Lymphatic Vessel Infiltration Research Articles

KLK7 expression in human tumors: a tissue microarray study on 13,447 tumors

BackgroundKallikrein-related peptidase 7 (KLK7) is a chymotrypsin-like serine protease which is essential for the desquamation of corneocytes and thus plays a pivotal role in maintaining skin homeostasis. In cancer, KLK7 overexpression was suggested to represent a route for metastasis through cleavage of cell junction and extracellular matrix proteins of cancer cells.MethodsTo comprehensively determine KLK7 protein expression in normal and neoplastic tissues, a tissue microarray containing 13,447 samples from 147 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry.ResultsKLK7 positivity was found in 64 of 147 tumor categories, including 17 tumor categories with at least one strongly positive case. The highest rate of KLK7 positivity was found in squamous cell carcinomas from various sites of origin (positive in 18.1%-63.8%), ovarian and endometrium cancers (4.8%-56.2%), salivary gland tumors (4.8%-13.7%), bilio-pancreatic adenocarcinomas (20.0%-40.4%), and adenocarcinomas of the upper gastrointestinal tract (3.3%-12.5%). KLK7 positivity was linked to nodal metastasis (p = 0.0005), blood vessel infiltration (p = 0.0037), and lymph vessel infiltration (p < 0.0001) in colorectal adenocarcinoma, nodal metastasis in hepatocellular carcinoma (p = 0.0382), advanced pathological tumor stage in papillary thyroid cancer (p = 0.0132), and low grade of malignancy in a cohort of 719 squamous cell carcinomas from 11 different sites of origin (p < 0.0001).ConclusionsThese data provide a comprehensive overview on KLK7 expression in normal and neoplastic human tissues. The prognostic relevance of KLK7 expression and the possible role of KLK7 as a drug target need to be further investigated.

Reduced expression of semaphorin 3A in osteoclasts causes lymphatic expansion in a Gorham-Stout disease (GSD) mouse model.

Gorham-Stout disease (GSD) is a sporadic chronic disease characterized by progressive bone dissolution, absorption, and disappearance along with lymphatic vessel infiltration in bone-marrow cavities. Although the osteolytic mechanism of GSD has been widely studied, the cause of lymphatic hyperplasia in GSD is rarely investigated. In this study, by comparing the RNA expression profile of osteoclasts (OCs) with that of OC precursors (OCPs) by RNA sequencing, we identified a new factor, semaphorin 3A (Sema3A), which is an osteoprotective factor involved in the lymphatic expansion of GSD. Compared to OCPs, OCs enhanced the growth, migration, and tube formation of lymphatic endothelial cells (LECs), in which the expression of Sema3A is low compared to that in OCPs. In the presence of recombinant Sema3A, the growth, migration, and tube formation of LECs were inhibited, further confirming the inhibitory effect of Sema3A on LECs in vitro. Using an LEC-induced GSD mouse model, the effect of Sema3A was examined by injecting lentivirus-expressing Sema3A into the tibiae in vivo. We found that the overexpression of Sema3A in tibiae suppressed the expansion of LECs and alleviated bone loss, whereas the injection of lentivirus expressing Sema3A short hairpin RNA (shRNA) into the tibiae caused GSD-like phenotypes. Histological staining further demonstrated that OCs decreased and osteocalcin increased after Sema3A lentiviral treatment, compared with the control. Based on the above results, we propose that reduced Sema3A in OCs is one of the mechanisms contributing to the pathogeneses of GSD and that expressing Sema3A represents a new approach for the treatment of GSD.

Loss of Upk1a and Upk1b expression is linked to stage progression in urothelial carcinoma of the bladder

BackgroundUroplakin-1a (Upk1a) and uroplakin-1b (Upk1b) have recently been identified as diagnostic markers for the distinction of urothelial carcinomas from other solid tumor entities. Both proteins play an important role in the stabilization and strengthening of epithelial cells that line the bladder.MethodsTo evaluate the prognostic role of uroplakin expression in urothelial carcinomas, more than 2700 urothelial neoplasms were analyzed in a tissue microarray format by immunohistochemistry. To further assess the diagnostic role of uroplakin immunohistochemistry, results were compared with preexisting GATA3 data.ResultThe fraction of Upk1a/Upk1b positive cases decreased slightly from pTaG2 low-grade (88% positive for Upk1a/87% positive for Upk1b) and pTaG2 high-grade (92%/89%) to pTaG3 (83%/88%; p > 0.05) and was lower in muscle-invasive (pT2-4) carcinomas (42%/64%; p < 0.0001/p < 0.0001 for pTa vs. pT2-4). Within pT2-4 carcinomas, high expression of Upk1a and Upk1b was linked to nodal metastasis and lymphatic vessel infiltration (p < 0.05) but unrelated to patient outcome. There were significant associations between Upk1a, Upk1b and GATA3 immunostaining (p < 0.0001 each), but 11% of GATA3 negative cancers were Upk1a/b positive and 8% of Upk1a/b negative cancers were GATA3 positive. Absence of GATA3/Upk1a/b staining was significantly linked to poor patient survival in the subgroup of 126 pT4 carcinomas (p = 0.0004) but not in pT2 and pT3 cancers.ConclusionsIn summary, the results of our study demonstrate that Upk1a and/or Upk1b immunohistochemistry can complement GATA3 for the distinction of urothelial carcinomas. Furthermore, a progressive loss of Upk1a/b expression during stage progression and a prognostic role of the combination GATA3/Upk1a/Upk1b in pT4 carcinomas is evident.

Prognostic impact of perioperative change in serum p53 antibody titers in esophageal squamous cell carcinoma.

The clinical effectiveness of tumor markers for estimating prognosis in esophageal squamous cell carcinoma (ESCC) remains unclear. We assessed the clinical impact of changes in perioperative serum p53 antibodies (s-p53-Abs) titers in ESCC. From January 2011 to March 2021, 249 patients were enrolled in this study. Titers of s-p53-Abs were measured before the initial treatment and 3months after esophagectomy. Patients were divided into a s-p53-Abs decreased or unchanged group (Group D, n = 217) and an increased group (Group I, n = 32). Short- and long-term outcomes were compared between the groups. There was no correlation between the changes in squamous cell carcinoma antigen and carcinoembryonic antigen titers and recurrence site, number of recurrent lesions, and prognosis. However, the recurrence rate was significantly higher in Group I than in Group D (53.1% vs. 28.6%, p = 0.008), especially for distant organ recurrence (37.5% vs. 18.4%, p = 0.019). Furthermore, the rate of polyrecurrence was higher in Group I than in Group D (34.4% vs. 14.3%, p = 0.009). Recurrence-free survival (RFS) was significantly worse in Group I than in Group D (median survival time, 21.2months vs. 36.7months, p = 0.015). Multivariate analysis revealed that lymphatic vessel infiltration (hazard ratio [HR], 1.721; 95% CI 1.069-2.772; p = 0.026), blood vessel infiltration (HR, 2.348; 95% CI 1.385-3.982; p = 0.002), advanced pathological stage (≥ III) (HR, 3.937; 95% CI 2.295-6.754; p < 0.001), and increased s-p53-Abs titers (HR, 2.635; 95% CI 1.488-4.667; p = 0.001) were independent predictors of poor RFS. Elevation of s-p53-Abs titers after esophagectomy can predict polyrecurrence in distant organs and poor prognosis.

Abstract 3302: KLK7 expression in human tumors: A tissue microarray study on 13,447 tumors

Abstract Background: Kallikrein-related peptidase 7 (KLK7) is a chymotrypsin-like serine protease which is essential for the desquamation of corneocytes and thus plays a pivotal role in maintaining skin homeostasis. In cancer, KLK7 overexpression was suggested to represent a route for metastasis through cleavage of cell junction and extracellular matrix proteins of cancer cells. Methods: To comprehensively determine KLK7 protein expression in normal and neoplastic tissues, a tissue microarray containing 13,447 samples from 147 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. Results: KLK7 positivity was found in 64 of 147 tumor categories, including 17 tumor categories with at least one strongly positive case. The highest rate of KLK7 positivity was found in squamous cell carcinomas from various sites of origin (positive in 18.1%-63.8%), ovarian and endometrium cancers (4.8%-56.2%), salivary gland tumors (4.8%-13.7%), bilio-pancreatic adenocarcinomas (20.0%-40.4%), and adenocarcinomas of the upper gastrointestinal tract (3.3%-12.5%). KLK7 positivity was linked to nodal metastasis (p=0.0005), blood vessel infiltration (p=0.0037), and lymph vessel infiltration (p&amp;lt;0.0001) in colorectal adenocarcinoma, nodal metastasis in hepatocellular carcinoma (p=0.0382), advanced pathological tumor stage in papillary thyroid cancer (p=0.0132), and low grade of malignancy in a cohort of 719 squamous cell carcinomas from 11 different sites of origin (p&amp;lt;0.0001). Conclusions: These data provide a comprehensive overview on KLK7 expression in normal and neoplastic human tissues. The prognostic relevance of KLK7 expression and the possible role of KLK7 as a drug target need to be further investigated. Citation Format: Simon Kind, Carolina Castillo, Ria Uhlig, Natalia Gorbokon, Maximilian Lennartz, Sebastian Dwertmann Rico, Viktor Reiswich, Florian Viehweger, Martina Kluth, Claudia Hube-Magg, Christian Bernreuther, Franziska Büscheck, Till Clauditz, Christroph Fraune, Andrea Hinsch, Till Krech, Patrick Lebok, Stefan Steurer, Eike Burandt, Sarah Minner, Andreas Marx, Ronald Simon, Waldemar Wilczak, Guido Sauter, Anne Menz, Frank Jacobsen. KLK7 expression in human tumors: A tissue microarray study on 13,447 tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3302.

Pattern of desmogleins 1 and 3 co-expression in human tumours: a TMA study on 16,100 tumours

Desmogleins are glycoproteins of the desmosomes of squamous epithelia. To understand the roles of desmogleins (Dsgs) 1 and 3 in cancer, tissue microarrays containing 16,100 samples from 138 different tumour types were analysed by IHC. Dsg1 and Dsg3 staining was detectable in 39 (28%) and 49 (36%) of 138 tumour categories. Four of 12 squamous cell cancer types showed ≥90% positivity for Dsg1 and/or Dsg3, and another 7 SQCC types showed 80–89% positivity. Dsg1 and/or Dsg3 positivity was also found in basal cell carcinomas (52% Dsg1/3 positive), Warthin tumours (39%), basal cell adenomas (30%), teratomas (26%) and muscle invasive urothelial carcinomas (22%). High Dsg1 expression was linked to high grade, loss of ER/PR positivity (p<0.0001 each) and reduced survival (p=0.0426) in breast cancer. High Dsg3 expression was linked to invasive growth in urothelial carcinoma (p<0.0001) and to high pT (p=0.0102), pN+ (p=0.0162), blood vessel infiltration (p=0.0189) and lymph vessel infiltration (p=0.0151) in colorectal cancer. Reduced expression of Dsg1/3 was linked to high grade in 599 squamous cell carcinomas from 12 different sites (p<0.0001 each). In summary, loss of Dsg1/3 goes along with dedifferentiation in squamous cell carcinomas, while upregulation is linked to adverse tumour features in non-squamous cancers.

Desmoglein 3 (Dsg3) expression in cancer: A tissue microarray study on 15,869 tumors.

Desmoglein-3 (Dsg3) is a transmembrane glycoprotein which is preferably found in desmosomes of keratinocytes in squamous epithelium. Both loss and upregulation of Dsg3 have been implicated in cancer progression. To comprehensively evaluate Dsg3 expression in normal and neoplastic tissues, a tissue microarray containing 15,869 samples from 137 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. Dsg3 immunostaining was detectable in 47 (34.3%) tumor categories including 15 (10.9%) tumor types with at least one strongly positive case. The highest rate of Dsg3 positivity was found in squamous cell carcinomas from various sites (71.2-97.3%), basal cell carcinomas of the skin (41.9%), various tumors from salivary glands (12.9-38.9%), and in urothelial neoplasms (2.1-20.7%). Dsg3 positivity in less than 10% of cases was seen in 23 additional cancer categories. Dsg3 staining was almost always weak and rarely moderate in these tumors. High Dsg3 expression was linked to invasive growth in urothelial carcinoma (p<0.0001), as well as to advanced pT stage (p=0.0102), nodal metastasis (p=0.0162), blood vessel infiltration (p=0.0189) and lymph vessel infiltration (p=0.0151) in colorectal cancer. Reduced Dsg3 expression was linked to high grade in a cohort of 599 squamous cell carcinomas from 11 different sites of origin (p<0.0001). Associations between Dsg3 immunostaining and clinicopathological features were not found in invasive breast cancer of no special type, ductal adenocarcinomas of the pancreas and in gastric adenocarcinomas. In summary, Dsg3 expression predominates in squamous cell carcinomas and loss of Dsg3 immunostaining goes along with dedifferentiation of these tumors. The identification of focal squamous differentiation in other neoplasms may constitute a diagnostic application of Dsg3 immunohistochemistry.

New approaches to improving corneal transplant survival in a pre‐clinical model

AbstractCornea transplantation has been a target for mesenchymal stromal cell (MSC) therapy for several years with a number of publications highlighting the therapeutic potential and mechanism of action of these cells. It is widely known that MSC possess potent anti‐inflammatory capabilities and are able to modulate the activity of a wide array of immune cells including T cells, B cells, dendritic cells and macrophages. This modulation occurs through both cell–cell contact and the paracrine release of soluble factors such as nitric oxide and prostaglandin E2.High risk cornea transplant recipients suffer from a much higher rate of rejection than the average patient. Factors which place patients at high risk of rejection include corneal ulcers, bullous keratopathy or a failed previous graft. These conditions frequently lead to increased blood and lymphatic vessel infiltration to the recipient graft bed and/or some pre‐existing high immunological risk. As outcomes for lower risk cornea transplant recipients, such as those who require a transplant as a result of keratoconus, improves the field is shifting its focus to improve outcomes for more complex cases.In this presentation, I will discuss the therapeutic potential of MSC to promote corneal transplant survival in both low‐ and high‐risk pre‐clinical models and its pathway to potential clinical translation.Funding received for this work.This work was supported by Science Foundation Ireland (12/IA/1624), by a grant from the European Commission [FP7 Collaborative Health Project VISICORT (grant number 602470), www.visicort.eu], by infrastructural funds from the European Regional Development Fund and by the European Union's Horizon 2020 research and innovation programme under grant agreement no. 814439.Keywords: corneal transplantation, high risk, mesenchymal stromal cells, immunomodulation, regulatory cells, tolerance.

Reticulocalbin3: A Ca2+ homeostasis regulator that promotes esophageal squamous cell carcinoma progression and cisplatin resistance.

Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent cancers worldwide. There is a critical need to identify new mechanisms that contribute to ESCC progression. Reticulocalbin3 (RCN3) is mainly located in the endoplasmic reticulum and Ca2+‐binding protein containing EF‐hands. The function of RCN3 in tumor progression has not been clarified. We observed that the expression level of RCN3 was higher in ESCC tissues than in paired normal tissues. Overexpression of RCN3 was positively associated with tumor size, lymph node metastasis, TNM stage, lymphatic vessel infiltration, and poor outcome in patients with ESCC. Increased malignant phenotypes were observed in RCN3 overexpressing ESCC cells, whereas the opposite effects were achieved in RCN3‐silenced cells. Reticulocalbin3 promoted the expression of MMP‐2 and MMP‐9 by regulating the inositol 1,4,5‐trisphosphate receptor 1 (IP3R1)–Ca2+–calcium/calmodulin‐dependent protein kinase II–c‐Jun signaling pathway. Reticulocalbin3 induced cisplatin resistance by regulating IP3R1/Ca2+ to maintain intracellular Ca2+ homeostasis and reduced reactive oxygen species in ESCC cells. Finally, the expression of RCN3 was regulated by hypoxia inducible factor‐1α. Collectively, these data strongly support that RCN3 regulates Ca2+ homeostasis by targeting IP3R1 to promote the progression and platinum resistance of ESCC. Our studies suggest that RCN3 could serve as predictive factor of poor prognosis and potential therapeutic target for ESCC patients.

Clinical Diagnosis and Treatment Analysis of 16 Cases of Gastric-Type Endocervical Adenocarcinoma

Objective: Cervical cancer classification based on human papillomavirus (HPV) infection status is necessary, as the popularity of HPV vaccination is increasing. Hence, this study aimed to explore the clinicopathological features, diagnosis, treatment, and prognosis of gastric-type endocervical adenocarcinoma (GAS) in west China. Methods: We performed a retrospective analysis and follow-up of patients with GAS who were hospitalized in West China Second University Hospital, a tertiary care center in west China, between September 2019 and April 2021. Results: A total of 16 cases were pathologically diagnosed as GAS at the hospital, most of which had no specific clinical manifestations. Among the 16 cases, 3 cases were confirmed preoperatively. The occurrence of full-layer cervix stroma infiltration, lymphatic vessel infiltration, and lymph node metastasis were 87.5%, 100%, and 50%, respectively. Among all cases, 8 cases were classified as stage III according to the International Federation of Gynecology and Obstetrics 2018 Clinical Staging Standard for cervical cancer. A total of 15 patients underwent a transabdominal or laparoscopic extensive hysterectomy, and the remaining 1 patient was pathologically diagnosed with GAS after a total hysterectomy and afterward underwent bilateral oophorectomy and pelvic lymph node dissection as supplementary surgeries. The follow-up data presented the survival of the 16 patients receiving concurrent chemoradiotherapy after surgery. However, GAS recurred in 3 non-medically-controlled patients among the 16 patients in 3 to 6 months after the treatment. Conclusions: GAS is a rare but highly malignant cancer that usually results in a poor prognosis. A few reports of GAS diagnosis and treatment, especially from developing countries, are available. Hitherto clinical routine screening methods might be insufficient to fulfill the requirements of GAS diagnosis owing to the difficulties in preoperative diagnosis and the probability of misdiagnosis. To reduce the rate of misdiagnosis, repeated deep multisite biopsies, cervical curettage, cervical conization, and hysteroscopy might be helpful in suspicious GAS cases.

Pattern of cervical lymph node metastases in squamous cell carcinoma of the upper oral cavity – How to manage the neck

ObjectivesOral squamous cell carcinoma (OSCC) arising from the upper oral cavity is rare compared to other localizations. While cervical lymph node metastasis (CLNM) can be predicted to some extent, the probability of occult CLNM remains high. The aim of this study is to determine risk factors affecting clinical decision making. Materials and methodsA retrospective analysis of patients surgically treated between 2012 and 2017 for OSCC of the upper oral cavity was performed. ResultsA total of 66 patients were included. Of these, 25 patients (37.9%) presented with CLNM after histopathological examination (pN+/cN0: 10/44 (22.7%); pN+/cN+: 15/22 (68.2%)). Lymph vessel infiltration (p = 0.03) and grade of differentiation (p = 0.03) were associated with an increased probability for CLNM. Patients with positive nodal disease at the time of primary surgery showed higher tumor depth of invasion (DOI) than patients without CLNM (mean 10.3 mm ± 6.9 versus mean 6.1 mm ± 4.9; p = 0.02). The optimal DOI cutoff value for the prediction of CLNM was 4.5 mm. The OS was significantly higher in patients with a tumor DOI ≤ 4.5 mm (p = 0.01). ConclusionElective neck dissection should be preferably performed for OSCC of the upper oral cavity. For early-stage and clinically node-negative patients, sentinel-lymph node biopsy can be an alternative, especially in patients with a DOI ≤ 4.5 mm. Since this group had no occult CLNM below this DOI cutoff value, watch and wait might be an alternative for selected patients.

Regulation of lymphangiogenesis by extracellular vesicles in cancer metastasis.

Metastasis is not only one of the hallmarks of cancer but, unfortunately, it also is the most accurate biomarker for poor prognosis. Cancer cells metastasize through two different but eventually merged routes, the vasculature and lymphatic systems. The processes of cancer metastasis through blood vessel have been extensively studied and are well documented in the literature. In contrast, metastasis through the lymphatic system is less studied. Most people believe that cancer cells metastasize through lymphatic vessel are passive because the lymphatic system is thought to be a sewage draining system that collects whatever appears in the tissue fluid. It was recently found that cancer cells disseminated from lymphatic vessels are protected from being destroyed by our body's defense system. Furthermore, some cancer cells or cancer-associated immune cells secrete lymphangiogenic factors to recruit lymphatic vessel infiltration to the tumor region, a process known as lymphangiogenesis. To ensure the efficiency of lymphangiogenesis, the lymphangiogenic mediators are carried or packed by nanometer-sized particles named extracellular vesicles. Extracellular vesicles are lipid bilayer particles released from eventually every single cell, including bacterium, with diameters ranging from 30 nm (exosome) to several micrometers (apoptotic body). Components carried by extracellular vesicles include but are not limited to DNA, RNA, protein, fatty acid, and other metabolites. Recent studies suggest that cancer cells not only secrete more extracellular vesicles but also upload critical mediators required for lymphatic metastasis onto extracellular vesicles. This review will summarize recent advances in cancer lymphatic metastasis and how cancer cells regulate this process via extracellular vesicle-dependent lymphangiogenesis.

Current Trends in Endoscopic Diagnosis and Treatment of Early Esophageal Cancer.

Simple SummaryEarly esophageal cancer is diagnosed in the context of reflux disease, surveillance of Barrett’s metaplasia, or during upper gastrointestinal endoscopy for other indications. High definition and virtual or dye chromoendoscopy are mandatory for the screening and evaluation of neoplasia. Endoscopic treatment options include endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD). Resection is considered curative if histopathology confirms low or absent risk of lymph node metastasis. Barrett’s high-grade dysplasia or early adenocarcinoma is treated by EMR or ESD, followed by ablation of Barrett’s epithelium to avoid metachronous cancer. ESD is the treatment of choice for squamous cell neoplasia. Excellent outcomes have been reported if the ESD of squamous cell cancer with slight submucosal infiltration and thus substantial risk for lymph node metastasis was combined with adjuvant chemo-radiotherapy. In contrast, infiltration of squamous cell cancer exceeding the lamina propria mucosae is not curative. However, despite a substantial risk of lymph node metastasis, excellent outcomes have recently been reported if endoscopic resection of tumors with up to 200 µm submucosal infiltration was combined with adjuvant chemo-radiotherapy.Diagnosis of esophageal adenocarcinoma mostly occurs in the context of reflux disease or surveillance of Barrett’s metaplasia. Optimal detection rates are obtained with high definition and virtual or dye chromoendoscopy. Smaller lesions can be treated with endoscopic mucosal resection. Endoscopic submucosal dissection (ESD) is an option for larger lesions. Endoscopic resection is considered curative (i.e., without significant risk of lymph node metastasis) if histopathology confirms en bloc and R0 resection of a well-differentiated (G1/2) tumor without infiltration of lymphatic or blood vessels and the maximal submucosal infiltration depth is 500µm. Ablation of remaining Barrett’s metaplasia is important, to reduce the risk of metachronous cancer. Esophageal squamous cell cancer is associated with different risk factors, and most of the detected lesions are diagnosed during upper gastrointestinal endoscopy for other indications. Virtual high definition and dye chromoendoscopy with Lugol’s solution are used for screening and evaluation. ESD is the preferred resection technique. The criteria for curative resection are similar to Barrett’s cancer, but the maximum infiltration depth must not exceed lamina propria mucosae. Although a submucosal infiltration depth of up to 200 µm carries a substantial risk of lymph node metastasis, ESD combined with adjuvant chemo-radiotherapy gives excellent results. The complication rates of endoscopic resection are low, and the functional outcomes are favorable compared to surgery.

MRI and the pathology of breast invasive micropapillary carcinoma.

Diagnosis of breast invasive micropapillary carcinoma (IMPC) before surgery is of great value for determining the optimal treatment strategy. The aim of the present study was to investigate the magnetic resonance imaging (MRI) and pathological features of IMPC. MRI features of IMPC were characterized in relation to the patients' clinicopathological features. Clinical manifestations, mammography results and/or MRI findings of patients with IMPC were retrospectively analyzed. Parameters included morphology, plain T2-weighted imaging (T2WI) signal intensity, the apparent diffusion coefficient (ADC), the internal enhancement mode, early enhancement rates and time-intensity curve (TIC) types during dynamic enhanced scanning. A total of 10 lesions were detected by MRI in eight patients, with one case having three lesions with the mean diameter of 34.44 mm. In plain T2WI scanning, the lesions appeared inhomogeneous with a moderate or high signal intensity. When the b value was 800 sec/mm2, the average ADC value was 0.823±0.12×10−3 mm2/sec. A total of four cases exhibited mass-like enhancement, including an oval rim in one case (three lesions), irregular inhomogeneous enhancement in two cases and irregular uniform enhancement in one case. The margins were clear in one case (three lesions), irregular in two cases and spiculate in one case. Among the four cases with non-mass enhancement, the distribution was focal in two cases, linear in one case and regional in one case, and the internal enhancement mode was cluster-like in one case, heterogeneous in one case and uniform in two cases. The average early enhancement rate was 116.96±45.26%. TICs of type III were observed in all cases. In conclusion, MRI of IMPC demonstrated typical features of malignant tumors and lymphatic vessel infiltration, suggesting that MRI may exhibit guiding significance for the diagnosis and treatment planning of IMPC.

Staging more important than grading? Evaluation of malignancy grading, depth of invasion, and resection margins in oral squamous cell carcinoma

ObjectivesThe present study evaluated the predictive value of staging and grading parameters concerning the presence of lymph-node metastases, overall survival (OS), and relapse-free survival (RFS) of patients with oral squamous cell carcinoma (OSCC).Materials and methodsHE-stains of 135 surgically treated (R0) primary OSCCs were analyzed using a both microscopic and software-based approach. Depth of invasion (DOI) and resection margins (RM) were measured, and each case was graded according to the malignancy grading system as described by Anneroth et al. and Bryne et al. on two different sites of the tumor (surface and invasion front; TS and IF).ResultsParameters that could be identified as significant predictors of OS and RFS were UICC cancer stage (p = 0.009 and p = 0.012); pT-stage as defined in the 7th edition (p = 0.029 and 0.015) and, after restaging using DOI, 8th edition (p = 0.023 and p = 0.005) of the TNM classification of malignant tumors; the presence of lymphonodular metastases (LM) (p = 0.004 and p = 0.011); degree of keratinization (p = 0.029 and p = 0.042); and pattern of growth (p = 0.029 and p = 0.024) at the TS after applying a binary scale for both parameters. Also, when directly comparing the most extreme subgroups (scores 1 and 4) of lymphoplasmacytic infiltration at the IF, there was a significant difference in OS (p = 0.046) and RFS (p = 0.005). Invasion of blood vessels (p = 0.013) and perineural invasion (p = 0.023) were significantly associated with a lower OS. Age lower than 60 years (univariate p = 0.029, multivariate p = 0.031), infiltration of lymphatic vessels (p = 0.003), infiltration of nerves (p = 0.010), pT-stage (8th edition) (p = 0.014), degree of keratinization at the IF (p = 0.033), and nuclear polymorphism at the IF (p = 0.043) after conversion to a binary scale were found to be significant prognostic parameters regarding the presence of LM. DOI evolved as a significant predictor for OS (p = 0.006), RFS (p = 0.003), and LM (p = 0.032) in metric and grouped analysis.ConclusionsThe current evaluation revealed depth of invasion as strongest histologic predictor of metastatic tumor growth, overall survival, and relapse-free survival in OSCC, confirming the current adaption of the T-classification. Other distinct histologic grading parameters investigated during this study can give valuable indications of a tumor’s potential aggressiveness, but the exact site, mode, and procedure need further exploration.Clinical relevanceIntegrating measurement of DOI also into the pretherapeutic staging process could aid in treatment planning.

The role of apical lymph node metastasis in right colon cancer.

The role of apical lymph node (APN) metastasis in colorectal cancer remains controversial. The main purpose of this study is to explore the prognostic value of APN metastasis in patients with right colon cancer. This is a retrospective study of patients with stage III right colon cancer between April 2007 and December 2016. Patients who underwent resection of right colon cancers with D3 lymph node dissection were divided into APN-positive (APN+) and APN-negative (APN-) groups according to the postoperative pathological presence or absence of APN metastasis. Relapse-free survival (RFS) and overall survival (OS) between groups were compared after Cox regression analysis and 1:1 propensity score matching (PSM). A total of 254 patients were included in this study: 28 (11.0%) were APN+ and 226 (89.0%) were APN-. Before matching, the rates of elevated carcinoembryonic antigen (CEA), T3-4 tumor invasion, and N2 lymph node metastasis were significantly higher in the APN+ group (CEA ≥ 5ng/mL, 53.6% vs. 37.6%, p < 0.001; T3-4, 92.9% vs. 85.4%, p < 0.001; N2 metastasis, 57.1% vs. 20.4%, p < 0.001), and APN+ tumors were associated with significantly higher postoperative relapse rates (39.3% vs. 21.2%; p = 0.03), especially with lung metastases (14.3% vs. 4.0%; p = 0.019), which conferred worse RFS (p = 0.013), although OS was similar (p = 0.078). However, after PSM, there were no apparent between-group differences in RFS (p = 0.29) or overall survival rate (p = 0.637). The Cox regression analysis indicated that lymphatic vessel infiltration and depth of invasion were independent risk factors for OS, while APN+ status was not a significant predictor for RFS or OS. APN metastasis was not a prognostic indicator for RFS or OS in right colon cancer. However, APN+ patients with elevated CEA levels and deeper tumor invasion should be closely monitored for lung metastasis during postoperative follow-up.

CXCL11-CXCR3 Axis Mediates Tumor Lymphatic Cross Talk and Inflammation-Induced Tumor, Promoting Pathways in Head and Neck Cancers

Tumor metastasis to the draining lymph nodes is critical in patient prognosis and is tightly regulated by molecular interactions mediated by lymphatic endothelial cells (LECs). The underlying mechanisms remain undefined in the head and neck squamous cell carcinomas (HNSCCs). Using HNSCC cells and LECs we determined the mechanisms mediating tumor-lymphatic cross talk. The effects of a pentacyclic triterpenoid, methyl 2-trifluoromethyl-3,11-dioxoolean-1,12-dien-30-oate (CF3DODA-Me), a potent anticancer agent, were studied on cancer-lymphatic interactions. In response to inflammation, LECs induced the chemokine (C-X-C motif) ligand 9/10/11 chemokines with a concomitant increase in the chemokine (C-X-C motif) receptor 3 (CXCR3) in tumor cells. CF3DODA-Me showed antiproliferative effects on tumor cells, altered cellular bioenergetics, suppressed matrix metalloproteinases and chemokine receptors, and the induction of CXCL11-CXCR3 axis and phosphatidylinositol 3-kinase/AKT pathways. Tumor cell migration to LECs was inhibited by blocking CXCL11 whereas recombinant CXCL11 significantly induced tumor migration, epithelial-to-mesenchymal transition, and matrix remodeling. Immunohistochemical analysis of HNSCC tumor arrays showed enhanced expression of CXCR3 and increased lymphatic vessel infiltration. Furthermore, The Cancer Genome Atlas RNA-sequencing data from HNSCC patients also showed a positive correlation between CXCR3 expression and lymphovascular invasion. Collectively, our data suggest a novel mechanism for cross talk between the LECs and HNSCC tumors through the CXCR3-CXCL11 axis and elucidate the role of the triterpenoid CF3DODA-Me in abrogating several of these tumor-promoting pathways.

Prognostic value of lymphovascular space invasion in patients with early stage cervical cancer in Jilin, China: A retrospective study.

The metastasis of cervical carcinoma is associated with the lymphovascular spread. The primary objective of the present study was to determine the prognostic value of lymphovascular space invasion (LVSI) in patients with early-stage cervical cancer in Jilin, China.In this retrospective cohort study, patients with early-stage cervical cancer (stage IB-IIA) at the Second Hospital of Jilin University from February 2014 to December 2016 were included in the analysis. All included participants underwent radical hysterectomy with pelvic lymphadenectomy. LVSI was identified by hematoxylin and eosin (H&E) staining. The primary outcomes are overall survival (OS) and progression-free survival (PFS). Kaplan-Meier curves were used to calculate the patient's survival. Survival was compared using the log-rank test, while risk factors for the prognosis were assessed by Cox regression analysis.The incidence of LVSI was positively associated with the depth of stromal invasion (P = .009) and lymph node metastasis (LNM, P < .001). LVSI is an independent factor that affects OS (P = .009) and PFS (P = .006) in patients with early stage cervical cancer. LNM status is an independent factor that affects postoperative OS (P = .005).The incidence of lymphatic vessel infiltration is positively associated with the depth of stromal invasion and LNM. LVSI is an independent risk factor for the prognosis of early cervical cancer. The results suggest that further large-scale studies are needed to improve the treatment for patients with LVSI.

Self-Management Strategies for Malignant Lymphedema: A Case Report with 1-Year and 4-Year Follow-Up Data.

Purpose: Malignant lymphedema is an accumulation of interstitial fluid caused by tumour infiltration or compression of lymphatic vessels. Our objective is to describe self-management strategies for malignant lymphedema using a case report. Client Description: A 50-year-old woman with advanced breast cancer was referred to our centre with a 3-month history of unexplained left-arm edema, subsequently diagnosed as malignant lymphedema caused by tumour compression of the axillary lymph nodes. Intervention: She undertook a physiotherapist-guided, modified lymphedema treatment programme, with self-management interventions including self-bandaging and exercise. Limb volumes and leisure exercise levels were measured over a 1-year period. Data were collected from her follow-up visit 4 years post-diagnosis of lymphedema. Measures and Outcome: Within the first month, the patient's excess limb volume reduced from 26.8% to 5.9% and, 1 year later, remained stable at 3%. Over time, her exercise levels increased (1-year follow-up: 33.5 MET-hours per week). At 4 years, her excess limb volume was 9.7%, and exercise levels were at 36 MET-hours per week. Implications: A woman with moderate malignant arm lymphedema caused by advanced breast cancer successfully adhered to a guided self-management programme and benefited from reduced swelling and improved self-reported physical function in the long term. This case provides oncology health professionals with knowledge about self-management options for malignant lymphedema.

Neuroendocrine tumors of the small intestine causing a desmoplastic reaction of the mesentery are a more aggressive cohort

Desmoplastic reaction of the mesentery is commonly seen in patients with neuroendocrine tumors of the small intestine. However, it is not clear whether desmoplastic reaction is associated with tumor-specific characteristics and diminished prognosis. Therefore, the aim of this study was to investigate whether the presence of a desmoplastic reaction correlates with prognostic and molecular markers of neuroendocrine tumors of the small intestine. Patients with neuroendocrine tumors of the small intestine operated at our department from 2000 to 2016 were analyzed. Patient and tumor characteristics were evaluated. Kaplan-Meier and multivariate analyses were performed. In total, 148 patients underwent surgery, and preoperative imaging was available in 113 patients. A total of 45 patients showed desmoplastic reaction of the mesentery and progression-free survival was significantly impaired (26 months versus 65.4 months) compared with patients without desmoplastic reaction. These patients had significantly more often distant metastases (84.4% vs 39.7%), lymphatic vessel (68.9% vs 44.1%), and perineural tissue infiltration (57.8% vs 17.6%) compared with patients without desmoplastic reaction. However, proliferation index (positive desmoplastic reaction 4.1% versus negative desmoplastic reaction 3.3%) and tumor size (positive desmoplastic reaction 2 cm versus negative desmoplastic reaction 1.9 cm) were not diverging significantly. This study revealed that tumors leading to desmoplastic reaction are more aggressive, despite similar Ki67 indices.