Chronic stress induces signalling from the sympathetic nervous system (SNS) and drives cancer progression, although the pathways of tumour cell dissemination are unclear. Here we show that chronic ...stress restructures lymphatic networks within and around tumours to provide pathways for tumour cell escape. We show that VEGFC derived from tumour cells is required for stress to induce lymphatic remodelling and that this depends on COX2 inflammatory signalling from macrophages. Pharmacological inhibition of SNS signalling blocks the effect of chronic stress on lymphatic remodelling in vivo and reduces lymphatic metastasis in preclinical cancer models and in patients with breast cancer. These findings reveal unanticipated communication between stress-induced neural signalling and inflammation, which regulates tumour lymphatic architecture and lymphogenous tumour cell dissemination. These findings suggest that limiting the effects of SNS signalling to prevent tumour cell dissemination through lymphatic routes may provide a strategy to improve cancer outcomes.
Myoid gonadal stromal tumor represents a rare testicular neoplasm displaying smooth muscular and gonadal stromal differentiation. This entity has very few cases reported in the literature that ...describe heterogeneous clinical and pathological characteristics. Bayesian statistics provides a useful framework to combine information from diverse sources. We here presented a case series—the largest so far reported—of myoid gonadal stromal tumor (4 cases) with extensive morphologic, immunohistochemical, and molecular characterization, performed a systematic review of the literature (that identified 9 papers), and used a Bayesian data analysis to understand the characteristics of this disease. Our study collectively described 16 cases. This neoplasm is mainly found in adults (mean age about 40 years) and often has a size of about 3 cm. By morphology, the tumor can infiltrate testicular tubules and is composed of spindle cells; few mitoses can be seen (usually 2/10 HPF). Neoplastic cells are diffusely positive with α-smooth muscle actin with a tram-track staining pattern. S100 protein, FOXL2, and SF1 are also characteristically positive. Moreover, this neoplasm can display epithelial differentiation, in about half of the cases. In conclusion, we foresee the use of this statistical approach in pathology: our analysis allowed a more precise description of this rare entity.
Purpose
To compare the efficacy of contrast-enhanced spectral mammography, with ultrasound, full field digital mammography and magnetic resonance imaging in detection and size estimation of ...histologically proven breast tumors.
Methods
This open-label, single center, prospective study, included 160 dense breast women with at least one suspicious mammary lesion evaluated by ultrasound, full field digital mammography and magnetic resonance imaging in whom a mammary tumor was histologically proven after surgery performed at the European Institute of Oncology between January 2013 and December 2015. Following the complete diagnostic procedure, the patients were further investigated by contrast-enhanced spectral mammography prior to surgery.
Results
Overall, the detection rate of malignant breast lesions (in situ and invasive) was 93.8% (165/176) for contrast-enhanced spectral mammography, 94.4% (168/178) for ultrasound, 85.5 (147/172) for full field digital mammography and 97.7% (173/177) for magnetic resonance imaging. Radiological measurements were concordant with the post-surgical pathological measurements of the invasive tumor (i.e., within 5 mm) in: 64.6% for contrast-enhanced spectral mammography, 62.0% for ultrasound, 45.2% for full field digital mammography (
p
< 0.0001) and 69.9% for magnetic resonance imaging (
p
= 0.28); underestimated in: 17.4% for contrast-enhanced spectral mammography, 19.6% for ultrasound, 24.2% for full field digital mammography (
p
= 0.03) and 6.7% for magnetic resonance imaging (
p
= 0.0005); and overestimated in: 16.2% for contrast-enhanced spectral mammography, 16.6% for ultrasound, 16.6% for full field digital mammography and 22.7% for magnetic resonance imaging (
p
= 0.02).
Conclusions
Our data suggest that contrast-enhanced spectral mammography improves on full field digital mammography and is comparable to ultrasound and magnetic resonance imaging in terms of detection sensitivity and size estimation of malignant lesions in dense breasts.
Most patients who initially respond to treatment with the multi-tyrosine kinase inhibitor sunitinib eventually relapse. Therefore, developing a deeper understanding of the contribution of sunitinib's ...numerous targets to the clinical response or to resistance is crucial. Here, we have shown that cancer cells respond to clinically relevant doses of sunitinib by enhancing the stability of the antiapoptotic protein MCL-1 and inducing mTORC1 signaling, thus evoking little cytotoxicity. Inhibition of MCL-1 or mTORC1 signaling sensitized cells to clinically relevant doses of sunitinib in vitro and was synergistic with sunitinib in impairing tumor growth in vivo, indicating that these responses are triggered as prosurvival mechanisms that enable cells to tolerate the cytotoxic effects of sunitinib. Furthermore, higher doses of sunitinib were cytotoxic, triggered a decline in MCL-1 levels, and inhibited mTORC1 signaling. Mechanistically, we determined that sunitinib modulates MCL-1 stability by affecting its proteasomal degradation. Dual modulation of MCL-1 stability at different dose ranges of sunitinib was due to differential effects on ERK and GSK3β activity, and the latter also accounted for dual modulation of mTORC1 activity. Finally, comparison of patient samples prior to and following sunitinib treatment suggested that increases in MCL-1 levels and mTORC1 activity correlate with resistance to sunitinib in patients.
Background
Several clinical trials have reported that therapies targeting programmed death-1 (PD1) and its ligand (PD-L1) improve patient outcomes, while tumor response has been related to PD-L1 ...expression.
Objective
To investigate the prognostic role of PD-L1 expression in patients affected by renal cell carcinoma (RCC).
Methods
MEDLINE/PubMed, the Cochrane Library, and ASCO University were searched for studies investigating the prognostic role of PD-L1 expression in RCC. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.
Results
Six studies and 1323 cases were included in the final analysis. PD-L1 was expressed in 24.2 % of clear cell tumors compared to 10.9 % of non-clear cell tumors (
p
= 0.002). In the overall population, a higher level of PD-L1 expression increased the risk of death by 81 % (HR; 1.81, 95 % CI 1.31–2.49;
p
< 0.001). When the analysis was restricted to cases evaluated by immunohistochemistry alone, the higher expression of PD-L1 more than doubled the risk of death (HR; 2.05, 95 % CI 1.38–3.05;
p
< 0.001). In clear cell histology, higher PD-L1 expression increased the risk of death by 53 % (HR; 1.53, 95 % CI 1.27–1.84;
p
< 0.001), while in metastatic patients, the evaluation of PD-L1 expression on primary tumors revealed that it retains its prognostic role (HR; 1.45, 95 % CI 1.08–1.93;
p
= 0.01).
Limitations
Significant heterogeneity has been identified among the included studies. As a consequence, cautious interpretation of the results is recommended.
Conclusion
This meta-analysis indicates that a higher level of PD-L1 expression is a negative prognostic factor in RCC. Its validation as an independent prognostic factor compared to other traditionally used clinical parameters in localized or advanced disease is recommended.
Fatal neuroendocrine differentiation (NED) of castration-resistant prostate cancer is a recurrent mechanism of resistance to androgen deprivation therapies (ADT) and antiandrogen receptor pathway ...inhibitors (ARPI) in patients. The design of effective therapies for neuroendocrine prostate cancer (NEPC) is complicated by limited knowledge of the molecular mechanisms governing NED. The paucity of acquired genomic alterations and the deregulation of epigenetic and transcription factors suggest a potential contribution from the microenvironment. In this context, whether ADT/ARPI induces stromal cells to release NED-promoting molecules and the underlying molecular networks are unestablished. Here, we utilized transgenic and transplantable mouse models and coculture experiments to unveil a novel tumor-stroma cross-talk that is able to induce NED under the pressure of androgen deprivation. Castration induced upregulation of GRP78 in tumor cells, which triggers
-mediated downregulation of the matricellular protein SPARC in the nearby stroma. SPARC downregulation enabled stromal cells to release IL6, a known inducer of NED. A drug that targets GRP78 blocked NED in castrated mice. A public, human NEPC gene expression dataset showed that
(encoding for GRP78) positively correlates with hallmarks of NED. Finally, prostate cancer specimens from patients developing local NED after ADT showed GRP78 upregulation in tumor cells and SPARC downregulation in the stroma. These results point to GRP78 as a potential therapeutic target and to SPARC downregulation in stromal cells as a potential early biomarker of tumors undergoing NED. SIGNIFICANCE: Tumor-stroma cross-talk promotes neuroendocrine differentiation in prostate cancer in response to hormone therapy via a GRP78/SPARC/IL6 axis, providing potential therapeutic targets and biomarkers for neuroendocrine prostate cancer.
The aim of this study was to investigate the prognostic performance of multiparametric magnetic resonance imaging (mpMRI) and Prostate Imaging Reporting and Data System (PIRADS) score in predicting ...pathologic features in a cohort of patients eligible for active surveillance who underwent radical prostatectomy.
A total of 223 patients who fulfilled the criteria for "Prostate Cancer Research International: Active Surveillance", were included. Mp-1.5 Tesla MRI examination staging with endorectal coil was performed at least 6-8 weeks after TRUS-guided biopsy. In all patients, the likelihood of the presence of cancer was assigned using PIRADS score between 1 and 5. Outcomes of interest were: Gleason score upgrading, extra capsular extension (ECE), unfavorable prognosis (occurrence of both upgrading and ECE), large tumor volume (≥ 0.5 ml), and seminal vesicle invasion (SVI). Receiver Operating Characteristic (ROC) curves and Decision Curve Analyses (DCA) were performed for models with and without inclusion of PIRADS score.
Multivariate analysis demonstrated the association of PIRADS score with upgrading (P < 0.0001), ECE (P < 0.0001), unfavorable prognosis (P < 0.0001), and large tumor volume (P = 0.002). ROC curves and DCA showed that models including PIRADS score resulted in greater net benefit for almost all the outcomes of interest, with the only exception of SVI.
mpMRI and PIRADS scoring are feasible tools in clinical setting and could be used as decision-support systems for a more accurate selection of patients eligible for AS.
Breast-conserving surgery (BCS) and whole breast radiation therapy (WBRT) are the standard of care for early-stage breast cancer (BC). Based on the observation that most local recurrences occurred ...near the tumor bed, accelerated partial breast irradiation (APBI), consisting of a higher dose per fraction to the tumor bed over a reduced treatment time, has been gaining ground as an attractive alternative in selected patients with low-risk BC. Although more widely delivered in postoperative setting, preoperative APBI has also been investigated in a limited, though increasing, and number of studies. The aim of this study is to test the feasibility, safety and efficacy of preoperative radiotherapy (RT) in a single fraction for selected BC patients.
This is a phase I/II, single-arm and open-label single-center clinical trial using CyberKnife. The clinical investigation is supported by a preplanning section which addresses technical and dosimetric issues. The primary endpoint for the phase I study, covering the 1st and 2nd year of the research project, is the identification of the maximum tolerated dose (MTD) which meets a specific target toxicity level (no grade 3-4 toxicity). The primary endpoint for the phase II study (3rd to 5th year) is the evaluation of treatment efficacy measured in terms of pathological complete response rate.
The study will investigate the response of BC to the preoperative APBI from different perspectives. While preoperative APBI represents a form of anticipated boost, followed by WBRT, different are the implications for the scientific community. The study may help to identify good responders for whom surgery could be omitted. It is especially appealing for patients unfit for surgery due to advanced age or severe co-morbidities, in addition to or instead of systemic therapies, to ensure long-term local control. Moreover, patients with oligometastatic disease synchronous with primary BC may benefit from APBI on the intact tumor in terms of tumor progression free survival. The study of response to RT can provide useful information about BC radiobiology, immunologic reactions, genomic expression, and radiomics features, to be tested on a larger scale.
The study was prospectively registered at clinicaltrials.gov ( NCT04679454 ).
The METastasis Reporting and Data System for Prostate Cancer (MET-RADS-P) guidelines are designed to enable reproducible assessment in detecting and quantifying metastatic disease response using ...whole-body magnetic resonance imaging (WB-MRI) in patients with advanced prostate cancer (APC). The purpose of our study was to evaluate the inter-observer agreement of WB-MRI examination reports produced by readers of different expertise when using the MET-RADS-P guidelines.
Fifty consecutive paired WB-MRI examinations, performed from December 2016 to February 2018 on 31 patients, were retrospectively examined to compare reports by a Senior Radiologist (9 years of experience in WB-MRI) and Resident Radiologist (after a 6-months training) using MET-RADS-P guidelines, for detection and for primary/dominant and secondary response assessment categories (RAC) scores assigned to metastatic disease in 14 body regions. Inter-observer agreement regarding RAC score was evaluated for each region by using weighted-Cohen's Kappa statistics (K).
The number of metastatic regions reported by the Senior Radiologist (249) and Resident Radiologist (251) was comparable. For the primary/dominant RAC pattern, the agreement between readers was excellent for the metastatic findings in cervical, dorsal, and lumbosacral spine, pelvis, limbs, lungs and other sites (K:0.81-1.0), substantial for thorax, retroperitoneal nodes, other nodes and liver (K:0.61-0.80), moderate for pelvic nodes (K:0.56), fair for primary soft tissue and not assessable for skull due to the absence of findings. For the secondary RAC pattern, agreement between readers was excellent for the metastatic findings in cervical spine (K:0.93) and retroperitoneal nodes (K:0.89), substantial for those in dorsal spine, pelvis, thorax, limbs and pelvic nodes (K:0.61-0.80), and moderate for lumbosacral spine (K:0.44).
We found inter-observer agreement between two readers of different expertise levels to be excellent in bone, but mixed in other body regions. Considering the importance of bone metastases in patients with APC, our results favor the use of MET-RADS-P in response to the growing clinical need for monitoring of metastasis in these patients.
: Considering highly selected patients with ductal carcinoma in situ (DCIS), active surveillance is a valid alternative to surgery. Our study aimed to show the reliability of post-biopsy complete ...lesion removal, documented by mammogram, as additional criterion to select these patients.
: A total of 2173 vacuum-assisted breast biopsies (VABBs) documented as DCIS were reviewed. Surgery was performed in all cases. We retrospectively collected the reports of post-VABB complete lesion removal and the histological results of the biopsy and surgery. We calculated the rate of upgrade of DCIS identified on VABB upon excision for patients with post-biopsy complete lesion removal and for those showing residual lesion.
: We observed 2173 cases of DCIS: 408 classified as low-grade, 1262 as intermediate-grade, and 503 as high-grade. The overall upgrading rate to invasive carcinoma was 15.2% (330/2173). The upgrade rate was 8.2% in patients showing mammographically documented complete removal of the lesion and 19% in patients without complete removal.
: The absence of mammographically documented residual lesion following VABB was found to be associated with a lower upgrading rate of DCIS to invasive carcinoma on surgical excision and should be considered when deciding the proper management DCIS diagnosis.
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