Mode Of Invasion Research Articles

Schwann cells: Rescuers of central demyelination.

The presence of peripheral myelinating cells in the central nervous system (CNS) has gained the neurobiologist attention over the years. Despite the confirmed presence of Schwann cells in the CNS in pathological conditions, and the long list of their beneficial effects on central remyelination, the cues that impede or allow Schwann cells to successfully conquer and remyelinate central axons remain partially undiscovered. A better knowledge of these factors stands out as crucial to foresee a rational therapeutic approach for the use of Schwann cells in CNS repair. Here, we review the diverse origins of Schwann cells into the CNS, both peripheral and central, as well as the CNS components that inhibit Schwann survival and migration into the central parenchyma. Namely, we analyze the astrocyte- and the myelin-derived components that restrict Schwann cells into the CNS. Finally, we highlight the unveiled mode of invasion of these peripheral cells through the central environment, using blood vessels as scaffolds to pave their ways toward demyelinated lesions. In short, this review presents the so far uncovered knowledge of this complex CNS-peripheral nervous system (PNS) relationship.

Validation of the Glasgow Microenvironment Score in patients with colon cancer: A pathology-based prognostic tool.

206 Background: The Glasgow Microenvironment Score (GMS), comprised of assessment of the tumour inflammatory cell infiltrate (using Klintrup-Mäkinen (KM) grade) and tumour-associated stroma (TSP), has been reported as a stage-independent prognostic score in patients with colorectal cancer. The present study aims to validate the GMS and examines its prognostic utility in the context of stage and MMR status. Methods: Patients who had undergone resection of stage I-III colon cancer were included ( n= 495). GMS was scored by combining KM and TSP as follows: high KM scores 0; low KM with low TSP scores 1; low KM and high TSP scores 2. Cancer specific (CSS) and overall survival (OS) were primary endpoints. Subgroup analysis was performed to assess the utility of GMS according to TNM, venous invasion and MMR status. Results: There were 30% of patients with GMS 0, 56% with GMS 1 and 14% with GMS 2. Five-year survival for GMS 0, 1 and 2 across the whole cohort were 89%, 74% and 66%, respectively. GMS was associated with age, mode of presentation, TNM, venous invasion and MMR status. On multivariate analysis, GMS was independently associated with CSS (HR 1.35, 95% CI: 1.02-1.79, p= 0.04) and OS (HR 1.23, 95% CI: 1.02-1.48, p= 0.03); this was independent of emergency presentation ( p< 0.01), T-stage ( p= 0.03) and N-stage ( p< 0.001) for CSS. Subgroup analysis found that GMS was able to stratify CSS regardless of node-negative or node-positive disease (both p< 0.01), venous invasion ( p< 0.05), elective presentation ( p< 0.01) and MMR-proficient tumours ( p< 0.001), although it was not able to stratify emergency presentation ( n= 154) or MMR-deficient disease ( n= 102) due to small sample size. Universally, the prognosis for GMS 0 was good, but was poor for GMS 2. The prognosis for GMS 1 varied depending on MMR and nodal status. Conclusions: This study validates the use of the GMS as an independent prognostic pathology-based tool for stratification of colon cancer. It could be readily applied to routine clinical practice and may be used to aid decision making regarding adjuvant treatments in colorectal cancer. It should be further validated in prospective randomised trials.

Caveolin-1 Expression at Metastatic Lymph Nodes Predicts Unfavorable Outcome in Patients with Oral Squamous Cell Carcinoma

We evaluated the clinical and prognostic value of the protein expression of caveolin-1 (CAV1) and p16 at the primary site and metastatic lymph nodes of oral squamous cell carcinoma (OSCC). Primary site specimens from 80 OSCC cases were randomly selected and lymph node specimens from 15 preserved metastatic lymph nodes from among those patients were selected for examination. We evaluated the CAV1 and p16 expression at both the primary site and metastatic lymph nodes, and analyzed the patients' clinicopathological data in relation to CAV1 and p16 expression. Our analysis revealed significant positive correlations between CAV1 expression at the primary site and pathological metastasis, cell differentiation, and mode of invasion (p = 0.019, p = 0.002, p = 0.015, respectively), but p16 expression was not associated with any clinicopathological factors. Patients with high CAV1 expression at the primary sites showed significantly worse prognoses than those with low or negative CAV1 expression (p = 0.002), and multivariate analysis showed that the T classification and CAV1 expression were independent OSCC prognostic factors. CAV1 expression was also present in the metastatic lymph nodes of the OSCC cases with particularly poor differentiation and high invasive grade, and patients with CAV1-positive metastatic lymph nodes showed significantly worse prognoses than those with CAV1-negative metastatic lymph nodes (p = 0.018). CAV1 may activate metastaticity and the invasive capacity of OSCC cells. CAV1 expression, particularly at metastatic lymph nodes, predicts a worse outcome for OSCC, suggesting that CAV1 could be used as a prognostic marker for OSCC.

Correlative study of tumor budding, mode of invasion and lymphocytic host response with known clinicopathological prognostic factors in oral squamous cell carcinoma.

Background:Oral squamous cell carcinoma (OSCC) is a significant public health problem in India, accounting to 30% of all cancers with a worrying rise in incidence and related mortality. Invasive tumor front (ITF) of OSCC has been an area of histopathologic research interest, where parameters like tumor budding (TB), mode of invasion (MOI) and lymphocytic host response (LHR) are being evaluated extensively.Objectives:The aim is to study and evaluate the possible association of ITF histological parameters such as TB, LHR and MOI with known clinicopathological prognostic factors in cases of OSCC.Subjects and Methods:We reviewed and analyzed 69 cases of OSCC for routine clinicopathological parameters, TB, MOI and LHR for any significant correlation (P < 0.05 by Chi-square test) with each other and with outcome in cases where follow-up was available.Results:TB correlated significantly with histological grade, worst pattern of invasion (WPOI), Lymphnodal involvement (LNI), Lymphovascular invasion (LVI), Perineural invasion (PNI) and age; MOI correlated with WPOI, LNI, LVI and PNI; and LHR significantly correlated with WPOI, PNI, Tumor size (pT) and outcome. TB showed a strong correlation with MOI (P < 0.001) and LHR; and no significant association was noted between LHR and MOI. Among all the clinicopathological parameters, depth of invasion, pT, WPOI, PNI and LHR showed significant correlation with outcome.Conclusion:TB, MOI and LHR showed good correlation with established parameters and as they are easy and helps in prognostication, they should be included in routine histopathological reporting guidelines.

Actinin-4 Expression Predicts Poor Disease-free Survival and Correlates with Delayed Lymph Node Metastasis in Patients with Completely Resected Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma is generally characterized by poor prognosis, and biomarkers are needed for development and selection of therapy. The purpose of this study was to assess expression of actinin-4, which has been implicated in cancer invasion and metastasis, to determine its viability as a prognostic indicator in oral squamous cell carcinoma. Clinical factors and tumor samples immunohistochemically stained for actinin-4 were retrospectively investigated in 55 patients who underwent curative surgery for oral squamous cell carcinoma. Overall survival and disease-free survival were estimated by Kaplan-Meier analysis. Significant differences were detected using the Pearson's chi-square and Fisher's exact tests. Univariate and multivariate analyses were performed with the Cox regression model. No association was found between expression of actinin-4 and clinical factors, including age or sex, or histopathological factors, including vascular invasion, lymphatic invasion, stage, mode of invasion, or histological atypicality. Expression of actinin-4 showed a positive correlation with delayed cervical lymph node metastasis. Disease-free survival was significantly lower in patients who were positive for expression of actinin-4 (p=0.010); overall survival showed no difference between patients with or without expression of actinin-4, however. The results revealed that actinin-4 was an independent prognostic factor for disease-free survival. Expression of actinin-4 showed a 73% sensitivity and 68% specificity for prediction of delayed cervical lymph node metastasis. In conclusion, actinin-4 may potentially be a useful biomarker for prediction of delayed cervical lymph node metastasis.

Podoplanin Drives Dedifferentiation and Amoeboid Invasion of Melanoma

Melanoma is an aggressive skin cancer developing from melanocytes, frequently resulting in metastatic disease. Melanoma cells utilise amoeboid migration as mode of local invasion. Amoeboid invasion is characterized by rounded cell morphology and high actomyosin contractility driven by the RhoA signalling pathway. Migrastatic drugs targeting actin polymerization and contractility to inhibit invasion and metastasis are therefore a promising treatment option. To predict amoeboid invasion and metastatic potential, there is a need for biomarkers functionally linked to contractility pathways. The glycoprotein podoplanin drives actomyosin contractility in lymphoid fibroblasts, and is overexpressed in several cancer types. Here, we show that podoplanin enhances amoeboid invasion in melanoma. Expression of podoplanin in murine melanoma models drives rounded cell morphology, increasing motility and invasion in vivo. Podoplanin expression is upregulated in a subset of dedifferentiated human melanoma, and in vitro is sufficient to suppress melanogenesis and upregulate melanoma-associated markers Mitf and Pou3f2 . Together, our data indicates that podoplanin is both a potential biomarker for dedifferentiated invasive melanoma and a promising migrastatic therapeutic target.

Christianity in India: The anti-colonial turn by Clara A.B. Joseph

Reviewed by: Christianity in India: The anti-colonial turn by Clara A.B. Joseph Binu Varghese Christianity in India: The anti-colonial turn By Clara A.B. Joseph. London: Routledge, 2019. Christianity in India: The anti-colonial turn makes an incredible contribution to the postcolonial historiography of India by focusing on subjugated, rather forgotten, readings of precolonial Indian Christianity. It offersa fresh approach to look further into postcolonial historiography to probe the existence and identity of Christians in precolonial India. The main purpose of the book is to educate and enlighten those who think Christianity is primarily colonial and a relic of European colonialism in India. The author investigates the historical challenge of proving the existence of St. Thomas Christians in Kerala, India. She admits the risk of scant historicity of Thomas' coming to India and evangelizing Brahmin families in Mylapore in AD 57 (p. 17). Since all internal pieces of evidence and sacred books of the community were burned by the Portuguese, external Western resources are summoned. Other modern sources of Indian Christian history call for reconciliation for categorizing Indian Christians as unpatriotic. Joseph argues that such categorizations are associated with the Eurocentric view of Christianity in India as a colonial enterprise (19). Joseph utilizes literary analysis with careful attention to genres and terminologies employed in a postcolonial reading. She exposes the resources to the hermeneutics of suspicion, exposing the pitfalls of a generic procolonial reading of Indian Christianity. Joseph uses Edward Said's secular criticism and critiques postcolonial interpretation of cultural hybridity between Portuguese traders and St. Thomas Christians (18). The trend of looking at foreign origins of a community as non-Christian and listing converts as unpatriotic and anti-nationalist is orientalism as its best, according to Joseph (19). The European imagination of Orientals in India was detrimental, as Joseph poignantly notes (27). The Portuguese employed civilizing techniques on the culture of St. Thomas Christians, deeming it uncivilized. The complex codes and associated meanings of Hinduism didn't appease valorizing colonial minds. Joseph traces these anti-sentiments to five hundred years of cultural imagination of India as a wealthy and hospitable country. These cultural prejudices resulted in a Western view of India as a "Christian nation." The existence of St. Thomas Christians in Kerala, India, was a surprising discovery for the colonialists. Joseph probes into the mysterious search of the Portuguese for Prester John, the legendary Christian king of India. During the early twelfth century, Europeans found the existence of a "Christian India" as a potential economic source and an ally for their crusade endeavors. The search for shared grounds was evident in colonial missions. Joseph identifies the "imperial logic of Christian expansion" (quoting Christopher Taylor) in which external threats of Islam would be repressed, and a global Christian network could rise once and for all. It sounded promising because the self-other dynamics of the colonizer and colonized work simultaneously for a common objective. The author contests the "self at the center" colonial hermeneutics, according to which, Paul Ricoeur writes, prioritizing the colonizing self over the colonial other would actually tend towards "solicitude for one's neighbor and… justice for each individual" (34). The commonness or sharedness was a distant dream for both parties since the ideals of mutuality were perturbed because of India's alleged heretic roots. In Chapter 3 Joseph explores the life-situations of St. Thomas Christians in relation to the cultural transmission with the Portuguese. The overarching narrative is adapted from the travelogues of Vasco Da Gama and Pedro Alvares Cabral. The main findings of Joseph circle around the literature available in the form of writings in the seventeenth century that were translated in the modern era. Gama and his comrades were highly militaristic and worked tenuously to defeat the Moors (Islamic invaders), which in turn caused fear of and resultant actions against Eastern Christians. The stiff competition in trade from the Muslims, as Joseph says, caused the Portuguese to switch to a colonial mode of invasion (64). In her own words, the fear of the Moor was "how colonial responsibility, whether civic or ecclesiastical, was meted out" (65). And the sheer resemblance of Eastern Christians to the Moors invoked a sense...

Characterizing the invasion of different breast cancer cell lines with distinct E-cadherin status in 3D using a microfluidic system

E-cadherin is a cell-cell adhesion protein that plays a prominent role in cancer invasion. Inactivation of E-cadherin in breast cancer can arise from gene promoter hypermethylation or genetic mutation. Depending on their E-cadherin status, breast cancer cells adopt different morphologies with distinct invasion modes. The tumor microenvironment (TME) can also affect the cell morphology and invasion mode. In this paper, we used a previously developed microfluidic system to quantify the three-dimensional invasion of breast cancer cells with different E-cadherin status, namely MCF-7, CAMA-1 and MDA-MB-231 with wild type, mutated and promoter hypermethylated E-cadherin, respectively. The cells migrated into a stable and reproducible microfibrous polycaprolactone mesh in the chip under a programmed stable chemotactic gradient. We observed that the MDA-MB-231 cells invaded the most, as single cells. MCF-7 cells collectively invaded into the matrix more than CAMA-1 cells, maintaining their E-cadherin expression. The CAMA-1 cells exhibited multicellular multifocal infiltration into the matrix. These results are consistent with what is seen in vivo in the cancer biology literature. In addition, comparison between complete serum and serum gradient conditions showed that the MDA-MB-231 cells invaded more under the serum gradient after one day, however this behavior was inverted after 3 days. The results showcase that the microfluidic system can be used to quantitatively assess the invasion behavior of cancer cells with different E-cadherin expression, for a longer period than conventional invasion models. In the future, it can be used to quantitatively investigate effects of matrix structure and cell treatments on cancer invasion.

Immunohistochemical assessment of Eph/ephrin expression in oral squamous cell carcinoma and precursor lesions.

To evaluate erythropoietin-producing hepatocellular carcinoma (Eph)/Eph receptor-interaction protein (ephrin) expression in oral squamous cell carcinoma (OSCC) and oral epithelial precursor lesions (OEPLs), EphA2, EphB4, and ephrinB2 were examined and compared with microvessel density (MVD) and lymphatic vessel density (LVD). Samples from 73 OSCC and 43 OEPLs patients were immunohistochemically analyzed with antibodies against EphA2, EphB4, ephrinB2, CD34, and D2-40. Results were compared with clinicopathological findings. Immunohistochemical reactivity for EphA2, EphB4, and ephrinB2 was detected in epithelial cells and some stromal vascular cells in OEPLs and OSCC, proportionately with the level of malignancy. The number of blood vessel endothelial cells stained with CD34 and lymphatic vessel endothelial cells stained with D2-40 was increased in OEPLs and OSCC. In OSCC, ephrinB2 and EphB4 exhibited significant correlation with recurrence and invasion depth, respectively. MVD was significantly lower in slight lymphocytic reaction than in prominent stromal reaction. Association was found between LVD and T classification, postoperative metastasis, survival, mode of invasion, and invasion depth. Expression of EphA2, EphB4, ephrinB2, MVD, and LVD might be associated with malignant potential of the oral epithelium. Angiogenesis and lymphangiogenesis appear to be related to progression of potentially malignant oral lesions.

Marine and freshwater taxa: some numerical trends

Most of the freshwater fauna originates from ancient or recent marine ancestors. In this study, we considered only completely aquatic non-parasitic animals, counting 25 phyla, 77 classes, 363 orders for a total that should include 236,070 species. We divided these taxa into three categories: exclusively marine, marine and freshwater, and exclusively freshwater. By doing so, we obtained three distribution curves which could reflect the marine species’ mode of invasion into continental waters. The lack of planktonic stages in the benthic fauna of inland waters, in addition to what we know about the effects of the impoundment of epicontinental seas following marine regressions, lead us to think that the main invasion mode into inland waters is more linked to the sea level fluctuations of the past than to slow and “voluntary” ascents of rivers by marine elements.

Superior photosynthetic performance of the invasive kelp Undaria pinnatifida may contribute to continued range expansion in a wave-exposed kelp forest community

In New Zealand, the kelp Undaria pinnatifida has colonized nearly all major coastal ports and has spread to colonize diverse habitats over a range of hydrodynamic environments. We report one of the earliest surveys of the distribution of this species in Macrocystis pyrifera dominated kelp forest habitats in New Zealand alongside experiments comparing the photosynthetic physiology of U. pinnatifida to nine native co-occurring macroalgal species. Undaria pinnatifida was identified at four locations that had previously been reported to be uninvaded and was found throughout the depth range of the kelp forest. Highest densities were observed at shallow depths, reflecting the commonly accepted mode of invasion via sheltered rock pools. Photosynthesis versus Irradiance (P vs. E) curves were constructed for 10 dominant brown macroalgal species. Undaria pinnatifida exhibited greater photosynthetic ability than native macroalgae with maximal rates of photosynthesis at least 1.6-times higher than the habitat forming native kelp species Macrocystis pyrifera and Ecklonia radiata and more than 2.5 times higher than eight other native species. The photosynthetic efficiency of U. pinnatifida under low light was at least as high as macroalgae common on deeper sections of surveyed reefs (e.g. M. pyrifera and E. radiata). Collectively, this information shows that U. pinnatifida has superior photosynthetic performance across all ecologically relevant light intensities. Our data show that the photosynthetic physiology of U. pinnatifida is not likely to limit invasion into deeper sections of reef. This trend could continue, with the potential to fundamentally alter the structure of these wave-exposed kelp communities.

Focal Adhesion Kinase (FAK) Overexpression and Phosphorylation in Oral Squamous Cell Carcinoma and their Clinicopathological Significance.

Focal adhesion kinase (FAK) is involved in progression of various cancers, and FAK overexpression has been associated with cancer invasion and metastasis. However, the involvement of FAK expression in the clinicopathological malignancy of oral squamous cell carcinoma (OSCC) remains unknown. In addition, there is no consensus regarding the role of p16 expression in OSCC. In this study, the immunohistochemically measured expression of FAK, phosphorylated FAK (FAKpY397) and p16 expressions and their associations with clinicopathological features and 5-year survival rates were examined in surgical samples from 70 patients with primary OSCC. FAK and FAKpY397 were expressed at high levels in 42 cases (60.0%) and 34 cases (48.6%), respectively, and 9 cases (12.9%) were positive for p16. FAK expression was significantly correlated with local recurrence, subsequent metastasis, and the mode of invasion. FAKpY397 expression was significantly correlated with both N classification and the mode of invasion. p16 expression was significantly correlated with clinical stage only. Patients having high expression of FAK, FAKpY397, or both showed significantly worse prognosis, but p16 expression showed no significant relation to prognosis. The results suggested that overexpression and phosphorylation of FAK in OSCC may affect cancer progression, such as local invasion and lymph node metastasis, and thereby contribute to life prognosis.

Piriformospora indica-induced phytohormone changes and root colonization strategies are highly host-specific

ABSTRACTPiriformospora indica, an endophytic fungus of Sebacinales, has a wide host range and promotes the performance of mono- and eudicot plants. Here, we compare the interaction of P. indica with the roots of seven host plants (Anthurium andraeanum, Arabidopsis thaliana, Brassica campestris, Lycopersicon esculentum, Oncidium orchid, Oryza sativa, and Zea mays). Microscopical analyses showed that the colonization time and the mode of hyphal invasion into the roots differ in the symbiotic interactions. Substantial differences between the species were also observed for the levels and accumulation of jasmonate (JA) and gibberellin (GA) and the transcript levels for genes involved in their syntheses. No obvious correlation could be detected between the endogenous JA and/or GA levels and the time point of root colonization in a given plant species. Our results suggest that root colonization strategies and changes in the two phytohormone levels are highly host-specific.

Progress on the Study of Tumor Spread Through Air Spaces in the Clinicopathological Characteristics of Lung Adenocarcinoma and Its Influence on the Surgical Treatment and Prognosis of Lung Cancer

肿瘤肺泡腔内播散（tumor spread through air spaces, STAS）作为一种新的病理侵袭方式，与诸多临床病理因素紧密相关。在肺腺癌中，微乳头和实体型病理亚型与之关系最为密切；针对早期肺腺癌存在STAS，手术类型的治疗上肺叶切除似乎优于亚肺叶切除而获益，可能上调早期肺癌的病理分期；同时，STAS与鳞癌等非小细胞肺癌（non-small cell lung cancer, NSCLC）关系密切。此外，STAS的术中冰冻切片病理检测困难，亦有争议存在。STAS作为肿瘤复发的独立危险因素，亦是提示预后不良的重要因素，本文将STAS的研究现状和进展作一综述。

ROCK2 inhibition triggers the collective invasion of colorectal adenocarcinomas.

The metastatic progression of cancer is a multi-step process initiated by the local invasion of the peritumoral stroma. To identify the mechanisms underlying colorectal carcinoma (CRC) invasion, we collected live human primary cancer specimens at the time of surgery and monitored them exvivo. This revealed that conventional adenocarcinomas undergo collective invasion while retaining their epithelial glandular architecture with an inward apical pole delineating a luminal cavity. To identify the underlying mechanisms, we used microscopy-based assays on 3D organotypic cultures of Caco-2 cysts as a model system. We performed two siRNA screens targeting Rho-GTPases effectors and guanine nucleotide exchange factors. These screens revealed that ROCK2 inhibition triggers the initial leader/follower polarization of the CRC cell cohorts and induces collective invasion. We further identified FARP2 as the Rac1 GEF necessary for CRC collective invasion. However, FARP2 activation is not sufficient to trigger leader cell formation and the concomitant inhibition of Myosin-II is required to induce invasion downstream of ROCK2 inhibition. Our results contrast with ROCK pro-invasive function in other cancers, stressing that the molecular mechanism of metastatic spread likely depends on tumour types and invasion mode.

Macrophage CCL22 expression in the tumor microenvironment and implications for survival in patients with squamous cell carcinoma of the tongue.

CCL22, mainly synthesized by monocyte-derived alternative (M2) macrophages, belongs to the CC family of chemokines. CCR4, the receptor for CCL22, is expressed in regulatory T cells (Tregs) and Th2 cells. The Yamamoto-Kohama (YK) mode of invasion has been associated with tumor prognosis. Herein, we investigated the role of CCL22 in the tumor microenvironment and its effect on the overall survival rate in patients with tongue squamous cell carcinoma (SCC). Tumor sections obtained from 92 patients with tongue SCC were graded based on the mode of invasion according to the YK classification. The expressions of several markers (CCL22, CD8, and Ki-67 by immunohistochemistry; CCR4 and FoxP3 by immunofluorescent staining) were evaluated. Student's t test and chi-square tests were used to compare differences between numerical variables and groups, respectively. Survival curves were plotted according to the Kaplan-Meier method and compared using a log-rank test. Hazard ratios and 95% confidence intervals were estimated using univariate or multivariate Cox proportional hazard models. The expression of CCL22 was significantly correlated with YK classification, overall survival rate (P<0.001), a decrease in the number of CD8-positive cells, and an increase in the tumor Ki-67 index. In addition, CCR4-positive cells were observed around CCL22-positive macrophages. These findings indicate that the expression of CCL22 in the tumor microenvironment led to a deterioration in the prognosis of patients with tongue SCC by influencing the balance of M1- and M2-like macrophages.

Control of Invasion by Epithelial-to-Mesenchymal Transition Programs during Metastasis.

Epithelial-to-mesenchymal transition (EMT) programs contribute to the acquisition of invasive properties that are essential for metastasis. It is well established that EMT programs alter cell state and promote invasive behavior. This review discusses how rather than following one specific program, EMT states are diverse in their regulation and invasive properties. Analysis across a spectrum of models using a combination of approaches has revealed how unique features of distinct EMT programs dictate whether tumor cells invade as single cells or collectively as cohesive groups of cells. It has also been shown that the mode of collective invasion is determined by the nature of the EMT, with cells in a trailblazer-type EMT state being capable of initiating collective invasion, whereas cells that have undergone an opportunist-type EMT are dependent on extrinsic factors to invade. In addition to altering cell intrinsic properties, EMT programs can influence invasion through non-cell autonomous mechanisms. Analysis of tumor subpopulations has demonstrated how EMT-induced cells can drive the invasion of sibling epithelial populations through paracrine signaling and remodeling of the microenvironment. Importantly, the variation in invasive properties controlled by EMT programs influences the kinetics and location of metastasis.

Immunohistochemical assessment of growth factor signaling molecules: MAPK, Akt, and STAT3 pathways in oral epithelial precursor lesions and squamous cell carcinoma.

Several growth factors and their receptors, such as epidermal growth factor receptor, have been studied as prognostic biomarkers for many epithelial malignancies. The signal transduction cascade of those receptors includes RAS/RAF/ERK, PI3K/Akt/mTOR, and STAT3 pathways. The aim of this study was to investigate the expression levels of several key proteins of those pathways in patients with oral squamous cell carcinoma (OSCC) and oral epithelial precursor lesions (OEPLs), and to correlate the expressions of these proteins with clinicopathologic features and prognosis. Fifteen leukoplakia (LP), 15 low-grade epithelial dysplasia, 15 high-grade epithelial dysplasia (HD), and 132 OSCC specimens were immunohistochemically examined for KRAS, HRAS, NRAS, BRAF, pERK1/2, pAkt, pmTOR, and pSTAT3 expression. Immunoreactivity for these molecules predominantly occurred in regions OEPL basal to prickle layers and in most OSCC cells. KRAS and NRAS expression was significantly lower in OSCC than in OEPLs, while pAkt and pmTOR showed higher expression in OSCC than in OEPLs. pERK1/2 expression was significantly higher in HD than in LP. In OSCC, KRAS and NRAS immunoreactivity was significantly higher in advanced age and male gender. In addition, higher immunoreactivity was shown in pERK1/2 in female gender and advanced TNM stage, pAkt in advanced T classification and cases without postoperative metastasis, pmTOR in advanced mode of invasion, and pSTAT3 in invasion depth. Correlations between these markers and clinicopathological variables were also noted. MAPK, Akt, and STAT3 pathways might play diverse roles in oral carcinogenesis.

Pilot study of the relationship between clinical classification of gallbladder cancer and prognosis: a retrospective multicenter clinical study

Objectives: To propose a novel clinical classification system of gallbladder cancer, and to investigate the differences of clinicopathological characteristics and prognosis based on patients who underwent radical resection with different types of gallbladder cancer. Methods: The clinical data of 1 059 patients with gallbladder cancer underwent radical resection in 12 institutions in China from January 2013 to December 2017 were retrospectively collected and analyzed.There were 389 males and 670 females, aged (62.0±10.5)years(range:22-88 years).According to the location of tumor and the mode of invasion,the tumors were divided into peritoneal type, hepatic type, hepatic hilum type and mixed type, the surgical procedures were divided into regional radical resection and extended radical resection.The correlation between different types and T stage, N stage, vascular invasion, neural invasion, median survival time and surgical procedures were analyzed.Rates were compared by χ(2) test, survival analysis was carried by Kaplan-Meier and Log-rank test. Results: Regional radical resection was performed in 940 cases,including 81 cases in T1 stage,859 cases in T2-T4 stage,119 cases underwent extended radical resection;R0 resection was achieved in 990 cases(93.5%).The overall median survival time was 28 months.There were 81 patients in Tis-T1 stage and 978 patients in T2-T4 stage.The classification of gallbladder cancer in patients with T2-T4 stage: 345 cases(35.3%)of peritoneal type, 331 cases(33.8%) of hepatic type, 122 cases(12.5%) of hepatic hilum type and 180 cases(18.4%) of mixed type.T stage(χ(2)=288.60,P<0.01),N stage(χ(2)=68.10, P<0.01), vascular invasion(χ(2)=128.70, P<0.01)and neural invasion(χ(2)=54.30, P<0.01)were significantly correlated with the classification.The median survival time of peritoneal type,hepatic type,hepatic hilum type and mixed type was 48 months,21 months,16 months and 11 months,respectively(χ(2)=80.60,P<0.01).There was no significant difference in median survival time between regional radical resection and extended radical resection in the peritoneal type,hepatic type,hepatic hilum type and mixed type(all P>0.05). Conclusion: With application of new clinical classification, different types of gallbladder cancer are proved to be correlated with TNM stage, malignant biological behavior and prognosis, which will facilitate us in preoperative evaluation,surgical planning and prognosis evaluation.

Submandibular Gland Invasion by Oral Cavity Cancers: A Systematic Review.

The submandibular gland (SMG) is typically included in level I neck dissection specimens despite limited data demonstrating SMG invasion. The main objective of this article is to determine the rate and pathways of SMG invasion by squamous cell carcinoma of the oral cavity and oropharynx. A systematic review of relevant studies was performed, evaluating articles identified via the PubMed, Cochrane, and Medline databases. Descriptive features of primary tumors, primary treatment modalities, the rate and pathway of SMG invasion, and survival outcomes, if present, were reported following the PRISMA guidelines. The initial literature search yielded 273 articles, of which 17 met inclusion criteria. A total of 2306 patients with 2792 SMG resections were analyzed. Fifty-eight resections (2.0%) were revealed to have tumor involvement. Among patients with SMG tumor involvement, the most common invasion pathway was direct SMG invasion by primary tumor (43 of 58, 74.1%). The second-most common mode of SMG invasion was from involved adjacent lymph nodes (10 of 58, 17.2%). Only 3 SMG resections out of 2792 (0.1%) had isolated metastatic parenchyma without evidence of direct tumor invasion or invasion by involved lymph nodes. Given this rarity of SMG involvement, preservation of SMG might be feasible in selected patient population. However, additional studies need to examine the functionality of preserved SMGs among patients who receive postoperative adjuvant radiation therapy.