Multiple Bowen's disease on the finger associated with human papillomavirus type 34.

Human papillomavirus (HPV) infection has been suggested as a potential risk factor for Bowen's disease. Here, we report a case of a 40-year-old man with Bowen's disease on the finger showing a discontinuous skip lesion, in which HPV-34 was detected. Our case is a reminder that the possibility of multiple lesions must be considered when Bowen's disease occurs on the finger.

Clinical benefit of switching from paclitaxel to docetaxel or vice versa in cutaneous angiosarcoma patients resistant to first taxane chemotherapy.

Cutaneous angiosarcoma (CAS) is a rare soft-tissue sarcoma of vascular endothelial origin. Paclitaxel (PTX) and docetaxel (DTX) are used as systemic chemotherapy; however, chemoresistance often occurs in CAS. Switching one taxane to the other (i.e., PTX to DTX, or vice versa) is an option when the first taxane is no longer effective in malignant cancers such as ovarian or breast cancer. However, the efficacy of the same strategy in CAS has not been reported. Herein, we report the clinical response of switching one taxane-based chemotherapy to the other in CAS patients with resistance to the first taxane. Twelve CAS patients were included for analyses. In all patients, the median overall survival from the start of the first taxane treatment was 29.0 months (range, 6.47-58.5). During the first taxane, the median PFS for all patients was 5.96 months (1.81-47.1). Similarly, the median (range) PFS for all patients during the second taxane was 5.87 months (1.60-18.2). Furthermore, the median OS was 22.7 months (PTX to DTX) and 39.5 months (DTX to PTX) (p = 0.307). The median PFS during the first taxane was 5.14 (PTX to DTX) and 12.5 months (DTX to PTX), respectively (p = 0.380). The median PFS during the second taxane was 3.5 (PTX to DTX) and 7.1 months (DTX to PTX), respectively (p = 0.906). The objective response rate, defined as the sum of complete response (CR) and partial response (PR) rates, was 16.7%. The disease control rate, defined as the sum of CR, PR, and stable disease rates, was 50%. The frequency of adverse events during the second taxane was the same between the two groups (p > 0.999). Our report suggests that CAS patients could benefit from the second taxane treatment if the tumor is resistant to the first taxane.

Corrigendum re "Impact of Body Mass Index on Survival Outcomes for Patients with Metastatic Renal Cell Carcinoma in the Immuno-oncology Era: A Systematic Review and Meta-analysis" [Eur Urol Open Sci 2022;39:62-71].

[This corrects the article DOI: 10.1016/j.euros.2022.03.002.].

Activation of the pentose phosphate pathway in macrophages is crucial for granuloma formation in sarcoidosis.

Sarcoidosis is a disease of unknown etiology in which granulomas form throughout the body and is typically treated with glucocorticoids, but there are no approved steroid-sparing alternatives. Here, we investigated the mechanism of granuloma formation using single-cell RNA-Seq in sarcoidosis patients. We observed that the percentages of triggering receptor expressed on myeloid cells 2-positive (TREM2-positive) macrophages expressing angiotensin-converting enzyme (ACE) and lysozyme, diagnostic makers of sarcoidosis, were increased in cutaneous sarcoidosis granulomas. Macrophages in the sarcoidosis lesion were hypermetabolic, especially in the pentose phosphate pathway (PPP). Expression of the PPP enzymes, such as fructose-1,6-bisphosphatase 1 (FBP1), was elevated in both systemic granuloma lesions and serum of sarcoidosis patients. Granuloma formation was attenuated by the PPP inhibitors in in vitro giant cell and in vivo murine granuloma models. These results suggest that the PPP may be a promising target for developing therapeutics for sarcoidosis.

A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers.

Antibiotics (ABX) compromise the efficacy of programmed cell death protein 1 (PD-1) blockade in cancer patients, but the mechanisms underlying their immunosuppressive effects remain unknown. By inducing the down-regulation of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in the ileum, post-ABX gut recolonization by Enterocloster species drove the emigration of enterotropic α4ß7+CD4+ regulatory T 17 cells into the tumor. These deleterious ABX effects were mimicked by oral gavage of Enterocloster species, by genetic deficiency, or by antibody-mediated neutralization of MAdCAM-1 and its receptor, α4ß7 integrin. By contrast, fecal microbiota transplantation or interleukin-17A neutralization prevented ABX-induced immunosuppression. In independent lung, kidney, and bladder cancer patient cohorts, low serum levels of soluble MAdCAM-1 had a negative prognostic impact. Thus, the MAdCAM-1-α4ß7 axis constitutes an actionable gut immune checkpoint in cancer immunosurveillance.

Epstein-Barr Virus-induced Gene 3 as a Novel Biomarker in Metastatic Melanoma With Infiltrating CD8+ T Cells: A Study Based on The Cancer Genome Atlas (TCGA).

BACKGROUND/AIM: Epstein-Barr virus-induced gene 3 (EBI3) is an immunomodulatory protein-coding gene. So far, the prognostic role of EBI3 in human metastatic melanoma has been unclear. This study aimed to evaluate the EBI3 expression as a potential biomarker using the public database with tumor-infiltrating lymphocytes (TILs) data. MATERIALS AND METHODS: Survival analyses were performed in the database of The Cancer Genome Atlas (TCGA) and GSE65904, GSE19234, GSE22153, and GSE22154. The mRNA levels, the distribution pattern of TILs, and the estimated fractions of TILs from the TCGA database were integrated. RESULTS: Higher EBI3 expression in tumors was significantly associated with longer overall survival in TCGA and the other independent cohorts. Interestingly, the patients with high EBI3 expression had a brisk pattern of TILs and increased CD8+ T cells over regulatory T cells with less pigmentation-related gene expressions. CONCLUSION: EBI3 could serve as a novel biomarker in metastatic melanoma with a favorable TILs profile.

FXYD3 Expression Predicts Poor Prognosis in Renal Cell Carcinoma with Immunosuppressive Tumor Microenvironment.

FXYD3 is a protein-coding gene, belonging to the FXYD protein family associated with Na+/K+-ATPase enzymes and chloride ion channels. Accumulating evidence suggests the biological role of FXYD3 in multiple cancers. However, the prognostic value of FXYD3 expression in clear renal cell carcinoma (KIRC) is unclear. Therefore, we evaluated the clinical data with tumor-infiltrating lymphocytes (TILs) and immunoinhibitory gene expression data using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) dataset (GSE29609). First, the FXYD3 high KIRC patients had distinct clinical characteristics, including age, sex, disease stage, histological grade, and hypoxia-related gene expressions. Next, FXYD3 gene expression was correlated with poor overall survival in both TCGA and GSE29609 cohorts. The ESTIMATE algorithm revealed that higher FXYD3 mRNA levels were associated with increased infiltration of immune cells and tumor purity. Moreover, the FXYD3 high KIRC tissue harbored increased TILs such as B cells, CD8+ T cells, and M1 macrophage, whereas NK cells and neutrophils were decreased. In addition, we showed FXYD3 was co-expressed with several immunoinhibitory genes related to T cell exhaustion such as LGALS9, CTLA4, BTLA, PDCD1, and LAG3. In conclusion, FXYD3 is an unfavorable prognostic biomarker associated with hypoxia, pro-tumor TILs, and T cell exhaustion.

Impact of Body Mass Index on Survival Outcomes of Patients with Metastatic Renal Cell Carcinoma in the Immuno-oncology Era: A Systematic Review and Meta-analysis.

Context: Body mass index (BMI) is a useful tool for measuring body composition. It is unclear whether high BMI is a favourable indicator in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICIs). Objective: To investigate the prognostic significance of BMI in patients with mRCC treated with ICIs in a systematic review and meta-analysis. Evidence acquisition: Ovid MEDLINE, Embase, and Web of Science were systematically searched in July 2021, and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Evidence synthesis: A total of 517 nonduplicate citations were screened by title and abstract, followed by full-text screening of 57 candidate articles to determine whether each study met the eligibility criteria. Overall, a total of 2281 patients from eight studies were included in the systematic review and meta-analysis. BMI levels were compared with overall survival (OS) and progression-free survival (PFS) in seven and three studies, respectively. Overweight/obese BMI was significantly associated with better OS compared to normal BMI (adjusted hazard ratio [aHR] 0.77, 95% confidence intervals [CI] 0.65-0.91; p = 0.002). A similar trend was observed for PFS (aHR 0.66, 95% CI 0.44-1.00; p = 0.050). There was no statistical heterogeneity or obvious publication bias among these studies. Conclusions: This is the first systematic review and meta-analysis to evaluate the impact of BMI on survival outcomes of patients with mRCC treated with ICIs. To confirm the existence of the obesity paradox for patients with mRCC in the immuno-oncology era, high-quality clinical trials and basic research are warranted. Patient summary: We reviewed published data on survival outcomes of 2281 patients with metastatic kidney cancer treated with immunotherapy drugs in relation to their body mass index (BMI). We found that higher BMI was associated with better survival when compared to normal BMI for this disease setting and treatment strategy.

Immune system and intestinal microbiota determine efficacy of androgen deprivation therapy against prostate cancer.

BACKGROUND: Prostate cancer (PC) responds to androgen deprivation therapy (ADT) usually in a transient fashion, progressing from hormone-sensitive PC (HSPC) to castration-resistant PC (CRPC). We investigated a mouse model of PC as well as specimens from PC patients to unravel an unsuspected contribution of thymus-derived T lymphocytes and the intestinal microbiota in the efficacy of ADT. METHODS: Preclinical experiments were performed in PC-bearing mice, immunocompetent or immunodeficient. In parallel, we prospectively included 65 HSPC and CRPC patients (Oncobiotic trial) to analyze their feces and blood specimens. RESULTS: In PC-bearing mice, ADT increased thymic cellularity and output. PC implanted in T lymphocyte-depleted or athymic mice responded less efficiently to ADT than in immunocompetent mice. Moreover, depletion of the intestinal microbiota by oral antibiotics reduced the efficacy of ADT. PC reduced the relative abundance of Akkermansia muciniphila in the gut, and this effect was reversed by ADT. Moreover, cohousing of PC-bearing mice with tumor-free mice or oral gavage with Akkermansia improved the efficacy of ADT. This appears to be applicable to PC patients because long-term ADT resulted in an increase of thymic output, as demonstrated by an increase in circulating recent thymic emigrant cells (sjTRECs). Moreover, as compared with HSPC controls, CRPC patients demonstrated a shift in their intestinal microbiota that significantly correlated with sjTRECs. While feces from healthy volunteers restored ADT efficacy, feces from PC patients failed to do so. CONCLUSIONS: These findings suggest the potential clinical utility of reversing intestinal dysbiosis and repairing acquired immune defects in PC patients.

Cancer Induces a Stress Ileopathy Depending on ß-Adrenergic Receptors and Promoting Dysbiosis that Contributes to Carcinogenesis.

Gut dysbiosis has been associated with intestinal and extraintestinal malignancies, but whether and how carcinogenesis drives compositional shifts of the microbiome to its own benefit remains an open conundrum. Here, we show that malignant processes can cause ileal mucosa atrophy, with villous microvascular constriction associated with dominance of sympathetic over cholinergic signaling. The rapid onset of tumorigenesis induced a burst of REG3γ release by ileal cells, and transient epithelial barrier permeability that culminated in overt and long-lasting dysbiosis dominated by Gram-positive Clostridium species. Pharmacologic blockade of ß-adrenergic receptors or genetic deficiency in Adrb2 gene, vancomycin, or cohousing of tumor bearers with tumor-free littermates prevented cancer-induced ileopathy, eventually slowing tumor growth kinetics. Patients with cancer harbor distinct hallmarks of this stress ileopathy dominated by Clostridium species. Hence, stress ileopathy is a corollary disease of extraintestinal malignancies requiring specific therapies. SIGNIFICANCE: Whether gut dysbiosis promotes tumorigenesis and how it controls tumor progression remain open questions. We show that 50% of transplantable extraintestinal malignancies triggered a ß-adrenergic receptor-dependent ileal mucosa atrophy, associated with increased gut permeability, sustained Clostridium spp.-related dysbiosis, and cancer growth. Vancomycin or propranolol prevented cancer-associated stress ileopathy. This article is highlighted in the In This Issue feature, p. 873.

EVI2B Is a New Prognostic Biomarker in Metastatic Melanoma with IFNgamma Associated Immune Infiltration.

BACKGROUND: To assess the prognostic role and the antitumor immunological relevance of ecotropic viral integration site 2B (EVI2B) in metastatic melanoma. METHODS: In this study, we integrated clinical data, mRNA expression data, and the distribution and fraction of tumor infiltrating lymphocytes (TILs) using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets (GSE65904 and GSE19234). RESULTS: The univariate and multivariate analyses showed that higher gene expression of EVI2B was significantly associated with longer prognoses. The EVI2B-high melanoma tissue had favorable histological parameters such as a brisk global distribution pattern and clustering structure of TILs (i.e., Banfield and Raftery index) with enriched CD8+ T cells over regulatory T cells and increased cytotoxicity scores. In addition, EVI2B expression positively correlated with IFN-γ signature genes (CXCL10, CXCL9, HLA-DRA, IDO1, IFNG, and STAT1) and other various immunomodulatory genes. CONCLUSION: EVI2B is a novel prognostic biomarker with IFN-γ associated immune infiltration in metastatic melanoma.

Multifaceted modes of action of the anticancer probiotic Enterococcus hirae.

A deviated repertoire of the gut microbiome predicts resistance to cancer immunotherapy. Enterococcus hirae compensated cancer-associated dysbiosis in various tumor models. However, the mechanisms by which E. hirae restored the efficacy of cyclophosphamide administered with concomitant antibiotics remain ill defined. Here, we analyzed the multifaceted modes of action of this anticancer probiotic. Firstly, E. hirae elicited emigration of thymocytes and triggered systemic and intratumoral IFNγ-producing and CD137-expressing effector memory T cell responses. Secondly, E. hirae activated the autophagy machinery in enterocytes and mediated ATG4B-dependent anticancer effects, likely as a consequence of its ability to increase local delivery of polyamines. Thirdly, E. hirae shifted the host microbiome toward a Bifidobacteria-enriched ecosystem. In contrast to the live bacterium, its pasteurized cells or membrane vesicles were devoid of anticancer properties. These pleiotropic functions allow the design of optimal immunotherapies combining E. hirae with CD137 agonistic antibodies, spermidine, or Bifidobacterium animalis. We surmise that immunological, metabolic, epithelial, and microbial modes of action of the live E. hirae cooperate to circumvent primary resistance to therapy.

Ileal immune tonus is a prognosis marker of proximal colon cancer in mice and patients.

Ileal epithelial cell apoptosis and the local microbiota modulate the effects of oxaliplatin against proximal colon cancer by modulating tumor immunosurveillance. Here, we identified an ileal immune profile associated with the prognosis of colon cancer and responses to chemotherapy. The whole immune ileal transcriptome was upregulated in poor-prognosis patients with proximal colon cancer, while the colonic immunity of healthy and neoplastic areas was downregulated (except for the Th17 fingerprint) in such patients. Similar observations were made across experimental models of implanted and spontaneous murine colon cancer, showing a relationship between carcinogenesis and ileal inflammation. Conversely, oxaliplatin-based chemotherapy could restore a favorable, attenuated ileal immune fingerprint in responders. These results suggest that chemotherapy inversely shapes the immune profile of the ileum-tumor axis, influencing clinical outcome.

Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade.

Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1ß in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.

Turning tolerogenic into immunogenic ileal cell death through ileal microbiota: the key to unlock the mystery of colon cancer immunoscore?

Why PD-1 blockade is ineffective in the vast majority of colorectal cancers (CCs) lacking microsatellite instability but harboring high densities of tumor infiltrating T cells and follicular T helper (TFH) and B cells remained so far an open conundrum. In a recent report published in Nature Medicine, we bring evidence in mice and patients that ileal microbiota turns tolerogenic apoptosis of ileal intestinal epithelial cells (IEC) into immunogenic cell demise capable of eliciting IL-1ß-dependent TFH responses that benefit from anti-PD1 antibodies.

Resolving the Paradox of Colon Cancer Through the Integration of Genetics, Immunology, and the Microbiota.

While colorectal cancers (CRC) are paradigmatic tumors invaded by effector memory lymphocytes, the mechanisms accounting for the relative resistance of MSI negative CRC to immunogenic cell death mediated by oxaliplatin and immune checkpoint inhibitors has remained an open conundrum. Here, we propose the viewpoint where its microenvironmental contexture could be explained -at least in part- by macroenvironmental cues constituted by the complex interplay between the epithelial barrier, its microbial ecosystem, and the local immune system. Taken together this dynamic ménage-à-trois offers novel coordinated actors of the humoral and cellular immune responses actionable to restore sensitivity to immune checkpoint inhibition. Solving this paradox involves breaking tolerance to crypt stem cells by inducing the immunogenic apoptosis of ileal cells in the context of an ileal microbiome shifted towards immunogenic bacteria using cytotoxicants. This manoeuver results in the elicitation of a productive Tfh and B cell dialogue in mesenteric lymph nodes culminating in tumor-specific memory CD8+ T cell responses sparing the normal epithelium.

The Prognostic Value of Systemic Inflammatory Markers in Advanced Renal Cell Carcinoma Patients Treated With Molecular Targeted Therapies.

BACKGROUND/AIM: The present study examined the impact of systemic inflammatory markers including C-reactive protein (CRP)/Albumin (Alb) and neutrophil lymphocyte ratio (NLR)/Alb on the prognosis of patients treated with first line molecular targeted therapy for advanced RCC. PATIENTS AND METHODS: A total of 131 patients with advanced RCC treated with molecular targeted therapy as first line treatment from May 2008 to April 2019 were retrospectively analyzed. RESULTS: High CRP, high NLR, low Alb and high CRP/Alb showed significantly worse progression-free survival (PFS) and overall survival (OS) than low CRP, low NLR, high Alb, low CRP/Alb and low NLR/Alb, respectively. In multivariate analyses, prior nephrectomy (p=0.0321) and NLR/Alb ratio (p=0.0327) were independent prognostic factors for PFS. Furthermore, prior nephrectomy (p=0.0013) and CRP/Alb ratio (p=0.0020) were independent prognostic factors for OS. CONCLUSION: CRP/Alb and NLR/Alb ratios are useful and independent prognostic biomarkers in patients with advanced RCC treated with molecular targeted therapy.

Comedications influence immune infiltration and pathological response to neoadjuvant chemotherapy in breast cancer.

Immunosurveillance plays an important role in breast cancer (BC) prognosis and progression, and can be geared by immunogenic chemotherapy. In a cohort of 1023 BC patients treated with neoadjuvant chemotherapy (NAC), 40% of the individuals took comedications mostly linked to aging and comorbidities. We systematically analyzed the off-target effects of 1178 concurrent comedications (classified according to the Anatomical Therapeutic Chemical (ATC) Classification System) on the density of tumor-infiltrating lymphocytes (TILs) and pathological complete responses (pCR). At level 1 of the ATC system, the main anatomical classes of drugs were those targeting the nervous system (class N, 39.1%), cardiovascular disorders (class C, 26.6%), alimentary and metabolism (class A, 16.9%), or hormonal preparations (class H, 6.5%). At level 2, the most frequent therapeutic classes were psycholeptics (N05), analgesics (N02), and psychoanaleptics (N06). Pre-NAC TIL density in triple-negative BC (TNBC) was influenced by medications from class H, N, and A, while TIL density in HER2+ BC was associated with the use of class C. Psycholeptics (N05) and agents acting on the renin-angiotensin system (C09) were independently associated with pCR in the whole population of BC or TNBC, and in HER2-positive BC, respectively. Importantly, level 3 hypnotics (N05C) alone were able to reduce tumor growth in BC bearing mice and increased the anti-cancer activity of cyclophosphamide in a T cell-dependent manner. These findings prompt for further exploration of drugs interactions in cancer, and for prospective drug-repositioning strategies to improve the efficacy of NAC in BC.