Honing the Hunt: A Comprehensive Review of Cell-free Tumor DNA to Predict Neoadjuvant Therapy Efficacy in Bladder Cancer.

OBJECTIVE: To provide an updated view on the role of cell-free DNA as a predictor of pathological response to neoadjuvant therapy in patients with muscle-invasive bladder cancer. METHODS: A systematic review was conducted from September 2023 to October 2023. Selected studies from the MEDLINE and clinical trial databases were critically analyzed regarding the clinical efficacy of cell-free DNA as a predictive instrument after neoadjuvant therapy in bladder cancer. The methodological quality assessment was based on the QUADAS-2 tool. RESULTS: In this systematic review, we analyzed 5 studies encompassing a cumulative patient cohort of 780 individuals diagnosed with muscle-invasive bladder cancer, with a median follow-up ranging from 6 to 23 months. Among these studies, 4 primarily focused on detecting and analyzing circulating tumor DNA in plasma, while 1 study uniquely utilized cell-free tumor DNA in urine samples. The diagnostic accuracy of cell-free DNA in plasma ranges from 79% to 100%, indicating a variable yet significant predictive capability. In contrast, the study utilizing urinary cell-free DNA demonstrated an accuracy of 81% in predicting treatment response post-neoadjuvant chemotherapy. CONCLUSION: Cell-free DNA is emerging as a valuable biomarker for predicting response to neoadjuvant chemotherapy in patients with muscle-invasive bladder tumors.

Neurovascular and hemodynamic responses to mental stress and exercise in severe COVID-19 survivors.

Previous studies show that COVID-19 survivors have elevated muscle sympathetic nerve activity (MSNA), endothelial dysfunction, and aortic stiffening. However, the neurovascular responses to mental stress and exercise are still unexplored. We hypothesized that COVID-19 survivors, compared with age- and body mass index (BMI)-matched control subjects, exhibit abnormal neurovascular responses to mental stress and physical exercise. Fifteen severe COVID-19 survivors (aged: 49 ± 2 yr, BMI: 30 ± 1 kg/m2) and 15 well-matched control subjects (aged: 46 ± 3 yr, BMI: 29 ± 1 kg/m2) were studied. MSNA (microneurography), forearm blood flow (FBF), and forearm vascular conductance (FVC, venous occlusion plethysmography), mean arterial pressure (MAP, Finometer), and heart rate (HR, ECG) were measured during a 3-min mental stress (Stroop Color-Word Test) and during a 3-min isometric handgrip exercise (30% of maximal voluntary contraction). During mental stress, MSNA (frequency and incidence) responses were higher in COVID-19 survivors than in controls (P < 0.001), and FBF and FVC responses were attenuated (P < 0.05). MAP was similar between the groups (P > 0.05). In contrast, the MSNA (frequency and incidence) and FBF and FVC responses to handgrip exercise were similar between the groups (P > 0.05). MAP was lower in COVID-19 survivors (P < 0.05). COVID-19 survivors exhibit an exaggerated MSNA and blunted vasodilatory response to mental challenge compared with healthy adults. However, the neurovascular response to handgrip exercise is preserved in COVID-19 survivors. Overall, the abnormal neurovascular control in response to mental stress suggests that COVID-19 survivors may have an increased risk to cardiovascular events during mental challenge.

Paclitaxel Reduces Tumor Growth by Reprogramming Tumor-Associated Macrophages to an M1 Profile in a TLR4-Dependent Manner.

Paclitaxel is an antineoplastic agent widely used to treat several solid tumor types. The primary mechanism of action of paclitaxel is based on microtubule stabilization inducing cell-cycle arrest. Here, we use several tumor models to show that paclitaxel not only induces tumor cell-cycle arrest, but also promotes antitumor immunity. In vitro, paclitaxel reprogrammed M2-polarized macrophages to the M1-like phenotype in a TLR4-dependent manner, similarly to LPS. Paclitaxel also modulated the tumor-associated macrophage (TAM) profile in mouse models of breast and melanoma tumors; gene expression analysis showed that paclitaxel altered the M2-like signature of TAMs toward an M1-like profile. In mice selectively lacking TLR4 on myeloid cells, for example, macrophages (LysM-Cre+/-/TLR4fl/fl), the antitumor effect of paclitaxel was attenuated. Gene expression analysis of tumor samples from patients with ovarian cancer before and after treatment with paclitaxel detected an enrichment of genes linked to the M1 macrophage activation profile (IFNγ-stimulated macrophages). These findings indicate that paclitaxel skews TAMs toward an immunocompetent profile via TLR4, which might contribute to the antitumor effect of paclitaxel and provide a rationale for new combination regimens comprising paclitaxel and immunotherapies as an anticancer treatment.Significance: This study provides new evidence that the antitumor effect of paclitaxel occurs in part via reactivation of the immune response against cancer, guiding tumor-associated macrophages toward the M1-like antitumor phenotype.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/20/5891/F1.large.jpg Cancer Res; 78(20); 5891-900. ©2018 AACR See related commentary by Garassino et al., p. 5729.

Evaluation of 18F-FDG PET-CT as a prognostic marker in advanced biliary tract cancer.

BACKGROUND: Advanced biliary tract cancers have a dismal prognosis. Treatment with gemcitabine plus cisplatin has resulted in a significant improvement in survival; however, early assessment of outcomes poses a challenge. OBJECTIVE: We carried out a prospective study to evaluate the prognostic role of fluorine-18 fluorodeoxyglucose (F-FDG) PET-CT scans in patients with advanced biliary tract cancer. PATIENTS AND METHODS: Patients with advanced unresectable or metastatic biliary tract cancer starting first-line chemotherapy with gemcitabine plus cisplatin underwent F-FDG PET-CT studies at baseline and after two cycles of therapy. The total lesion glycolysis (TLG) measured at baseline as well as the variation in TLG between the two studies were analyzed as prognostic indicators of overall survival. The survival analyses were carried out using Kaplan-Meier curves and the comparison of survival curves was performed using the Breslow test. RESULTS: Of the 42 patients included, 37 had the first F-FDG PET-CT and 27 had the second F-FDG PET-CT. Patients with lower TLG values at baseline or after two cycles of therapy presented a higher median survival than patients with higher baseline TLG values. Patients with a higher decrease in the TLG values between the two studies also had a higher median survival time. However, these results only trended for statistical significance (P values ranging between 0.05 and 0.16). CONCLUSION: Lower baseline TLG measured by F-FDG PET-CT as well as a decrease in metabolic uptake after chemotherapy were associated with a trend toward longer median survival among patients with advanced biliary cancers.

Post-Sepsis State Induces Tumor-Associated Macrophage Accumulation through CXCR4/CXCL12 and Favors Tumor Progression in Mice.

Survivors from sepsis are in an immunosuppressed state that is associated with higher long-term mortality and risk of opportunistic infections. Whether these factors contribute to neoplastic proliferation, however, remains unclear. Tumor-associated macrophages (TAM) can support malignant cell proliferation, survival, and angiogenesis. We addressed the relationship between the post-sepsis state, tumor progression and TAM accumulation, and phenotypic and genetic profile, using a mouse model of sepsis resolution and then B16 melanoma in mice. In addition, we measured the serum concentrations of TNFα, TGFß, CCL2, and CXCL12 and determined the effect of in vivo CXCR4/CXCL12 inhibition in this context. Mice that survived sepsis showed increased tumor progression both in the short and long term, and survival times were shorter. TAM accumulation, TAM local proliferation, and serum concentrations of TGFß, CXCL12, and TNFα were increased. Naïve mice inoculated with B16 together with macrophages from post-sepsis mice also had faster tumor progression and shorter survival. Post-sepsis TAMs had less expression of MHC-II and leukocyte activation-related genes. Inhibition of CXCR4/CXCL12 prevented the post-sepsis-induced tumor progression, TAM accumulation, and TAM in situ proliferation. Collectively, our data show that the post-sepsis state was associated with TAM accumulation through CXCR4/CXCL12, which contributed to B16 melanoma progression.

Target Inhibition of IL-1 Receptor Prevents Ifosfamide Induced Hemorrhagic Cystitis in Mice.

PURPOSE: Hemorrhagic cystitis is an important dose limiting side effect of ifosfamide based cancer chemotherapy. Despite chemoprophylaxis inflammation can still be found in cystoscopy guided biopsies. Previous studies confirmed the role of TNF-α and IL-1ß. We evaluated the protective effect of the IL-1R antagonist anakinra and the anti-TNF-α antibody infliximab in experimental ifosfamide induced hemorrhagic cystitis. MATERIALS AND METHODS: Hemorrhagic cystitis was induced by an injection of ifosfamide (400 mg/kg intraperitoneally) in Swiss wild-type C57Bl/6, IL-1R-/-, TNFR1-/- or TNFR1/R2-/- mice. Mice were treated 30 minutes before ifosfamide with anakinra (100 mg/kg intraperitoneally), infliximab (5 mg/kg intraperitoneally) or vehicle. Visceral nociception was evaluated after hemorrhagic cystitis induction. At 12 hours the animals were sacrificed. Bladders were harvested to assess bladder wet weight, vascular permeability, macroscopic and microscopic findings, muscle contractility, and for cystometrography. Inflammatory cell infiltration was assessed by myeloperoxidase assay and flow cytometry. RESULTS: Anakinra attenuated hemorrhage, edema, neutrophil infiltration, visceral hyperalgesia and bladder dysfunction. IL-1R-/- mice also showed milder hemorrhagic cystitis. Infliximab inhibited bladder edema and visceral hyperalgesia without preventing hemorrhage, bladder dysfunction, neutrophils or accumulation. Additionally, the lack of TNFR1 decreased bladder edema but not cell infiltration whereas concomitant deficiency of TNFR1 and TNFR2 resulted in worse hemorrhagic cystitis. CONCLUSIONS: Anakinra is effective for preventing experimentally ifosfamide induced hemorrhagic cystitis. It seems that neutrophil and macrophage infiltration in this circumstance depends on IL-1 signaling through IL1R. Possibly TNFR2 has a protective role in hemorrhagic cystitis.

Interleukin-11 attenuates ifosfamide-induced hemorrhagic cystitis.

OBJECTIVE: To investigate the possible protective effect of recombinant human interleukin-11 (rhIL-11) against ifosfamide (IFS)-induced hemorrhagic cystitis (HC). MATERIALS AND METHODS: Male Swiss mice (20-30g) were pretreated with rhIL-11 (25-625 mg, subcutaneously.) 30 min before intraperitoneal injection of IFS (400 mg/kg) or with saline (control group). Twelve hours later, HC was evaluated by bladder wet weight (BWW) to quantify edema, Evans blue extravasation (EBE) to measure vascular permeability, and macroscopic and microscopic analysis. All bladders were assessed by histopathological analysis. RESULTS: rhIL-11 (at 125 and 625 mg) attenuated the IFS- induced increase of BWW (37.48% and 45.44%, respectively, p < 0.05) and EBE (62.35% and 56.47%, respectively, p < 0.05). IFS- induced macroscopic edema and hemorrhage and microscopic alterations, were also prevented by rhIL-11 at 625 microg. (p < 0.05). CONCLUSION: Our results demonstrate a protective effect of rhIL-11 on experimental IFS- induced HC, not previously reported.

Interleukin-11 attenuates ifosfamide-induced hemorrhagic cystitis

OBJECTIVE: To investigate the possible protective effect of recombinant human interleukin-11 (rhIL-11) against ifosfamide (IFS)-induced hemorrhagic cystitis (HC) MATERIALS AND METHODS: Male Swiss mice (20-30g) were pretreated with rhIL-11 (25-625 mg, subcutaneously.) 30 min before intraperitoneal injection of IFS (400 mg/kg) or with saline (control group). Twelve hours later, HC was evaluated by bladder wet weight (BWW) to quantify edema, Evans blue extravasation (EBE) to measure vascular permeability, and macroscopic and microscopic analysis. All bladders were assessed by histopathological analysis RESULTS: rhIL-11 (at 125 and 625 mg) attenuated the IFS- induced increase of BWW (37.48 percent and 45.44 percent, respectively, p < 0.05) and EBE (62.35 percent and 56.47 percent, respectively, p < 0.05). IFS- induced macroscopic edema and hemorrhage and microscopic alterations, were also prevented by rhIL-11 at 625 mg. (p < 0.05) CONCLUSION: Our results demonstrate a protective effect of rhIL-11 on experimental IFS- induced HC, not previously reported.