Predicting individual outcomes after radical cystectomy in urothelial variants with Cancer of the Bladder Risk Assessment (COBRA) score.

OBJECTIVE: To validate the Cancer of the Bladder Risk Assessment (COBRA) score in patients with urothelial variants. METHODS: Epidemiological, clinical, radiological, and anatomopathological data were collected from patients with urothelial carcinoma who underwent radical cystectomy at the Institute of Cancer of São Paulo between May 2008 and December 2022. Patients with the presence of at least 10% of any urothelial variants in the radical cystectomy specimens' anatomopathological exam were included in the study. The COBRA score and derivatives were applied and correlated with oncological outcomes. RESULTS: A total of 680 patients [482 men (70.9%) and 198 women (29.1%)]; 66 years (IQR 59-73) underwent radical cystectomy for bladder tumor, and of these patients, a total of 167 patients presented any type of urothelial variant. The median follow-up time was 28.77 months (IQR 12-85). The three most prevalent UV were squamous differentiation (50.8%), glandular differentiation (31.3%), and micropapillary differentiation (11.3%). The subtypes with the worst prognosis were sarcomatoid with a median survival of 8 months (HR 1.161; 95% CI 0.555-2.432) and plasmacytoid with 14 months (HR 1.466; 95% CI 0.528-4.070). The COBRA score for patients with micropapillary variants demonstrated good predictive accuracy for OS (log-rank P = 0.009; 95% IC 6.78-29.21) and CSS (log-rank P = 0.002; 95% IC 13.06-26.93). CONCLUSIONS: In our study, the COBRA score proved an effective risk stratification tool for urothelial histological variants, especially for the micropapillary urothelial variant. It may be helpful in the prognosis evaluation of UV patients after radical cystectomy.

The Rising Incidence of Younger Patients With Colorectal Cancer: Questions About Screening, Biology, and Treatment.

OPINION STATEMENT: Colorectal cancer (CRC) is the third leading cancer diagnosed globally and an important cause of cancer-related mortality. Of interest, while we have witnessed a declining incidence trend over the past few decades in the older population, incidence rates for adolescents and young adults have been increasing steadily. Several factors may well explain this apparent epidemic in the young, namely a lack of routine screening and emerging lifestyle issues such as obesity, lack of exercise, and dietary factors. It is known that both environmental and genetic factors can increase the likelihood of developing CRC. Although inherited susceptibility is associated with the most striking increases in risk, and must always be considered in a young patient with CRC, the majority of CRCs are in fact sporadic rather than familial. Early-onset CRC is a truly heterogeneous disease, with mounting evidence to suggest that this patient population has a distinctive molecular profile, very different to late-onset CRC cases. Currently, both younger and older patients with CRC are treated in essentially the same manner, but with a better understanding of the molecular mechanisms underlying CRC in the young, we will have the opportunity to specifically tailor screening and clinical management strategies in this unique patient population in an effort to improve outcomes. The aim of this review is to outline our current knowledge of the distinguishing features of early-onset CRC, the ongoing research efforts, and the evolving evidence in this field.

Robotic-assisted approaches to urachal carcinoma: A comprehensive systematic review of the safety and efficacy outcomes.

Introduction: Surgical intervention is the treatment of choice in patients with urachal carcinoma. Due to complications and to reduce hospital stay from open surgery, minimally invasive approaches are desirable. Nowadays, robotic-assisted surgery has become increasingly popular, and robot-assisted cystectomy can be performed in patients with urachal carcinoma with low complication rates. Methods: We performed a systematic review to search for studies that evaluated patients who underwent robotic-assisted surgery for urachal carcinoma. The outcomes of interest were the type of cystectomy performed, whether there was umbilicus resection, total operative time, console time, intraoperative complications, estimated blood loss, postoperative complications, time of hospitalisation, positive surgical margins and the presence of documented tumour recurrence. Results: In this study, we evaluated three cohorts comprising a total of 21 patients. The median follow-up period ranged from 8 to 40 months. Medium age was between 51 and 54 years, with a majority (63.1%) being male. One patient (5.2%) underwent a radical cystectomy, and 19 patients (94.7%) underwent to partial cystectomy. Umbilical resections were performed in all cases, and pelvic lymphadenectomy in 14 cases (73.6%). Recurrence occurred in three patients at a median of 17 months postoperation, two cases in the trocar insertion site. Additionally, there was one death, which was attributed to postoperative cardiovascular complications. Conclusion: Robotic-assisted partial cystectomy has a low incidence of adverse outcomes in patients with urachal carcinoma. Controlled studies, ideally randomised, are warranted to establish the comparative efficacy and safety of the robotic-assisted cystectomy approach relative to open surgery.

Scoring system for prediction of overall survival in patients with renal cell carcinoma T3aN0M0.

Objective: We aim to create a new score to predict postoperative overall survival in patients with nonmetastatic T3aN0 renal cell carcinoma. Methods: We reviewed the clinical data of adult patients who underwent radical nephrectomy for renal cell carcinoma between December 2007 and January 2022 in a single tertiary oncological institution. Clinical characteristics, clinical-pathological staging and histopathological characteristics were analysed. Survival analyses were determined using the Kaplan-Meier curve. A nomogram was established using Cox proportional hazard regression to identify the prognostic factors affecting the overall survival. The area under the curve, calibration curves and decision curve analysis were used to evaluate prognostic efficacy. Results: We analyzed 362 patients classified as pT3aN0M0 stage with a median follow-up of 40 months. According to Cox univariate and multivariate analyses, weight loss greater than 5% in 6 months before surgery, stage V chronic kidney disease after radical nephrectomy, sarcomatoid pattern, and coagulative tumor necrosis were identified as predictors of overall survival. We developed a score and performed internal and external validation. The time-dependent receiver operating characteristic curve, area under the curve value and calibration curve analysis showed good prediction ability of the score. The nomogram can effectively predict and stratify overall survival after radical nephrectomy in patients with pT3aN0M0 renal cell carcinoma. Conclusion: Patients with pT3aN0MO renal cell carcinoma exhibited different characteristics, and those with unfavourable characteristics deserve greater attention during follow-up. This nomogram provides an accurate prediction of overall survival after radical nephrectomy.

High Dose Chemotherapy With Autologous Stem Cell Transplant for Patients With Advanced Germ Cell Tumors: Real-World Evidence From a Tertiary Cancer Center in Brazil.

BACKGROUND: High-dose chemotherapy followed by stem cell transplant (HDCT) is potentially curative for patients with refractory germ cell tumors (rGCT). There is scarce real-world data supporting its implementation in low- and middle-income countries. We described the experience of our tertiary cancer center in Sao Paulo, Brazil. METHODS: We identified male patients ≥18 years-old with rGCT referred to HDCT after board discussion. Clinical data, including delays in HDCT protocol, were extracted from medical records, and survival outcomes were estimated using the Kaplan-Meier method. The log-rank test and Cox proportional hazard were used to determine effects on overall survival (OS). RESULTS: From January 2013 to January 2023, 34 patients were referred and considered eligible to receive 2 cycles of HDCT. Most patients had primary testicular tumors (82%), nonseminomatous histology (88%), and poor International Germ Cell Collaborative Group (IGCCCG) (79%). Twenty-three patients received HDCT (1 cycle, n = 8; 2 cycles, n = 15). Main reasons for not receiving any HDCT were death due to progressive disease (n = 1), performance deterioration (n = 7), and failure of stem cell mobilization (n = 3). OS at 2 years was 36.7% for the eligible population, 56.1% for patients who underwent at least 1 HDCT, and 77.1% for those who had ≥2 cycles. The 2-year OS rate for patients not given HDCT was 0%. All patients had delays in protocol, and poor-risk patients had longer intervals from referral to protocol initiation (0.7 vs. 1.8 month, P < .01). CONCLUSION: Outcomes of patients who received ≥1 HDCT were encouraging; however, only 15 from 34 eligible patients were able to receive the planned 2 cycles of HDCT. Further strategies to minimize treatment delays in low- and middle-income countries are needed.

Surviving the Storm: Challenges of Bladder Cancer Care During the COVID-19 Pandemic.

PURPOSE: To evaluate the impact of the COVID-19 pandemic on the care of patients with bladder cancer in a tertiary oncology center. MATERIALS AND METHOD: We performed a retrospective analysis of patients admitted to a tertiary cancer center for the treatment of bladder cancer between 2019 and 2022. Surgical volumes, patient demographics, clinical characteristics, and postoperative outcomes were compared across these years. RESULTS: A total of 463 patients with bladder cancer were admitted in the period, and 78 patients underwent radical cystectomy . The distribution of TMN stages between admitted patients remained consistent across the years, with no statistically significant differences. Patients who underwent RC in 2020 presented more advanced disease at surgery (pT3/pT4 stage) (P = .045; 95% CI, 0.18-0.55) and had a longer hospital stay compared to other years (P = .024; 95% CI, 10.26-41.27). CONCLUSIONS: The COVID-19 pandemic posed significant challenges for the treatment of patients with bladder cancer. These results highlight the need to adapt health systems to unforeseen challenges, emphasizing the clinical impact on patients with advanced stages of the disease and the repercussions on their overall survival.

Inflammatory intestinal damage induced by 5-fluorouracil requires IL-4.

BACKGROUND: 5-Fluorouracil (5-FU) induces intestinal mucositis, which is characterized by epithelial ulcerations in the mucosa and clinical manifestations, such as pain and dyspeptic symptoms. Cytokines participate in the inflammatory and functional events of intestinal mucositis. IL-4 is an important mediator of intestinal inflammation, with either anti-inflammatory or pro-inflammatory functions, depending on the model of intestinal inflammation. This study aimed to evaluate the role of IL-4 in 5-FU-induced intestinal mucositis. METHODS: IL-4+/+ or IL-4-/- mice (25-30 g) were intraperitoneally injected with 5-FU (450 mg/Kg) or saline (C). After 3 days, the mice were sacrificed and the duodenum was evaluated for epithelial damage, MPO activity and cytokine concentration. RESULTS: 5-FU induced significant damage in the intestinal epithelium of IL-4+/+ mice (reduction in the villus/crypt ratio: control=3.31±0.21 µm, 5-FU=0.99±0.10 µm). However, the same treatment did not induce significant damage in IL-4-/- mice (5-FU=2.87±0.19 µm) compared to wild-type mice. 5-FU-induced epithelial damage increased the MPO activity (neutrophil number) and the level of pro-inflammatory cytokines (IL-4, TNF-α, IL-1ß and CXCL-8) in the duodenum. These results were not observed in IL-4-/- mice treated with 5-FU. CONCLUSION: Our data suggest that IL-4 participates as a pro-inflammatory cytokine in a 5-FU-induced intestinal damage model and suggests that IL-4 antagonists may be novel therapeutics for this condition.

M2 macrophages drive leukemic transformation by imposing resistance to phagocytosis and improving mitochondrial metabolism.

It is increasingly becoming clear that cancers are a symbiosis of diverse cell types and tumor clones. Combined single-cell RNA sequencing, flow cytometry, and immunohistochemistry studies of the innate immune compartment in the bone marrow of patients with acute myeloid leukemia (AML) reveal a shift toward a tumor-supportive M2-polarized macrophage landscape with an altered transcriptional program, with enhanced fatty acid oxidation and NAD+ generation. Functionally, these AML-associated macrophages display decreased phagocytic activity and intra-bone marrow coinjection of M2 macrophages together with leukemic blasts strongly enhances in vivo transformation potential. A 2-day in vitro exposure to M2 macrophages results in the accumulation of CALRlow leukemic blast cells, which are now protected against phagocytosis. Moreover, M2-exposed "trained" leukemic blasts display increased mitochondrial metabolism, in part mediated via mitochondrial transfer. Our study provides insight into the mechanisms by which the immune landscape contributes to aggressive leukemia development and provides alternatives for targeting strategies aimed at the tumor microenvironment.

PD-1/PD-L1 Inhibition Enhances Chemotherapy-Induced Neuropathic Pain by Suppressing Neuroimmune Antinociceptive Signaling.

Cytotoxic agents synergize with immune checkpoint inhibitors and improve outcomes for patients with several cancer types. Nonetheless, a parallel increase in the incidence of dose-limiting side effects, such as peripheral neuropathy, is often observed. Here, we investigated the role of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis in the modulation of paclitaxel-induced neuropathic pain. We found that human and mouse neural tissues, including the dorsal root ganglion (DRG), expressed basal levels of PD-1 and PD-L1. During the development of paclitaxel-induced neuropathy, an increase in PD-L1 expression was observed in macrophages from the DRG. This effect depended on Toll-like receptor 4 activation by paclitaxel. Furthermore, PD-L1 inhibited pain behavior triggered by paclitaxel or formalin in mice, suggesting that PD-1/PD-L1 signaling attenuates peripheral neuropathy development. Consistent with this, we observed that the combined use of anti-PD-L1 plus paclitaxel increased mechanical allodynia and chronic neuropathy development induced by single agents. This effect was associated with higher expression of inflammatory markers (Tnf, Il6, and Cx3cr1) in peripheral nervous tissue. Together, these results suggest that PD-1/PD-L1 inhibitors enhance paclitaxel-induced neuropathic pain by suppressing PD-1/PD-L1 antinociceptive signaling.

Role of capsaicin-sensitive primary afferent neurons and non-protein sulphydryl groups on gastroprotective effect of amifostine against ethanol-induced gastric damage in rats.

BACKGROUND: Amifostine has been widely tested as a cytoprotective agent against a number of aggressors in different organs. Recently, a gastroprotective effect was observed for this drug in a model of indomethacin-induced gastric injury. Our objective was to investigate the effect of amifostine on ethanol-induced gastric injury and the role played in this mechanism by afferent sensory neurons, non-protein sulfhydryl groups, nitric oxide, ATP-sensitive potassium channels, and cyclooxygenase-2. METHODS: Rats were treated with amifostine (22.5, 45, 90, or 180 mg/kg, PO or SC). After 30 min, the rats received absolute ethanol (5 ml kg(-1), PO). One hour later, gastric damage was quantified with a planimeter. Samples from the stomach were also taken for histopathological assessment and for assays of non-protein sulfhydryl groups. The other groups were pretreated with L-NAME (10 mg kg(-1), IP), glibenclamide (10 mg kg(-1), PO), or celecoxib (10 mg kg(-1), PO). After 30 min, the animals were given amifostine (90 mg kg(-1), PO or SC), followed 30 min later by gavage with absolute ethanol (5 ml kg(-1)). Other rats were desensitized with capsaicin (125 mg kg(-1), SC) 8 days prior to amifostine treatment. RESULTS: Amifostine administration PO and SC significantly and dose-dependently reduced ethanol-induced macroscopic and microscopic gastric damage by restoring glutathione levels in the stomach mucosa. Amifostine-promoted gastroprotection against ethanol-induced stomach injury was reversed by pretreatment with neurotoxic doses of capsaicin, but not by L-NAME, glibenclamide, or celecoxib. CONCLUSIONS: Amifostine protects against ethanol-induced gastric injury by increasing glutathione levels and stimulating the afferent sensory neurons in the stomach.

Pretreatment Eosinophil Counts in Patients With Advanced or Metastatic Urothelial Carcinoma Treated With Anti-PD-1/PD-L1 Checkpoint Inhibitors.

Eosinophils influence antitumor immunity and may predict response to treatment with immune checkpoint inhibitors (ICIs). To examine the association between blood eosinophil counts and outcomes in patients with advanced or metastatic urothelial carcinoma (mUC) treated with ICIs, we identified 2 ICI-treated cohorts: discovery (n=60) and validation (n=111). Chemotherapy cohorts were used as comparators (first-line platinum-based chemotherapy, n=75; second-line or more pemetrexed, n=77). The primary endpoint was overall survival (OS). Secondary endpoints were time on treatment (ToT) and progression-free survival. Univariate and multivariate analyses were performed using Cox proportional hazard models. Associations between changes in eosinophil count at weeks 2/3 and 6 after the start of ICI treatment were analyzed using landmark analyses. Baseline characteristics of the ICI cohorts were similar. In the discovery cohort, an optimal cutoff for pretreatment eosinophil count was determined [Eos-Lo: <100 cells/µL; n=9 (15%); Eos-Hi: ≥100 cells/µL; n=51 (85%)]. Eos-Lo was associated with inferior outcomes [OS: hazard ratio (HR), 3.98; 95% confidence interval (CI), 1.85-8.56; P<0.013; ToT: HR, 2.45; 95% CI, 1.17-5.10; P=0.017]. This was confirmed in the validation cohort [Eos-Lo: n=17 (15%); Eos-Hi: n=94 (85%)] (OS: HR, 2.51; 95% CI, 1.31-4.80; P=0.006; ToT: HR, 2.22; 95% CI, 1.2-3.80; P=0.004), and remained significant after adjustment for other prognostic factors. Changes in eosinophil counts at weeks 2/3 and 6 were not clearly associated with outcomes. In chemotherapy cohorts, eosinophil counts were not associated with outcomes. In conclusion, low pretreatment eosinophil count was associated with poorer outcomes in patients with mUC treated with ICIs, and may represent a new predictive biomarker.

Phase 3 Randomized Controlled Trial of Androgen Deprivation Therapy with or Without Docetaxel in High-risk Biochemically Recurrent Prostate Cancer After Surgery (TAX3503).

BACKGROUND: No standard of care exists for patients with high-risk biochemical recurrence (BCR) after prostatectomy. OBJECTIVE: To evaluate whether addition of docetaxel to androgen deprivation therapy (ADT) improved progression-free survival (PFS) in high-risk BCR patients. DESIGN, SETTING, AND PARTICIPANTS: TAX3503 was a multicenter phase 3 trial that randomized patients with high-risk BCR to ADT for 18 mo ± docetaxel (75 mg/m2 q3w for ten cycles). Eligibility included prostate-specific antigen (PSA) ≥1.0 ng/ml after prostatectomy alone or after postoperative radiation therapy, PSA doubling time ≤9 mo, and absence of metastases on computed tomography and bone scintigraphy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was PFS following testosterone recovery to noncastrate levels (testosterone >50 ng/dl). Secondary endpoints included time to testosterone recovery, overall survival (OS), quality of life, and safety. RESULTS AND LIMITATIONS: Between September 2007 and May 2011, 413 patients were assigned to ADT ± docetaxel. In 2012, following completion of accrual and treatment, the sponsor withdrew support of the study, and in 2013, a registry was created to secure the primary endpoint. The final analysis included data from the original trial and registry. At a median follow-up of 33.6 mo, 260 patients demonstrated testosterone recovery, which occurred similarly between groups. ADT plus docetaxel trended toward a nonclinically meaningful improvement in PFS (median 26.2 vs 24.7 mo) for the testosterone-recovered population (218 events, hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.61-1.04) and in OS for the intention-to-treat population (medians not reached, HR 0.51, 95% CI 0.23-1.10). Grade ≥3 adverse events occurred more frequently in the ADT plus docetaxel group (48.0% vs 10.8%). CONCLUSIONS: TAX3503 did not demonstrate a meaningful benefit of adding docetaxel to ADT in patients with high-risk BCR. Testosterone recovery was unaffected by addition of docetaxel to ADT. PATIENT SUMMARY: Addition of docetaxel to androgen deprivation therapy did not meaningfully improve outcomes for men with high-risk biochemically recurrent prostate cancer.

Platinum-Based Chemotherapy in Metastatic Prostate Cancer With DNA Repair Gene Alterations.

PURPOSE: Alterations in DNA damage repair (DDR) genes occur in up to 25% of patients with metastatic castration-resistant prostate cancer (mCRPC) and may sensitize to platinum chemotherapy. We aimed to evaluate the efficacy of platinum-based chemotherapy in DDR-mutant (DDRmut) mCRPC. METHODS: We assessed response to platinum chemotherapy based on DDR gene alteration status in men with mCRPC who underwent tumor and germline genomic profiling. Patients with deleterious alterations in a gene panel that included BRCA2, BRCA1, ATM, PALB2, FANCA, and CDK12 were considered DDRmut. RESULTS: A total of 109 patients with mCRPC received platinum-based chemotherapy between October 2013 and July 2018. Sixty-four of 109 patients were taxane refractory and poly (ADP-ribose) polymerase inhibitor (PARPi) naïve. Within this subset, DDRmut was found in 16/64 patients (25%) and was associated with an increased likelihood of achieving a prostate-specific antigen (PSA) decline of 50% or more from baseline (PSA50; odds ratio, 7.0; 95% CI, 1.9 to 29.2). Time on platinum chemotherapy tended to be longer in the DDRmut group (median, 3.0 v 1.6 months; hazard ratio, 0.55, 95% CI, 0.29 to 1.24). No difference in survival was detected. Of 8 patients with DDRmut disease who received platinum-based therapy after a PARPi, 3/7 evaluable patients had radiographic partial response or stable disease, and 2/7 had a PSA50 response. None of 4 patients with ATM mutations had platinum responses regardless of prior PARPi exposure. CONCLUSION: Patients with DDRmut disease had better response to platinum-based chemotherapy, suggesting that DDR status warrants prospective validation as a potential biomarker for patient selection. Responses to platinum chemotherapy were observed in BRCA-altered prostate cancer after PARPi progression. Additional studies are needed to determine the predictive role of individual genes on platinum sensitivity in the context of other clinical and genomic factors.

Pan-cancer Analysis of CDK12 Alterations Identifies a Subset of Prostate Cancers with Distinct Genomic and Clinical Characteristics.

BACKGROUND: CDK12 genomic alterations occur in several tumor types, but little is known about their oncogenic role and clinical significance. OBJECTIVE: To describe the landscape of CDK12 alterations across solid cancers and the clinical features of CDK12-altered prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: A single-center retrospective study of 26743 patients across 25 solid tumor types who underwent tumor sequencing was performed. Clinicopathologic features and outcomes were assessed in prostate cancer. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: CDK12 alterations and their association with genomic characteristics are described. For prostate cancer patients, overall survival and time to castration resistance were assessed using univariable and multivariable Cox regression analysis. RESULTS AND LIMITATIONS: CDK12 alterations were identified in 404/26743 patients (1.5%) overall, but were most frequent in prostate (100/1875, 5.3%) and ovarian cancer (43/1034, 4.2%), in which they were associated with a high prevalence of truncating variants and biallelic inactivation. CDK12 alterations defined a genomic subtype of prostate cancer with a unique copy-number alteration profile and involvement of distinct oncogenic pathway alterations, including cell-cycle pathway genes. CDK12-altered prostate cancer was associated with somewhat more aggressive clinical features and shorter overall survival (median 64.4 vs 74.9 mo; p=0.032) independent of standard clinical factors and tumor copy-number alteration burden (adjusted hazard ratio 1.80, 95% confidence interval 1.12-2.89; p=0.024). The study is limited by its retrospective nature. CONCLUSIONS: CDK12 alteration is a rare event across solid cancers but defines a clinically distinct molecular subtype of prostate cancer associated with unique genomic alterations and slightly more aggressive clinical features. PATIENT SUMMARY: CDK12 gene alterations occur rarely across tumor types, but more frequently in prostate cancer, where they are associated with genomic instability, cell-cycle pathway gene alterations, and somewhat worse clinical outcomes, warranting further investigation of therapeutic targeting of this disease subset.

Fibroblast Growth Factor Receptor 3 Alteration Status is Associated with Differential Sensitivity to Platinum-based Chemotherapy in Locally Advanced and Metastatic Urothelial Carcinoma.

BACKGROUND: Alterations in fibroblast growth factor receptor 3 (FGFR3) occur in ∼15% of muscle-invasive bladder cancers (MIBCs) and metastatic urothelial carcinomas (mUCs). OBJECTIVE: To determine the association between FGFR3 status and response to platinum-based chemotherapy in patients with MIBC or mUC. DESIGN, SETTING, AND PARTICIPANTS: The authors conducted a retrospective review and comparison of patients having (1) MIBC treated with neoadjuvant chemotherapy (NAC), (2) mUC treated with first-line platinum-based chemotherapy (M1 cohort), and (3) MIBC who were from The Cancer Genome Atlas (TCGA). INTERVENTION: Platinum-based chemotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Pathologic response, recurrence-free (RFS) or progression-free (PFS) survival, and overall survival (OS) were compared between patients with FGFR3 alteration (FGFR3alt) and those without it (FGFR3wild type [FGFR3wt]) in the three cohorts. RESULTS AND LIMITATIONS: Nine of 72 NAC patients (13%) had FGFR3alt, of whom none had pathologic complete response and three had residual non-MIBC (carcinoma in situ, n = 1; pT1, n = 2). FGFR3alt was associated with shorter RFS (hazard ratio, 2.74; p = 0.044) but not OS. Among TCGA patients who underwent adjuvant chemotherapy (n = 74), FGFR3alt patients had shorter RFS as well. Conversely, among chemotherapy-naive TCGA patients, FGFR3alt was associated with longer RFS and OS. In the M1 cohort (FGFR3alt, n = 27; FGFR3wt, n = 81), FGFR3alt was associated with higher rates of pulmonary metastases and nonregional lymphadenopathy. Despite lower response rates among FGFR3alt patients (37% vs 49%; p = 0.056), PFS and OS were not significantly different from FGFR3wt patients. CONCLUSIONS: FGFR3 status is associated with lower responses to platinum-based chemotherapy, which may prompt exploration of nonchemotherapeutic approaches for perioperative management of FGFR3alt urothelial cancers. PATIENT SUMMARY: Approximately 15% of bladder cancers harbor mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Our findings suggest that FGFR3 mutations might be associated with lower responses and shorter time to recurrence among patients with muscle-invasive bladder cancer who received perioperative platinum-based chemotherapy. FGFR3 status does not significantly impact response to chemotherapy among those with metastatic urothelial cancers.

Paradoxical interaction between cancer and long-term postsepsis disorder: impairment of de novo carcinogenesis versus favoring the growth of established tumors.

BACKGROUND: Previous data have reported that the growth of established tumors may be facilitated by postsepsis disorder through changes in the microenvironment and immune dysfunction. However, the influence of postsepsis disorder in initial carcinogenesis remains elusive. METHODS: In the present work, the effect of postsepsis on inflammation-induced early carcinogenesis was evaluated in an experimental model of colitis-associated colorectal cancer (CAC). We also analyzed the frequency and role of intestinal T regulatory cells (Treg) in CAC carcinogenesis. RESULTS: The colitis grade and the tumor development rate were evaluated postmortem or in vivo through serial colonoscopies. Sepsis-surviving mice (SSM) presented with a lower colonic DNA damage, polyp incidence, reduced tumor load, and milder colitis than their sham-operated counterparts. Ablating Treg led to restoration of the ability to develop colitis and tumor polyps in the SSM, in a similar fashion to that in the sham-operated mice. On the other hand, the growth of subcutaneously inoculated MC38luc colorectal cancer cells or previously established chemical CAC tumors was increased in SSM. CONCLUSION: Our results provide evidence that postsepsis disorder has a dual effect in cancer development, inhibiting inflammation-induced early carcinogenesis in a Treg-dependent manner, while increasing the growth of previously established tumors.

Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer.

Despite the development of second-generation antiandrogens, acquired resistance to hormone therapy remains a major challenge in treating advanced prostate cancer. We find that cancer-associated fibroblasts (CAFs) can promote antiandrogen resistance in mouse models and in prostate organoid cultures. We identify neuregulin 1 (NRG1) in CAF supernatant, which promotes resistance in tumor cells through activation of HER3. Pharmacological blockade of the NRG1/HER3 axis using clinical-grade blocking antibodies re-sensitizes tumors to hormone deprivation in vitro and in vivo. Furthermore, patients with castration-resistant prostate cancer with increased tumor NRG1 activity have an inferior response to second-generation antiandrogen therapy. This work reveals a paracrine mechanism of antiandrogen resistance in prostate cancer amenable to clinical testing using available targeted therapies.

Measuring the unmeasurable: automated bone scan index as a quantitative endpoint in prostate cancer clinical trials.

BACKGROUND: Up to 90% of men with metastatic castration-resistant prostate cancer (mCRPC) will have a distribution of disease that includes bone metastases demonstrated on a Technetium-99m (99mTc-MDP) bone scan. The Prostate Cancer Working Group 2 and 3 Consensus Criteria standardized the criteria for assessing progression based on the development of new lesions. These criteria have been recognized by regulatory authorities for drug approval. The bone scan index (BSI) is a method to quantitatively measure the burden of bony disease, and can assess both disease progression and regression. The automated BSI (aBSI) is a method of computer analysis to assess BSI, and is being qualified as a clinical trials endpoint. METHODS: Manual searching was used to identify the literature on BSI and aBSI. We summarize the most relevant aspects of the retrospective and prospective studies evaluating aBSI measurements, and provide a critical discussion on the potential advantages and caveats of aBSI. RESULTS: The development of neural artificial networks (EXINI boneBSI) to automatically determine the BSI reduces the turnaround time for assessing BSI with high reproducibility and accuracy. Several studies showed that the concordance between aBSI and BSI, as well as the interobserver concordance of aBSI, was >0.95. In a phase 3 assessment of aBSI, a doubling value increased the risk of death in 20%, pre-treatment aBSI values independently correlated with overall survival (OS) and time to symptomatic progression. Retrospective studies suggest that a decrease in aBSI after treatment may correlate with higher survival when compared with increasing aBSI. CONCLUSIONS: aBSI provides a quantitative measurement that is feasible, reproducible, and in analyses to date correlates with OS and symptomatic progression. These findings support the aBSI to risk-stratify men with mCRPC for clinical trial enrollment. Future studies quantifying aBSI change over time as an intermediate endpoint for evaluating new systemic therapies are needed.

CCR5-Positive Inflammatory Monocytes are Crucial for Control of Sepsis.

Neutrophils and inflammatory monocytes control sepsis by migration to the site of infection via their chemokine receptors. CCR5 is a chemokine receptor that is not expressed on neutrophils and inflammatory monocytes under homeostatic conditions. However, it has been demonstrated that CCR5 can become expressed on these cells during different models of inflammation. In the present study, we investigated if CCR5 is also expressed on neutrophil and inflammatory monocytes during sepsis, exerting an important role in the migration of these cells to the infectious focus. Using cecal ligation and puncture model to induce polymicrobial sepsis, we demonstrated that the expression of CCR5 is induced on CD11bLy6GLy6C inflammatory monocytes, but not on neutrophils (CD11bLy6GLy6C). Furthermore, CCR5 plays an important role for the migration of the inflammatory monocytes to infection focus during sepsis. CCR5-expressing inflammatory monocytes migrate from the bone marrow to the circulation and then into the site of infection, where they phagocytize and kill the bacteria. Consequently, CCR5 mice showed increased systemic inflammatory response and mortality compared to wild-type mice. These data therefore demonstrate a hitherto unrecognized protective role of CCR5 in sepsis.