The fact that the identity of the cells that initiate metastasis in most human cancers is unknown hampers the development of antimetastatic therapies. Here we describe a subpopulation of CD44
cells ...in human oral carcinomas that do not overexpress mesenchymal genes, are slow-cycling, express high levels of the fatty acid receptor CD36 and lipid metabolism genes, and are unique in their ability to initiate metastasis. Palmitic acid or a high-fat diet specifically boosts the metastatic potential of CD36
metastasis-initiating cells in a CD36-dependent manner. The use of neutralizing antibodies to block CD36 causes almost complete inhibition of metastasis in immunodeficient or immunocompetent orthotopic mouse models of human oral cancer, with no side effects. Clinically, the presence of CD36
metastasis-initiating cells correlates with a poor prognosis for numerous types of carcinomas, and inhibition of CD36 also impairs metastasis, at least in human melanoma- and breast cancer-derived tumours. Together, our results indicate that metastasis-initiating cells particularly rely on dietary lipids to promote metastasis.
Tumor-associated macrophages (TAMs) are the most abundant inflammatory infiltrates in the tumor microenvironment and contribute to lymph node (LN) metastasis. However, the precise mechanisms of ...TAMs-induced LN metastasis remain largely unknown. Herein, we identify a long noncoding RNA, termed Lymph Node Metastasis Associated Transcript 1 (LNMAT1), which is upregulated in LN-positive bladder cancer and associated with LN metastasis and prognosis. Through gain and loss of function approaches, we find that LNMAT1 promotes bladder cancer-associated lymphangiogenesis and lymphatic metastasis. Mechanistically, LNMAT1 epigenetically activates CCL2 expression by recruiting hnRNPL to CCL2 promoter, which leads to increased H3K4 tri-methylation that ensures hnRNPL binding and enhances transcription. Furthermore, LNMAT1-induced upregulation of CCL2 recruits macrophages into the tumor, which promotes lymphatic metastasis via VEGF-C excretion. These findings provide a plausible mechanism for LNMAT1-modulated tumor microenvironment in lymphatic metastasis and suggest that LNMAT1 may represent a potential therapeutic target for clinical intervention in LN-metastatic bladder cancer.
The ability of CD8
T lymphocytes to eliminate tumors is limited by their ability to engender an immunosuppressive microenvironment. Here we describe a subset of tumor-infiltrating CD8
T cells marked ...by high expression of the immunosuppressive ATP ecto-nucleotidase CD39. The frequency of CD39
CD8
T cells increased with tumor growth but was absent in lymphoid organs. Tumor-infiltrating CD8
T cells with high CD39 expression exhibited features of exhaustion, such as reduced production of TNF and IL2 and expression of coinhibitory receptors. Exhausted CD39
CD8
T cells from mice hydrolyzed extracellular ATP, confirming that CD39 is enzymatically active. Furthermore, exhausted CD39
CD8
T cells inhibited IFNγ production by responder CD8
T cells. In specimens from breast cancer and melanoma patients, CD39
CD8
T cells were present within tumors and invaded or metastatic lymph nodes, but were barely detectable within noninvaded lymph nodes and absent in peripheral blood. These cells exhibited an exhausted phenotype with impaired production of IFNγ, TNF, IL2, and high expression of coinhibitory receptors. Although T-cell receptor engagement was sufficient to induce CD39 on human CD8
T cells, exposure to IL6 and IL27 promoted CD39 expression on stimulated CD8
T cells from human or murine sources. Our findings show how the tumor microenvironment drives the acquisition of CD39 as an immune regulatory molecule on CD8
T cells, with implications for defining a biomarker of T-cell dysfunction and a target for immunotherapeutic intervention.
The tumor microenvironment elicits a subset of functionally exhausted CD8
T cells by creating conditions that induce cell surface expression of CD39, an immunosuppressive molecule that can be therapeutically targeted to restore effector T-cell function.
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Many research studies show the connection between a previous stressful event and an increase in health problems. These usually include heart disease, diabetes, and hypertension. However, whether this ...could affect the immune system and be a trigger for developing carcinoma remains open for discussion.
To develop and validate 2 iodine maps based radiomics nomograms for preoperatively predicting cervical lymph node metastasis (LNM) and central lymph node metastasis (CLNM) in papillary thyroid cancer ...(PTC).
A total of 346 patients with PTC were enrolled and allocated to training (242) and validation (104) sets. Radiomics features were extracted from arterial and venous phase iodine maps, respectively. Aggregated machine-learning strategy was applied for features selection and construction of 2 radiomics scores (LN rad-score; CLN rad-score). Logistic regression model was employed to establish two radiomics nomograms (nomogram 1: predicting LNM; nomogram 2: predicting CLNM) after incorporating LN or CLN rad-score with clinical predictors. Nomograms performance was determined by discrimination, calibration and clinical usefulness.
Nomogram 1 incorporated LN rad-score, age (categorized by 55) and CT reported LN status; Nomogram 2 incorporated CLN rad-score, capsule contact >25% and CT reported CLN status. 2 nomograms both showed good discrimination and calibration in the training (AUC = 0.847; AUC = 0.837) and validation cohorts (AUC = 0.807; AUC = 0.795). Significant improved AUC, net reclassification index (NRI) and integrated discriminatory improvement (IDI) confirmed additional great predictive value of 2 rad-scores, compared with clinical models without radiomics. Decision curve analysis indicated clinical utility of nomograms. 2 nomograms both demonstrated favorable predictive efficacy in CT reported LN or CLN negative subgroup (AUC = 0.766; AUC = 0.744).
The presented 2 radiomics nomograms are useful tools for preoperative prediction of LNM and CLNM in PTC.
Ultrasound and prophylactic dissections have facilitated identification of small-volume cervical lymph node (LN) metastases in patients with papillary thyroid carcinoma (PTC). Since most staging ...systems do not stratify risk based on size or number of LN metastases, even a single-microscopic LN metastasis can upstage a patient with low-risk papillary thyroid microcarcinoma (PMC) to an intermediate risk of recurrence in the American Thyroid Association (ATA) system and to an increased risk of death in the American Joint Committee on Cancer (AJCC) staging system (stage III if the metastatic node is in the central neck or stage IVA if the microscopic LN metastasis is identified in the lateral neck). Such microscopic upstaging may lead to potentially unnecessary or additional treatments and follow-up studies. The goal of this review is to determine if the literature supports the concept that specific characteristics (clinically apparent size, number, and extranodal extension) of LN metastases can be used to stratify the risk of recurrence in PTC.
In patients with pathological proven cervical LN metastases (pathological N1 disease; pN1), the median risk of loco-regional LN recurrence varies markedly by clinical staging, with recurrence rates for patients who are initially clinically N0 (clinical N0 disease; cN0) of 2% (range 0%-9%) versus rates of recurrence for patients who are initially clinically N-positive (clinical N1 disease; cN1) of 22% (range 10%-42%). Furthermore, the median risk of recurrence in pN1 patients varies markedly by the number of positive nodes, <5 nodes (4%, range 3%-8%) vs. >5 nodes (19%, range 7%-21%). Additionally, the presence of extranodal extension was associated with a median risk of recurrence of 24% (range 15%-32%) and possibly a worse disease-specific survival.
Our previous paradigm assigned the same magnitude of risk for all patients with N1 disease. However, small-volume subclinical microscopic N1 disease clearly conveys a much smaller risk of recurrence than large-volume, macroscopic clinically apparent loco-regional metastases. Armed with this information, clinicians will be better able to tailor initial treatment and follow-up recommendations. Implications of N1 stratification for PTC into small-volume microscopic disease versus clinically apparent macroscopic disease importantly relate to issues of prophylactic neck dissection utility, need for pathologic nodal size description, and suggest potential modifications to the AJCC TNM (tumor, nodal disease, and distant metastasis) and ATA risk recurrence staging systems.
N-staging is a determining factor for prognostic assessment and decision-making for stage-based cancer therapeutic strategies. Visual inspection of whole-slides of intact lymph nodes is currently the ...main method used by pathologists to calculate the number of metastatic lymph nodes (MLNs). Moreover, even at the same N stage, the outcome of patients varies dramatically. Here, we propose a deep-learning framework for analyzing lymph node whole-slide images (WSIs) to identify lymph nodes and tumor regions, and then to uncover tumor-area-to-MLN-area ratio (T/MLN). After training, our model's tumor detection performance was comparable to that of experienced pathologists and achieved similar performance on two independent gastric cancer validation cohorts. Further, we demonstrate that T/MLN is an interpretable independent prognostic factor. These findings indicate that deep-learning models could assist not only pathologists in detecting lymph nodes with metastases but also oncologists in exploring new prognostic factors, especially those that are difficult to calculate manually.
•We revealed the practicability of NIC and λHU from spectral CT of LM in lung cancer.•The NIC and λHU of patients with LM was significantly lower than that of non-LM patients.•NIC and λHU in the ...arterial phase identified lymphatic metastasis better than short-axis diameter.
This study evaluated the use of quantitative spectral computed tomography (CT) parameters to identify lymph node metastasis (LM) in lung cancer.
Literature about LM in lung cancer diagnosed using spectral CT up to September 2022 was retrieved from the PubMed, EMBASE, Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure, and Wanfang databases. The literature was strictly screened according to the inclusion and exclusion criteria. Data were extracted, quality assessment was performed, and heterogeneity was evaluated. The pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (+LR), -LR, and diagnostic odds ratio (DOR) for normalized iodine concentration (NIC) and spectral attenuation curve (λHU) were calculated. The subject receiver operating characteristic (SROC) curves were used, and the area under the curve (AUC) was calculated.
Eleven studies, including 1,290 cases, without obvious publication bias were enrolled. In eight articles, the pooled AUC of NIC in the arterial phase (AP) was 0.84 (SEN = 0.85, SPE = 0.74, +LR = 3.3, −LR = 0.20, DOR = 16) while that of NIC in the venous phase (VP) was 0.82 (SEN = 0.78, SPE = 0.72). Additionally, the pooled AUC for λHU (AP) was 0.87 (SEN = 0.74, SPE = 0.84, +LR = 4.5, −LR = 0.31, DOR = 15) and that for λHU (VP) was 0.81 (SEN = 0.62, SPE = 0.81). Lymph node (LN) short-axis diameter was ranked last, with a pooled AUC of 0.81 (SEN = 0.69, SPE = 0.79).
Spectral CT is a suitable noninvasive and cost-effective method for determining LM in lung cancer. Additionally, NIC and λHU in the AP have good discrimination ability than short-axis diameter, providing a valuable basis and reference for preoperative evaluation.
Tumor‐lymph node (LN) metastasis is the dominant prognostic factor for tumor staging and therapeutic decision‐making. However, concurrently visualizing metastasis and performing imaging‐guided lymph ...node surgery is challenging. Here, a multiplexed‐near‐infrared‐II (NIR‐II) in vivo imaging system using nonoverlapping NIR‐II probes with markedly suppressed photon scattering and zero‐autofluorescence is reported, which enables visualization of the metastatic tumor and the tumor metastatic proximal LNs resection. A bright and tumor‐seeking donor–acceptor–donor (D‐A‐D) dye, IR‐FD, is screened for primary/metastatic tumor imaging in the NIR‐IIa (1100–1300 nm) window. This optimized D‐A‐D dye exhibits greatly improved quantum yield of organic D‐A‐D fluorophores in aqueous solutions (≈6.0%) and good in vivo performance. Ultrabright PbS/CdS core/shell quantum dots (QDs) with dense polymer coating are used to visualize cancer‐invaded sentinel LNs in the NIR‐IIb (>1500 nm) window. Compared to clinically used indocyanine green, the QDs show superior brightness and photostability (no obvious bleaching even after continuous laser irradiation for 5 h); thus, only a picomolar dose is required for sentinel LNs detection. This combination of dual‐NIR‐II image‐guided surgery can be performed under bright light, adding to its convenience and appeal in clinical use.
Tumor–lymph‐node metastasis is the dominant prognostic factor for tumor staging and therapeutic decision‐making. However, concurrently visualizing metastasis and performing imaging‐guided lymph node surgery is challenging. A multiplexed near‐infrared‐II (NIR‐II) imaging system is reported using two bright fluorophores for visualizing metastatic tumors and guiding intraoperative surgery.
As one effective treatment for lateral pelvic lymph node (LPLN) metastasis (LPNM), laparoscopic LPLN dissection (LPND) is limited due to the complicated anatomy of the pelvic sidewall and various ...complications after surgery. With regard to improving the accuracy and completeness of LPND as well as safety, we tried an innovative method using indocyanine green (ICG) visualized with a near-infrared (NIR) camera system to guide the detection of LPLNs in patients with middle-low rectal cancer.
To investigate whether ICG-enhanced NIR fluorescence-guided imaging is a better technique for LPND in patients with rectal cancer.
A total of 42 middle-low rectal cancer patients with clinical LPNM who underwent total mesorectal excision (TME) and LPND between October 2017 and March 2019 at our institution were assessed and divided into an ICG group and a non-ICG group. Clinical characteristics, operative outcomes, pathological outcomes, and postoperative complication information were compared and analysed between the two groups.
Compared to the non-ICG group, the ICG group had significantly lower intraoperative blood loss (55.8 ± 37.5 mL
108.0 ± 52.7 mL,
= 0.003) and a significantly larger number of LPLNs harvested (11.5 ± 5.9
7.1 ± 4.8,
= 0.017). The LPLNs of two patients in the non-IVG group were residual during LPND. In addition, no significant difference was found in terms of LPND, LPNM, operative time, conversion to laparotomy, preoperative complication, or hospital stay (
> 0.05).
ICG-enhanced NIR fluorescence-guided imaging could be a feasible and convenient technique to guide LPND because it could bring specific advantages regarding the accuracy and completeness of surgery as well as safety.
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