs Ataxia-telangiectasia mutated kinase (ATM) vs checkpoint kinase 2 (CHEK2) vs cyclin-dependent kinase 12 (CDK12) vs Fanconi anaemia complementation Group A (FANCA) vs positive for other mutations. Of these, 30% received a PARPi. OS differed significantly between HRR-positive vs -negative patients. Specifically in hormone-sensitive prostate cancer, the median OS was 63 (HRR positive) vs 57 (BRCA1/2 positive) vs 113 months (HRR negative) (P ≤ 0.01). In mCRPC, OS was 42 (HRR positive) vs 41 (BRCA1/2 positive) vs 70 months (HRR negative) (P ≤ 0.01). HRR and BRCA1/2 alterations were associated with worse OS after multivariable adjustment. Finally, patients with mCRPC with BRCA1/2 mutation treated without PARPi harboured worse OS than patients with BRCA1/2 mutation and PARPi therapy (median OS: 33 vs 48 months, P < 0.03)., Conclusion: Incidence of HRR alteration in a clinical real-world setting is high when using blood- and tissue-based tests. Patients with HRR/BRCA alterations have worse outcomes resulting in significant OS differences between HRR/BRCA-positive patients with mCRPC with and without PARPi usage vs HRR/BRCA-negative patients., (© 2024 The Author(s). BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Aims: Anti-claudin-18.2 (CLDN18.2) therapy was recently approved for the treatment of gastric or gastro-oesophageal junction adenocarcinoma. The aim of the present study was to investigate the expression of CLDN18.2 in cholangiocarcinoma (CCA) to determine whether there is a subgroup of patients who might also benefit from anti-CLDN18.2 therapy., Methods and Results: A tissue microarray (TMA) cohort of all CCA patients who underwent surgical resection with curative intent between August 2005 and December 2021 at University Hospital Frankfurt were immunohistochemically evaluated using the VENTANA ® CLDN18 (43-14A) antibody. Tumour positivity for CLDN18.2 was determined as follows: ≥ 75% of tumour cells with moderate-to-strong CLDN18 membranous staining. In total, 160 patients with surgically resected CCA were suitable for immunohistochemistry (IHC) analysis. Of the patients, 13.1% (n = 21) showed moderate to strong membranous staining of VENTANA ® CLDN18 antibody, while 86.9% (n = 139) were negative. Subtype analysis revealed strong differences in CLDN18 expression. Positive staining of CLDN18 could be observed in 26.5% (n = nine of 34) and 7.4% (n = seven of 95) of the perihilar (pCCA) and intrahepatic (iCCA) subgroup, respectively. CCA patients with CLDN18 expression had a more frequently intraoperative finding of distant metastasis (P = 0.002), lymph node metastasis (P = 0.008) and positive perineural invasion (Pn1) status (P = 0.022)., Conclusions: The present study suggests that a subset of patients with CCA exhibited a marked expression of CLDN18.2. These findings underline the need to perform a clinical study evaluating the efficacy of anti-CLDN18.2 therapy in patients suffering from CCA., (© 2024 The Author(s). Histopathology published by John Wiley & Sons Ltd.)

Aims: Adjuvant chemotherapy after radical cystectomy can reduce the risk of recurrence and death in advanced muscle-invasive urothelial bladder cancer (MIBC). Molecular subtypes have been shown to be associated with survival. However, their predictive value to guide treatment decisions is controversial and data to use subtypes as guidance for adjuvant chemotherapy is sparse. We aimed to assess survival rates based on MIBC consensus molecular subtypes with and without adjuvant chemotherapy., Methods: Gene expression profiles of 143 patients with MIBC undergoing radical cystectomy were determined from formalin-fixed, paraffin-embedded specimen to assign consensus molecular subtypes. Expression of programmed cell death ligand-1 (PD-L1) and immune cell infiltration were determined using multiplex immunofluorescence. Matched-pair analysis was performed to evaluate the effect of adjuvant chemotherapy on overall survival (OS) for molecular subtypes applying Kaplan-Meier and Cox regression survival analyses., Results: Samples were luminal papillary: 9.1% (n=13), luminal non-specified: 6.3% (n=9), luminal unstable: 4.9% (n=7), stroma-rich: 27.9% (n=40), basal/squamous (Ba/Sq): 48.9% (n=70) and neuroendocrine-like (NE-like): 2.8% (n=4). Ba/Sq tumours had the highest concentration of PD-L1+ tumour and immune cells. Patients with luminal subtypes had better OS than those with NE-like (HR 0.2, 95% CI 0.1 to 0.7, p<0.05) and Ba/Sq (HR 0.5, 95% CI 0.2 to 0.9, p<0.05). No survival benefit with adjuvant chemotherapy was observed for luminal tumours, whereas Ba/Sq had significantly improved survival rates with adjuvant chemotherapy. Retrospective design and sample size are the main limitations., Conclusion: Consensus molecular subtypes can be used to stratify patients with MIBC. Luminal tumours have the best prognosis and less benefit when receiving adjuvant chemotherapy compared with Ba/Sq tumours., Competing Interests: Competing interests: PW has received consulting fees and honoraria for lectures by Bayer, Janssen-Cilag, Novartis, Roche, MSD, Astellas Pharma, Bristol-Myers Squibb, Thermo Fisher Scientific, Molecular Health, Guardant Health, Sophia Genetics, Qiagen, Eli Lilly, Myriad, Hedera Dx and AstraZeneca. Research Support was provided by AstraZeneca and Roche. HTG Transcriptome Panel was funded by HTG Molecular Diagnostics. HR was on an advisory board of Bristol-Myers Squibb, received honoraria from Roche, Bristol-Myers Squibb, Janssen-Cilag, Novartis, AstraZeneca, MCI, CHOP GmbH and Diaceutics, received travel support from Philips, Roche, and Bristol-Myers Squibb, and received grants from Bristol-Myers Squibb., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Cancer immunotherapies with antibodies blocking immune checkpoint molecules are clinically active across multiple cancer entities and have markedly improved cancer treatment 1 . Yet, response rates are still limited, and tumour progression commonly occurs 2 . Soluble and cell-bound factors in the tumour microenvironment negatively affect cancer immunity. Recently, growth differentiation factor 15 (GDF-15), a cytokine that is abundantly produced by many cancer types, was shown to interfere with antitumour immune response. In preclinical cancer models, GDF-15 blockade synergistically enhanced the efficacy of anti-PD-1-mediated checkpoint inhibition 3 . In a first-in-human phase 1-2a study (GDFATHER-1/2a trial, NCT04725474 ), patients with advanced cancers refractory to anti-PD-1 or anti-PD-L1 therapy (termed generally as anti-PD-1/PD-L1 refractoriness) were treated with the neutralizing anti-GDF-15 antibody visugromab (CTL-002) in combination with the anti-PD-1 antibody nivolumab. Here we show that durable and deep responses were achieved in some patients with non-squamous non-small cell lung cancer and urothelial cancer, two cancer entities identified as frequently immunosuppressed by GDF-15 in an in silico screening of approximately 10,000 tumour samples in The Cancer Genome Atlas database. Increased levels of tumour infiltration, proliferation, interferon-γ-related signalling and granzyme B expression by cytotoxic T cells were observed in response to treatment. Neutralizing GDF-15 holds promise in overcoming resistance to immune checkpoint inhibition in cancer., Competing Interests: Competing interests: M.H. and J.W. are co-founders and stock owners of CatalYm. A.d.S., M. Rüdiger, P.L’H., M.H., J.A., A.D., A.A., A.G., F.H., M.A., M.L., D.R., C.S.-W., F.S.L., P.F., K.K., F.H., B.R. and E.L. are current or former employees of and/or hold stock options in Catalym. R.D., M.H., J.W., K.K., E.L., F.H., M. Rüdiger and C.S.-W. are inventors on patents related to visugromab and anti-GDF-15 treatment (WO2014049087, WO2015144855, WO2017055613, WO2022101263, WO2024052532, WO2024126808 and unpublished). I. Melero, H.H., R.B., R.D., J.W., F.J.K., A.M.M.E., W.H.F., T.F.G., P.L., M.M., S.S., A.T. and J.R. have received research funding or consulting or advisory fees from CatalYm. Several authors and investigators declare potentially competing interests (grants or contracts and/or royalties or licences, stock or stock options, consulting fees, honoria, travel or meeting support, or advisory or data safety monitoring board participation) apart from their relationship with CatalYm: I. Melero (Agenus, Alligator, Allmiral, AstraZeneca, Biontech, BMS, Boehringer Ingelheim, Bright Peak, Crescendo Biologics, Curon, Dynamicure, F-Star, Genmab, Highlight Therapeutics, HotSpot, Merck Serono, MSD, Merus, Mestag, Numab, PharmaMar, Pieris, Pierre Fabre, Pioneering Medicines, Roche, Sanofi and Servier); G.d.V. (Astellas, AstraZeneca, Bayer, BMS, Ipsen, Janssen MSD, Merck Serono, Pfizer and Roche); E.G. (Anaveon, BeiGene, Boehringer Ingelheim, Ellipses Pharma, F-Star Therapeutics, Hengrui, Incyte, Janssen Global Services, MabDiscovery, Medscape, MSD, Novartis, Seattle Genetics, Sanofi, Roche, SeaGen, Taiho and Thermo Fisher); J.M.-L. (Astellas, BMS, Highlight Therapeutics, Merck Serono, MSD, Novartis, Ipsen, Roche, Sanofi and Pierre Fabre); M.J. (Adoram, AstraZeneca, Debiopharm, Novartis, Roche, Sanofi and Takeda); M.-E.G. (BMS, Janssen, Novartis and Roche); M.S. (Amgen, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Janssen, MSD, Novartis, Roche, Sanofi and Tacalyx); D.K. (AstraZeneca, Amgen, BMS, Merck Serono, MSD, Mirati, PharmaMar, Sanofi and Swiss Oncology in Motion); R.D. (Alligator, Amgen, BMS, MSD, Novartis, Pierre Fabre, Roche, Sun Pharma, Takeda, Sanofi, Second-Genome, Regeneron, T3 Pharma, MaviVax, Pfizer, Simcere and touchIME); M. Reig (AstraZeneca, Bayer, BMS, Boston Scientific, Biotoscana Pharma, Engitix Therapeutics, Eli Lilly, Geneos, Gilead, Ipsen, Merck, Roche and Universal DC); M.-E.R.R. (BMS, Imcore-Roche, Roche and Highlight Therapeutics); E.C. (Achilles, Adcendo, Alkermes, Amunix, Anaveon, Amcure, AstraZeneca, BeiGene, BMS, Boehringer, Chugai, Debiopharm, Diaccurate, Ellipses, Incyte, iTeos, Janssen, Merus, MonTa, MSD, Nanobiotix, Nouscom, Novartis, OncoDNA, PharmaMar, PsiOxus Therapeutics, Roche/Genentech, Sanofi, Servier, Shionogi, Syneos Health, TargImmune, T-knife and Tolremo); J.E.-V. (BMS, MSD and Pfizer); J.J.S.-C. (Eisai, Novartis, Pfizer and Seagen); K.-L.K. (Janssen and Takeda); O.S. (Affimed); C.S. (BMS, Eli Lilly and Boehringer Ingelheim); E.R. (BMS, Eli Lilly, Kyowa Kirin, Leo Pharma, MSD, Pierre Fabre and Sanofi); A.L.-M. (Incyte, Merck, PharmaMar, Pfizer, Roche, Rovi and Sanofi); I. Moreno (Digicore Initiative, Fondacion Intheos, Exafield, Guidepoint and Ellipses Pharma); A.H.-C. (BMS, Gilead, Kyowa Kirin, Merus and MSD); D.H. (Novartis and Roche); M.S.-Z. (Bayer, Instituto de Salud Carlos III (grant FI19/00222), BTG, MSD and Roche); A.V.-L. (AstraZeneca, BMS, Health in Code and Roche); J.T. (Amgen, AstraZeneca, Bristol Myers Squibb, Eisai, EXACT Therapeutics, Institut für Qualitätssicherung und Transparenz im Gesundheitswesen, Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, Ipsen, Lilly ImClone, medupdate, Merck Serono, Merck Sharp & Dome, Oncolytics Biotech, onkowissen.de, Roche, Servier and streamedup!); C.K. (AstraZenca, BMS, DGVS, Incyte, MCI Deutschland, MSD, Servier, Ipsen, Merck Serono and Roche); P.R.G. (AstraZeneca, Bayer, BMS, Boston Scientific, Eisai, Guerbet, Ipsen, MSD, Lilly, Roche and Sirtex); F.F. (AstraZeneca, BMS, Eisai, Merck Serono, Servier and Roche); Z.T. (Boehringer Ingelheim); H.H. (Secarna); F.J.K. (German Cancer Aid (Deutsche Krebshilfe)); H. Reis (AstraZeneca, BMS, Boehringer Ingelheim, Chop GmbH, Diaceutics, GSK, HUeG, Janssen, MCI, Merck, Novartis, Roche Pharma and Sanofi); M.M. (LYO-X AG and TATAA Biocenter); T.G. (Allogene, Bicara, BMS, Merck, Pyxis and Samyang); W.H.F. (Anaveon, Atreca, Incendia, Ichnos Sciences, Genenta, OSE Immunotherapeutics, Oxford Biotherapeutics, Mestag, Novartis, Roche and Tabby); A.M.M.E. (Acetra, Agenus, BMS, Boehringer Ingelheim, BioInvent, BioNTech, Ellipses, Galecto, GSK, IO Biotech, IQVIA, Isa Pharmaceuticals, Merck & Co, MSD, Pfizer, Pierre Fabre, Sairopa, Sellas, SkylineDX, TigaTx and Trained Immunity); R.B. (Amgen, Avencell); J.R. (Astellas, AstraZeneca, BMS, Daiichi Sankyo, GSK, MSD, Merck and Sanofi); F.H. (Thermosome); P.F. (Curevac); J.W. (Bayrische Forschungsstiftung (FORTiTher) and the German Ministry for Education & Research (Transcan-3)). The remaining authors declare no competing interests., (© 2024. The Author(s).)

The prognostication of individual disease trajectory and selection of optimal therapy in patients with localized, low-grade prostate cancer often presents significant difficulty. The phosphatase and tensin homolog on chromosome 10 (PTEN) has emerged as a potential novel biomarker in this clinical context, based on its demonstrated prognostic significance in multiple retrospective studies. Incorporation into standard clinical practice necessitates exceptional diagnostic accuracy, and PTEN's binary readout-retention or loss-suggests its suitability as a biomarker. This multi-institutional ring trial aimed to validate the diagnostic precision of PTEN immunohistochemistry in localized, low- to intermediate-risk prostate cancer, across ten university pathology institutes in Germany. The trial incorporated 90 cases of patients diagnosed with acinar adenocarcinoma of the prostate of grade groups 1 (n = 8, 8.9%) and 2 (n = 82, 91.1%) post-radical prostatectomy. Remarkably, the interpretation of PTEN immunohistochemistry displayed substantial variation (12.5-51.2% PTEN loss rates) within an identical cohort of prostate cancer. Fluorescence in situ hybridization analysis demonstrated PTEN hemizygous deletions in 5.5% (5/90) of cases. All cases with hemizygous deletions presented a distinct loss of PTEN expression by immunohistochemistry and were unanimously identified as PTEN loss by all participants (sensitivity 100%). However, negative (loss) immunohistochemistry was relatively non-specific for an underlying genomic deletion. Improved inter-observer agreement was observed in a subsequent ring trial. Finally, we identify S473-pAKT immunohistochemistry as a useful marker in equivocal cases. In summary, this multi-institutional ring trial illustrates surprisingly heterogeneous outcomes in defining PTEN status by immunohistochemistry., Competing Interests: Declarations. Ethics approval: This study was conducted under institutional ethics approval. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

(1) Background: Breast cancer (BC) has a high incidence in Europe, particularly in older adults. Traditionally under-represented in clinical trials, this age group is often undertreated due to ageism. This study aims to characterize frail older adults (≥70 years) with BC based on a comprehensive geriatric assessment, to guide individualized treatment decision-making. (2) Methods: A descriptive analysis of older adults with BC treated from January 2021 to December 2022 was performed. Data were analyzed based on anonymized electronic medical records. (3) Results: Of 123 patients (mean age 84.0 ± 5.6 years), 122 (99.2%) were women. The mean G8 screening score was 12.1 ± 2.5. Most had functional dependence (69.9% Barthel Index, 81.3% Lawton/Brody Scale) and a moderate-to-high risk of falling (76.4% Tinetti index). Cognitive impairment and malnutrition risk were present in 15.4% and 30.1%, respectively. Prehabilitation inclusive strategies led to adapted treatment in 55.3% of cases. Endocrine therapy, surgery, radiotherapy, and chemotherapy was used in 99.2%, 56.1%, 35.0%, and 8.9% of patients, respectively. (4) Conclusions: Our comprehensive oncogeriatric strategy promotes personalized oncologic treatment, improves outcomes by addressing frailty, and enhances treatment tolerability in older patients with BC, validating the expansion of this combined team approach to other cancer types and institutions.

Purpose: Several tumor gene mutations are known for metastatic castration-resistant prostate cancer (mCRPC). The individual response to 177-lutetium prostate specific membrane antigen radioligand therapy (Lu-PSMA) is under current investigation regarding the genomic profile of patients with mCRPC., Materials and Methods: We relied on the FRAMCAP database and compared progression-free survival (PFS) and overall survival (OS) rates of patients with mCRPC with breast cancer-related antigen ( BRCA ) or tumor suppressor gene mutations ( TP53 , PTEN , RB1 ). Specifically, subgroup analyses were performed for patients with Lu-PSMA-treated mCRPC., Results: Of 194 patients with mCRPC, 22% was BRCA1/2 versus 14% PTEN/TP53/RB1 versus 63% without one of these mutations. Patients with no mutation harbored a significantly lower Gleason score of 8-10, relative to BRCA and PTEN/TP53/RB1 patients. In PFS analyses of first-line mCRPC, no difference between all three groups was observed, whereas the median OS differed significantly with 46.3 versus 48.7 versus 95.4 months for BRCA versus PTEN/TP53/RB1 versus no mutated patients ( P < .05). In univariable Cox regression models, BRCA-mutated patients were at higher risk of death (hazard ratio, 2.57; P < .01), whereas PTEN/TP53/RB1 patients were not ( P = .4). Of 87 patients with Lu-PSMA-treated mCRPC, significant differences in PFS and OS were observed (both P ≤ .02). In univariable and multivariable Cox regression models, BRCA-mutated Lu-PSMA patients were at higher risk of death, whereas PTEN/TP53/RB1 patients had similar outcomes as no mutated patients., Conclusion: In real-world setting, substantially lower OS in mCRPC is observed for BRCA - and PTEN/TP53/RB1 -mutated patients, whereas no difference in first-line PFS could be computed. In Lu-PSMA-treated patients, worst outcomes were observed for BRCA patients.

Aims: Tumour content in prostatic biopsies is an important indicator of prostate cancer volume and patient prognosis. Consequently, guidelines typically recommend reporting it as a percentage or linear length (mm). This study aimed to determine the current practices for reporting tumour content in prostatic biopsies and evaluated the consistency among pathologists in diagnosing 10 standard biopsy cases of prostate cancer to assess interobserver variability., Methods and Results: A web-based survey gathered data on demographics, experience and attitudes regarding the reporting of prostate cancer and its extent in biopsies. Virtual microscopy allowed analysis of 10 biopsy cases, each consisting of a single slide of prostate cancer. Self-reports from 304 participants recruited via the International Society of Urological Pathology and the German Society of Pathology were analysed. Most participants (43.4%) reported tumour extent as percentage of the biopsy core, 37.6% reported percentages and mm and 18.3% reported mm exclusively. The methods used to determine percentages showed an unexpected spread of choices, leading to considerable variability in results. Additionally, 40.8% of participants took part in the practical segment of the survey. The reported measures of tumour extent confirmed a notable interobserver variability, which was significantly higher for reported percentages., Conclusion: A high rate of interobserver variability in reporting tumour content in prostatic biopsies was found. This matter is especially critical for patients who are candidates for active surveillance. Reporting absolute measures of tumour content has the advantage of lower variability in comparison to percentages., (© 2024 The Author(s). Histopathology published by John Wiley & Sons Ltd.)

The gold standard for precise diagnostic classification of brain tumors requires tissue sampling, which carries relevant procedural risks. Brain biopsies often have limited sensitivity and fail to address tumor heterogeneity, because small tissue parts are being examined. This study aims to explore the detection and quantification of diagnostically relevant somatic copy number aberrations (SCNAs) in cell-free DNA (cfDNA) extracted from cerebrospinal fluid (CSF) in a real-world cohort of patients with defined brain tumor subtypes. A total of 33 CSF samples were collected from 30 patients for cfDNA extraction. Shallow whole-genome sequencing was conducted on CSF samples containing > 3ng of cfDNA and corresponding tissue DNA from nine patients. The sequencing cohort encompassed 26 samples of 23 patients, comprising 12 with confirmed CNS cancer as compared to 11 patients with either ambiguous CNS lesions (n = 5) or non-cancer CNS lesions (n = 6). After mapping and quality filtering SCNAs were called by depth-of-coverage analyses with a binning of 5.5 Mbp. SCNAs were exclusively identified in CSF cfDNA from brain tumor patients (10/12, 83%). In tumor patients, SCNAs were detectable in cfDNA from all patients with, but also in five of seven patients without tumor cells detected by CSF cytopathology. A substantial number of shared SCNAs were traceable between tissue and CSF in matched pair analyses. Additionally, some SCNAs unique to either CSF or tissue indicating spatial heterogeneity or tumor evolution. Also, diagnostically relevant genomic alterations as well as essential and desirable SCNAs as implemented in the current WHO classification of CNS tumors for certain primary brain tumor subtypes were traceable. In summary, this minimally invasive cfDNA-based LB approach employing shallow whole genome sequencing demonstrates potential for providing a molecularly informed diagnosis of CNS cancers, mapping tumor heterogeneity, tracking tumor evolution, and surveilling tumor patients. Further prospective trials are warranted., Competing Interests: Declarations. Ethics approval and consent to participate: This retrospective investigation and use of patient material and data was approved by the Ethics Committee of the University Hospital Frankfurt (SNO-9-2022). Consent for publication: Not applicable. Competing interests: NGS was conducted and analyzed at Chronix Biomedical by JB, KBK and ES, who are employees of Chronix Biomedical an Oncocyte Company. JPS has received honoraria for lectures, advisory board participation, consulting, and travel grants from Abbvie, Roche, Boehringer, Bristol-Myers Squibb, Medac, Mundipharma, and UCB. PJW has received consulting fees and honoraria for lectures by Bayer, Sanofi, Janssen-Cilag, Novartis, Roche, MSD, Astellas Pharma, Bristol-Myers Squibb, Thermo Fisher Scientific, Molecular Health, Guardant Health, Sophia Genetics, Qiagen, Eli Lilly, Myriad, Hedera Dx, and Astra Zeneca and research support was provided by Astra Zeneca and Roche. HR received honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Chop GmbH, Diaceutics, GlaxoSmithKline, HUeG, Janssen-Cilag, MCI, Merck, Novartis, Roche Pharma, Sanofi and Wolfsburg Klinikum and funding from Bristol-Myers Squibb. MWR has received a research grant from UCB. PSZ has received a lecture honorarium from Bristol-Myers Squibb. The remaining authors declare that the research was carried out without any commercial or financial relationships that could potentially create a conflict of interest., (© 2024. The Author(s).)

Background: Localized prostate cancer (PCa) is a largely heterogeneous disease regarding its clinical behavior. Current risk stratification relies on clinicopathological parameters and distinguishing between indolent and aggressive cases remains challenging. To improve risk stratification, we aimed to identify new prognostic markers for PCa., Methods: We performed an in silico analysis on publicly available PCa transcriptome datasets. The top 20 prognostic genes were assessed in PCa tissue samples of our institutional cohort (n = 92) using the NanoString nCounter technology. The three most promising candidates were further assessed by immunohistochemistry (IHC) in an institutional (n = 121) and an independent validation cohort from the EMPACT consortium (n = 199). Cancer-specific survival (CSS) and progression-free survival (PFS) were used as endpoints., Results: Our in silico analysis identified 113 prognostic genes. The prognostic values of seven of the top 20 genes were confirmed in our institutional radical prostatectomy (RPE) cohort. Low CENPO, P2RX5, ABCC5 as well as high ASF1B, NCAPH, UBE2C, and ZWINT gene expressions were associated with shorter CSS. IHC analysis confirmed the significant associations between NCAPH and UBE2C staining and worse CSS. In the external validation cohort, higher NCAPH and ZWINT protein expressions were associated with shorter PFS. The combination of the newly identified tissue protein markers improved standard risk stratification models, such as D'Amico, CAPRA, and Cambridge prognostic groups., Conclusions: We identified and validated high tissue levels of NCAPH, UBE2C, and ZWINT as novel prognostic risk factors in clinically localized PCa patients. The use of these markers can improve routinely used risk estimation models., Competing Interests: Competing interests BH: Advisory boards for Janssen, Bayer, ABX, Lightpoint, Amgen, MSD, Pfizer, Novartis. Invited speaker for Accord, Astellas, Janssen R&D. Honoraria from Uromed. Research funding from AAA/Novartis, Bristol Myers Squibb, and German Research Foundation. Leadership roles for DKG AUO and DGU. The authors declare no potential conflicts of interest with the present project and publication. Ethics The study was performed in compliance with the Declaration of Helsinki and the institutional ethics committees approved the study protocol (21-9991-BO and KEK-BE128/2015)., (© 2024. The Author(s).)

Lymphoepithelioma-like carcinoma of the bladder (LELC-B) is a rare histologic subtype characterized by strong immune cell (IC) infiltrates. A better prognosis and favorable response rates to immune checkpoint inhibitors have been described. We aimed to characterize the molecular profiles and IC infiltration of LELC-B for a better understanding of its therapeutic implications. We identified 11 muscle-invasive bladder cancer cases with pure and mixed LELC-B. Programmed cell death ligand-1 (PD-L1) expression and mismatch repair proteins were evaluated using immunohistochemistry. We calculated the tumor mutational burden and characterized mutational profiles using whole-exome DNA sequencing data. Transcriptomic signatures were detected using the NanoString nCounter PanCancer IO360 Panel. Multiplex immunofluorescence of tumor microenvironment (PD-L1, PanCK, α-SMA, vimentin, CD45, and Ki67) and T cells (CD4, CD3, PD-1, CD163, CD8, and FoxP3) was used to quantify cell populations. All LELC-B cases were highly positive for PD-L1 (median tumor proportion score/tumor cell, 70%; range, 20%-100%; median combined positive score, 100; range, 50-100) and mismatch repair proficient and negative for Epstein-Barr virus infection. IC infiltrates were characterized by a high CD8+ T-cell count and high PD-1/PD-L1 expression on immune and tumor cells. LELC-B showed upregulation of signaling pathways involved in IC response. Most common mutations were found in chromatin remodeling genes causing epigenetic dysregulation. All LELC-B cases showed high tumor mutational burden with a median of 39 mutations/Mb (IQR, 29-66 mutations/Mb). In conclusion, LELC-B is a highly immunogenic tumor, showing strong upregulation of PD-1/PD-L1 and making immune checkpoint inhibitors a promising treatment option., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The 5th edition of the World Health Organization (WHO) classification of tumors of the urinary tract and male genital organs introduced both general and specific changes in structure, classification, and nomenclature. This also applies to rarer tumors and tumor subtypes of the urinary system. Knowledge of these changes is relevant for routine histopathological work. This article provides an overview of the main new features of the rarer tumors and tumor subtypes of the urinary system in the new edition of the WHO classification., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Competing Interests: Einhaltung ethischer Richtlinien. Interessenkonflikt: H. Reis und F. Bremmer geben an, dass kein Interessenkonflikt besteht. Für diesen Beitrag wurden von den Autor/-innen keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. The supplement containing this article is not sponsored by industry

The risk of recurrence in patients with muscle invasive bladder cancer (MIBC) after radical cystectomy depends on the pathological tumor stage. In particular, patients with lymph node metastasis (pN+), locally advanced (≥pT3), or residual muscle invasive tumor despite neoadjuvant chemotherapy are at high risk. Currently, the importance of adjuvant therapy with immune checkpoint inhibitors is increasing in the context of perioperative systemic therapeutic concepts. The indication for the PD‑1 inhibitor nivolumab currently approved in the European Union requires testing of PD-L1 (programmed cell death ligand 1) protein expression by immunochemistry in tumor tissue. Focusing on MIBC patients at high risk of recurrence, new questions arise regarding the implementation and interpretation of PD-L1 testing. An interdisciplinary group of experts from Germany has discussed relevant issues from a clinicopathological point of view and developed practical recommendations to facilitate the implementation of validated and quality-assured PD-L1 testing for the approved indications in daily clinical practice., (© 2024. The Author(s).)

Background: This study aimed to validate a previously published risk model (RM) which combines clinical and multiparametric MRI (mpMRI) parameters to predict extraprostatic extension (EPE) of prostate cancer (PC) prior to radical prostatectomy (RP)., Materials and Methods: A previously published RM combining clinical with mpMRI parameters including European Society of Urogenital Radiology (ESUR) classification for EPE was retrospectively evaluated in a cohort of two urological university hospitals in Germany. Consecutive patients (n = 205, January 2015 -June 2021) with available preoperative MRI images, clinical information including PSA, prostate volume, ESUR classification for EPE, histopathological results of MRI-fusion biopsy and RP specimen were included. Validation was performed by receiver operating characteristic analysis and calibration plots. The RM's performance was compared to ESUR criteria., Results: Histopathological T3 stage was detected in 43% of the patients (n = 89); 45% at Essen and 42% at Düsseldorf. Discrimination performance between pT2 and pT3 of the RM in the entire cohort was AUC = 0.86 (AUC = 0.88 at site 1 and AUC = 0.85 at site 2). Calibration was good over the entire probability range. The discrimination performance of ESUR classification alone was comparable (AUC = 0.87)., Conclusions: The RM showed good discriminative performance to predict EPE for decision-making for RP as a patient-tailored risk stratification. However, when experienced MRI reading is available, standardized MRI reading with ESUR scoring is comparable regarding information outcome. A main limitation is the potentially limited transferability to other populations because of the high prevalence of EPE in our subgroups., (© 2024. The Author(s).)

Purpose: The purpose of this research was to investigate the impact of dietary factors on developmental trajectories in young autistic children., Methods: A gluten-free and casein-free diets, as well as six types of food (meat and eggs, vegetables, uncooked vegetables, sweets, bread, and "white soft bread that never molds") were investigated observationally for up to three years in 5,553 children 2 to 5 years of age via parent-report measures completed within a mobile application. Children had a parent-reported diagnosis of Autism Spectrum Disorder (ASD); 78% were males; the majority of participants resided in the USA. Outcome was monitored on five orthogonal subscales: Language Comprehension, Expressive Language, Sociability, Sensory Awareness, and Health, assessed by the Autism Treatment Evaluation Checklist (ATEC) (Rimland & Edelson, 1999) and Mental Synthesis Evaluation Checklist (MSEC) (Arnold & Vyshedskiy, 2022; Braverman et al., 2018)., Results: Consumption of fast-acting carbohydrates - sweets, bread, and "white soft bread that never molds" - was associated with a significant and a consistent Health subscale score decline. On the contrary, a gluten-free diet, as well as consumption of meat, eggs, and vegetables were associated with a significant and consistent improvement in the Language Comprehension score. Consumption of meat and eggs was also associated with a significant and consistent improvement in the Sensory Awareness score., Conclusion: The results of this study demonstrate a strong correlation between a diet and developmental trajectories and suggest possible dietary interventions for young autistic children., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The emergence of mutational signatures in cancer research represents a paradigm shift, offering profound insights into tumor biology, therapeutic strategies, and risk assessment. A recent article published in The Journal of Pathology delves into the significance of mutational signatures, assessing their role as molecular fingerprints that illuminate the etiology of individual cancer cases. By deciphering the diverse patterns of DNA alterations, in the context of urachal and nonurachal bladder adenocarcinomas, researchers can unravel intrinsic and environmental risk factors shaping cancer development. The study highlighted a predominance of environmental risk factors in Chinese populations affected by bladder adenocarcinomas. In this context, in this commentary, we highlight some of the potential applications of molecular signatures in differential diagnosis and therapy prediction. As the field continues to evolve, a deeper understanding of mutational signatures promises to revolutionize precision oncology by offering personalized approaches informed by comprehensive mutational patterns of tumors. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Background: Urachal cancer (UrC) is a rare disease with limited availability of representative incidence and clinical data. Although, the prevalence is accounting for less than 1% of bladder tumors, the 5-year survival rate is around only 50% for patients with resectable tumors, and even worse for patients with metastatic disease. Due to the lack of comprehensive prospective studies, our current knowledge of UrC is still limited., Objective: The present study aimed to summarize the available registry-based studies with unselected UrC patients to evaluate its incidence and clinicopathological characteristics., Material and Methods: We conducted a systematic literature search of registry-based UrC publications on the 15th of May 2023 in 5 databases, which identified 4,748 publications. After duplicate removal and selection by 2 independent investigators, 6 publications proved to be appropriate for the final meta-analysis. Estimated incidence and clinicopathological parameters were extracted., Results: Estimated incidence ranged between 0.022 and 0.060/ 100.000 person-years, with the highest occurrence in Japan and the lowest in Canada, while the random effect model calculated an overall incidence rate of 0.04 (95%CI: 0.03-0.05) 100.000 person-years. The median age at first diagnosis was 60 years (range: 58-64). The female to male ratio was 2:3. Lymph node or distant metastases were present in 9% and 14% of patients. The predominant tumour type was adenocarcinoma (86%) followed by urothelial carcinoma (12%) and squamous cell carcinoma (2%). The 5-year survival rate was 51.0% with 95%CI: 45.2-57.4., Conclusions: Our study provides an up-to-date comparison of estimated incidence rates between 6 countries of 3 continents based on rigorously selected registry-based studies. The results suggest low incidence rates for UrC with considerable geographic differences. The present meta-analysis provides unbiased registry-based data on the incidence, clinicopathological parameters and survival of UrC., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The extent of pelvic lymphadenectomy (PLND) as part of radical cystectomy (RC) for bladder cancer (BC) remains unclear. Sentinel-based and lymphangiographic approaches could lead to reduced morbidity without sacrificing oncologic safety., Objective: To evaluate the feasibility and diagnostic value of fluorescence-guided template sentinel region dissection (FTD) using a handheld near-infrared fluorescence (NIRF) camera in open radical cystectomy., Design, Setting, and Participants: After peritumoral cystoscopic injection of indocyanine green (ICG) 21 patients underwent open RC with FTD due to BC between June 2019 and June 2021. Intraoperatively, the FIS-00 Hamamatsu Photonics® NIRF camera was used to identify and resect fluorescent template sentinel regions (FTRs) followed by extended pelvic lymphadenectomy (ePLND) as oncological back-up., Outcome Measurement and Statistical Analysis: Descriptive analysis of positive and negative results per template region., Results and Limitations: FTRs were identified in all 21 cases. Median time (range) from ICG injection to fluorescence detection was 75 (55-125) minutes. On average (SD), 33.4 (9.6) lymph nodes were dissected per patient. Considering template regions as the basis of analysis, 67 (38.3%) of 175 resected regions were NIRF-positive, with 13 (7.4%) regions harboring lymph node metastases. We found no metastatic lymph nodes in NIRF-negative template regions. Outside the standard template, two NIRF-positive benign nodes were identified., Conclusion: The concept of NIRF-guided FTD proved for this group all lymph node metastases to be found in NIRF-positive template regions. Pending validation in a larger collective, resection of approximately 40% of standard regions may be sufficient and may result in less morbidity., (© 2024 The Authors. Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Antibodies targeting the immune checkpoint molecules PD-1, PD-L1 and CTLA-4, administered alone or in combination with chemotherapy, are the standard of care in most patients with metastatic non-small-cell lung cancers. When given before curative surgery, tumor responses and improved event-free survival are achieved. New antibody combinations may be more efficacious and tolerable. In an ongoing, open-label phase 2 study, 60 biomarker-unselected, treatment-naive patients with resectable non-small-cell lung cancer were randomized to receive two preoperative doses of nivolumab (anti-PD-1) with or without relatlimab (anti-LAG-3) antibody therapy. The primary study endpoint was the feasibility of surgery within 43 days, which was met by all patients. Curative resection was achieved in 95% of patients. Secondary endpoints included pathological and radiographic response rates, pathologically complete resection rates, disease-free and overall survival rates, and safety. Major pathological (≤10% viable tumor cells) and objective radiographic responses were achieved in 27% and 10% (nivolumab) and in 30% and 27% (nivolumab and relatlimab) of patients, respectively. In 100% (nivolumab) and 90% (nivolumab and relatlimab) of patients, tumors and lymph nodes were pathologically completely resected. With 12 months median duration of follow-up, disease-free survival and overall survival rates at 12 months were 89% and 93% (nivolumab), and 93% and 100% (nivolumab and relatlimab). Both treatments were safe with grade ≥3 treatment-emergent adverse events reported in 10% and 13% of patients per study arm. Exploratory analyses provided insights into biological processes triggered by preoperative immunotherapy. This study establishes the feasibility and safety of dual targeting of PD-1 and LAG-3 before lung cancer surgery.ClinicalTrials.gov Indentifier: NCT04205552 ., (© 2024. The Author(s).)

We synthesized a series of four parent aza-β -ketoiminate organoboron complexes and performed spectroscopic studies using both experimental and computational techniques. We studied how benzannulation influences the vibronic structure of the UV/Vis absorption bands with a focus on the bright lowest-energy π → π* electronic excitation. Theoretical simulations, accounting for inhomogeneous broadening effects using different embedding schemes, allowed gaining in-depth insights into the observed differences in band shapes induced by structural modifications. We observed huge variations in the distributions of vibronic transitions depending on the position of benzannulation. By and large, the harmonic approximation combined with the adiabatic hessian model delivers qualitatively correct band shapes for the one-photon absorption spectra, except in one case. We also assessed the importance of non-Condon effects (accounted for by the linear term in Herzberg-Teller expansion of the dipole moment) for S 0 → S 1 band shapes. It turned out that non-Condon contributions have no effect on the band shape in one-photon absorption spectra. In contrast, these effects significantly change the Franck-Condon band shapes of the two-photon absorption spectra. For one of the studied organoboron complexes we also performed a preliminary exploration of mechanical anharmonicity, resulting in an increase of the intensity of the 0-0 transition, which improves the agreement with the experimental data compared to the harmonic model.

Aims: The histological subtype of intrahepatic cholangiocarcinoma (iCCA) is associated with different mutational characteristics that impact clinical management. So far, data are lacking on the presence of small duct iCCA (SD-iCCA) and large duct iCCA (LD-iCCA) in a single patient. The aim of the current study was to determine the presence and degree of intratumoural heterogeneity of SD- and LD-iCCA features in different tumour regions., Methods and Results: All patients treated with surgically resected iCCA at Frankfurt University Hospital between December 2005 and March 2023 were retrospectively analysed. Histomorphological features of SD- and LD-iCCA were evaluated by an expert hepatobiliary pathologist. Tissue samples suspicious for subtype heterogeneity were further investigated. Immunohistochemistry for N-cadherin, S100P, MUC5AC, MUC6, TFF1 and AGR2 and mutational profiling with the Illumina TruSight Oncology 500 (TSO500) assay were performed separately for the SD- and LD-iCCA regions. Of 129 patients with surgically resected iCCA, features of either SD- or LD-iCCA were present in 67.4% (n = 87) and 24.8% of the patients (n = 32), respectively; 7.8% (n = 10) had histomorphological features of both SD- and LD-iCCA, seven patients (5.4%) of which had sufficient formalin-fixed, paraffin-embedded tissue for further analysis. Heterogeneity of both subtypes could be confirmed with immunohistochemistry. In five of seven (71.4%) patients, molecular profiling revealed intratumoural differences in genetic alterations between the SD- and LD-iCCA region. In one patient, a BRAF mutation (p.V600E) was found in the SD-iCCA but not in the LD-iCCA region of the tumour., Conclusions: A marked portion of patients with iCCA exhibits both SD- and LD-iCCA in different tumour regions. In case of the presence of histopathological heterogeneity, mutational profiling should be considered to avoid missing therapeutically relevant genetic alterations., (© 2024 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Background: Heart failure (HF), a common cause of hospitalization, is associated with poor short-term clinical outcomes. Little is known about the long-term prognoses of patients with HF in Latin America., Methods: BREATHE was the first nationwide prospective observational study in Brazil that included patients hospitalized due to acute heart failure (HF). Patients were included during 2 time periods: February 2011-December 2012 and June 2016-July 2018 In-hospital management, 12-month clinical outcomes and adherence to evidence-based therapies were evaluated., Results: A total of 3013 patients were enrolled at 71 centers in Brazil. At hospital admission, 83.8% had clear signs of pulmonary congestion. The main cause of decompensation was poor adherence to HF medications (27.8%). Among patients with reduced ejection fraction, concomitant use of beta-blockers, renin-angiotensin-aldosterone inhibitors and spironolactone decreased from 44.5% at hospital discharge to 35.2% at 3 months. The cumulative incidence of mortality at 12 months was 27.7%, with 24.3% readmission at 90 days and 44.4% at 12 months., Conclusions: In this large national prospective registry of patients hospitalized with acute HF, rates of mortality and readmission were higher than those reported globally. Poor adherence to evidence-based therapies was common at hospital discharge and at 12 months of follow-up., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), or non-alcoholic fatty liver disease (NAFLD), is a common disease that is diagnosed through manual evaluation of liver biopsies, an assessment that is subject to high interobserver variability (IBV). IBV can be reduced using automated methods., Objectives: Many existing computer-based methods do not accurately reflect what pathologists evaluate in practice. The goal is to demonstrate how these differences impact the prediction of hepatic steatosis. Additionally, IBV complicates algorithm validation., Materials and Methods: Forty tissue sections were analyzed to detect steatosis, nuclei, and fibrosis. Data generated from automated image processing were used to predict steatosis grades. To investigate IBV, 18 liver biopsies were evaluated by multiple observers., Results: Area-based approaches yielded more strongly correlated results than nucleus-based methods (⌀ Spearman rho [ρ] = 0.92 vs. 0.79). The inclusion of information regarding tissue composition reduced the average absolute error for both area- and nucleus-based predictions by 0.5% and 2.2%, respectively. Our final area-based algorithm, incorporating tissue structure information, achieved a high accuracy (80%) and strong correlation (⌀ Spearman ρ = 0.94) with manual evaluation., Conclusion: The automatic and deterministic evaluation of steatosis can be improved by integrating information about tissue composition and can serve to reduce the influence of IBV., (© 2024. The Author(s).)

Background and Objective: With European Medicines Agency approval of PARP inhibitors in metastatic castration-resistant prostate cancer and ongoing trials in metastatic hormone-sensitive prostate cancer, detection of genetic alterations in BRCA1/2 and other homologous recombination repair genes has gained an important role. Our aim was to investigate the feasibility and comparability of comprehensive next-generation sequencing (NGS) of liquid biopsy (LB; circulating tumor DNA) and tumor tissue (TT) samples in a real-world clinical setting., Methods: The study cohort consisted of 50 patients with metastatic prostate cancer (mPC) who had TT NGS performed for BRCA1/2 alterations and consent for additional LB NGS. The Oncomine Comprehensive Assay v3 (Thermo Fisher Scientific, Waltham, MA, USA) was used for TT NGS. The Guardant360 83-gene assay (Guardant Health, Palo Alto, CA, USA) was used for LB NGS, including all types of somatic alterations, microsatellite instability, and blood tumor mutational burden. We calculated BRCA1/2 alteration rates and the negative percentage agreement (NPA) and positive percentage agreement (PPA) between TT and LB results., Key Findings and Limitations: TT NGS was successful in 44/50 patients (88%), with pathogenic BRCA1/2 alterations detected in four (9%). LB NGS was successful in all 50 patients (100%), with BRCA1/2 alterations detected in ten (20%). In a subgroup analysis for the 44 patients with successful TT NGS, NPA was 85% and PPA was 50%. The median time between TT sample collection and blood sampling for NGS was 132 wk (IQR 94-186). The limited sample size and differences in the time of NGS assessment are limitations., Conclusions and Clinical Implications: LB NGS resulted in a higher detection rate for BRCA1/2 alterations in comparison to conventional TT NGS (20% vs 9%). Ideally, BRCA1/2 testing should be based on both approaches to identify all patients with mPC eligible for PARP inhibitor therapy., Patient Summary: Our study shows that genetic tests for both tumor tissue and blood samples results in higher rates of detection of BRCA1/2 gene alterations in patients with metastatic prostate cancer., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Artificial intelligence (AI) holds the potential to make significant advancements in pathology. However, its actual implementation and certification for practical use are currently limited, often due to challenges related to model transferability. In this context, we investigate the factors influencing transferability and present methods aimed at enhancing the utilization of AI algorithms in pathology., Materials and Methods: Various convolutional neural networks (CNNs) and vision transformers (ViTs) were trained using datasets from two institutions, along with the publicly available TCGA-MIBC dataset. These networks conducted predictions in urothelial tissue and intrahepatic cholangiocarcinoma (iCCA). The objective was to illustrate the impact of stain normalization, the influence of various artifacts during both training and testing, as well as the effects of the NoisyEnsemble method., Results: We were able to demonstrate that stain normalization of slides from different institutions has a significant positive effect on the inter-institutional transferability of CNNs and ViTs (respectively +13% and +10%). In addition, ViTs usually achieve a higher accuracy in the external test (here +1.5%). Similarly, we showcased how artifacts in test data can negatively affect CNN predictions and how incorporating these artifacts during training leads to improvements. Lastly, NoisyEnsembles of CNNs (better than ViTs) were shown to enhance transferability across different tissues and research questions (+7% Bladder, +15% iCCA)., Discussion: It is crucial to be aware of the transferability challenge: achieving good performance during development does not necessarily translate to good performance in real-world applications. The inclusion of existing methods to enhance transferability, such as stain normalization and NoisyEnsemble, and their ongoing refinement, is of importance., (© 2024. The Author(s).)

Background: Of all urothelial carcinomas (UCs), 25% are muscle invasive and associated with a 5-year overall survival rate of 50%. Findings regarding the molecular classification of muscle-invasive urothelial carcinomas (MIUCs) have not yet found their way into clinical practice., Objectives: Prediction of molecular consensus subtypes in MIUCs with artificial intelligence (AI) based on histologic hematoxylin-eosin (HE) sections., Methods: Pathologic review and annotation of The Cancer Genome Atlas (TCGA) Bladder Cancer (BLCA) Cohort (N = 412) and the Dr. Senckenberg Institute of Pathology (SIP) BLCA Cohort (N = 181). An AI model for the prediction of molecular subtypes based on annotated histomorphology was trained., Results: For a five-fold cross-validation with TCGA cases (N = 274), an internal TCGA test set (N = 18) and an external SIP test set (N = 27), we reached mean area under the receiver operating characteristic curve (AUROC) scores of 0.73, 0.8 and 0.75 for the classification of the used molecular subtypes "luminal", "basal/squamous" and "stroma-rich". By training on correlations to individual molecular subtypes, rather than training on one subtype assignment per case, the AI prediction of subtypes could be significantly improved., Discussion: Follow-up studies with RNA extraction from various areas of AI-predicted molecular heterogeneity may improve molecular classifications and thereby AI algorithms trained on these classifications., (© 2024. The Author(s).)

Glandular lesions in the urinary tract or their associated pathologies can pose a diagnostic challenge. There is a variety of benign alterations and tumor types that need to be taken into account in differential diagnostic considerations. In recent times, efforts for better defining these alterations or lesions both on the histopathological and molecular levels have been undertaken. This article will provide an update on current diagnostic and molecular considerations of these lesions., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Non-small-cell lung cancer (NSCLC) shows a high incidence of brain metastases (BM). Early detection is crucial to improve clinical prospects. We trained and validated classifier models to identify patients with a high risk of developing BM, as they could potentially benefit from surveillance brain MRI., Methods: Consecutive patients with an initial diagnosis of NSCLC from January 2011 to April 2019 and an in-house chest-CT scan (staging) were retrospectively recruited at a German lung cancer center. Brain imaging was performed at initial diagnosis and in case of neurological symptoms (follow-up). Subjects lost to follow-up or still alive without BM at the data cut-off point (12/2020) were excluded. Covariates included clinical and/or 3D-radiomics-features of the primary tumor from staging chest-CT. Four machine learning models for prediction (80/20 training) were compared. Gini Importance and SHAP were used as measures of importance; sensitivity, specificity, area under the precision-recall curve, and Matthew's Correlation Coefficient as evaluation metrics., Results: Three hundred and ninety-five patients compromised the clinical cohort. Predictive models based on clinical features offered the best performance (tuned to maximize recall: sensitivity∼70%, specificity∼60%). Radiomics features failed to provide sufficient information, likely due to the heterogeneity of imaging data. Adenocarcinoma histology, lymph node invasion, and histological tumor grade were positively correlated with the prediction of BM, age, and squamous cell carcinoma histology were negatively correlated. A subgroup discovery analysis identified 2 candidate patient subpopulations appearing to present a higher risk of BM (female patients + adenocarcinoma histology, adenocarcinoma patients + no other distant metastases)., Conclusion: Analysis of the importance of input features suggests that the models are learning the relevant relationships between clinical features/development of BM. A higher number of samples is to be prioritized to improve performance. Employed prospectively at initial diagnosis, such models can help select high-risk subgroups for surveillance brain MRI., Competing Interests: Disclosure M.S. reports research funding to institution (but not for this specific project) from Astra Zeneca, honoraria for advisory boards from Astra Zeneca, BMS, MSD/Merck, Roche, Pfizer, Novartis, Boehringer Ingelheim, Takeda, Abbvie, Johnson & Johnson, Amgen, Tesaro, Eli Lilly, honoraria for educational lectures from Astra Zeneca, BMS, Novartis, Pfizer, Boehringer Ingelheim, Amgen and Eli Lilly. The authors have no conflicts of interest to report with regard to this project., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Fluorescence confocal microscopy (FCM) is a rapidly evolving tool that provides real-time virtual HE images of native tissue. Data about the potential of FCM as an alternative to frozen sections for the evaluation of donor liver specimens are lacking so far. The aim of the current study was to determine the value of FCM in liver specimens according to the criteria of the German Society for Organ Procurement. In this prospective study, conventional histology and FCM scans of 50 liver specimens (60% liver biopsies, 26% surgical specimens, and 14% donor samples) were evaluated according to the German Society for Organ Procurement. A comparison of FCM scans and conventional frozen sections revealed almost perfect levels of agreement for cholangitis (κ = 0.877), fibrosis (κ = 0.843), and malignancy (κ = 0.815). Substantial levels of agreement could be obtained for macrovesicular steatosis (κ = 0.775), inflammation (κ = 0.763), necrosis (κ = 0.643), and steatohepatitis (κ = 0.643). Levels of agreement were moderate for microvesicular steatosis (κ = 0.563). The strength of agreement between frozen sections and FCM was superior to the comparison of conventional HE and FCM imaging. We introduce FCM as a potential alternative to the frozen section that may represent a novel approach to liver transplant pathology where timely feedback is crucial and the deployment of human resources is becoming increasingly difficult., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Ovarian cancer is a common malignant genital neoplasm in women. Due to its frequent diagnosis only in advanced stages, prognosis is poor, although biomarker-driven targeted therapeutic approaches are evolving. These are currently based on molecular pathological analyses of homologous recombination deficiency (HRD) and the BRCA1/2 mutational status. The current CME article focuses on the histo- and molecular pathology of ovarian cancer, relevant molecular mechanisms, and test systems. These are discussed in the context of biomarker-driven targeted therapy., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Data on the impact of autophagy in primary cholangiocarcinoma (CCA) remain scarce. Here, we therefore investigated the role of active autophagy and its impact on survival in CCA patients. All CCA patients who underwent surgical resection with curative intent between 08/2005 and 12/2021 at University Hospital Frankfurt were evaluated. Autophagic key proteins were studied by immunohistochemistry. iCCA processed for gene expression profiling of immune-exhaustion gene sets was used for an autophagy approach in silico. Active autophagy was present in 23.3% of the 172 CCA patients. Kaplan-Meier curves revealed median OS of 68.4 months (95% CI = 46.9-89.9 months) and 32.7 months (95% CI = 23.6-41.8 months) for active and non-active autophagy, respectively ( p ≤ 0.001). In multivariate analysis, absence of active autophagy (HR = 2, 95% CI = 1.1-3.5, p = 0.015) was an independent risk factor for OS. Differential-expression profiling revealed significantly upregulated histone deacetylases (HDAC) mRNA in patients showing non-active autophagy. In line with this, pan-acetylated lysine was significantly more prominent in CCA patients with ongoing autophagy ( p = 0.005). Our findings strengthen the role of active autophagy as a prognostically relevant marker and a potential therapeutic target.

Pathologic examination of prostate biopsies is time consuming due to the large number of slides per case. In this retrospective study, we validate a deep learning-based classifier for prostate cancer (PCA) detection and Gleason grading (AI tool) in biopsy samples. Five external cohorts of patients with multifocal prostate biopsy were analyzed from high-volume pathology institutes. A total of 5922 H&E sections representing 7473 biopsy cores from 423 patient cases (digitized using three scanners) were assessed concerning tumor detection. Two tumor-bearing datasets (core n = 227 and 159) were graded by an international group of pathologists including expert urologic pathologists (n = 11) to validate the Gleason grading classifier. The sensitivity, specificity, and NPV for the detection of tumor-bearing biopsies was in a range of 0.971-1.000, 0.875-0.976, and 0.988-1.000, respectively, across the different test cohorts. In several biopsy slides tumor tissue was correctly detected by the AI tool that was initially missed by pathologists. Most false positive misclassifications represented lesions suspicious for carcinoma or cancer mimickers. The quadratically weighted kappa levels for Gleason grading agreement for single pathologists was 0.62-0.80 (0.77 for AI tool) and 0.64-0.76 (0.72 for AI tool) for the two grading datasets, respectively. In cases where consensus for grading was reached among pathologists, kappa levels for AI tool were 0.903 and 0.855. The PCA detection classifier showed high accuracy for PCA detection in biopsy cases during external validation, independent of the institute and scanner used. High levels of agreement for Gleason grading were indistinguishable between experienced genitourinary pathologists and the AI tool., (© 2023. Nature Publishing Group UK.)

Background: Policy initiatives have provided funding for non-acute nutrition interventions to address food insecurity as a social determinant of health, but more research is needed to understand the outcomes of these initiatives in order to determine the areas of highest impact. Therefore, the purpose of this systematic review was to evaluate the outcomes that were assessed in three nutrition interventions (produce prescription programs, medically tailored meals, and community supported agriculture) that aim to address food insecurity as a social determinant of health, and this was undertaken in order to identify future areas of study that can heighten impact., Methods: This systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) criteria. A list of search terms and keywords were compiled by the research team. A Boolean search was conducted from 1 January 2000 to 1 January 2023 in the PubMed advanced search database., Results: A total of 1015 articles were initially pulled from the PubMed database, and, after a screening process, 21 articles were included in our review. Nineteen of the articles focused on adult populations or families and two focused on children. The main outcomes assessed were changes in self-reported dietary intake, while a few of the articles addressed feasibility and cost-related outcomes., Conclusions: More research is needed to assess whether nutritional interventions to address food insecurity as a social determinant of health are feasible and more cost effective in the long term. Additionally, more work should be conducted in pediatric populations, which could have a robust return on investment in terms of both healthcare utilization and healthcare expenditure.

A recently developed computational scheme is employed to interpret changes in the infrared spectra of halogen-bonded systems in terms of intermolecular interaction energy components (electrostatic, exchange, induction, dispersion) taking pyridine⋯perfluorohaloarene complexes as examples. For all complexes, we find a strong linear correlation between the different terms of the interaction-induced changes of the IR band associated with an intermolecular halogen bond stretching mode and the corresponding terms of the interaction energy, which implies that the interaction components play similar roles in both properties. This is not true for other vibrational modes localized in one of the monomers studied here, for which the corresponding interaction-induced changes in IR bands may present a completely different decomposition than the interaction energy.

Purpose: IDH1 mutation is a known biomarker for targeted therapy of intrahepatic cholangiocarcinoma (iCCA), while its prognostic relevance for current palliative chemotherapy is still unclear. Aim of this study was to analyze clinicopathological characteristics of patients with IDH1 mutations and to outline a potential impact on the outcome after state-of-the-art palliative chemotherapy regimens., Methods: All patients with iCCA receiving large panel molecular profiling and follow-up treatment at Frankfurt University Hospital until 04/2022 were retrospectively analyzed. Clinicopathological characteristics were assessed for IDH1 mutated (mut) and IDH1 wild type (wt) patients, and progression-free survival (PFS) and overall survival (OS) were determined., Results: In total, 75 patients with iCCA received molecular profiling. Of the patients with available DNA data, pathogenic mutations in IDH1 were found in 14.5% (n = 10). IDH1 mut status was associated with lower serum CA-19/9 (p = 0.023), lower serum lactate dehydrogenase (p = 0.006), and a higher proportion of primary resectability (p = 0.028) as well as response to chemotherapy after recurrence (p = 0.009). Median PFS was 5.9 months (95% CI 4.4-7.3 months) for IDH1 wt in comparison to 9.8 months (95% CI 7.7-12 months) for patients with IDH1 mut (p = 0.031). IDH1 wt was a significant risk factor for shortened PFS in univariate (p = 0.043), but not in multivariate analysis (p = 0.061). There was no difference in OS between both groups., Conclusion: Patients with IDH1 mutated iCCA seem to have a favorable tumor biology including a longer PFS for palliative chemotherapy regimens compared to IDH1 wild type., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The first-, second-, and third-order molecular nonlinear optical properties, including two-photon absorption of a series of derivatives, involving two dithienylethene (DTE) groups connected by several molecular linkers (bis(ethylene-1,2-dithiolato)Ni- (NiBDT), naphthalene, quasilinear oligothiophene chains), are investigated by employing density functional theory (DFT). These properties can be efficiently controlled by DTE switches, in connection with light of appropriate frequency. NiBDT, as a linker, is associated with a greater contrast, in comparison to naphthalene, between the first and second hyperpolarizabilities of the "open-open" and the "closed-closed" isomers. This is explained by invoking the low-lying excited states of NiBDT. It is shown that the second hyperpolarizability can be used as an index, which follows the structural changes induced by photochromism. Assuming a Förster type transfer mechanism, the intramolecular excited-state energy transfer (EET) mechanism is studied. Two important parameters related to this are computed: the electronic coupling (V DA ) between the donor and acceptor fragments as well as the overlap between the absorption and emission spectra of the donor and acceptor groups. NiBDT as a linker is associated with a low electronic coupling, V DA , value. We found that V DA is affected by molecular geometry. Our results predict that the linker strongly influences the communication between the open-closed DTE groups. The sensitivity of the molecular nonlinear optical properties could assist with identification of molecular isomers.

Purpose: High-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN G3) are rare and heterogeneous malignancies with poor prognosis. Aim of this study was to develop prognosticators identifying those patients that derive the most benefit from currently available systemic therapies., Methods: This retrospective analysis included 78 patients with metastatic GEP-NEN G3. For patients with imaging data available (n = 52), the overall response rate (ORR) and disease control rate (DCR) were evaluated according to the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). A Cox proportional hazard model was used to analyze the prognostic value of selected clinical and blood-based biomarkers. The impact of palliative chemotherapy regimens on time-to-treatment-failure (TTF) and overall survival (OS) was assessed., Results: Median OS of the study cohort was 9.0 months (95% CI 7.0-11.1). The majority of patients received first-line treatment with platinum plus etoposide (83.3%). The ORR and DCR of the RECIST-evaluable subgroup were 34.6% and 76.9%. Median TTF upon first-line treatment was 4.9 months (95% CI 3.4-6.4). Multivariate analysis identified the Eastern Cooperative Oncology Group performance status (ECOG PS), lactate dehydrogenase (LDH) and absolute lymphocyte count as independent prognostic factors. A prognostic score based on these parameters discriminated patients with favorable and unfavorable outcomes., Conclusion: Outcomes of patients with GEP-NEN G3 are still limited. A new prognostic score identifying those patients benefitting from current platinum/etoposide-based chemotherapy protocols may help as stratification factor in future trial design., (© 2022. The Author(s).)

Objectives: Radioactive iodine therapy is considered for patients with certain clinicopathological factors that predict a significant risk of recurrence, distant metastases of thyroid cancer or disease-specific mortality. The aim of the study was to investigate the association between polymorphisms of genes, products of which are involved in the processes of DNA damage response and autophagy, and the adverse reactions of radioiodine therapy in thyroid cancer patients., Methods: The study included 181 patients (37 men, 144 women; median age 56 [41; 66.3] years) with histologically confirmed thyroid cancer and a history of thyroidectomy who received radioiodine therapy. NFKB1 , ATM , ATG16L2 , ATG10 , TGFB1 , and TNF polymorphisms were determined by allele-specific realtime-PCR., Results: The frequency of adverse reactions was the following: gastrointestinal symptoms - 57.9 %, local symptoms - 65.8 %, cerebral symptoms - 46.8 %, fatigue - 54.4 %; signs of sialoadenitis six months after radioiodine therapy - 25.2 %. TT genotype carriers of ATG10 rs1864183 had higher frequency of gastrointestinal symptoms (vs. CC+CT), the CC genotype carriers of ATG10 rs10514231 had significantly more frequent cerebral symptoms (vs. CT+TT), as well as AA genotype carriers of TGFB1 rs1800469 (vs. AG+GG). CC genotype of ATG10 rs10514231 increased the incidence of radioiodine-induced fatigue, whereas GA genotype of the ATM rs11212570 had a protective role against fatigue. TGFB1 rs1800469 was associated with signs of sialoadenitis six months after radioiodine therapy., Conclusions: Genetic factors may contribute to the occurrence of adverse reactions of radioiodine therapy in thyroid cancer patients., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Objectives: Radioactive iodine therapy is considered for patients with certain clinicopathological factors that predict a significant risk of recurrence, distant metastases of thyroid cancer or disease-specific mortality. The aim of the study was to investigate the association between polymorphisms of genes, products of which are involved in the processes of DNA damage response and autophagy, and the adverse reactions of radioiodine therapy in thyroid cancer patients., Methods: The study included 181 patients (37 men, 144 women; median age 56 [41; 66.3] years) with histologically confirmed thyroid cancer and a history of thyroidectomy who received radioiodine therapy. NFKB1 , ATM , ATG16L2 , ATG10 , TGFB1 , and TNF polymorphisms were determined by allele-specific realtime-PCR., Results: The frequency of adverse reactions was the following: gastrointestinal symptoms - 57.9 %, local symptoms - 65.8 %, cerebral symptoms - 46.8 %, fatigue - 54.4 %; signs of sialoadenitis six months after radioiodine therapy - 25.2 %. TT genotype carriers of ATG10 rs1864183 had higher frequency of gastrointestinal symptoms (vs. CC+CT), the CC genotype carriers of ATG10 rs10514231 had significantly more frequent cerebral symptoms (vs. CT+TT), as well as AA genotype carriers of TGFB1 rs1800469 (vs. AG+GG). CC genotype of ATG10 rs10514231 increased the incidence of radioiodine-induced fatigue, whereas GA genotype of the ATM rs11212570 had a protective role against fatigue. TGFB1 rs1800469 was associated with signs of sialoadenitis six months after radioiodine therapy., Conclusions: Genetic factors may contribute to the occurrence of adverse reactions of radioiodine therapy in thyroid cancer patients., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Objective: To explore the experiences, needs and preferences of a group of parents regarding the parenting support received during prenatal and well-child care in the Portuguese National Health Service., Design and Setting: We undertook descriptive-interpretive qualitative research running multiple focus groups in Porto, Northern Portugal., Participants, Data Collection and Analysis: Purposive sampling was used between April and November 2018. Focus groups were conducted with 11 parents of a 0-3 years old with well-child visits done in primary care units. Thematic analysis was performed in a broadly inductive coding strategy and findings are reported in accordance with Consolidated Criteria for Reporting Qualitative Research guidelines., Results: Three main themes were identified to describe parents' experience when participating in their children's healthcare: (1) logistics/delivery matter, including accessibility, organisation and provision of healthcare activities, unit setting and available equipment; (2) prenatal and well-child care: a relational place to communicate, with parents valuing a tripartite space for the baby, the family and the parent himself, where an available and caring health provider plays a major role and (3) parenting is challenging and looks for support, based on key points for providers to watch for and ask about, carefully explained and consensual among health providers., Conclusion: This study provides insight into parents' needs and healthcare practices that affect the parenting experience. To meet parents' preferences, sensitive health providers should guarantee a relational place to communicate and person-centredness, accounting for the whole family system to support healthy parenting collaboratively. Future studies are warranted to further strengthen the knowledge in the field of a population-based approach for parenting support., Competing Interests: Competing interests: FF is the author responsible for creating the project ‘Crescer em Grande!’; MRX is also involved in the development of CeG! and is member of the Administrative Board of the Fundação Brazelton/Gomes-Pedro para as Ciências do Bebé e da Família (Brazelton/Gomes-Pedro Foundation for the Sciences of Baby and Family), Portugal. FF and MRX are certified trainers in the Touchpoints Approach by Brazelton Touchpoints Center, Boston, USA., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In this prospective two-center feasibility study, we evaluate the diagnostic value of intraoperative ex vivo specimenPET/CT imaging of radical prostatectomy (RP) and lymphadenectomy specimens. Ten patients with high-risk prostate cancer underwent clinical prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) preoperatively on the day of surgery. Six patients received 68 Ga-PSMA-11 and four 18 F-PSMA-1007. Radioactivity of the resected specimen was measured again using a novel specimenPET/CT device (AURA10; XEOS Medical, Gent, Belgium) developed for intraoperative margin assessment. All index lesions of staging multiparametric magnetic resonance imaging could be visualized. Overall, specimenPET/CT correlated well with conventional PET/CT regarding detection of suspicious tracer foci (Pearson coefficient 0.935). In addition, specimenPET/CT demonstrated all lymph node metastases detected on conventional PET/CT ( n  = 3), as well as three previously undetected lymph node metastases. Importantly, all positive or close (<1 mm) surgical margins could be visualized in agreement with histopathology. In conclusion, specimenPET/CT enables detection of PSMA-avid lesions and warrants further investigation to tailor RP, based on a good correlation with final pathology. Future trials will prospectively compare ex vivo specimenPET/CT with a frozen section analysis for the detection of positive surgical margins and assessment of biochemical recurrence-free survival., Patient Summary: In this report, we examined prostatectomy and lymphadenectomy specimens for suspicious positron emission tomography (PET) signals after preoperative tracer injection. It was found that in all cases, a good signal could be visualized, with a promising correlation of surface assessment compared with histopathology. We conclude that specimenPET imaging is feasible and may help improve oncological outcomes in the future., (© 2023 The Author(s).)

Background: Molecular subtypes predict prognosis in muscle-invasive bladder cancer (MIBC) and are explored as predictive markers. To provide a common base for molecular subtyping and facilitate clinical applications, a consensus classification has been developed. However, methods to determine consensus molecular subtypes require validation, particularly when FFPE specimens are used. Here, we aimed to evaluate two gene expression analysis methods on FFPE samples and to compare reduced gene sets to classify tumors into molecular subtypes., Methods: RNA was isolated from FFPE blocks of 15 MIBC patients. Massive analysis of 3' cDNA ends (MACE) and the HTG transcriptome panel (HTP) were used to retrieve gene expression. We used normalized, log2-transformed data to call consensus and TCGA subtypes with the consensusMIBC package for R using all available genes, a 68-gene panel (ESSEN1), and a 48-gene panel (ESSEN2)., Results: Fifteen MACE-samples and 14 HTP-samples were available for molecular subtyping. The 14 samples were classified as Ba/Sq in 7 (50%), LumP in 2 (14.3%), LumU in 1 (7.1%), LumNS in 1 (7.1%), stroma-rich in 2 (14.3%) and NE-like in 1 (7.1%) case based on MACE- or HTP-derived transcriptome data. Consensus subtypes were concordant in 71% (10/14) of cases when comparing MACE with HTP data. Four cases with aberrant subtypes had a stroma-rich molecular subtype with either method. The overlap of the molecular consensus subtypes with the reduced ESSEN1 and ESSEN2 panels were 86% and 100%, respectively, with HTP data and 86% with MACE data., Conclusion: Determination of consensus molecular subtypes of MIBC from FFPE samples is feasible using various RNA sequencing methods. Inconsistent classification mainly involves the stroma-rich molecular subtype, which may be the consequence of sample heterogeneity with (stroma)-cell sampling bias and highlights the limitations of bulk RNA-based subclassification. Classification is still reliable when analysis is reduced to selected genes., (© 2023. The Author(s).)

Competing Interests: Declaration of Competing Interest None.

Immune-checkpoint-inhibitor (ICI) therapy has been one of the major advances in the treatment of a variety of advanced or metastatic tumors in recent years. Therefore, ICI-therapy is already approved in first-line therapy for multiple tumors, either as monotherapy or as combination therapy. However, there are relevant differences in approval among different tumor entities, especially with respect to PD-L1 testing. Different response to ICI-therapy has been observed in the pivotal trials, so PD-L1 diagnostic testing is used for patient selection. In addition to PD-L1 testing of tumor tissue, liquid biopsy provides a noninvasive way to monitor disease in cancer patients and identify those who would benefit most from ICI-therapy. This overview focuses on the use of ICI-therapy and how it relates to common and potential future biomarkers for patient-directed treatment planning., Competing Interests: C.K. reports consulting fees Apogepha, research funding Advanced Accelerator Applications (Novartis). B.A.H. reports personal fees from ABX, Bayer, LightPoint Medical Inc., Janssen R&D, Bristol-Myers-Squibb and Astellas; research funding from Profound Medical, German Cancer Aid, German Research Foundation, Janssen R&D, Bristol-Myers-Squibb, MSD, Pfizer and Astellas; and travel fees from AstraZeneca, Janssen R&D and Astellas. V.G. reports fees from Astellas, AstraZeneca, BMS, EISAI, Ipsen, Janssen-Cilag, Merck Serono, MSD, Novartis, Pfizer, Roche, and research grants from BMS, Ipsen, MSD and Pfizer. The remaining authors have no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)