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Background: Neuroendocrine carcinoma of the bladder (NEC-bladder) is a rare disease with poor outcomes and variable treatment approaches., Materials and Methods: Patients with localized NEC-bladder treated with surgery or radiation between 2001-2021 were retrospectively identified. Rates of pathologic complete response (pCR) and downstaging were evaluated following NAC in surgically-treated patients. Progression-free survival (PFS) and overall survival (OS) were analyzed with univariable (log-rank) and multivariable (MVA; Cox regression) methods., Results: Sixty-five patients were identified having a median age of 73. The tumor histology distribution was small cell (64.6%) or urothelial with NE differentiation (35.4%). Most patients (69.2%) received NAC. Patients received local therapy by surgery (78.5%) or chemoradiation (21.5%). The majority (62.7%) of surgical patients had ≥ pT2 with 37.3% having nodal involvement (pN+). The pCR and downstaging rates were 21.6% and 35.1%, respectively. At a median follow-up of 60 months (m), the median PFS and OS were 16.4m and 25.9m, respectively. NAC improved PFS (p=0.04) and downstaging improved PFS (p=0.012) and OS (p<0.001). Patients receiving NAC with ypN0 vs. ypN+ had median OS of 69.9m vs 15.3m, respectively (p<0.001). MVA identified receipt of NAC and pN as predictors of PFS; pN was predictive of OS. No differences in PFS or OS were seen between histology of primary tumor. The brain metastasis rate was 10.8% with all patients having small cell histology., Conclusions: Optimized therapy in NEC-bladder includes NAC followed by local consolidation. Ascertainment of ypN0 is associated with long term survival, while pN+ remains associated with poor outcomes., Competing Interests: Disclosure Austin Sim: leadership role (ASTRO non-voting member board of directors). Jingsong Zhang: honoraria (Seagen); participation on Data Safety Monitoring Board (Seagen). Philippe E. Spiess: NCCN panel member for bladder and penile cancer. Roger Li: research support (predicine; veracyte; CG oncology; Valar Labs; Merck); clinical trial protocol committee (CG oncology; Merck; Janssen); Scientific advisor/consultant (Bristol Myers Squibb; Merck, Fergene, Arquer Diagnostics, Urogen Pharma, Lucence, CG Oncology, Janssen, Thericon); Honoraria (SAI MedPartners, Solstice Health Communications, Putnam Associates, UroToday). Javier F. Torres-Roca: intellectual property (RSI) and stock in Cvergenx . G. Daniel Grass: research support (ArteraAI). All other authors state that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: In squamous cell carcinoma of the penis (PeCa), treatment options for primary tumors vary by disease stage and may include surgery, radiation, topical chemotherapy, or laser excision. This review aims to highlight the current evidence on the value of radiotherapy as an organ-preserving strategy in primary PeCa., Material and Methods: Manuscripts on primary PeCa treatment with external beam radiotherapy (EBRT) and brachytherapy were evaluated via Scopus, PubMed/MEDLINE, and Web of Science TM (2013-2023) to assess their efficacy and safety. Animal studies, studies with <5 patients, and case reports were excluded., Results: Radiotherapy offers the potential for organ preservation with tumor control rates comparable to radical surgery, while disease-specific survival rates up to 70 % were experienced with EBRT. Brachytherapy (BT) is the preferred method of irradiation for glans-limited tumors, whereas a higher relapse risk is expected for tumors >4 cm. BT shows 73 % amputation-free survival at 8-10 years and 81 % progression-free survival at 5-10 years. Compared with BT, total amputation significantly improves 5-year disease-free survival rate. BT offers a superior 5-year local control and penile preservation rates compared to EBRT. Common acute toxicities of brachytherapy include radiodermatitis, sterile urethritis, and urethral adhesions. The primary late adverse events of BT are soft tissue necrosis (0-31 %) and meatal stenosis (0-43 %)., Conclusion: BT is a favorable radiation modality, offering an efficient and conservative approach. HDR BT is favored for its enhanced dose distribution and radiation protection. Collaboration between radiation oncologists and urologists is essential in order to provide an optimal patient selection and manage toxicities thus optimizing patient outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Objectives: Bacillus anthracis clinical breakpoints, representing a systematic approach to guide clinicians in selecting the most appropriate antimicrobial treatments, are not part of the guidance from the European Committee on Antimicrobial Susceptibility Testing (EUCAST). This is because defined distributions of MIC values and of epidemiological cut-off values (ECOFFs) have been lacking. In this study, a Europe-wide network of laboratories in collaboration with EUCAST, aimed at establishing standardized antimicrobial susceptibility testing methods, wild-type MIC distributions, and ECOFFs for ten therapeutically relevant antimicrobials., Methods: About 335 B. anthracis isolates were tested by broth microdilution and disc diffusion methodologies. MIC and inhibition zone diameters were curated according to EUCAST SOP 10.2 and the results were submitted to EUCAST for ECOFFs and clinical breakpoint determination., Results: Broth microdilution and disc diffusion data distributions revealed putative wild-type distributions for the tested agents. For each antimicrobial agent, ECOFFs were defined. Three highly resistant strains with MIC values of 32 mg/L benzylpenicillin were found. MIC values slightly above the defined ECOFFs were observed in a few isolates, indicating the presence of resistance mechanisms to doxycycline, tetracycline, and amoxicillin., Discussion: B. anthracis antimicrobial susceptibility testing results were used by EUCAST to determine ECOFFs for ten antimicrobial agents. The MIC distributions were used in the process of determining clinical breakpoints. The ECOFFs can be used for the sensitive detection of isolates with resistance mechanisms, and for monitoring resistance development. Genetic changes causing phenotypic shifts in isolates displaying slightly elevated MICs remain to be investigated., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Radiotherapy efficacy is the result of radiation-mediated cytotoxicity coupled with stimulation of antitumor immune responses. We develop an in silico 3-dimensional agent-based model of diverse tumor-immune ecosystems (TIES) represented as anti- or pro-tumor immune phenotypes. We validate the model in 10,469 patients across 31 tumor types by demonstrating that clinically detected tumors have pro-tumor TIES. We then quantify the likelihood radiation induces antitumor TIES shifts toward immune-mediated tumor elimination by developing the individual Radiation Immune Score (iRIS). We show iRIS distribution across 31 tumor types is consistent with the clinical effectiveness of radiotherapy, and in combination with a molecular radiosensitivity index (RSI) combines to predict pan-cancer radiocurability. We show that iRIS correlates with local control and survival in a separate cohort of 59 lung cancer patients treated with radiation. In combination, iRIS and RSI predict radiation-induced TIES shifts in individual patients and identify candidates for radiation de-escalation and treatment escalation. This is the first clinically and biologically validated computational model to simulate and predict pan-cancer response and outcomes via the perturbation of the TIES by radiotherapy., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: Cancer sequencing efforts have revealed that cancer is the most complex and heterogeneous disease that affects humans. However, radiation therapy (RT), one of the most common cancer treatments, is prescribed on the basis of an empirical one-size-fits-all approach. We propose that the field of radiation oncology is operating under an outdated null hypothesis: that all patients are biologically similar and should uniformly respond to the same dose of radiation., Methods: We have previously developed the genomic-adjusted radiation dose, a method that accounts for biological heterogeneity and can be used to predict optimal RT dose for an individual patient. In this article, we use genomic-adjusted radiation dose to characterize the biological imprecision of one-size-fits-all RT dosing schemes that result in both over- and under-dosing for most patients treated with RT. To elucidate this inefficiency, and therefore the opportunity for improvement using a personalized dosing scheme, we develop a patient-specific competing hazards style mathematical model combining the canonical equations for tumor control probability and normal tissue complication probability. This model simultaneously optimizes tumor control and toxicity by personalizing RT dose using patient-specific genomics., Results: Using data from two prospectively collected cohorts of patients with NSCLC, we validate the competing hazards model by revealing that it predicts the results of RTOG 0617. We report how the failure of RTOG 0617 can be explained by the biological imprecision of empirical uniform dose escalation which results in 80% of patients being overexposed to normal tissue toxicity without potential tumor control benefit., Conclusions: Our data reveal a tapestry of radiosensitivity heterogeneity, provide a biological framework that explains the failure of empirical RT dose escalation, and quantify the opportunity to improve clinical outcomes in lung cancer by incorporating genomics into RT., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: The appropriate follow-up frequency after definitive chemoradiotherapy (CRT) for locally advanced non-small-cell lung cancer patients is unknown. Although surveillance guidelines have been proposed, very few data support current recommendations. Here we analyze relapse events after CRT and investigate whether symptomatic relapses versus those detected by surveillance imaging influences outcomes., Patients and Methods: Stage III non-small-cell lung cancer patients treated with CRT at our institution between 2005 and 2014 were retrospectively analyzed. Relapse events were grouped into posttreatment intervals and analyzed with cumulative tables. Time to relapse and overall survival (OS) were compared between patients with relapse detection via symptomatic presentation versus surveillance imaging., Results: A total of 211 patients were identified for analysis. The median follow-up was 43 months for patients alive at the time of analysis. The median age was 63 years, and equal proportions had IIIA or IIIB disease. A total of 135 patients (64%) experienced disease relapse, and of these, 74% did so within 12 months. In those who did not experience relapse at ≤ 12 months, 16%, 6%, and < 5% experienced relapse during 12 to 24, 24 to 36, and > 36 months of follow-up, respectively. In patients with relapse, 56% presented symptomatically, which led to inferior median OS compared to those identified by surveillance imaging (23 vs. 36 months; P = .013)., Conclusion: This study identified that most relapses occur within 1 year of completing CRT, and approximately half of these occur within 6 months. A symptomatic relapse led to inferior OS. More aggressive surveillance imaging may therefore identify asymptomatic relapses that are amenable to earlier salvage therapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: We assessed the radiosensitivity of lung metastases on the basis of primary histologic type by using a validated gene signature and model lung metastases for the gnomically adjusted radiation dose (GARD)., Methods: Tissue samples were identified from our prospective observational protocol. The radiosensitivity index (RSI) 10-gene assay was run on samples and calculated alongside the GARD by using the previously published algorithms. A cohort of 105 patients with 137 lung metastases treated with stereotactic body radiation therapy (SBRT) at our institution was used for clinical correlation., Results: A total of 138 unique metastatic lung lesions from our institution's tissue biorepository were identified for inclusion. There were significant differences in the RSI of lung metastases on the basis of histology. In order of decreasing radioresistance, the median RSIs for the various histologic types of cancer were endometrial adenocarcinoma (0.49), soft-tissue sarcoma (0.47), melanoma (0.44), rectal adenocarcinoma (0.43), renal cell carcinoma (0.33), head and neck squamous cell cancer (0.33), colon adenocarcinoma (0.32), and breast adenocarcinoma (0.29) (p = 0.002). We modeled the GARD for these samples and identified the biologically effective dose necessary to optimize local control. The 12- and 24-month Kaplan-Meier rates of local control for radioresistant versus radiosensitive histologic types from our clinical correlation cohort after lung SBRT were 92%/87% and 100%, respectively (p = 0.02)., Conclusions: In this analysis, we have noted significant differences in radiosensitivity on the basis of primary histologic type of lung metastases and have modeled the biologically effective dose necessary to optimize local control. This study suggests that primary histologic type may be an additional factor to consider in selection of SBRT dose to the lung and that dose personalization may be feasible., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Infections caused by endospore-forming bacteria have been associated with severe illness and death among persons who inject drugs. Analysis of the bacteria residing in heroin has thus been biased towards species that affect human health. Similarly, exploration of the bacterial diversity of seized street market heroin correlated with the skin microflora of recreational heroin users insofar as different Staphylococus spp. or typical environmental endospore formers including Bacillus cereus and other Bacilli outside the B. cereus sensu lato group as well as diverse Clostridia were identified. In this work 82 samples of non-street market ("wholesale") heroin originating from the German Federal Criminal Police Office's heroin analysis program seized during the period between 2009 and 2014 were analyzed for contaminating bacteria. Without contact with the end user and with only little contaminations introduced by final processing, adulteration and cutting this heroin likely harbors original microbiota from the drug's original source or trafficking route. We found this drug to be only sparsely populated with retrievable heterotrophic, aerobic bacteria. In total, 68 isolates were retrieved from 49 out of 82 samples analyzed (60% culture positive). All isolates were endospore-forming, Gram-positive Bacilli. Completely absent were non-endospore-formers or Gram-negatives. The three most predominant species were Bacillus clausii, Bacillus (para)licheniformis, and Terribacillus saccharophilus. Whole genome sequencing of these 68 isolates was performed using Illumina technology. Sequence data sets were assembled and annotated using an automated bioinformatics pipeline. Average nucleotide identity (ANI) values were calculated for all draft genomes and all close to identical genomes (ANI>99.5%) were compared to the forensic data of the seized drug, showing positive correlations that strongly warrant further research on this subject., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Major determinants that influence negative outcome in cancer patients are the abilities of cancer cells to resist current therapies and to invade surrounding host tissue, consequently leading to local and metastatic dissemination. Hyaluronan (HA), a prominent constituent of the tumor microenvironment, not only provides structural support but also interacts with cell surface receptors, especially CD44, that influence cooperative signaling pathways leading to chemoresistance and invasiveness. CD147 (emmprin; basigin) is a member of the Ig superfamily that has also been strongly implicated in chemoresistance and invasiveness. CD147 both regulates HA synthesis and interacts with the HA receptors, CD44, and LYVE-1. Increased CD147 expression induces formation of multiprotein complexes containing CD44 (or LYVE-1) as well as members of the membrane-type matrix metalloproteinase, receptor tyrosine kinase, ABC drug transporter, or monocarboxylate transporter families, which become assembled in specialized lipid raft domains along with CD147 itself. In each case, multivalent HA-receptor interactions are essential for formation or stabilization of the lipid raft complexes and for downstream signaling pathways or transporter activities that are driven by these complexes. We conclude that cooperativity between HA, HA receptors, and CD147 may be a major driver of the interconnected pathways of invasiveness and chemoresistance widely critical to malignancy., (© 2014 Elsevier Inc. All rights reserved.)

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., (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The interactions between the plasmid-borne copper resistance determinant, pco, and the main copper export system in Escherichia coli have been investigated and no direct interaction has been found. The PcoE and PcoC proteins are periplasmic and PcoC binds one Cu ion per protein molecule. PcoA is also periplasmic and can substitute for the chromosomally encoded CueO protein. The pco determinant is proposed to exert its effect through periplasmic handling of excess copper ions and to increase the level of resistance to copper ions above that conferred by copA alone., ((c) 2002 Elsevier Science (USA).)

The putative multi-copper oxidase CueO had previously been implicated in intrinsic copper resistance in Escherichia coli. In this report we showed that the presence of CueO in the periplasm protected alkaline phosphatase from copper-induced damage. CueO contained four copper atoms per molecule and displayed spectroscopic properties typical of blue copper oxidases. CueO catalyzed the oxidation of p-phenylenediamine (pPD), 2,6-dimethoxyphenol (DMP) and exhibited ferroxidase activity in vitro., (Copyright 2001 Academic Press.)

Escherichia coli CopA is a Cu(I)-translocating P-type ATPase that is involved in copper export and resistance. It is an orthologue of the human Menkes and Wilson disease-related proteins. Each of those two human copper pumps has six N-terminal Cys(X)(2)Cys sequences, but their function in transport is unclear. CopA has two N-terminal Cys(X)(2)Cys sequences, GLSC(14)GHC(17) and GMSC(110)ASC(113). The requirement of these cysteine motifs was investigated by mutagenesis of the codons for all four cysteine residues, singly and in combination. Cells of a copA deletion strain expressing genes for the mutant genes were nearly as resistant to copper as the wild type. In addition, everted membrane vesicles from cells expressing the mutant copA genes exhibited ATP-coupled accumulation of copper similar to that of the wild type. The results indicate that neither of two N-terminal Cys(X)(2)Cys motifs is required for either resistance or transport., (Copyright 2001 Academic Press.)

Current understanding of the mechanism of corneal penetration by organic molecules proposes the epithelial layer as the rate-limiting membrane for water-soluble compounds and the stromal layer as rate limiting for lipid-soluble compounds. This suggests that the relationship between corneal permeability and the logarithm of oil/water partition coefficients, for a series of drugs, should not be the typical, single, continuous, parabolic-shaped curve. Corneal penetration studies have been conducted in unanesthetized albino rabbits using various organic compounds, representing five orders of magnitude in partition coefficient, at a constant concentration of 4 X 10(-5) M dispensed in either a 1- or 90-centipoise (cps) solution. It has been shown that for non-ionizable compounds, a pair of bell-shaped curves were generated, one for lipid-soluble and one for water-soluble compounds. Small water-soluble species demonstrate very high apparent permeabilities, which may relate to the presence of aqueous pores or other paracellular drug movement. Penetration of ionizable compounds does not appear to correlate well with the structural relationships invoked for un-ionized compounds. Consistent with the proposed mechanisms of corneal penetration, oil-soluble drug substances show no improvement in drug bioavailability when dosed from a 90-cps solution, and water-soluble drugs show a modest improvement in ocular drug bioavailability. Small water-soluble substances demonstrate no improvement due to their already high bioavailability. The importance of nonproductive absorption and precorneal drainage on bioavailability is addressed.

Corneal penetration studies were conducted in unanesthetized albino rabbits using various organic compounds representing both polar and nonpolar species. Very low molecular weight compounds demonstrate rapid uptake into the aqueous humor despite the lipid-like barrier imposed by the corneal epithelium. Evidence that these compounds may have access to a diffusional channel for corneal transport is presented. In vitro permeability studies were also conducted in an effort to quantitate the corneal diffusion of compounds covering a range of molecular weights and partition coefficients; the results corresponded well with the results of in vivo experiments. Calculations of energies of activation, taken from Arrhenius plots, indicate that the diffusion of drug across the cornea may be by two different mechanisms that depend on the physical-chemical characteristics of the perfusant. One mechanism appears similar to drug movement in an aqueous environment and is characterized by an activation energy similar to that for diffusion in water. The other relates to the expected partitioning of a compound across cellular membranes represented by a relatively high activation energy for diffusion. For hyrdophilic compounds, the epithelium appears to be rate limiting to drug movement, whereas for hydrophobic compounds, the stroma is rate limiting. In the presence of calcium-chelating agents, glycerol demonstrated an increase in corneal penetration in vivo. This effect appears to be reversible at specific concentrations of chelator. In contrast, divalent cations reduced corneal penetration of glycerol. The known calcium chelator EDTA was shown to penetrate the cornea, conjunctiva, and iris/ciliary body from a topically applied dose. The implications of this observation pertain to toxicity effects when EDTA is incorporated into ocular drug products for stability purposes, or novel stratagems for improving ocular bioavailability of topically applied drugs are employed. The addition of calcium-chelating agents to in vivo mounted corneas demonstrated increases in permeability of the cornea to glycerol which were directly related to the concentration of chelating agent used. These results paralleled the findings of similar in vivo studies. The results of these studies are consistent with a currently proposed 'pore' model for the penetration of drugs through the cornea which demonstrates both a partition coefficient and molecular weight dependency on the permeability of the cornea to transported compounds.

Ultrastructure analysis was conducted in an effort to augment the results of classical kinetic studies. Scanning electron microscopy (SEM) allowed visual inspection of cellular junctions on corneal epithelium and endothelium. The addition of calcium-chelating agents to in vivo and in vitro mounted corneas demonstrated a concentration-dependent progressive expansion of the intercellular spaces of epithelium and endothelium, as seen by SEM. The expansion of these cellular junctions correlates with increases in permeability of the cornea to glycerol under similar conditions. The size of the intercellular space was estimated by transmission electron microscopy. Use of lanthanum as a marker of aqueous diffusional pathways demonstrated that the epithelial surface is not a totally occlusive barrier to transport of small hydrophilic compounds. Development of a method whereby an administered drug could be visualized in its actual pathway of movement through the cornea was undertaken, involving precipitation of specific compounds in the tissue with osmium tetroxide vapor. Results suggest that separate pathways of drug movement exist in the cornea for hydrophilic and hydrophobic compounds. Hydrophilic compounds were preferentially located in intercellular spaces, whereas hydrophobic compounds were associated with the lipid structures of the tissue. The results of these studies are consistent with a currently proposed 'pore' model for the penetration of drugs through the cornea.

A model relating the parameters of permeability coefficient in the cornea with partition coefficient and molecular weight of the penetrating species is presented. The development of the model is unique in that it includes the availability of a "pore" pathway with the corresponding kinetic data to substantiate this premise. The "pore" pathway is applied to small hydrophilic compounds and assumes that an aqueous diffusional space is available for transport of these compounds. This is in contrast to an alternate "partitioning" mechanism which is the most probable route of transport for larger or more lipophilic entities. The model is consistent with published data from this and other laboratories.

The present study examined the feasibility of sustaining the release of a water-soluble drug, pilocarpine, to the tear film. Both gels and dried films were utilized as drug delivery systems. In vitro studies demonstrated significant prolongation of drug release from these systems as compared with simple aqueous or viscous solutions. The in vitro results were supported by in vivo miosis studies in albino rabbits.