From Detection to Cure - Emerging Roles for Urinary Tumor DNA (utDNA) in Bladder Cancer.

PURPOSE OF REVIEW: This review sought to define the emerging roles of urinary tumor DNA (utDNA) for diagnosis, monitoring, and treatment of bladder cancer. Building from early landmark studies the focus is on recent studies, highlighting how utDNA could aid personalized care. RECENT FINDINGS: Recent research underscores the potential for utDNA to be the premiere biomarker in bladder cancer due to the constant interface between urine and tumor. Many studies find utDNA to be more informative than other biomarkers in bladder cancer, especially in early stages of disease. Points of emphasis include superior sensitivity over traditional urine cytology, broad genomic and epigenetic insights, and the potential for non-invasive, real-time analysis of tumor biology. utDNA shows promise for improving all phases of bladder cancer care, paving the way for personalized treatment strategies. Building from current research, future comprehensive clinical trials will validate utDNA's clinical utility, potentially revolutionizing bladder cancer management.

PATH-SURVEYOR: pathway level survival enquiry for immuno-oncology and drug repurposing.

Pathway-level survival analysis offers the opportunity to examine molecular pathways and immune signatures that influence patient outcomes. However, available survival analysis algorithms are limited in pathway-level function and lack a streamlined analytical process. Here we present a comprehensive pathway-level survival analysis suite, PATH-SURVEYOR, which includes a Shiny user interface with extensive features for systematic exploration of pathways and covariates in a Cox proportional-hazard model. Moreover, our framework offers an integrative strategy for performing Hazard Ratio ranked Gene Set Enrichment Analysis and pathway clustering. As an example, we applied our tool in a combined cohort of melanoma patients treated with checkpoint inhibition (ICI) and identified several immune populations and biomarkers predictive of ICI efficacy. We also analyzed gene expression data of pediatric acute myeloid leukemia (AML) and performed an inverse association of drug targets with the patient's clinical endpoint. Our analysis derived several drug targets in high-risk KMT2A-fusion-positive patients, which were then validated in AML cell lines in the Genomics of Drug Sensitivity database. Altogether, the tool offers a comprehensive suite for pathway-level survival analysis and a user interface for exploring drug targets, molecular features, and immune populations at different resolutions.

Effectiveness and Safety of Prostatic Artery Embolization for the Treatment of Lower Urinary Tract Symptoms from Benign Prostatic Hyperplasia in Men with Concurrent Localized Prostate Cancer.

PURPOSE: To assess the effectiveness and safety of prostatic artery embolization (PAE) on lower urinary tract symptoms (LUTS) in the setting of localized prostate cancer (PCa). MATERIALS AND METHODS: This was a retrospective, single-center, institutional review board-approved study from December 2016 to June 2020 of 21 patients (median age, 72; range, 63-83 years) with moderate LUTS and localized PCa. Clinical effectiveness was evaluated at 6 and 12 weeks using International Prostate Symptom Score (IPSS) and quality of life (QoL) improvement. Seventeen patients were scheduled to receive definitive radiotherapy (RT) after PAE; 13 patients completed RT. Short-term imaging signs of oncologic progression were evaluated at 6 and 12 weeks defined by at least one of the following on magnetic resonance imaging: increased Prostate Imaging-Reporting and Data System score of index lesion(s) to at least 4, new extracapsular extension, seminal vesicle involvement, or pelvic lymphadenopathy. Nonparametric Wilcoxon signed-rank test was used for analysis. RESULTS: IPSS improved by a median of 12 (n = 19, P < .0001) and 14 (n = 14, P < .0001) at 6 and 12 weeks, respectively. QoL improved by a median of 2 (n = 19, P < .0001) and 3 (n = 3, P < .0001) at 6 and 12 weeks. Prostate volume decreased by a median of 24% (n = 19, P < .0001) and 36% (n = 12, P = .015) at 6 and 12 weeks. No patients demonstrated disease progression at 6 (n = 16) or 12 (n = 8) weeks by imaging. No patients experienced increased prostate-specific antigen after RT, grade ≥3 adverse events, or greater genitourinary toxicity. CONCLUSIONS: PAE is effective and safe for the treatment of men with LUTS from benign prostatic hyperplasia in the setting of concomitant, localized, non-obstructive PCa.

Intrinsic radiosensitivity, genomic-based radiation dose and patterns of failure of penile cancer in response to adjuvant radiation therapy.

PURPOSE: Optimal postoperative radiation therapy (PORT) dose is unclear in penile squamous cell carcinoma (PeSCC). Herein, we characterized the radiosensitivity index (RSI) and genomic-adjusted radiation dose (GARD) profiles in a cohort of patients with PeSCC, and assessed the application of GARD to personalize PORT. METHODS: A total of 25 PeSCC samples were identified for transcriptomic profiling. The RSI score and GARD were derived for each sample. A cohort of 34 patients was reviewed for clinical correlation. RESULTS: The median RSI for PeSCC was 0.482 (range 0.215-0.682). The majority (n = 21; 84%) of cases were classified as radioresistant. PeSCC GARD ranged from 9.56 to 38.39 (median 18.25), suggesting variable therapeutic effects from PORT. We further determined the optimal GARD-based RT doses to improve locoregional control. We found that therapeutic benefit was only achieved in 52% of PeSCC lesions with PORT of 50 Gy, in contrast to 84% benefit from GARD-modeled PORT of 66 Gy. In the clinical cohort, the majority of patients presented with pathological N2 or N3 disease (n = 31; 91%) and was treated with adjuvant concurrent platinum-based chemoradiotherapy (CRT, n = 30; 88%). Fourteen of the 34 patients (41%) had locoregional recurrence (LRR), of which half had LRR within six months of completion of PORT. CONCLUSIONS: The majority of PeSCC are intrinsically radioresistant with a low GARD-based therapeutic effect from PORT dose of 50 Gy, consistent with the observed high rate of LRR in the clinical cohort. A GARD-based strategy will allow personalizing PORT dose prescription to individual tumor biology and improve outcomes.

Having Medicaid insurance negatively impacts outcomes in patients with head and neck malignancies.

BACKGROUND: Patients covered by Medicaid insurance appear to have poorer cancer outcomes. Herein, the authors sought to test whether Medicaid was associated with worse outcomes among patients with head and neck cancer (HNC). METHODS: The records of 1698 patients with squamous cell HNC without distant metastatic disease were retrospectively reviewed from an institutional database between 1998 and 2011. At the time of diagnosis, insurance status was categorized as Medicaid, Medicare/other government insurance, or private insurance. Outcomes including locoregional control (LRC) and overall survival (OS) were estimated using the Kaplan-Meier method and Cox regression multivariate analysis (MVA). RESULTS: The median follow-up for all patients was 35 months. Medicaid patients comprised 11% of the population; the remaining patients were privately insured (56%) or had Medicare/government insurance (34%). On MVA, Medicaid patients were younger, were current smokers, had higher tumor T and N classifications, and experienced a longer time from diagnosis to treatment initiation (all P<.005). Medicaid insurance status was associated with a deficit of 13% in LRC (69% vs 82%) and 26% in OS (46% vs 72%) at 3 years (all with P<.001). A time from diagnosis to treatment initiation of >45 days was found to be associated with worse 3-year LRC (77% vs 83%; P = .009) and OS (68% vs 71%; P = .008). On MVA, Medicaid remained associated with a deficit in LRC (P = .002) and OS (P<.001). CONCLUSIONS: Patients with Medicaid insurance more often present with locally advanced HNC and experience a higher rate of treatment delays compared with non-Medicaid patients. Medicaid insurance status appears to be independently associated with deficits in LRC and OS. Improvements in the health care system, such as expediting treatment initiation, may improve the outcomes of patients with HNC. Cancer 2016;122:3529-3537. © 2016 American Cancer Society.

CD147, CD44, and the epidermal growth factor receptor (EGFR) signaling pathway cooperate to regulate breast epithelial cell invasiveness.

The immunoglobulin superfamily glycoprotein CD147 (emmprin; basigin) is associated with an invasive phenotype in various types of cancers, including malignant breast cancer. We showed recently that up-regulation of CD147 in non-transformed, non-invasive breast epithelial cells is sufficient to induce an invasive phenotype characterized by membrane type-1 matrix metalloproteinase (MT1-MMP)-dependent invadopodia activity (Grass, G. D., Bratoeva, M., and Toole, B. P. (2012) Regulation of invadopodia formation and activity by CD147. J. Cell Sci. 125, 777-788). Here we found that CD147 induces breast epithelial cell invasiveness by promoting epidermal growth factor receptor (EGFR)-Ras-ERK signaling in a manner dependent on hyaluronan-CD44 interaction. Furthermore, CD147 promotes assembly of signaling complexes containing CD147, CD44, and EGFR in lipid raftlike domains. We also found that oncogenic Ras regulates CD147 expression, hyaluronan synthesis, and formation of CD147-CD44-EGFR complexes, thus forming a positive feedback loop that may amplify invasiveness. Last, we showed that malignant breast cancer cells are heterogeneous in their expression of surface-associated CD147 and that high levels of membrane CD147 correlate with cell surface EGFR and CD44 levels, activated EGFR and ERK1, and activated invadopodia. Future studies should evaluate CD147 as a potential therapeutic target and disease stratification marker in breast cancer.

Regulation of invadopodia formation and activity by CD147.

A defining feature of malignant tumor progression is cellular penetration through the basement membrane and interstitial matrices that separate various cellular compartments. Accumulating evidence supports the notion that invasive cells employ specialized structures termed invadopodia to breach these structural barriers. Invadopodia are actin-based, lipid-raft-enriched membrane protrusions containing membrane-type-1 matrix metalloproteinase (MT1-MMP; also known as matrix metalloproteinase 14; MMP14) and several signaling proteins. CD147 (emmprin, basigin), an immunoglobulin superfamily protein that is associated with tumor invasion and metastasis, induces the synthesis of various matrix metalloproteinases in many systems. In this study we show that upregulation of CD147 is sufficient to induce MT1-MMP expression, invasiveness and formation of invadopodia-like structures in non-transformed, non-invasive, breast epithelial cells. We also demonstrate that CD147 and MT1-MMP are in close proximity within these invadopodia-like structures and co-fractionate in membrane compartments with the properties of lipid rafts. Moreover, manipulation of CD147 levels in invasive breast carcinoma cells causes corresponding changes in MT1-MMP expression, invasiveness and invadopodia formation and activity. These findings indicate that CD147 regulates invadopodia formation and activity, probably through assembly of MT1-MMP-containing complexes within lipid-raft domains of the invadopodia.

CD147-dependent heterogeneity in malignant and chemoresistant properties of cancer cells.

CD147 (alias emmprin or basigin), an integral plasma membrane glycoprotein and a member of the Ig superfamily, is widespread in normal tissues, but highly up-regulated in many types of malignant cancer cells. CD147 is multifunctional, with numerous binding partners. Recent studies suggest that complexes of CD147 with the hyaluronan receptor CD44 and associated transporters and receptor tyrosine kinases are enriched in the plasma membrane of cancer stem-like cells. Here, we show that subpopulations of tumor cell lines constitutively expressing high levels of cell-surface CD147 exhibit cancer stem-like cell properties; that is, they exhibit much greater invasiveness, anchorage-independent growth, spheroid formation, and drug resistance in vitro and higher tumorigenicity in vivo than those constitutively expressing low levels of cell-surface CD147. Primary CD147-rich cell subpopulations derived from mouse mammary adenocarcinomas also exhibit high levels of invasiveness and spheroid-forming capacity, whereas CD147-low cells do not. Moreover, localization at the plasma membrane of CD44, the EGF receptor, the ABCB1 and ABCG2 drug transporters, and the MCT4 monocarboxylate transporter is elevated in cells constitutively expressing high levels of cell-surface CD147. These results show that CD147 is associated with assembly of numerous pro-oncogenic proteins in the plasma membrane and may play a fundamental role in properties characteristic of cancer stem-like cells.

Multi-institutional experience of MR-guided stereotactic body radiation therapy for adrenal gland metastases.

Purpose: While dose escalation is associated with improved local control (LC) for adrenal gland metastases (AGMs), the proximity of gastrointestinal (GI) organs-at-risk (OARs) limits the dose that can be safely prescribed via CT-based stereotactic body radiation therapy (SBRT). The advantages of magnetic resonance-guided SBRT (MRgSBRT), including tumor tracking and online plan adaptation, facilitate safe dose escalation. Methods: This is a multi-institutional review of 57 consecutive patients who received MRgSBRT on a 0.35-T MR linac to 61 AGMs from 2019 to 2021. The Kaplan-Meier method was used to estimate overall survival (OS), progression-free survival (PFS), and LC, and the Cox proportional hazards model was utilized for univariate analysis (UVA). Results: Median follow up from MRgSBRT was 16.4 months (range [R]: 1.1-39 months). Median age was 67 years (R: 28-84 years). Primary histologies included non-small cell lung cancer (N = 38), renal cell carcinoma (N = 6), and melanoma (N = 5), amongst others. The median maximum diameter was 2.7 cm (R: 0.6-7.6 cm), and most AGMs were left-sided (N = 32). The median dose was 50 Gy (R: 30-60 Gy) in 5-10 fractions with a median BED10 of 100 Gy (R: 48-132 Gy). 45 cases (74 %) required adaptation for at least 1 fraction (median: 4 fractions, R: 0-10). Left-sided AGMs required adaptation in at least 1 fraction more frequently than right-sided AGMs (88 % vs 59 %, p = 0.018). There were 3 cases of reirradiation, including 60 Gy in 10 fractions (N = 1) and 40 Gy in 5 fractions (N = 2). One-year LC, PFS, and OS were 92 %, 52 %, and 78 %, respectively. On UVA, melanoma histology predicted for inferior 1-year LC (80 % vs 93 %, p = 0.012). There were no instances of grade 3+ toxicity. Conclusions: We demonstrate that MRgSBRT achieves favorable early LC and no grade 3 + toxicity despite prescribing a median BED10 of 100 Gy to targets near GI OARs.

Multiplex Immunofluorescence Captures Progressive Immune Exhaustion with Advancing Penile Squamous Cell Cancer Stage.

Penile squamous cell carcinoma (PSCC) is a rare and deadly malignancy. Therapeutic advances have been stifled by a poor understanding of disease biology. Specifically, the immune microenvironment is an underexplored component in PSCC and the activity of immune checkpoint inhibitors observed in a subset of patients suggests immune escape may play an important role in tumorigenesis. Herein, we explored for the first time the immune microenvironment of 57 men with PSCC and how it varies with the presence of human papillomavirus (HPV) infection and across tumor stages using multiplex immunofluorescence of key immune cell markers. We observed an increase in the density of immune effector cells in node-negative tumors and a progressive rise in inhibitory immune players such as type 2 macrophages and upregulation of the PD-L1 checkpoint in men with N1 and N2-3 disease. There were no differences in immune cell densities with HPV status.

Comparative Effectiveness of Neoadjuvant Pembrolizumab Versus Cisplatin-based Chemotherapy or Upfront Radical Cystectomy in Patients with Muscle-invasive Urothelial Bladder Cancer.

BACKGROUND: Recent progresses in the use of immune checkpoint inhibitor (ICI) have challenged the therapeutic standards in patients with muscle-invasive urothelial bladder carcinoma (MIBC). OBJECTIVE: To compare neoadjuvant pembrolizumab followed by radical cystectomy (RC) versus neoadjuvant chemotherapy (NAC) and RC or upfront RC, according to cisplatin eligibility. DESIGN, SETTING, AND PARTICIPANTS: We conducted two separate analyses for cisplatin-eligible and cisplatin-ineligible cT2-4N0M0 MIBC patients. We used a propensity score adjustment that relied on inverse probability of treatment-weighting (IPTW). INTERVENTION: Pembrolizumab within the PURE-01 trial, and NAC and RC or upfront RC from a high-volume tertiary care referral center. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint in both analyses was event-free survival (EFS), defined as freedom from recurrence, and/or death from any cause indexed from the date of treatment initiation or RC. The secondary endpoints included EFS in propensity score-matched patients, pathologic response rate, and recurrence-free survival (RFS) after RC. RESULTS AND LIMITATIONS: A total of 458 patients who underwent RC, with or without NAC, at Moffitt Cancer Center between October 2005 and October 2020, and 146 patients enrolled in PURE-01 were analyzed. In cisplatin-ineligible patients, EFS was superior in those receiving pembrolizumab (p < 0.001). The estimated 3-yr EFS was 77.8% (95% confidence interval [CI]: 63.5-95.2) for pembrolizumab and RC, and 36.1% (95% CI: 28.6-45.5) for upfront RC. EFS remained superior in those receiving neoadjuvant ICI (NICI) following IPTW (p < 0.001). In cisplatin-eligible patients, EFS was superior in those receiving pembrolizumab and RC (p < 0.001). The estimated 3-yr EFS was 86.9% (95% CI: 80.9-93.3) for pembrolizumab and 63.5% (95% CI: 56.5-71.4) for NAC. EFS remained superior in those receiving NICI following IPTW (p < 0.001). Pathologic responses and RFS in pembrolizumab-treated patients were also superior to those in NAC-treated patients. Results are limited by the retrospective nature of the study. CONCLUSIONS: In the first ever reported comprehensive comparison of outcomes between neoadjuvant ICI and NAC, followed by RC, or upfront RC, we report increased responses and improved oncologic outcomes with neoadjuvant ICI in patients with MIBC. PATIENT SUMMARY: We compared the results obtained from the use of pembrolizumab and radical cystectomy with standard-of-care treatments in patients with bladder carcinoma infiltrating the muscle layer. We reported increased response and survival rates possibilities with the use of immunotherapy, anticipating the possibility to set new therapeutic standards in these patients, pending the results of ongoing randomized studies.

Novel Use of Circulating Tumor DNA to Identify Muscle-invasive and Non-organ-confined Upper Tract Urothelial Carcinoma.

BACKGROUND: Optimal patient selection for neoadjuvant chemotherapy prior to surgical extirpation is limited by the inaccuracy of contemporary clinical staging methods in high-risk upper tract urothelial carcinoma (UTUC). OBJECTIVE: To investigate whether the detection of plasma circulating tumor DNA (ctDNA) can predict muscle-invasive (MI) and non-organ-confined (NOC) UTUC. DESIGN, SETTING, AND PARTICIPANTS: Plasma cell-free DNA was prospectively collected from chemotherapy-naïve, high-risk UTUC patients undergoing surgical extirpation and sequenced using a 152-gene panel and low-pass whole-genome sequencing. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: To test for concordance, whole-exome sequencing was performed on matching tumor samples. The performance of ctDNA for predicting MI/NOC UTUC was summarized using the area under a receiver-operating curve, and a variant count threshold for predicting MI/NOC disease was determined by maximizing Youden's J statistic. Kaplan-Meier methods estimated survival, and Mantel-Cox log-rank testing assessed the association between preoperative ctDNA positivity and clinical outcomes. RESULTS AND LIMITATIONS: Of 30 patients enrolled prospectively, 14 were found to have MI/NOC UTUC. At least one ctDNA variant was detected from 21/30 (70%) patients, with 52% concordance with matching tumor samples. Detection of at least two panel-based molecular alterations yielded 71% sensitivity at 94% specificity to predict MI/NOC UTUC. Imposing this threshold in combination with a plasma copy number burden score of >6.5 increased sensitivity to 79% at 94% specificity. Furthermore, the presence of ctDNA was strongly prognostic for progression-free survival (PFS; 1-yr PFS 69% vs 100%, p < 0.001) and cancer-specific survival (CSS; 1-yr CSS 56% vs 100%, p = 0.016). CONCLUSIONS: The detection of plasma ctDNA prior to extirpative surgery was highly predictive of MI/NOC UTUC and strongly prognostic of PFS and CSS. Preoperative ctDNA demonstrates promise as a biomarker for selecting patients to undergo neoadjuvant chemotherapy prior to nephroureterectomy. PATIENT SUMMARY: Here, we show that DNA from upper tract urothelial tumors can be detected in the blood prior to surgical removal of the kidney or ureter. This circulating tumor DNA can be used to predict that upper tract urothelial carcinoma is invasive into the muscular lining of the urinary tract and may help identify those patients who could benefit from chemotherapy prior to surgery.

Sphingosine 1-phosphate (S1P) carrier-dependent regulation of endothelial barrier: high density lipoprotein (HDL)-S1P prolongs endothelial barrier enhancement as compared with albumin-S1P via effects on levels, trafficking, and signaling of S1P1.

Sphingosine 1-phosphate (S1P) is a blood-borne lysosphingolipid that acts to promote endothelial cell (EC) barrier function. In plasma, S1P is associated with both high density lipoproteins (HDL) and albumin, but it is not known whether the carriers impart different effects on S1P signaling. Here we establish that HDL-S1P sustains EC barrier longer than albumin-S1P. We showed that the sustained barrier effects of HDL-S1P are dependent on signaling by the S1P receptor, S1P1, and involve persistent activation of Akt and endothelial NOS (eNOS), as well as activity of the downstream NO target, soluble guanylate cyclase (sGC). Total S1P1 protein levels were found to be higher in response to HDL-S1P treatment as compared with albumin-S1P, and this effect was not associated with increased S1P1 mRNA or dependent on de novo protein synthesis. Several pieces of evidence indicate that long term EC barrier enhancement activity of HDL-S1P is due to specific effects on S1P1 trafficking. First, the rate of S1P1 degradation, which is proteasome-mediated, was slower in HDL-S1P-treated cells as compared with cells treated with albumin-S1P. Second, the long term barrier-promoting effects of HDL-S1P were abrogated by treatment with the recycling blocker, monensin. Finally, cell surface levels of S1P1 and levels of S1P1 in caveolin-enriched microdomains were higher after treatment with HDL-S1P as compared with albumin-S1P. Together, the findings reveal S1P carrier-specific effects on S1P1 and point to HDL as the physiological mediator of sustained S1P1-PI3K-Akt-eNOS-sGC-dependent EC barrier function.

Towards Data Driven RT Prescription: Integrating Genomics into RT Clinical Practice.

The genomic era has significantly changed the practice of clinical oncology. The use of genomic-based molecular diagnostics including prognostic genomic signatures and new-generation sequencing has become routine for clinical decisions regarding cytotoxic chemotherapy, targeted agents and immunotherapy. In contrast, clinical decisions regarding radiation therapy (RT) remain uninformed about the genomic heterogeneity of tumors. In this review, we discuss the clinical opportunity to utilize genomics to optimize RT dose. Although from the technical perspective, RT has been moving towards a data-driven approach, RT prescription dose is still based on a one-size-fits all approach, with most RT dose based on cancer diagnosis and stage. This approach is in direct conflict with the realization that tumors are biologically heterogeneous, and that cancer is not a single disease. Here, we discuss how genomics can be integrated into RT prescription dose, the clinical potential for this approach and how genomic-optimization of RT dose could lead to new understanding of the clinical benefit of RT.

An Analysis of Nectin-4 (PVRL4) in Penile Squamous Cell Carcinoma.

Penile squamous cell carcinoma (PSCC) remains a worldwide healthcare concern with poor outcomes and inadequate therapeutic options. Molecular characterization continues to describe the intricacies of PSCC biology, which vary by human papillomavirus (HPV) infection. Despite these advancements in our understanding, utilization of targeted therapies remains limited and underexplored. In this study, we evaluated the transcript and protein expression of Nectin-4 (PVRL4) in PSCC tumors and evaluated whether this is related to tumor features or clinical outcomes. Using two separate PSCC cohorts, we demonstrate that the majority of tumors have active transcription of Nectin-4. We then validated our findings using immunohistochemistry in a tissue microarray representing 57 patients with PSCC. We identified that Nectin-4 was expressed at higher levels in patients with high-risk HPV infection. No significant differences were identified in tumor characteristics or various clinical endpoints when comparing tumors with high and low Nectin-4 expression. This study demonstrates that Nectin-4 is expressed in PSCC and may represent a novel therapeutic target. Patient summary: In this study, we evaluated the expression of Nectin-4, a cell surface protein, in tumors from patients with nonmetastatic penile squamous cell carcinoma (PSCC). To our knowledge, this is the first study to describe elevated expression of Nectin-4 in PSCC, which may suggest its utility as a therapeutic target.

[Proposal for participation in intensive care and emergency medicine studies for patients unable to give informed consent (Cologne Model)]. / Vorschlag für ein Verfahren zur Teilnahme an intensiv- und notfallmedizinischen Studien bei nichteinwilligungsfähigen Patient*innen (Kölner Modell).

When conducting clinical trials in intensive care and emergency medicine, physicians, ethics committees, and legal experts have differing views regarding the inclusion of patients who are incapable of giving consent. These different views on the participation of patients who are not capable of giving consent also complicate how clinical trials are prepared and conducted. Based on the results of a literature search, a consensus model (Cologne Model) was developed by physicians performing clinical research, ethics committees, and lawyers in order to provide patients, those scientifically responsible for the study, ethics committees, and probate (guardianship) judges with a maximum of patient safety and legal certainty, while simultaneously enabling scientific research.

The Prognostic Role of Human Papillomavirus and p16 Status in Penile Squamous Cell Carcinoma-A Systematic Review.

PSCC is a rare cancer, with approximately half of all cases related to HPV. While HPV and p16 IHC testing have proven their prognostic value for oropharyngeal cancer, this is not yet established for PSCC. The current level of evidence exploring the relation between PSCC and HPV is moderate, so we conducted a systematic review following PRISMA guidelines to evaluate the prognostic role of HPV and p16 IHC in PSCC clinical outcomes. We searched the PubMed, Embase, and Cochrane databases and identified 34 relevant studies that met our inclusion criteria. Of these, 33 were retrospective cohort studies, and one was a cross-sectional study. Nine studies reported that HPV-positive and p16-positive PSCC had better overall survival (OS) and disease-free survival (DFS). This study highlights the need for a meta-analysis to determine the role of routine HPV status or p16 staining testing as part of the initial diagnosis and staging of PSCC patients worldwide.

DRPPM-PATH-SURVEIOR: Plug-and-Play Survival Analysis of Pathway-level Signatures and Immune Components.

Pathway-level survival analysis offers the opportunity to examine molecular pathways and immune signatures that influence patient outcomes. However, available survival analysis algorithms are limited in pathway-level function and lack a streamlined analytical process. Here we present a comprehensive pathway-level survival analysis suite, DRPPM-PATH-SURVEIOR, which includes a Shiny user interface with extensive features for systematic exploration of pathways and covariates in a Cox proportional-hazard model. Moreover, our framework offers an integrative strategy for performing Hazard Ratio ranked Gene Set Enrichment Analysis (GSEA) and pathway clustering. As an example, we applied our tool in a combined cohort of melanoma patients treated with checkpoint inhibition (ICI) and identified several immune populations and biomarkers predictive of ICI efficacy. We also analyzed gene expression data of pediatric acute myeloid leukemia (AML) and performed an inverse association of drug targets with the patient's clinical endpoint. Our analysis derived several drug targets in high-risk KMT2A-fusion-positive patients, which were then validated in AML cell lines in the Genomics of Drug Sensitivity database. Altogether, the tool offers a comprehensive suite for pathway-level survival analysis and a user interface for exploring drug targets, molecular features, and immune populations at different resolutions.

Survival Benefits of Adjuvant Chemotherapy for Positive Soft Tissue Surgical Margins Following Radical Cystectomy in Bladder Cancer with Extravesical Extension.

INTRODUCTION AND OBJECTIVE: Muscle invasive bladder cancer with extravesical extension is an aggressive disease entity that requires multimodal therapy. The benefits of adjuvant chemotherapy (AC) in patients with a positive soft-tissue surgical margin (STSM), however, are relatively unknown due to exclusion of this population in randomized controlled trials of AC. We sought to define survival benefits in this patient population through our institutional bladder cancer database. METHODS: Retrospective review of all patients undergoing radical cystectomy for urothelial carcinoma of the bladder from 2004-2020 with ≥pT3b disease irrespective of neoadjuvant chemotherapy (NAC) use was conducted. Progression-free survival (PFS) and overall survival (OS) estimates were obtained using the Kaplan-Meier method with log-rank test, and the Cox-proportional hazards model was used to identify predictors of improved PFS and OS. AC was defined by any chemotherapy use within 90 days of cystectomy, regardless of STSM status. RESULTS: 476 patients with pT3b disease or worse were identified. Median follow-up was 12.3 months. An amount of 21% of patients were treated with AC. An amount of 24% of patients had positive STSM. Median OS for patients with positive STSM was 8.4 months [95% CI 7-11.5] and 18.3 months [95% CI 15.6-20.8] (p < 0.001) for patients with negative STSM. In the overall cohort, positive STSM (HR 1.93, 95% CI 1.45-2.57, p < 0.001), AC use (HR 0.68, 95% CI 0.51-0.90, p = 0.007), and pN1-3 disease (HR 1.47, 95% CI 1.16-1.87, p = 0.002) were independent predictors of OS when adjusted for performance status, pT-stage, and neoadjuvant chemotherapy use. In patients with positive STSM, median survival was seven months [95% CI 5.2-8.4] without AC, compared to 16.2 months [95% CI 11.5-52.5] with AC (p = 0.0038). For patients with negative STSM, median survival was 17.4 months [95% CI 14-20.1] without AC compared to 22.3 months [95% CI 17.2-36.9] with AC (p = 0.23). In patients with positive STSM, AC use was the only factor associated with an OS benefit with a HR of 0.41 (95% CI 0.21-0.78, p = 0.007). In patients with negative STSM, pT4 and pN1-3 disease were the only factors associated with worse overall survival with a HR of 1.32 (95% CI 1.00-1.74, p = 0.050) and 1.97 (95% CI 1.49-2.60, p < 0.001), respectively. CONCLUSIONS: Administration of adjuvant chemotherapy is of particular benefit in patients with positive STSM following radical cystectomy for gross extravesical disease. Positive STSM may be a representative of "early metastatic" or micrometastatic disease.