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Background There is limited epidemiological evidence describing contemporary neuro-urological management of persons with acute spinal cord injury (SCI). Objective To describe neurogenic lower urinary tract dysfunction (NLUTD) management at discharge from SCI rehabilitation. Design setting and participants The population-based Swiss Spinal Cord Injury (SwiSCI) cohort study prospectively collected data from 602 adults undergoing specialized postacute SCI rehabilitation from 2013 to 2020. The management strategy was based on the European Association of Urology (EAU) Guidelines on Neuro-Urology. Outcome measurements and statistical analysis Data were collected at discharge using the International SCI Lower Urinary Tract Function Basic Data Set. Multivariable logistic regression adjusting for demographics, SCI characteristics, and center, with inverse probability weighting accounting for sampling bias, was used to produce prevalence estimates and identify predictors of lower urinary tract symptoms (LUTS) and NLUTD management outcomes. Results and limitations At discharge (median time after SCI: 5.0 mo [Q1-Q3: 3.0-7.2]), the prevalence of LUTS or managed NLUTD was 82% (95% confidence interval [CI]: 79-85%). SCI completeness was the main predictor of LUTS and managed NLUTD. The risk of urinary incontinence was elevated in females (odds ratio 1.98 [95% CI: 1.18-3.32]) and with complete lesions (odds ratio 4.71 [95% CI: 2.52-8.81]). Voiding dysfunction was most commonly managed with intermittent catheterization (prevalence 39% [95% CI: 35-42%]), followed by indwelling catheterization (prevalence 22% [95% CI: 18-25%]). The prevalence of antimuscarinic or mirabegron use was 29% (95% CI: 26-33%). Urodynamic and renal function data were not collected. Conclusions Our population-based description of urological management in Swiss SCI centers utilizing the EAU Guidelines on Neuro-Urology may be used as a reference for evaluation in other settings. Data further indicate a need for sex-specific neuro-urological management research. Patient summary At discharge from spinal cord injury (SCI) rehabilitation, a majority of patients have lower urinary tract problems, especially those with complete SCI. Women have a higher risk of urinary incontinence.

Background: The prognostic factors and optimal choice of treatment for primary neuroendocrine neoplasms of the breast (BNEN) remain to be defined. Methods: Patients diagnosed with BNEN in China were retrospectively reviewed from the literature following the systematic search of China National Knowledge Infrastructure (CNKI), Chinese biomedical literature service system (sinomed), wanfang medical network, and Pubmed database. The clinical characteristics and different treatment modalities of patients with BNEN were evaluated. Results: A total of 209 cases with BNEN were enrolled. There were 204 female and 5 male patients. The median age was 51 years old (range, 17–82). Out of 209 patients with BNEN, 208 (99.5%) patients were treated with surgery (SG), 44 patients (21.1%) had received radiotherapy (RT), 173 patients (82.8%) experienced chemotherapy (CT). A total of 158 patients with hormone receptor (HR) positive (87.8%, 158/180) were treated with endocrine treatment (ET). The median follow-up time was 52.4 months (range, 6–144). The 3-year overall survival (OS) rate and 3-year disease-free survival (DFS) rate for the whole group were 93.7% and 85.3%, respectively. In univariate analyses, Ki67 expression ≥20%, HR negative, neuroendocrine carcinomas (NECs) were associated with decreased OS and DFS (P 0.05). Conclusions: The best selection of patients to get the most benefit from different treatment modalities warrant further exploration. The clinicopathological parameters including gender, HR expression, ki67 expression, pathologic type, stage, tumor size, and lymph node status may serve as both indicators of diagnosis and prognosis, and guide treatment decisions for BNEN.

After the expiration of trastuzumab data exclusivity, biosimilar drugs were approved by regulatory agencies; among them, CT-P6 which was approved for the treatment of HER2-positive early- and advanced-breast cancer (BC) in 2018. Yet, reference trastuzumab (RTZ) is often combined with pertuzumab in early BC (EBC) patients treated with chemotherapy as it significantly improves the pathological complete response rate. Unfortunately, scarce preclinical and clinical data exists about the combination of CT-P6, pertuzumab and chemotherapy. Therefore, our aim was to study in vitro and in a retrospective cohort of EBC patients, whether CT-P6 was equivalent to RTZ when combined with pertuzumab with or without taxanes. In BT-474 and SKBR3 HER2+ cells we found that CT-P6 alone or in combination with pertuzumab had the same negative effect on cell proliferation, colony formation and HER2 downregulation as well as downstream activation, as RTZ. Adding paclitaxel to these treatments increased their effectivity to a similar extent. In HER2 1+ neuregulin-secreting MB-MDA-175 cells, combinations of CT-P6 or RTZ with pertuzumab were also effective, and mainly dependent on HER3:HER2 heterodimerization. In a retrospective cohort of 44 EBC HER2+ patients treated with neoadjuvant RTZ or CT-P6 in combination with pertuzumab and chemotherapy, we found no differences in efficacy or in adverse events. Moreover, the costs of CT-P6-based treatments were reduced by 1474.07 €/patient. All together we provide pre-clinical and clinical evidence of the equivalence of CT-P6 in combination with pertuzumab and chemotherapy and suggest studying these combinations also in HER2 low/negative BC patients., Highlights • CT-P6 or RTZ + pertuzumab + paclitaxel are equivalent treatments in HER2+ BC cells. • Equivalent efficacy and safety of CT-P6 or RTZ in HER2+ EBC patients. • Using CT-P6 represents important savings for the health system. • HER2 low BC is a promising scenario for new anti-HER2 therapies.

Background: Palbociclib plus endocrine therapy (ET) demonstrated significant progression-free survival (PFS) benefit in Young Pearl, a randomized phase ll trial comparing palbociclib + ET versus capecitabine in premenopausal women with hormone receptor positive, HER2 negative metastatic breast cancer (MBC). This exploratory analysis investigated potential biomarkers of palbociclib plus ET on PFS. Patients and methods: Of 178 patients randomized (92 palbociclib plus ET; 86 capecitabine), we performed targeted sequencing (141 patients) and whole transcriptome sequencing (165 patients) using baseline tumor samples to examine genomic alteration in relation to drug response on PFS. Hazard ratios (HRs) were estimated using unstratified Cox proportional hazards models. Results: PIK3CA (41%) and TP53 (33%) mutations and CCND1 copy number variation (29%) were found most frequently in targeted sequencing of 141 patients. ESR1 mutations were found only in 3.5% of patients of this population. Luminal type showed better prognosis in palbociclib + ET arm but no impact on PFS difference in capecitabine arm. High TMB, TP53 mutation, PTEN loss of function mutation and RB1 pathway alteration showed worse prognosis in palbociclib plus ET arm. Patients with BRCA2 pathogenic mutations showed worse prognosis regardless of PAM50 subtypes. AURKA mutation/amplification, BRIP1/MYC/RAD51C amplification were significantly associated to the patients with short PFS

Fear of cancer recurrence (FCR) is a normal response in cancer survivors and one of the most prevalent reactions reported by up to 87% of them. However, elevated levels of FCR impair well-being, quality of life and professional functioning, and lead to anxiety, depression or PTSD. COVID-19 pandemic can exacerbate FCR symptoms, given the restricting access to follow-up investigations and treatment, the isolation restrictions imposed and the possibility of the medical system becoming overworked. This scoping review's objective was to synthesize the literature investigating the factors associated with higher levels of FCR in cancer survivors during the COVID-19 pandemic. The focus was on FCR in breast cancer patients, including most of the studies (5 out of 9) on this topic. However, given the novelty of the subject, the increased interest in it, and the fact that there are few studies in this field, the review included 4 other studies with mixed samples of patients with breast cancer and other oncological pathologies. Following rigorous methodological criteria, 9 studies with quantitative or mixed methodology were included (N = 4831 patients). The results indicate that high levels of FCR are associated with distress and concerns regarding the pandemic impact, with most common concerns of patients being changes in treatment plan (delays and interruptions), dysfunctional communication with medical staff or difficult access to food or medicine. The most common correlates of FCR during the pandemic are marital status, childlessness, low financial status, level of education, type of cancer diagnosis, generalized anxiety and depression.

Introduction: We provide a critical assessment regarding current evidence for the use of moderately hypofractionated irradiation for patients with breast cancer. The aim of the study was to summarize the available evidence regarding outcomes after moderately hypofractionated compared with conventional radiation doses in the post-operative treatment of patients with breast cancer. Material and methods: The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and LILACS databases were searched until March 25, 2021. All randomized phase 3 clinical trials that compared moderately hypofractionated with conventional radiation doses in the post-operative treatment of patients with breast cancer were selected. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. Results: Eight clinical trials satisfied the eligibility criteria and were the focus of the analysis. A total of 12,139 breast cancer patients was randomly assigned for moderately hypofractionated compared with conventional irradiation. Meta-analysis of the trials regarding local recurrence, loco-regional recurrence, disease-free survival, and overall survival outcomes did not demonstrate any significant difference between moderately hypofractionated irradiation and conventional radiation doses groups. The rate of severe side effects was low in both groups; acute and late side effects and cosmesis were similar or even tended to be lower after moderately hypofractionated than after conventional irradiation. Conclusions: Moderately hypofractionated is at least as effective and safe as conventional radiation irradiation regimens and should be considered as a treatment option for most, if not all, breast cancer patients.

Glioblastoma (GBM) is the deadliest primary brain tumor and is generally resistant to immunotherapy because of severe dysfunction of T cells. Novel treatment options are critically needed to overcome the immunotherapy resistance of GBM. Here we demonstrate that Zika virus (ZIKV) treatment improves the efficacy of anti-PD ligand 1 (PD-L1) immunotherapy in GBM. We found that ZIKV induces a strong pro-inflammatory response and increases CD4+ and CD8+ T cell intratumoral infiltration and activation in GBM mouse models. ZIKV treatment of mice bearing GBM tumors inhibits tumor growth and prolongs survival. These therapeutic effects of ZIKV on GBM tumors are negated in mice depleted of T cells. Moreover, ZIKV dramatically promotes activation of the type I interferon signaling pathway in GBM cells. ZIKV treatment potently sensitizes GBM to PD-L1 blockade and provides significant and durable survival benefits. Our findings reveal that ZIKV overcomes the resistance of GBM to immune checkpoint blockade, which may lead to therapeutic applications of ZIKV in individuals with GBM receiving immunotherapy.

Ras family proteins are membrane-bound GTPases that control proliferation, survival, and motility. Many forms of cancers are driven by the acquisition of somatic mutations in a RAS gene. In pancreatic cancer (PC), more than 90% of tumors carry an activating mutation in KRAS. Mutations in components of the Ras signaling pathway can also be the cause of RASopathies, a group of developmental disorders. In a subset of RASopathies, the causal mutations are in the LZTR1 protein, a substrate adaptor for E3 ubiquitin ligases that promote the degradation of Ras proteins. Here, we show that the function of LZTR1 is regulated by the glycogen synthase kinase 3 (GSK3). In PC cells, inhibiting or silencing GSK3 led to a decline in the level of Ras proteins, including both wild type Ras proteins and the oncogenic Kras protein. This decline was accompanied by a 3-fold decrease in the half-life of Ras proteins and was blocked by the inhibition of the proteasome or the knockdown of LZTR1. Irrespective of the mutational status of KRAS, the decline in Ras proteins was observed and accompanied by a loss of cell proliferation. This loss of proliferation was blocked by the knockdown of LZTR1 and could be recapitulated by the silencing of either KRAS or GSK3. These results reveal a novel GSK3-regulated LZTR1-dependent mechanism that controls the stability of Ras proteins and proliferation of PC cells. The significance of this novel pathway to Ras signaling and its contribution to the therapeutic properties of GSK3 inhibitors are both discussed.

Peritoneal carcinomatosis of gastrointestinal malignancies remains fatal. CF33-hNIS-antiPDL1, a chimeric orthopoxvirus expressing the human sodium iodide symporter (hNIS) and anti-human programmed death-ligand 1 antibody, has demonstrated robust preclinical activity against pancreatic adenocarcinoma (PDAC). We investigated the ability of CF33-hNIS-antiPDL1 to infect, help detect, and kill peritoneal tumors following intratumoral (i.t.) injection of subcutaneous (s.c.) tumors in vivo. Human PDAC AsPC-1-ffluc cells were inoculated in both the s.c. space and the peritoneal cavity of athymic mice. After successful tumor engraftment, s.c. tumors were injected with CF33-hNIS-antiPDL1 or PBS. We assessed the ability of CF33-hNIS-antiPDL1 to infect, replicate in, and allow the imaging of tumors at both sites (immunohistochemistry [IHC] and 124I-based positron emission tomography/computed tomography [PET/CT] imaging), tumor burden (bioluminescence imaging), and animal survival. IHC staining for hNIS confirmed expression in s.c. and peritoneal tumors following virus treatment. Compared to the controls, CF33-hNIS-antiPDL1-treated mice showed significantly decreased s.c. and peritoneal tumor burden and improved survival (p < 0.05). Notably, 2 of 8 mice showed complete regression of disease. PET/CT avidity for 124I uptake in s.c. and peritoneal tumors was visible starting at day 7 following the first i.t. dose of CF33-hNIS-antiPDL1. We show that CF33-hNIS-antiPDL1 can help detect and kill both s.c. and peritoneal tumors following s.c. i.t. treatment., Graphical abstract, CF33-hNIS-anti-PD-L1 can detect both locally injected tumors and peritoneal tumors distant from the injection site in a xenograft model of PDAC. Our study demonstrates the diagnostic capability of the virus, highlighting the collective efficacy of CF33-hNIS-anti-PD-L1 with direct oncolysis and imaging/radiotherapy.

Background: Recent reports with a small number of patients showed an association of red blood cell distribution width (RDW) with prostate cancer (PCa) progression. Objective: To investigate whether preoperative RDW can serve as a prognostic marker in patients with PCa undergoing radical prostatectomy (RP) in a large, equal access, and diverse patient cohort. Design, setting, and participants: Data were retrospectively collected on 4756 men treated with RP at eight Veteran Affairs medical centers within the Shared Equal Access Regional Cancer Hospital (SEARCH) database from 1999 through 2017. Outcome measurements and statistical analysis: Biochemical recurrence (BCR) was the primary outcome, while metastasis, all-cause mortality (ACM), and prostate cancer–specific mortality (PCSM) were secondary outcomes. Results and limitations: The mean (standard deviation) age was 62 yr (6.1), and 1589 (33%) men were black. The median (interquartile range) follow-up was 82 mo (46–127). Preoperative RDW either as a continuous variable or when stratified by quartiles was not associated with BCR. Likewise, preoperative RDW was not associated with metastases or PCSM. However, higher RDW was significantly associated with higher ACM, both as a continuous variable (p < 0.001) and when stratified by quartiles in univariable and multivariable models (p < 0.001). RDW was found to be correlated with D’Amico risk classification of PCa. Study limitations include its retrospective nature and lack of data regarding advanced PCa. Conclusions: Preoperative RDW was not associated with PCa outcomes in men treated with RP but was associated with ACM. While RDW may be a biomarker of overall health, it is not a biomarker for PCa outcomes. These results emphasize the importance of diverse, larger sized studies in genitourinary cancer research. Patient summary: Prostate cancer includes a wide spectrum of diseases with different genetic, pathological, and oncological behaviors. Red blood cell distribution width is helpful in predicting the overall survival for a localized prostate cancer patient, and hence, it can help inform personalized treatment decisions and operative care.

Background: Elderly patients diagnosed with high-risk prostate cancer (PCa) present a therapeutic dilemma of balancing treatment of a potentially lethal malignancy with overtreatment of a cancer that may not threaten life expectancy. Objective: To investigate treatment patterns and overall survival outcomes in this group of patients. Design, setting, and participants: A retrospective cohort study was conducted. We queried the National Cancer Database for high-risk PCa in patients aged 80 yr or older diagnosed during 2004–2016. Intervention: Eligible patients underwent no treatment following biopsy (ie, observation), androgen deprivation therapy (ADT) alone, radiation therapy (RT) alone, RT + ADT, or surgery. Outcome measurements and statistical analysis: Kaplan-Meier, log rank, and multivariate Cox proportional hazard regression was performed to compare overall survival (OS). Results and limitations: A total of 19 920 men were eligible for analysis, and the most common treatment approach was RT + ADT (7401 patients; 37.2%). Observation and ADT alone declined over time (59.3% in 2004 vs 47.5% in 2016). There was no observed difference in OS between observation and ADT alone (adjusted hazard ratio [HR] 1.04, 95% confidence interval [CI], 0.99–1.09; p = 0.105). Definitive local treatment was associated with improved OS compared with ADT alone (RT alone, HR 0.54, 95% CI, 0.50–0.59, p 5 yr; minimal comorbidity) should be offered definitive, life-prolonging therapy.

Background: Some health care systems have set up referral trauma centers to centralize expertise to improve trauma management. There is scant and controversial evidence regarding the impact of provider’s volume on the outcomes of trauma management. Objective: To evaluate the impact of hospital volume on the outcomes of renal trauma management in a European health care system. Design, setting, and participants: A retrospective multicenter study, including all patients admitted for renal trauma in 17 French hospitals between 2005 and 2015, was conducted. Intervention: Nephrectomy, angioembolization, or nonoperative management. Outcome measurements and statistical analysis: Four quartiles according to the caseload per year: low volume (eight or fewer per year), moderate volume (nine to 13 per year), high volume (14–25/yr), and very high volume (≥26/yr). The primary endpoint was failure of nonoperative management defined as any interventional radiology or surgical procedure needed within the first 30 d after admission. Results and limitations: Of 1771 patients with renal trauma, 1704 were included. Nonoperative management was more prevalent in the very-high- and low-volume centers (p = 0.02). In a univariate analysis, very high hospital volume was associated with a lower risk of nonoperative management failure than low (odds ratio [OR] = 0.54; p = 0.05) and moderate (OR = 0.48; p = 0.02) hospital volume. There were fewer nephrectomies in the high- and very-high-volume groups (p = 0.003). In a multivariate analysis, very high volume remained associated with a lower risk of nonoperative management failure than low (OR = 0.48; p = 0.04) and moderate (OR = 0.42; p = 0.01) volume. Study limitations include all the shortcomings inherent to its retrospective multicenter design. Conclusions: In this multicenter study, management of renal trauma varied according to hospital volume. There were lower rates of nephrectomy and failure of nonoperative management in very-high-volume centers. These results raise the question of centralizing the management of renal trauma, which is currently not the case in our health care system. Patient summary: In this study, management of renal trauma varied according to hospital volume. Very-high-volume centers had lower rates of nephrectomy and failure of nonoperative management.

α-Enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a glycolytic enzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid during glycolysis. It is a multifunctional oncoprotein that is present both in cell surface and cytoplasm, contributing to hit seven out of ten "hallmarks of cancer." ENO1's glycolytic function deregulates cellular energetic, sustains tumor proliferation, and inhibits cancer cell apoptosis. Moreover, ENO1 evades growth suppressors and helps tumors to avoid immune destruction. Besides, ENO1 "moonlights" on the cell surface and acts as a plasminogen receptor, promoting cancer invasion and metastasis by inducing angiogenesis. Overexpression of ENO1 on a myriad of cancer types together with its localization on the tumor surface makes it a great prognostic and diagnostic cancer biomarker as well as an accessible oncotherapeutic target. This review summarizes the up-to-date knowledge about the relationship between ENO1 and cancer, examines ENO1's potential as a cancer biomarker, and discusses ENO1's role in novel onco-immunotherapeutic strategies.

Carborane is a carbon-boron molecular cluster that can be viewed as a 3D analog of benzene. It features special physical and chemical properties, and thus has the potential to serve as a new type of pharmacophore for drug design and discovery. Based on the relative positions of two cage carbons, icosahedral closo-carboranes can be classified into three isomers, ortho-carborane (o-carborane, 1,2-C2B10H12), meta-carborane (m-carborane, 1,7-C2B10H12), and para-carborane (p-carborane, 1,12-C2B10H12), and all of them can be deboronated to generate their nido- forms. Cage compound carborane and its derivatives have been demonstrated as useful chemical entities in antitumor medicinal chemistry. The applications of carboranes and their derivatives in the field of antitumor research mainly include boron neutron capture therapy (BNCT), as BNCT/photodynamic therapy dual sensitizers, and as anticancer ligands. This review summarizes the research progress on carboranes achieved up to October 2021, with particular emphasis on signaling transduction pathways, chemical structures, and mechanistic considerations of using carboranes.

Background: The AnTIC trial linked continuous low-dose antibiotic prophylaxis treatments to a lower incidence of symptomatic urinary tract infections (UTIs) among individuals performing clean intermittent self-catheterisation (CISC). Objective: To explore potential mechanisms underlying the protective effects of low-dose antibiotic prophylaxis treatments, blood and urine samples and uro-associated Escherichia coli isolates from AnTIC participants were analysed. Design, setting, and participants: Blood samples (n = 204) were analysed for TLR gene polymorphisms associated with UTI susceptibility and multiple urine samples (n = 558) were analysed for host urogenital responses. E.coli sequence data for 45 temporal isolates recovered from the urine samples of 16 trial participants in the prophylaxis (n = 9) and no-prophylaxis (n = 7) study arms, and characterised by multidrug resistance (MDR), were used to classify individual strains. Outcome measurements and statistical analysis: TLR polymorphism data were analysed using Poisson regression. Concentrations of urine host defence markers were analysed using linear mixed-effects models, which accounted for repeated urine samples. Results and limitations: Urine samples from CISC users, irrespective of antibiotic treatment regimens, were associated with robust urothelial innate responses. No links were identified between TLR genotype and CISC user susceptibility to recurrent UTIs. Microbiological study data were limited to the predominant MDR E. coli population; participants prescribed low-dose prophylactic antibiotics were predominantly colonised by a single uro-associated E. coli strain, while participants given acute antibiotic treatments were each colonised by more than one E. coli strain. Conclusions: Antibiotic treatments did not impact urogenital responses to infection in CISC users. Host genetics in terms of TLR polymorphisms played no role in determining CISC user susceptibility to or protection from recurrent UTIs. Prophylactic antibiotic treatments associated with MDR E. coli were associated with colonisation by stable uro-associated E. coli genotypes. Patient summary: Our findings show that the natural urogenital defences of clean intermittent self-catheterisation (CISC) users were not impacted by antibiotic treatments. For some CISC users, prophylaxis with low-dose antibiotics selected for a stable, predominantly, Esherichia coli rich uromicrobiota.

Although chimeric antigen receptor T cell (CAR-T) therapy has been successful for hematological malignancies, it is less effective for solid tumors. The primary reason is that the immune microenvironment restricts CAR-T cells from infiltrating and proliferating in tumors. Oncolytic virotherapy has emerged as a novel immunogenic therapy to augment antitumor immune response. Here we combined an oncolytic adenovirus carrying decorin with a CAR-T targeting carbonic anhydrase IX (CAIX) to perform the antitumor activity for renal cancer cells. We found that OAV-Decorin combined with CAIX-CAR-T exhibited significantly reduced tumor burden, altered the composition of extracellular matrix (ECM) by inhibiting the distribution of collagen fibers, decreased the expression of TGF-β in tumor cells, enhanced IFN-γ secretion, and obtained higher numbers of CAR-T cells. The combination treatment modality showed prolonged mice survival. The intratumoral injection of OAV-Decorin into tumor-bearing immunocompetent mice activated the inflammatory immune status and resulted in tumor regression. These data supported further investigation of the combination of OAV-Decorin and CAIX-CAR-T cells in solid tumors., Graphical abstract, It was shown that decorin expression mediated by oncolytic adenovirus activated the inflammatory immune status. OAV-Decorin combined with CAIX-targeted CAR-T cells exhibited significantly reduced renal tumor burden and altered the composition of extracellular matrix. OAV-Decorin is potent to be developed as an effective enhancer of CAR-T cells therapeutic approach.

Sarcomas are a heterogeneous group of rare mesenchymal tumors. The migration of immune cells into these tumors and the prognostic impact of tumor-specific factors determining their interaction with these tumors remain poorly understood. The current risk stratification system is insufficient to provide a precise survival prediction and treatment response. Thus, valid prognostic models are needed to guide treatment. This study analyzed the gene expression and outcome of 980 sarcoma patients from seven public datasets. The abundance of immune cells and the response to immunotherapy was calculated. Immune-related genes (IRGs) were screened through a weighted gene co-expression network analysis (WGCNA). A least absolute shrinkage and selection operator (LASSO) Cox regression was used to establish a powerful IRG signature predicting prognosis. The identified IRG signature incorporated 14 genes and identified high-risk patients in sarcoma cohorts. The 14-IRG signature was identified as an independent risk factor for overall and disease-free survival. Moreover, the IRG signature acted as a potential indicator for immunotherapy. The nomogram based on the risk score was built to provide a more accurate survival prediction. The decision tree with IRG risk score discriminated risk subgroups powerfully. This proposed IRG signature is a robust biomarker to predict outcomes and treatment responses in sarcoma patients., Graphical abstract, Immune-related gene (IRG) signature serves as a robust and independent prognostic biomarker in various sarcoma subtypes and guides more effective immunotherapy strategies. The nomogram and the decision tree based on the IRG signature could be useful predictive tools and could help to identify high-risk sarcoma patients.

Background: Mini percutaneous nephrolithotomy (MPCNL) is a newer surgical procedure that has changed the management of paediatric renal stones. Objective: To evaluate MPCNL morbidity and success rates for renal stones as a function of patient age in a paediatric cohort. Design, setting, and participants: This was a retrospective case series that included 143 consecutive patients younger than 17 yr who underwent MPCNL at our institution between January 2016 and November 2020. The patients were categorised into three different age groups

Ad5-delta-24-RGD is currently the most clinically advanced recombinant adenovirus (rAd) for glioma therapy. We constructed a panel of fiber-modified rAds (Ad5RGD, Ad5/3, Ad5/35, Ad5/3RGD, and Ad5/35RGD, all harboring the delta-24 modification) and compared their infectivity, replication, reproduction, and cytolytic efficacy in human and rodent glioma cell lines and short-term cultures from primary gliomas. In human cells, both Ad5/35-delta-24 and Ad5/3-delta-24 displayed superior infectivity and cytolytic efficacy over Ad5-delta-24-RGD, while Ad5/3-delta-24-RGD and Ad5/35-delta-24-RGD did not show further improvements in efficacy. The expression of the adenoviral receptors/coreceptors CAR, DSG2, and CD46 and the integrins αVβ3/αVβ5 did not predict the relative cytolytic efficacy of the fiber-modified rAds. The cytotoxicity of the fiber-modified rAds in human primary normal cultures of different origins and in primary glioma cultures was comparable, indicating that the delta-24 modification did not confer tumor cell selectivity. We also revealed that CT-2A and GL261 glioma cells might be used as murine cell models for the fiber chimeric rAds in vitro and in vivo. In GL261 tumor-bearing mice, Ad5/35-delta-24, armed with the immune costimulator OX40L as the E2A/DBP-p2A-mOX40L fusion, produced long-term survivors, which were able to reject tumor cells upon rechallenge. Our data underscore the potential of local Ad5/35-delta-24-based immunovirotherapy for glioblastoma treatment., Graphical abstract, The oncolytic fiber chimeric recombinant adenoviruses based on serotype 5 with the fiber proteins consisting of the shaft and/or knob domains derived from serotypes 3 or 35 display superior infectivity and cytolytic efficacy over clinically advanced Ad5-delta-24-RGD in human brain tumor (glioblastoma) cultures.

Highlights • NBTXR3 is a radioenhancer composed of functionalized hafnium oxide nanoparticles. • This report describes the first patient with pancreatic cancer treated with NBTXR3. • First demonstration of local endoscopic delivery of NBTXR3 to a deep visceral tumor. • Multidisciplinary care critical for treating pancreatic cancer patients with NBTXR3., Background and purpose Pancreatic ductal adenocarcinoma (PDAC) remains one of the leading causes of cancer-related deaths in the world. For patients with PDAC who are not eligible for surgery, radiation therapy improves local disease control, yet safely delivering therapeutic doses of radiation remains challenging due to off-target toxicities in surrounding normal tissues. NBTXR3, a novel radioenhancer composed of functionalized hafnium oxide crystalline nanoparticles, has recently shown clinical activity in soft tissue sarcoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, and advanced solid malignancies with lung or liver metastases. Here we report the first patient with pancreatic cancer treated with NBTXR3. Materials and methods A 66-year-old male with unresectable locally advanced PDAC was enrolled on our clinical trial to receive NBTXR3 activated by radiation therapy. Local endoscopic delivery of NBTXR3 was followed by intensity modulated radiation therapy (IMRT). Follow-up assessment consisted of physical examination, laboratory studies including CA19-9, and CT of the chest, abdomen, and pelvis. Results The patient received NBTXR3 by local endoscopic delivery without any acute adverse events. Radiation treatment consisted of 45 Gy in 15 daily fractions using IMRT. The patient began radiation twelve days after NBTXR3 injection. Daily CT-on-rails imaging demonstrated retention of NBTXR3 within the tumor for the duration of treatment. At initial follow-up evaluation, the lesion remained radiographically stable and the patient did not demonstrate treatment-related toxicity. Conclusion This report demonstrates initial feasibility of local endoscopic delivery of NBTXR3 activated by radiation therapy for patients with pancreatic cancer who are not eligible for surgery.

Aberrant expression of SNX5 can contribute to tumorigenesis, invasion, and metastasis of several human cancers. However, the clinicopathological and biological significance of SNX5 in clear cell renal cell carcinoma (ccRCC) remain unclear. In this study, we found that SNX5 expression was downregulated and negatively correlated with tumor size, American Joint Committee on Cancer stage, tumor thrombus of inferior vena cava, and poor prognosis in human ccRCC. Ectopic expression of SNX5 inhibited ccRCC cell proliferation and metastasis, whereas knockdown of SNX5 increased these activities both in vitro and in vivo. Mechanistically, overexpression of SNX5 blocked internalization and intracellular trafficking of CD44 in ccRCC cells. Knockdown of SNX5 was associated with epithelial-to-mesenchymal transition (EMT) in ccRCC cells. Overexpression of SNX5 inhibited TGF-β-induced migration, invasion, and EMT in ccRCC cells. KLF9 directly bound to the SNX5 promoter and increased SNX5 transcription. Moreover, we found that the combination of SNX5 and CD44 or E-cadherin or KLF9 was a more powerful predictor of poor prognosis than either parameter alone. Collectively, our data reveal a mechanism that KLF9-mediated SNX5 expression was associated with poor prognosis via trafficking of CD44 and promoting EMT in ccRCC. SNX5 may be a potential prognostic biomarker and therapeutic target for patients with ccRCC., Graphical abstract, This study aimed at researching the function of SNX5 in clear cell renal cell carcinoma (ccRCC). The authors showed that SNX5 expression was downregulated by KLF9, leading to trafficking of CD44 and epithelial-to-mesenchymal transition and poor prognosis in ccRCC. SNX5 was a potential prognostic biomarker and therapeutic target in ccRCC.

Targeted modulation of the immune system against tumors can achieve responses in otherwise refractory cancers, which has spurred efforts aimed at optimizing such strategies. To this end, we have previously investigated cancer immunotherapy approaches using recombinant adenovirus vectors, as well as via modulation of the self-ligand receptor SLAMF7. Here, we present a gene transfer-based immunotherapy approach using targeted expression of a SLAMF7-Fc fusion construct directly into tumors at high concentrations via a recombinant adenoviral vector (Ad-SF7-Fc). Using multiple murine cancer models, we show that Ad-SF7-Fc can induce tumor control via augmentation of innate immunity; specifically, induction of type I interferons and activation of dendritic cells (DCs) and macrophages. Analogously, we find that modulating SLAMF7 signaling via an adenoviral vector expressing its intracellular adaptor, EAT-2, is also capable of inducing tumor control. Finally, we employ a novel in vivo prediction approach and dataset integration with machine learning to dissect how Ad-SF7-Fc modulates cell-type-specific responses in the tumor microenvironment to achieve tumor control. Thus, our novel combinatorial cancer immunotherapy highlights the benefit of multimodal immune modulation and lays a framework for combination with complementary approaches capable of inducing adaptive immune responses., Graphical abstract, In this study, Aldhamen and colleagues develop a novel combination cancer immunotherapy combining an adenovirus vector with manipulation of the SLAMF7 self-ligand immune receptor. They show this immunotherapy is capable of inducing tumor control via activation of type I interferon, macrophage, and dendritic cell (DC) responses.

Non-small cell lung cancer (NSCLC) has a high morbidity and mortality, and it is imperative to explore the latent pathogenesis mechanism of NSCLC progression to find potential prognostic biomarkers and therapeutic targets. The present study aimed to explore the biological function of circSHKBP1 in NSCLC. circSHKBP1 was found to be upregulated in NSCLC tissues and cell lines and was enriched in exosomes derived from NSCLC cells. Exosomal circSHKBP1 enhanced the proliferation, migration, invasion, and stemness of NSCLC cells. miRNA-1294 was identified as a target for circSHKBP1, and circSHKBP1 upregulated PKM2 expression by sponging miR-1294. Exosomal circSHKBP1 regulated glycolysis through PKM2 in a HIF-1α-dependent manner in NSCLC cells and promoted M2 polarization and macrophage recruitment. Moreover, exosomal circSHKBP1 promoted NSCLC cell growth, metastasis, and M2 infiltration in vivo. Thus, exosomal circSHKBP1 participated in the progression of NSCLC via the miR-1294/PKM2 axis. circSHKBP1 may be potential biomarker for the diagnosis and treatment of NSCLC.

Take Home Message Our analysis demonstrates a repair rate of 6.5%, equivalent to 15 ureteroscopy procedures between flexible ureteroscope repairs and a repair cost of 441 USD per procedure., Context The refined mechanics of a flexible ureteroscope (fURS) are vulnerable to damage. Sending the fURS for repair is costly and has driven interest toward estimating the resources used for fURS repairs. Objective To systematically review available literature and to estimate the total weighted repair rate of an fURS and the average repair cost per ureteroscopy. Evidence acquisition A systematic review was conducted by searching the MEDLINE, Embase, Web of Science, and Cochrane Library databases. The average costs of all repairs identified in the included studies were extracted. A random-effect model was used to calculate the pooled total fURS repair rate. The total weighted repair rate and average cost per repair were multiplied to provide an average cost of repair per ureteroscopy procedure. Evidence synthesis We identified 18 studies that fulfilled the inclusion criteria, which included 411 repairs from 5900 investigated ureteroscopy procedures. The calculated weighted repair rate was 6.5% ± 0.745% (95% confidence interval: 5.0–7.9%; I2 = 75.3%), equivalent to 15 ureteroscopy procedures before repair. The average cost per repair was 6808 USD; according to the weighted repair rate of 6.5%, this corresponds to an average repair cost of 441 USD per procedure. Egger’s regression test did not reveal a significant publication bias (p = 0.07). Conclusions This is the first meta-analysis to estimate the repair rate of the fURS used for ureteroscopy. Our analysis demonstrates a repair rate of 6.5%, equivalent to 15 ureteroscopy procedures between fURS repairs and a repair cost of 441 USD per procedure. Ureteroscopy practices should consider fURS breakage rates and repair costs to optimize the use of reusable versus disposable devices. Patient summary We reviewed available literature investigating the repair rate of a flexible ureteroscope (fURS). We found that fURSs are sent for repair after every 15 ureteroscopy procedures, corresponding to 441 USD per procedure in repair cost.

Chimeric antigen receptor (CAR)-modified T cells have exhibited impressive anti-tumor effects in both B cell malignancies and some types of solid tumors. However, single-chain variable fragment (scFv) of a murine monoclonal antibody will induce immune responses, limit CAR-T cell persistence, and thus increase the risk of relapse. This study successfully constructed a CAR-targeting interleukin-13 receptor α2 (IL-13Rα2) according to a murine antibody, and then humanized the scFv sequence to generate another CAR. T cells expressing any of these two CARs demonstrated superior tumor inhibitory effects in vitro and in two xenograft mouse models. However, T cells transduced with humanized CAR have an increased expansion and reduced cytokines, including interleukin-6 and interferon-γ. The top expressed genes clustered in leukocyte-mediated cytotoxicity, and T cell migration and immunological synapse formation contributed to the anti-glioblastoma (GBM) activity of the humanized CAR. In conclusion, we successfully generated a humanized third-generation CAR-targeting IL-13Rα2 and confirmed its anti-GBM efficacy, which provide a candidate method for clinical GBM treatment.

Nasopharyngeal carcinoma (NPC) is one of the most predominant cancers occurring in China with high morbidity. Lately, large quantities of long non-coding RNAs (lncRNAs) have been highlighted to regulate the biological activities in multiple tumors, including NPC. Our study centered on whether TTN-AS1 was involved in NPC and how it modulated the progression of NPC. Here, RT-qPCR data uncovered that TTN-AS1 expression was conspicuously high in NPC cells. Based on the results of functional assays, TTN-AS1 silence hampered the proliferative, migratory and invasive abilities but stimulated apoptotic capability of NPC cells. After a series of mechanism assays, TTN-AS1 was found to competitively bind with miR-876-5p and recruit UPF1 to enhance NETO2 expression. In addition, TTN-AS1 could be transcriptionally activated by YY1 in NPC cells. It was also found miR-876-5p overexpression or NETO2 down-regulation had inhibitory effects on cell proliferation, migration and invasion in NPC. Moreover, NETO2 up-regulation could restore the suppressive impacts of TTN-AS1 depletion on NPC cell and tumor growth. In conclusion, YY1-activated TTN-AS1 interacted with both miR-876-5p and UPF1 to up-regulate NETO2, thus strengthening NPC cell malignant behaviors, which might provide more useful information for people to develop effective NPC treatments.

Human telomerase reverse transcriptase (hTERT) is highly expressed in many tumors and is essential for tumorigenesis and metastasis in multiple cancers. However, the molecular mechanisms underlying its high expression level in hepatocellular carcinoma (HCC) remain unclear. In this study, we identified X-ray repair cross-complementing 5 (XRCC5), a novel hTERT promoter-binding protein in HCC cells, using biotin-streptavidin-agarose pull-down assay. We found that XRCC5 was highly expressed in HCC cells, in which it transcriptionally upregulated hTERT. Functionally, the transgenic expression of XRCC5 promoted HCC progression and 5-fluorouracil resistance, whereas short hairpin RNA knockdown of XRCC5 had converse effects in vitro and in vivo. Moreover, hTERT overexpression reversed XRCC5 knockdown- or 5-fluorouracil (5-Fu)-mediated HCC inhibition. Mechanistically, nuclear-factor-erythroid-2-related factor 2 (NRF2) interacted with XRCC5, which in turn upregulated hTERT. However, the upregulation was insignificant when NRF2 was reduced, suggesting that the XRCC5-mediated hTERT expression was NRF2 dependent. The HCC patients with high expression levels of XRCC5 and hTERT had shorter overall survival times compared with those with low XRCC5 and hTERT levels in their tumor tissues. Collectively, our study demonstrates the molecular mechanisms of the XRCC5/NRF2/hTERT signaling in HCC metastasis, which will aid in the identification of novel strategies for the diagnosis and treatment of HCC., Graphical abstract, We have explored the molecular mechanisms underlying the tumor-specific expression and activation of hTERT. Moreover, we have demonstrated for the first time that hTERT is transcriptionally activated by XRCC5 in a NRF2-dependent manner, thereby throwing light on the molecular mechanisms underlying the activation and upregulation of hTERT in HCC.

Highlights • MRI radiomics is promising for NAC early response prediction in NPC patients. • Predictive performance could be improved by the optimized strategy. • The model could help with NPC individualized treatment., Background and purpose Neoadjuvant Chemotherapy (NAC) followed by concurrent chemoradiotherapy (CCRT) is promising in improving the survival rate for advanced nasopharyngeal carcinoma (NPC) patients relative to CCRT alone. However, not all patients respond well to NAC. Therefore, we aimed to develop and evaluate a modified radiomics model for the NAC response prognosis in NPC patients. Methods A total of 165 patients with biopsy-proven locally advanced NPC were retrospectively selected from the database of our hospital. 85 out of them were for training and cross-validation, while the other 80 patients were for independent testing. All patients were treated with NAC and underwent MRI inspection, including T1-weighted (T1), T2-weighted (T2), and contrast-enhanced T1-weighted (T1-cs) sequences before and after two cycles of NAC. We classified the patients into the response or non-response groups by the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). Radiomics features were extracted from the primary and lymph node gross tumor volume in each sequence. To further improve the predictive performance, the permutation of multiple combinations of extraction parameters has first ever been investigated in the NAC prognosis for NPC patients. The model was constructed by logistic regression and cross-validated by bootstrapping with a resampling number of 1000. Independent testing was also implemented. In addition, we also applied an imbalance-adjusted bootstrap strategy to decrease the bias of small samples. Results For the cross-validation cohort, the resultant AUC, sensitivity, and specificity in terms of 95% confidence interval were 0.948 ± 0.004, 0.849 ± 0.005, and 0.840 ± 0.010. For the independent testing cohort, the model reached an AUC of 0.925, a sensitivity of 0.821, and a specificity of 0.792. There was a significant difference in the estimated radiomics score between the response and non-response groups (P

Tumor DNA vaccine as an effective therapeutic approach can induce systemic immunity against malignant tumors, but its therapeutic effect is still not satisfactory in advanced renal cancer. Herein, a novel DNA vaccine containing dual antigens of fibrinogen-like protein 1 (FGL1) and carbonic anhydrase IX (CAIX) was developed and intramuscularly delivered by PLGA/PEI nanoparticles for renal cancer therapy. Compared with PLGA/PEI-pCAIX immunization, PLGA/PEI-pFGL1/pCAIX co-immunization significantly inhibited the subcutaneous tumor growth and promoted the differentiation and maturation of CD11c+ DCs and CD11c+CD11b+ DCs subset. Likewise, the increased capabilities of CD8 T cell proliferation, CTL responses, and multi-functional CD8+ T cell immune responses were observed in PLGA/PEI-pFGL1/pCAIX vaccine group. Interestingly, depletion of CD8+ T cells by using CD8 mAb resulted in a loss of anti-tumor function of PLGA/PEI-pFGL1/pCAIX vaccine, suggesting that the anti-tumor activity of the vaccine was dependent on CD8+ T cell immune responses. Furthermore, PLGA/PEI-pFGL1/pCAIX co-immunization also suppressed the lung metastasis of tumor mice by enhancing the multi-functional CD8+ T cell responses. Therefore, these results indicate that PLGA/PEI-pFGL1/pCAIX vaccine could provide an effective protective effect for renal cancer by enhanced DC-mediated multi-functional CD8+ T cell immune responses. This vaccine strategy offers a potential approach for solid or metastatic tumor treatment., Graphical abstract, Here, Chai et al. investigate the therapy effect of dual-targeting vaccine of FGL1/CAIX in renal cancer. They found that the vaccine could induce DC-mediated multi-functional CD8 T cell immunity to suppress tumor growth and metastasis. This vaccine strategy offers a potential approach for cancer care.

Exosomes are extracellular vesicles with a diameter of 30–150 nm that function in mediating intercellular communication and intercellular material exchange. The liposomal membrane of exosomes protects the cargo carried by exosomes from degradation and assists in transporting cargo to recipient cells to regulate a variety of physiological and pathological processes. The incidence of gynecologic cancers is increasing annually, which is extremely harmful to the lives and health of women because such cancers are challenging to detect at the early stage. Recently, exosomes have emerged as novel biomarkers for diagnosing and predicting the development of gynecologic cancers. In particular, non-coding RNAs (microRNAs [miRNAs], long non-coding RNAs [lncRNAs], and circular RNAs [circRNAs]) carried by exosomes have been extensively investigated in gynecologic cancers. Therefore, the purpose of this review is to focus on the potential roles of exosomes of different origins in ovarian cancer, cervical cancer, and endometrial cancer, which will help to determine the molecular mechanism of carcinogenesis., Graphical abstract, Exosomes can mediate intercellular communication and material exchange. This review focuses on the potential roles of exosomes of different origins in ovarian cancer, cervical cancer, and endometrial cancer, which will determine the molecular mechanisms of carcinogenesis and discover the potential biomarkers for gynecologic cancers.

The anticancer effects of immune checkpoint inhibitors (ICIs) have been widely examined recently. Although ICIs have been progressively improved for successful gastric cancer treatment, different trials of ICIs such as pembrolizumab and nivolumab have yielded widely variable response rates. Strategies to further improve the efficacy of ICIs are still needed. Previous studies have shown that de novo DNA methylation is acquired by PD1+CD8+ tumor-infiltrating T cells (TILs), which cause a hierarchical downregulation of cytokines such as interferon-γ (IFN-γ). The epigenetic agent 5-Aza-2′-deoxycytidine (DAC) blocks de novo DNA methylation in activated PD1+CD8+ TILs. Such a feature might help enhance the anti-tumor effect of immune checkpoint blockade (ICB) treatment. In this study, polyethylene glycol-poly(ε-caprolactone) (PEG-PCL) nanoparticles (NPs) were linked to the anti-programmed death-1 monoclonal antibody nivolumab to yield αPD1-NPs for targeting TILs with PD1 overexpression using DAC. In addition, the NPs increased DAC stability and improved IFN-γ secretion and the anti-tumor effect of ICB in vitro. Therefore, targeted delivery of DAC reverses the exhaustion of PD1+CD8+ TILs and improves T cell responses and the treatment effect of ICB. These findings suggest that nivolumab-NPs are a potential tool for the delivery of epigenetic drugs, which could enhance the anti-tumor effect of ICB in gastric cancer., Graphical Abstract, PEG-PCL NPs were linked to the αPD1 antibody nivolumab to yield αPD1-NPs for targeting TILs with PD1 overexpression. We found that the NPs increased DAC stability and improved IFN-γ secretion and the anti-tumor effect of ICB in vitro, suggesting that nivolumab-NPs are a potential tool for delivering epigenetic drugs in gastric cancer.

Aim: To investigate the clinical relevance of the radiotherapy (RT) dose bath in patients treated for lower grade glioma (LGG).Methods: Patients (n = 17) treated with RT for LGG were assessed with neurocognitive function (NCF) tests and structural Magnetic Resonance Imaging (MRI) and categorized in subgroups based on tumour lateralisation. RT dose, volumetric results and cerebral microbleed (CMB) number were extracted for contralateral cerebrum, contralateral hippocampus, and cerebellum. The RT clinical target volume (CTV) was included in the analysis as a surrogate for focal tumour and other treatment effects. The relationships between RT dose, CTV, NCF and radiological outcome were analysed per subgroup.Results: The subgroup with left-sided tumours (n = 10) performed significantly lower on verbal tests. The RT dose to the right cerebrum, as well as CTV, were related to poorer performance on tests for processing speed, attention, and visuospatial abilities, and more CMB.In the subgroup with right-sided tumours (n = 7), RT dose in the left cerebrum was related to lower verbal memory performance, (immediate and delayed recall, r = -0.821, p = 0.023 and r = -0.937, p = 0.002, respectively), and RT dose to the left hippocampus was related to hippocampal volume (r = -0.857, p = 0.014), without correlation between CTV and NCF.Conclusion: By using a novel approach, we were able to investigate the clinical relevance of the RT dose bath in patients with LGG more specifically. We used combined MRI-derived and NCF outcome measures to assess radiation-induced brain damage, and observed potential RT effects on the left-sided brain resulting in lower verbal memory performance and hippocampus volume.

A genome editing tool targeting the high-risk human papillomavirus (HPV) oncogene is a promising therapeutic strategy to treat HPV-related cervical cancer. To improve gene knockout efficiency, we developed a gene knockout chain reaction (GKCR) method for continually generating mutagenic disruptions and used this method to disrupt the HPV18 E6 and E7 genes. We verified that the GKCR Cas9/guide RNA (gRNA) cassettes could integrated into the targeted loci via homology-independent targeted insertion (HITI). The qPCR results revealed that the GKCR method enabled a relatively higher Cas9/gRNA cassette insertion rate than a control method (the common CRISPR-Cas9 strategy). Tracking of Indels by DEcomposition (TIDE) assay results showed that the GKCR method produced a significantly higher percentage of insertions or deletions (indels) in the HPV18 E6 and E7 genes. Furthermore, by targeting the HPV18 E6/E7 oncogenes, we found that the GKCR method significantly upregulated the P53/RB proteins and inhibited the proliferation and motility of HeLa cells. The GKCR method significantly improved the gene knockout efficiency of the HPV18 E6/E7 oncogenes, which might provide new insights into treatment of HPV infection and related cervical cancer.

Transurethral resection of bladder tumor (TURBT) followed by intravesical therapy remains the most effective strategy for the management of non-muscle-invasive bladder cancer worldwide. TURBT has two purposes: to remove all visible tumors and to obtain tumor specimens for histopathological analysis. However, the detection of flat and small malignant lesions under white-light cystoscopy is extremely challenging, and residual lesions are still the main reason for the high recurrence rate of bladder cancer. We hypothesized that visual enhancement of malignant lesions using targeted optical molecular imaging could potentially highlight residual tumors in the bladder during surgery, and near-infrared photoimmunotherapy (NIR-PIT) could kill exfoliated cancer cells and residual tumors. A mouse model of complete or partial bladder tumor resection was established under the guidance of optical molecular imaging mediated by indocyanine green and anti-CD47-Alexa Fluor 790, respectively. Once the tumor recurred, mouse model received repeated CD47-targeted NIR-PIT. After complete resection, there was no tumor recurrence. Furthermore, the growth rate of recurrent tumor decreased significantly after repeated NIR-PIT. Therefore, CD47-targeted optical molecular imaging can potentially assist urologists to detect and remove all tumors, and repeated NIR-PIT shows the potential to reduce tumor recurrence rates and inhibit the growth of recurrent tumor., Graphical abstract, This study aimed at researching the role of CD47-targeted optical molecular imaging and near-infrared photoimmunotherapy (NIR-PIT) in the management of bladder cancer. The authors showed that CD47-targeted optical molecular imaging can potentially help urologists detect and remove all tumors, and NIR-PIT shows the potential to inhibit tumor growth.

The discovery of immune checkpoints (ICs) and the development of specific blockers to relieve immune effector cells from this inhibiting mechanism has changed the view of anti-cancer therapy. In addition to cytotoxic T lymphocyte antigen 4 (CTLA4) and programmed death 1 (PD1), classical ICs of T lymphocytes and recently described also on a fraction of natural killer (NK) cells, several NK cell receptors, including killer immunoglobulin-like inhibitory receptors (KIRs) and NGK2A, have been recognized as checkpoint members typical of the NK cell population. This offers the opportunity of a dual-checkpoint inhibition approach, targeting classical and non-classical ICs and leading to a synergistic therapeutic effect. In this review, we will overview and discuss this new perspective, focusing on the most relevant candidates for this role among the variety of potential NK ICs. Beside listing and defining classical ICs expressed also by NK cells, or non-classical ICs either on T or on NK cells, we will address their role in NK cell survival, chronic stimulation or functional exhaustion, and the potential relevance of this phenomenon on anti-tumor immune response. Furthermore, NK ICs will be proposed as possible new targets for the development of efficient combined immunotherapy, not forgetting the relevant concerns that may be raised on NK IC blockade. Finally, the impact of epigenetic drugs in such a complex therapeutic picture will be briefly addressed., Graphical abstract, NK cell immune checkpoints (ICs) include classical ICs of T lymphocytes and inhibitory receptors typical of NK cells (non-classical ICs). NK ICs regulate cell function, survival, and exhaustion modulating anti-tumor responses. The presence of a new type of IC on NK cells offers new targets for combined immunotherapies, including epigenetic drugs.

Tongue squamous cell carcinoma (TSCC) is closely linked to head and neck cancers. Here, we sought to explore the role and mechanism of lncRNAs in the occurrence and progression of TSCC and cisplatin resistance. The results of next-generation transcriptomic sequencing revealed that lncRNA-SNHG26 was differentially expressed and was associated with TSCC cisplatin resistance. The Cancer Genome Atlas dataset and tumor tissue analysis revealed that high SHNG26 expression was associated with the occurrence, progression, and poor prognosis of TSCC. Evidence from cell and animal experiments showed that SNHG26 expression was positively correlated with TSCC proliferation, epithelial-mesenchymal transformation, migration, invasion, and cisplatin resistance. Furthermore, in TSCC cells, SNHG26 was found to bind directly to the PGK1 protein, inhibiting its ubiquitination and activating the Akt/mTOR signaling pathway. These findings suggest that lncRNA-SNHG26 may be a promising target for inhibiting TSCC progression and improving sensitivity to cisplatin chemotherapy in TSCC., Graphical abstract, lncRNA-SNHG26 can be used as a prognostic indicator for tongue cancer patients and has potential value in targeted diagnosis and development of targeted therapy.

Myelofibrosis (MF)-associated anemia and transfusion dependency are associated with inferior quality of life and poor prognosis. JAK2 inhibitors and TGF-β superfamily ligand traps are being explored as treatment options for MF-associated anemia. Here, we present the case of a 66-year-old man with heavily pretreated intermediate-2 (INT-2) risk primary MF who had an exceptional response to combination fedratinib and luspatercept therapy. He achieved transfusion independence and experienced a reduction in spleen size from 20 cm to 12 cm, with remarkable improvement in performance status. Compared with other JAK inhibitors, the mechanism of action of fedratinib may explain its milder effect on anemia. It is possible that the addition of luspatercept may result in an additive or synergistic effect of one or both medications. Although the exact biological pathways have not yet been elucidated, combination fedratinib and luspatercept nevertheless is a promising therapy for anemia in patients with transfusion-dependent INT-2 risk MF.

Oxaliplatin, a third-generation platinum-based agent, is a constitutive part of systemic treatment for colorectal cancer in adjuvant and metastatic settings. Ocular toxicity is an extremely rare adverse effect of Oxaliplatin. Ocular toxicities have been documented in the form of (a) common (≥1/100

Gastric signet-ring-cell adenocarcinoma (SRCC) is a rare disease entity, often characterized by early age of the onset and sometimes attributable to heritable genetic mutations. Overall prognosis is usually poor due to diagnosis at late stages. There are a handful of case reports that describe patient presentation with retroperitoneal fibrosis secondary to malignancy from a concurrent gastric SRCC found on the workup. No information exists on timing from primary tumor development to retroperitoneal disease. Further, there is speculation that gastric SRCC may have an indolent phase prior to symptomatic disease, but its natural history is essentially entirely unknown. In this case report, we describe a 39-year-old male with an incidentally discovered gastric SRCC who then underwent multimodality treatment with curative intent. No evidence of recurrence was documented on interval surveillance scans for 4.5 years, at which point, he rapidly developed a large retroperitoneal mass that was biopsied for metastatic disease. He succumbed to his pathology within 6 months. This presentation suggests that gastric SRCC could have both a relatively long indolent phase and an unpredictable propensity for explosive metastatic progression. Tumor biology factors that affect this balance are not understood.

Primary cutaneous adenoid cystic carcinoma (PCACC) is extremely rare, and although distant metastasis has been reported, to date, there are no reports regarding metastasis to the nasal septum. We report a rare case of PCACC that metastasized to the nasal septum 17 years after the first surgery in a 59-year-old woman. She initially presented with a mass under the skin of her left mammary papilla. After a biopsy revealed the presence of an adenoid cystic carcinoma, the tumor was excised and definitively diagnosed as a PCACC. Five years after surgery, the patient presented with left lung metastasis and underwent a partial resection of the left lung. However, 8 years after this procedure, the patient had to undergo a partial resection of the right lung because of right lung metastasis. Four years thereafter, the patient presented with nasal septal metastasis. The tumor was excised successfully using a combined technique integrating intranasal and extranasal approaches. The patient is currently undergoing regular follow-up tests. Thus, in such cases, lifelong follow-up is necessary while checking for both distant metastasis and instances of local recurrence.

Advances in the treatment of non-small-cell lung cancers (NSCLCs) lacking an actionable driver mutation have included the approval of immunotherapies, such as monotherapy or in combination with chemotherapy. However, limited evidence exists to guide clinical decision-making after progression with immunotherapy. The vascular endothelial growth factor (VEGF) signaling pathway promotes tumor angiogenesis and the development of an immunosuppressive tumor microenvironment (TME). Anti-VEGF treatment is postulated to favor an immunosupportive TME through an “angio-immunogenic switch.” Nintedanib, an anti-VEGF receptor treatment, is approved in the EU and other countries, in combination with docetaxel for the treatment of locally advanced, metastatic, or locally recurrent adenocarcinoma NSCLC after failure of first-line chemotherapy. We present a case series from 5 patients treated with nintedanib plus docetaxel, after chemotherapy and immunotherapy, during routine clinical practice in Austria and Hungary. Four patients were treated with nintedanib plus docetaxel as a second- or third-line treatment after chemotherapy and immunotherapy, and a fifth patient received immunotherapy before and after nintedanib plus docetaxel. Although these patients would typically have a poor prognosis, each achieved a partial response with nintedanib plus docetaxel, with response duration from 8 months to over 30 months. Adverse events were manageable. The fifth patient case shows that nintedanib does not preclude later-line immunotherapy or chemotherapy, supporting the angio-immunogenic switch hypothesis. Overall, the case studies indicate that nintedanib plus docetaxel is an effective and well tolerated treatment, after sequential or combined chemo-immunotherapy for advanced NSCLC, and is compatible with a rechallenge with immunotherapy.

Background Breast cancer in young adults is rare and accounts for 5 to 6% of all cancers in this age group. We conducted the present study to look at the demographic features, clinical presentation, and outcomes in this group of patients treated at our center. Patients and Methods The study included breast cancer patients between the age of 15 and 30 years treated at our institute from January 2009 to December 2016. Data were analyzed retrospectively from case records. Event-free survival (EFS) and overall survival (OS) were calculated using the Kaplan–Meier method. Results Young adult breast cancers were reported in 145 out of 6,000 patients (2.41%) diagnosed with breast cancer in the study period. The median age of the patients was 29 years (range: 21–30 years). Stage I, II, III, and IV was observed in 3.4, 33.7, 46.2, and 16.5% of patients, respectively. The median follow-up was 45 months (range: 1.7–128.1 months). The 5-year EFS and OS for stage I, II, III, and IV was 100, 74.5, 47.9, and 0% and 100, 90.8, 55.1, and 0%, respectively. On univariate analysis, stage of the disease and pregnancy-associated breast cancers were found to have a significant association with decreased EFS and OS (p Conclusion Breast cancers in young adults are rare but need to be diagnosed at an early stage to improve survival. Pregnancy-associated breast cancers need to be managed optimally without delay owing to their aggressive tumor biology.

Liquid biopsy is a valuable tool in advanced and metastatic cancers for detection of genomic alterations in tumors that facilitate personalized targeted therapy approaches. Analyzing circulating tumor DNA (ctDNA) using next-generation sequencing (NGS) provides an opportunity to detect tumor genomic changes during therapy and capture inter- and intra-heterogeneity of genomically divergent cancer cell evolution. Herein, we present a patient with metastatic castration-resistant prostate cancer, with progression to soft tissues, bone, and regional lymph nodes, who was treated with abiraterone plus prednisone, with excellent prostate-specific antigen response. At the time of progression, NGS analysis of ctDNA using the FoundationOne®Liquid test revealed a CHEK2 mutation and a BRAF V600E mutation, the latter being exceedingly rare in prostate cancer. At the time of biochemical recurrence, the patient was referred to hematology for evaluation of chronic but stable thrombocytopenia prior to initiating new systemic therapy. Results of a bone marrow biopsy were consistent with hairy-cell leukemia, where the BRAF V600E mutation is considered the disease-defining mutation detectable in nearly all cases at diagnosis. In this case, liquid biopsy served as a noninvasive, highly sensitive approach to help reveal tumor genomic heterogeneity but also identified an unexpected genomic alteration leading to secondary cancer diagnosis and changes to treatment-related decision-making.

Desmoid tumors are clonal fibroblastic neoplasms that arise in soft tissues. Patients with familial adenomatous polyposis (FAP) can develop intra-abdominal desmoid tumors. However, metachronous appearance of intra-abdominal desmoid tumor is rare, and its clinical course is not well known. Here, we report a case of spontaneous regression of metachronous intra-abdominal desmoid tumor in a 36-year-old man with FAP. The patient was diagnosed with FAP and underwent laparoscopic total colorectomy. Intra-abdominal desmoid tumor appeared 2 years later and progressed despite treatment with tamoxifen and sulindac. He received four cycles of combinatory therapy with dacarbazine and adriamycin, resulting in shrinkage and stabilization of the desmoid tumor even after cessation of chemotherapy. A new intra-abdominal desmoid tumor developed 2 years later at a different site from the first lesion and progressed from 65 mm to 70 mm in diameter within a month. The size of the first lesion, however, remained unchanged. We prepared for chemotherapy because the second lesion progressed, but follow-up computed tomography showed spontaneous shrinkage of the second lesion. The patient still has not needed additional therapy as of more than 4 years after the appearance of the second lesion. Immunohistochemical staining showed the presence of macrophages in the second lesion. Although metachronous intra-abdominal desmoid tumor is rare and management protocols have yet to be established, this case suggests that an active surveillance approach may be applicable under careful follow-up in asymptomatic patients.

A family with multiple members diagnosed with prostate cancer was identified, and genetic variants were analyzed. Three brothers were diagnosed with prostate cancer. Germline variants in BRCA1, BRCA2, TINF2, and CD19 were found through next-generation DNA sequencing using a hereditary cancer panel. The BRCA1 G275D variant was present in patients, but absent in the healthy member. An ELAC2 variant was found in 1 patient. Several mutations were predicted to be deleterious by a set of computation programs. Multiple gene mutations might contribute to the overall predisposition to prostate cancer in the family. Even in cases with potentially deleterious variants in BRCA1 or BRCA2, there could be diverse clinical manifestations.

Endometrial dedifferentiated carcinoma is a new concept among endometrial malignancies, is rare, and has a poor prognosis as it is discovered in advanced stages and has no established treatment. It has higher rates of gene mutations, such as mismatch repair, than general endometrial cancer and has been associated with Lynch syndrome. However, due to its heterogeneity, case-by-case searches are needed. Comprehensive genomic profiling by Foundation One® CDx can comprehensively identify over 300 gene mutations via a next-generation sequencer and can evaluate biomarkers, such as the microsatellite status and tumor mutation burden. Therefore, it may be beneficial in identifying therapeutic targets and drugs for diseases whose treatment has not been established. In this case, 13 therapies, including immune checkpoint inhibitor therapy for microsatellite instability-High and 40 clinical trials for several gene mutations might be beneficial. We report a case of endometrial dedifferentiated carcinoma for which Foundation One® CDx gene profiling was used to propose treatment.

Anorectal malignant melanoma (AMM) is a rare and aggressive neoplasm. Here, we report a case of AMM that was treated with robotic-assisted abdominoperineal resection (APR) after immunotherapy. A 68-year-old Japanese woman presented at our hospital because of diagnosis AMM. Computed tomography revealed a mass in the lower anorectal region and enlarged perirectal lymph nodes, but showed no evidence of distant metastases. We determined that radical resection would be difficult; therefore, the patient received immunotherapy with pembrolizumab for nine cycles. The size of pararectal lymph nodes was reduced, and the patient subsequently underwent robot-assisted APR and lymph node dissection. Histopathological examination showed spindle-shaped atypical melanocytes with acidophilic changes indicative of tumor cell necrosis in the rectal mucosa. We found no viable tumor cells in all 48 lymph nodes that were resected, and resection margins were tumor free. The patient was able to complete 15 cycles of adjuvant immunotherapy with pembrolizumab and remained relapse free at the 2-year postoperative follow-up. The present case showed that combination of complete surgical resection and immunotherapy is expected to improve outcomes in AMM patients if immunotherapy is effective.

Introduction Many multiparametric models and scoring systems had been proposed in oral tongue squamous cell carcinoma (OTSCC) to predict the survival and recurrence, out of which pattern of invasion (POI) is gaining focus recently. Objective We conducted a retrospective study with the aim to see the prognostic significance of the POI and other parameters such as depth of invasion, perineural invasion (PNI), and lymph node status in OTSCC. Materials and Methods The slides of already diagnosed OTSCC cases were prepared from January 2015 to December 2017 records and studied by two pathologists for different patterns using Brandwein-Gensler scoring system. The different clinicopathologic parameters were compared with different POI. Statistical analysis was performed to present cumulative survival outcomes and for comparison. Results Most of our patients were > 40 years of age with male preponderance. Tumor differentiation pattern was assessed using Broders' system of grading that showed 85% of tumors were well, 12.5% tumors were moderately differentiated, and 2.5% tumors were poorly differentiated. The worst POI was predominantly pattern III (50%) followed by pattern II (32.5%) and pattern IV (13.8%). Most patients were in stage II (33.8%) followed by stage III (32.5%), stage IV (26.3%), and stage I (7.5%). There was an inverse relationship between POI with tumor stage and recurrence. A strong statistically significant association was found between POI with perineural infiltration and lymph node metastasis. Conclusion We concluded from our study that worst POI is significantly associated with number of lymph nodes metastasis and perineural infiltration and hence can be used as an independent prognostic factor.

Dr. Sithara Aravind, MD Background Oral metronomic chemotherapy (OMCT) represents an emerging concept in cancer treatment involving frequent administration of chemotherapeutic drugs at doses below maximum tolerated doses and with no prolonged drug-free break. OMCT is being tried preoperatively in developing nations with constrained resources to prevent disease progression during the waiting period from diagnosis to surgery (bridge OMCT). The aim of the present study was to assess the spectrum of histomorphological changes and pathological tumor response following bridge OMCT in oral squamous cell carcinoma (OSCC) and to propose a new pathological response scoring system. Materials and Methods A retrospective single-center study comprised of tissue sections of tumor proper and metastatic lymph nodes of 50, locally advanced OSCC patients treated with bridge OMCT, and had completed definitive surgery were analyzed. The present study evaluated the histomorphological features and proposed a new scoring system for pathologic tumor response. The pathologic tumor response was categorized as complete response (pCR), no response (pNR), and partial response (pPR). Results Of the total 50 patients, 2 patients had pCR, 3 had pNR, and 45 patients had pPR as per the new proposed scoring system. Note that 96% of the cases showed no disease progression. Conclusion Bridge OMCT is a novel treatment method that can be used to tide over the waiting period between the diagnosis and surgery in resource-constrained institutions with heavy patient load. This mode of treatment in locally advanced OSCC seems to provide promising results in this setting. Large multicentric trials are warranted to confirm these results.

Purpose Women under 40 years old are at increased risk for developing human epidermal growth factor receptor 2 (HER2) positive or triple negative subtype and more advanced breast cancer, yet young age itself has also historically been an independent prognostic factor. Methods Using the Surveillance, Epidemiology, and End Results (SEER) Program, we examined data for 271,173 women with stage I-III breast cancer between 2010 and 2015. Using Fine and Gray regression models to account for competing risks, we examined the risk of breast cancer-specific death by age and clinical subtypes, considering grade, hormone receptor (HR) and HER2 status, adjusting for demographic, clinical and treatment variables. Results Of 271,173 women eligible for analysis, 14,109 were 75 had increased breast cancer mortality in all subtypes. Conclusion With modern clinical subtyping, age under 40 remains independently associated with worse outcomes in 30 months follow-up only in HR-positive, lower grade disease., Highlights • Young women present with more advanced and aggressive types of breast cancer. • Young age is not an independent prognostic factor in HER2+ breast cancer or TNBC. • Young age is independently associated with poor outcomes in HR+/lower grade disease.