Locoregional Invasion Research Articles

Pre-operative chemotherapy (ctx) in plasmacytoid urothelial carcinoma (PUC).

522 Background: PUC is characterized by E-cadherin loss, diffuse growth pattern and aggressive natural history. Management of this entity is controversial. This retrospective study aims to evaluate the impact of PUC histology on clinical outcomes with ctx compared to UC-NOS. Methods: Consecutive cases of nonmetastatic PUC were identified as either (1) localized disease (LD: cT2-3 cN0) or (2) locally-advanced (LA: fixed bladder or radiographic nodal disease). All cases were reviewed by a GU pathologist to confirm PUC histology per WHO classification (2016). A separate cohort of neoadjuvant(NAC)-treated UC-NOS (Tully et al, ASCO GU 2014) served as comparator for clinical outcomes. Kaplan-Meier estimates and logrank test were used for analysis of recurrence free (RFS) and overall survival (OS) defined from date of cystectomy (RC). Results: Between 2000 and 2017, eighty one PUC were identified, with median age of 65 years (range: 22 - 84) and 65% male. Thirty patients (pts) had up-front RC; 51 pts had ctx. In the former group, all pts had LD but upstaging was seen on post-op pathology: 63% pT3, 17% pT4 and 37% pN+. Among ctx pts, 33/51(65%) were LD and had NAC: 70% had ctx doublet and 24% triplet; 82% had 4 cycles and 18% had up to 6 cycles. Response ( < pT2 pN0) was seen in 7/33(22%), four (12%) of which had no residual disease (pCR). Six RC were aborted after NAC for pT4b disease. NAC response was not associated superior RFS (NR vs. 17.3 months; HR 0.52 95% CI 0.18 – 1.47, p = .218) or OS (41.3 vs. 25.5 months; HR 0.65 95% CI 0.23 – 1.87, p = .428). Compared to UC-NOS, PUC responders had significantly inferior outcomes (table). In LA cohort, majority had triplet chemotherapy (72%) and up to 6 cycles (89%). Response was seen in 4/18(22%) pts, with two pCR (11%). Five RC were aborted for pT4b disease. Median RFS and OS were 5.8 and 10.5 months, respectively, with 19% alive at 2-years. Most common sites of recurrence/progression for PUC were peritoneal (42%) and locoregional invasion (26%). Conclusions: Outcomes for PUC are poor with conventional NAC-RC approach. [Table: see text]

Effecst of Patho- Biological Factors on the Survival of Recurrent Breast Cancer Cases

Background:Recurrence of breast cancer after treatment is generally due to loco-regional invasion or distant metastasis. Although patients with metastasis are considered incurable, existing treatments might prolong a patient’s life while also improving its quality. Choice of approach for individual patients requires identification of relevant survival factors. This study concerns factors influencing survival after recurrence in Iranian breast cancer patients.Methods:This study was performed on 442 recurrent breast cancer patients referred to the Cancer Research Center of Shahid Beheshti University between 1985 and 2015. After confirming recurrence as a distant metastasis or loco-regional invasion, the effects of demographic, clinic-pathologic, biological, type of surgery and type of adjuvant treatment on survival were evaluated using univariate and multivariate stratified Cox models.Results:The mean survival after recurrence was 18 months (5 days to 13 years), 219 patients (70.42%) survived two years, 75 patients (24.12%) survived from 2 to 5 years, and 17 patients (5.47%) survived more than 5 years. In this study, it was found through univariate analysis that the factors of age, lymph node status, DFI, place of recurrence and nodal ratio demonstrated greatest influence on survival after recurrence. On multivariate analysis, the most important factors influencing survival were the place of recurrence and the lymph node status.Conclusion:The results of this study enhance our knowledge of effects of different factors on survival of patients after breast cancer recurrence. Thus, they may be used to inform treatment choice.

P1.08-005 Preoperative Analysis of 18FDG-PET Features May Predict Loco-Regional Invasiveness in NSCLC

P1.08-005 Preoperative Analysis of 18FDG-PET Features May Predict Loco-Regional Invasiveness in NSCLC

Zinc finger AN1-type containing 4 is a novel marker for predicting metastasis and poor prognosis in oral squamous cell carcinoma

AimsHead and neck cancer, including oral squamous cell carcinoma (OSCC), is the sixth most common cancer worldwide and has a high potential for locoregional invasion and nodal metastasis. Therefore, discovery...

Microenvironmental regulation of the progression of oral potentially malignant disorders towards malignancy.

Oral potentially malignant disorders (OPMD) develop in a complex tissue microenvironment where they grow sustainably, acquiring oral squamous cell carcinoma (OSCC) characteristics. The malignant tumor depends on interactions with the surrounding microenvironment to achieve loco-regional invasion and distant metastases. Unlike abnormal cells, the multiple cell types in the tissue microenvironment are relatively stable at the genomic level and, thus, become therapeutic targets with lower risk of resistance, decreasing the risk of OPMD acquiring cancer characteristics and carcinoma recurrence. However, deciding how to disrupt the OPMD and OSCC microenvironments is itself a daunting challenge, since their microenvironments present opposite capacities, resulting in diverse consequences. Furthermore, recent studies revealed that tumor-associated immune cells also participate in the process of differentiation from OPMD to OSCC, suggesting that reeducating stromal cells may be a new strategy to prevent OPMD from acquiring OSCC characteristics and to treat OSCC. In this review, we discuss the characteristics of the microenvironment of OPMD and OSCC as well as new therapeutic strategies.

A comparative analysis of dual-phase dual-energy CT and FDG-PET/CT for the prediction of histopathological invasiveness of non-small cell lung cancer

PurposeTo compare dual-phase dual-energy CT (DE-CT) with FDG-PET/CT for predicting histopathological locoregional invasiveness of non-small cell lung cancers (NSCLCs). Materials and methodsWe selected 63 consecutive patients with NSCLC lesions (37 males, 26 females; age range, 44–85 years; mean age, 69 years) who were evaluated preoperatively by both DE-CT and PET/CT at our institution. Postoperative microscopic invasiveness (lymphatic permeation, vascular invasion, and/or pleural involvement) was reviewed, and we defined locoregionally invasive tumors as those that had at least one positive finding of microscopic invasiveness. DE-CT scanning in the arterial and delayed phases was performed after injection of iodinated contrast media using 140-kVp and 80-kVp tube voltages. Three-dimensional iodine-related attenuation of primary tumors in the arterial and delayed phases was quantified automatically using “syngo Dual Energy Lung Nodules” application software, and the ratio of arterial phase to delayed phase enhancement (A/D ratio) was calculated. The A/D ratio and SUVmax on PET/CT were evaluated with respect to postoperative invasiveness by univariate logistic regression analysis. ResultsThe A/D ratio was significantly correlated with lymphatic permeation, vascular invasion, and pleural involvement (p=0.011, p=0.021, and p=0.010, respectively). In contrast, the SUVmax was significantly correlated with pleural involvement (p=0.020) but not with lymphatic permeation or vascular invasion (p=0.088 and p=0.100, respectively). In the subgroup of patients with lesion diameters ≤2cm, the A/D ratio was significantly correlated with locoregional invasiveness (p=0.040), while the SUVmax was not (p=0.121). ConclusionFor the prediction of microscopic invasiveness of NSCLCs, the diagnostic performance of dual-phase DE-CT may be comparable to that of FDG-PET/CT.

Morbidity of total thyroidectomy for substernal goiter: A series of 70 patients

Total thyroidectomy for substernal goiter occasionally requires a sternotomy associated with a cervical incision. We sought to analyze the postoperative complications of thyroidectomy for substernal goiters in our center and more precisely the complications related to the sternotomy. All patients who underwent total thyroidectomy for substernal goiter in our center between 2007 and 2016 were reviewed retrospectively. Patients with combined cervical incision and sternotomy (ST group, n=16) were compared to those with cervical incision alone (CT group, n=54), with regard to postoperative complications. Risk factors for the occurrence of postoperative complications were investigated in this population. A total of 24 patients (34.2%) had one or more postoperative complications. The incidence of transient hypoparathyroidism and recurrent laryngeal nerve injury were higher in the ST group (P=0.001 and P=0.052, respectively). The median duration of hospitalization was longer in the ST group (P<0.001). Eighteen patients (25.8%) had a malignant tumor on final pathology. In univariate analysis, the following risk factors for transient postoperative hypoparathyroidism were identified: sternotomy, preoperative symptomatic character and thyroid height (P=0.001, P=0.009 and P=0.013, respectively). In multivariable analysis, only sternotomy was an independent risk factor for postoperative transient hypoparathyroidism (OR=4.48 [1.1; 18], P=0.035). Sternotomy is associated with added morbidity that is not negligible. This surgical approach should be reserved for substernal goiters that descend into the posterior mediastinum, below the level of the aortic arch, when there is suspicion of carcinoma with loco-regional invasion, or when the thyroid tissue is located mainly intrathoracically (conical shaped thyroid, asymptomatic goiter, ectopic thyroid).

Ameloblastoma: current etiopathological concepts and management.

Ameloblastoma is a benign odontogenic tumor of epithelial origin. It is locally aggressive with unlimited growth capacity and has a high potential for malignant transformation as well as metastasis. Ameloblastoma has no established preventive measures although majority of patients are between ages 30 and 60years. Molecular and genetic factors that promote oncogenic transformation of odontogenic epithelium to ameloblastoma are strongly linked to dysregulation of multiple genes associated with mitogen-activated protein kinase, sonic hedgehog, and WNT/β-catenin signaling pathways. Treatment of ameloblastoma is focused on surgical resection with a wide margin of normal tissue because of its high propensity for locoregional invasion; but this is often associated with significant patient morbidity. The relatively high recurrence rate of ameloblastoma is influenced by the type of molecular etiological factors, the management approach, and how early the patient presents for treatment. It is expected that further elucidation of molecular factors that orchestrate pathogenesis and recurrence of ameloblastoma will lead to new diagnostic markers and targeted drug therapies for ameloblastoma.

Morphological background of intraoperative radiation therapy appliance to prevent locoregional progression in patients with pancreatic ductal adenocarcinoma

Background. It is well recognized that pancreatic ductal adenocarcinoma (PDAC) is associated with very poor prognosis, early locoregional invasion and distant metastases. One reason for this is the proliferation of tumor growth through perineural spaces. Aim. To evaluate the efficacy of intraoperative radiation therapy (IORT) for the extrapancreatic perineural invasion (EPPI) in the development of locoregional recurrence in patients with PDAC. Results. In 14.5% (22/152) the tumor was pT1–2, pN0, extraPn 0, R0. R1 detected in 32.1% (49/152). ExtraPn was detected in 36.8% of cases (56/152). Metastases in regional lymph nodes was found in 62.5% (95/152) of cases. In the study of autopsy basic morphological parameters speakers include locoregional tumor progression and / or a distant progression. Locoregional recurrence was found in 85% of cases (29/34), which is manifested by the presence of perineural invasion. The mean time from surgery until locoregional recurrence without extraPn –14 months, with the presence of extraPn – 9 months. Conclusion. Thus, the absence of regional lymph nodes and/or with positive surgical margin does not preclude the development of locoregional recurrence in patients with PDAC. This is what necessitates a combined approach to the treatment of these patients, including surgery, supplemented by conducting IORT that effectively influences on tissues and reduces the number of local recurrence.

Clinicopathologic Features of Fatal Non-Anaplastic Follicular Cell-Derived Thyroid Carcinomas.

The vast majority of thyroid cancers, in particular the non-anaplastic follicular cell-derived thyroid carcinomas (non-ANA FCDC), are considered indolent tumors with very low mortality. Hence, it is crucial to analyze the subgroup of these patients who die of disease (DOD) in order to identify clinicopathologic features predictive of disease-specific mortality. All non-ANA FCDC operated at a tertiary cancer center between 1985 and 2010 who were DOD were identified and submitted to a meticulous clinicopathologic analysis. Out of 3750 non-ANA FCDC, 58 (1.5%) DOD cases were identified. The DOD group was composed of 33 (57%) poorly differentiated carcinomas (PDTC), 14 (24%) tall-cell variant papillary thyroid carcinomas (TCVPTC), four (7%) Hürthle cell carcinomas, three (5%) papillary microcarcinomas, two (3%) classical variant PTC, and two (3%) follicular variant PTC. Twenty-seven (47%) patients presented with distant metastases (DM), 28 (48%) developed DM during follow-up, while the remaining three (5%) had locally advanced non-resectable recurrence. Gross extension beyond the thyroid (GET) was present in 36 (62%) and extensive vascular invasion (VI) in 21 (36%) of cases. All microcarcinomas had PDTC in their clinically apparent cervical lymph nodes at presentation. Encapsulated thyroid carcinomas were responsible for 17% of DOD cases, and all had extensive VI and/or DM at presentation. All patients had at least one of these high-risk features at diagnosis: DM at presentation, PDTC, GET, and/or extensive VI. The majority of patients died from DM (n = 51; 88%), three (5%) from locoregional disease, three (5%) from both, and one (2%) from unknown cause. PDTC and TCVPTC are responsible for the vast majority of deaths in differentiated thyroid carcinomas, while the few fatal classical, follicular variant PTC and microcarcinomas all harbor a PDTC component, DM, or GET. Encapsulated differentiated thyroid carcinoma with focal capsular and/or VI without DM at presentation does not seem to cause death. Lack of DM at presentation, PDTC, GET, and extensive VI identify thyroid carcinomas that are at almost no risk of DOD. The vast majority of patients die of DM rather than locoregional invasion, prompting the need for effective systemic treatment.

Evaluation of locoregional invasiveness of small-sized non-small cell lung cancers by enhanced dual-energy computed tomography.

BackgroundTo investigate the correlation between iodine-related attenuation of dual-energy computed tomography (DE-CT) and the histopathological invasiveness of surgically resected primary non-small cell lung cancers (NSCLCs) ≤ 3 cm in diameter.MethodsWe selected 63 consecutive NSCLC lesions from 60 patients (32 males, 28 females; age range, 39–85 years; mean age, 68 years). After injection of iodinated contrast media, arterial phases were scanned using 140-kVp and 80-kVp tube voltages. Three-dimensional iodine-related attenuation (3D-IRA) of primary tumors at the arterial phase was computed using “lung nodule” application software. The corrected 3D-IRA normalized to the patient’s body weight and contrast medium concentration was then calculated. Single-factor analysis of variance (ANOVA) was used for comparison among tumor differentiation grade groups. Univariate and multivariate logistic regression analysis was used for the correlation between locoregional invasive tumor and clinical factors.ResultsResected tumors were histopathologically classified into well-differentiated (G1; n = 24), moderately-differentiated (G2; n = 28), and poorly-differentiated (G3; n = 11) groups by degree of tumor differentiation. The mean ± standard deviation of the 3D-IRA was 56.1 ± 22.6 HU in G1 tumours, 48.5 ± 23.9 HU in G2 tumours, and 28.4 ± 15.8 HU in G3 tumours; significant differences were observed between groups by ANOVA. (p = 0.005). Univariate logistic analysis showed that the 3D-IRA and corrected 3D-IRAs were significantly correlated with locoregional invasive tumors (p = 0.002 and p < 0.001, respectively). Multivariate logistic analysis revealed that only the corrected 3D-IRA was significantly correlated with tumor invasiveness (p = 0.003), while gender, clinical size, and solid/subsolid type were not (p = 0.950, p = 0.057 and p = 0.456, respectively).ConclusionsThe 3D-IRA of small-sized NSCLCs was significantly associated with and invasiveness. Low 3D-IRA tumors tended to have greater invasiveness than high 3D-IRA tumors.

LEM domain containing 1 promotes oral squamous cell carcinoma invasion and endothelial transmigration.

Background:Oral squamous cell carcinomas have high potential for locoregional invasion and nodal metastasis. Thus, early detection and elucidation of detailed molecular mechanisms of OSCCs are important. Roles of LEM domain containing 1 (LEMD1), a novel cancer–testis antigen, in OSCCs are unclear.Methods:We performed immunohistochemical analysis of LEMD1 in 289 OSCC patients and examined functions of LEMD1 in these carcinomas.Results:Immunohistochemical analysis showed that 101 patients were positive for LEMD1. LEM domain containing 1 expression levels in OSCCs significantly correlated with tumour progression (T factor and clinical stage), nodal metastasis, and poor prognosis. LEM domain containing 1 expression was an independent predictor of disease-free survival in OSCC patients. In OSCCs, LEMD1 knockdown suppressed cancer cell invasion. Moreover, downregulation of LEMD1 expression inhibited adhesion and transmigration of OSCCs and vascular or lymphatic vascular endothelial cells.Conclusions:Our findings suggest that LEMD1 is a novel tumour progressive factor and may be a useful diagnostic and therapeutic target in OSCCs.

The utility of hyperthermic intra-abdominal chemotherapy with gemcitabine for the inhibition of tumor progression in an experimental model of pancreatic peritoneal carcinomatosis, in relation to their behavior with pancreatic cancer stem cells CD133+ CXCR4+

ObjectiveThe origin of pancreatic cancer has been identified as a population of malignant pancreatic stem cells CD133+ CXCR4+ immunophenotype. These cells have high capacity for early locoregional invasion, being responsible for early recurrence and high mortality rates of pancreatic cancer. We propose a study for decreasing tumor progression of pancreatic cancer by reducing the volume and neoplastic subpopulation of pancreatic cancer stem cells CD133+ CXCR4+. Therefore, we develop a new therapeutic model, characterized by the application of HIPEC (Hyperthermic Intraperitoneal Chemotherapy) with gemcitabine. DesignPancreatic tumor cell line: human cell line BxPC-3. The animal model involved 18 immunosuppressed rats 5 weeks weighing 150–200 gr. The implantation of 13 × 106 cells/mL was performed with homogeneous distribution in the 13 abdominopelvic quadrants according to the peritoneal carcinomatosis index (PCI) and were randomized into three treatment groups. Group I (4 rats) received intravenous saline. Group II (6 rats) received intravenous gemcitabine. Group III (8 rats) received HIPEC at 41 °C for 30 min with gemcitabine + gemcitabine IV. A histological study confirmed pancreatic cancer and immunohistochemical quantification of pancreatic cancer stem cells CD133+ CXCR4+ tumor cells. ResultsThere was a population decline of pancreatic cancer stem cells CD133+ CXCR4+ in the HIPEC group with respect to the other two groups (p < 0.001). There was a decrease in PCI between treatment groups (p < 0.05). ConclusionThe initial results are encouraging since there is a declining population of cancer stem cells CD133+ CXCR4+ in the HIPEC group and decreased tumor volume compared to the other two treatment groups. All the conclusions are only valid for BxPC3 cell line, and the effects HIPEC on Kras-driven pancreatic tumors remain to be determined.

Behind and Beyond the Masaoka Staging: A 25-Year Follow-up Study of Tumor Recurrence in Completely Resected Thymic Epithelial Tumors in a Single Institution.

We analyzed prognosticators for recurrence and post-recurrence survival in completely resected thymic epithelial tumors for the past 25 years in a single institution.Between June 1988 and December 2013, 238 patients undergoing intent-to-treat surgery for thymic epithelial tumors were reviewed. Sex, age, myasthenia gravis (MG), tumor histology, Masaoka staging, characteristic of locoregional invasion and recurrence, and the treatment for recurrence were collected. Comparison between groups was conducted using the Student t test and χ2 test. Survival analysis was performed using the Kaplan–Meier method and log-rank test. The Cox proportional hazards model was used for univariate and multivariate analyses of prognostic factors.One hundred sixteen of 135 patients with completely resected thymoma and 35 of 56 patients with thymic carcinoma remained free of recurrence. In patients with completely resected thymoma, Masaoka staging, MG, tumor invasion into the lung, pericardium, and innominate vein or superior vena cava (SVC) invasion were associated with recurrence-free survival in univariate analysis (P = 0.004, 0.003, 0.001, 0.007, and 0.039, respectively). In multivariate analysis, MG was the positive independent prognosticator (P = 0.039). In patients with completely resected thymic carcinoma, Masaoka staging and innominate vein or SVC invasion were associated with recurrence-free survival in univariate analysis (P = 0.045 and 0.005, respectively), whereas innominate vein or SVC invasion was the negative independent prognosticator (P = 0.012). In patients with recurrent thymoma, those treated with surgery followed by chemotherapy had a significantly better post-recurrence survival than those undergoing chemoradiotherapy (P = 0.029) and those without treatment (P = 0.007). Patients with recurrent thymic carcinoma undergoing surgery followed by chemotherapy had a significantly better post-recurrence survival than those without treatment (P = 0.004), but not significantly better than those undergoing chemoradiotherapy (P = 0.252).In patients with completely resected thymoma, MG was the positive independent prognosticators of recurrence-free survival. Surgery should be attempted for recurrent disease for better post-recurrence survival. In patients with completely resected thymic carcinoma, innominate vein or SVC invasion was the negative independent prognosticator. Surgery for recurrence could be considered since it provided benefit for post-recurrence survival as chemoradiotherapy did.

Carcinomes épidermoïdes sur cicatrices d’ulcère de Buruli en Afrique de l’Ouest

Buruli ulcer is an infection caused by Mycobacterium ulcerans occurring in tropical areas. In West Africa, it is an emerging threat mainly affecting children aged under 15years. This chronic disease is complicated by dystrophic scars in which squamous cell carcinoma can occur in the long term. This is a retrospective study of squamous cell carcinomas in Buruli ulcer scars seen at the Treichville University Hospital (Abidjan, Ivory Coast) over a five-year period. During the study period, 8cases were observed and concerned young adults presenting Buruli ulcer in their childhood. Tumours were restricted to the limbs, with loco-regional invasion. Treatment was primarily surgical. Four of the patients died. The risk of recurrence of cancer in these scars remains poorly evaluated, highlighting the importance of long-term monitoring strategies for human patients in order to ensure rapid identification of any changes in Buruli ulcer scars.

An Unordinary Recurrence of Urothelial Bladder Carcinoma in the Colon Presenting as Hematochezia

The conventional route of recurrence and metastasis in primary urothelial cell carcinoma of the bladder is through lymphatics and hematogenous system with regional lymph nodes, lungs, liver, brain and bone being the most commonly involved sites. Invasive urothelial cancers could also spread locoregionally to surrounding organs including female genital tract, prostate and gastrointestinal tract especially colo-rectum. However, recurrence of this cancer inside the colon in the absence of locoregional invasion, and after achieving complete long-term remission is extremely unusual. A review of the literature revealed a single case reported by Yang et al. of an urothelial cancer recurrence in the colon with mixed urothelial/colonic malignant pathology [1]. Herein we report the second case, to our knowledge, of an urothelial cell bladder carcinoma that recurred inside the colon in the form of a mass causing hematochezia, which on pathology and immunohistostaining proved to be primarily of urothelial rather than colonic origin. 67 year old male heavy smoker with stage III (T3a, N0, M0) transitional cell carcinoma of the bladder had undergone radical cystectomy, neo-bladder reconstruction and adjuvant chemotherapy following initial diagnosis. He poved repetitively to have no evidence of disease until he presented 4 years later with intermittent hematochezia and anemia. Colonoscopy revealed a fungating, ulcerated mass in the sigmoid colon suggestive of a primary colon cancer (fig 1). Pathology disclosed high grade/poorly differentiated carcinoma invading the colonic mucosa that surprisingly favored an urothelial origin. Upon further immunostaining, final diagnosis of a metastatic high-grade urothelial carcinoma was confirmed by positive cytokeratin (CK) 7 stain (specific for urothelial cells) and negative villin and CDX2 stains that are both specific for gastrointestinal differentiation (fig 2). CT scan of abdomen and pelvis, and PET scan did not reveal any other sites of cancer recurrence. Patient received a tailored chemotherapy and responded appropriately.Figure 1Figure 2This case illustrates a rare kind of recurrence of urothelial cancer in the form of a colonic mass resembling primary colon cancer. This unordinary way of recurrence could pose a clinico-pathological diagnostic challenge in distinguishing this disease treated basically with chemotherapy, from a primary colon cancer managed primarily by surgical resection. Immunohistochemical stains are essential for an accurate diagnosis. Heightened awareness is of utmost importance in such patients with history of urothelial cancer in order to appropriately tailor further treatment strategies that differ between primary and secondary colonic tumors.

Malignant neuroendocrine tumour of the appendix in childhood with loco-regional lymph node invasion

Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1006600359152743Electronic supplementary materialThe online version of this article (doi:10.1186/s13000-015-0287-z) contains supplementary material, which is available to authorized users.

Abstract B07: Using magnetic resonance and hyperpolarized tracers to monitor solid tumor progression, metastasis, and response to treatment

Abstract Purpose: To optimize translational fidelity of a murine model of anaplastic thyroid carcinoma (ATC) using real-time metabolic imaging. Background: Anaplastic thyroid carcinoma (ATC) is an aggressive solid malignancy with rapid growth, invasion of critical cervical structures and a high rate of pulmonary metastasis. Although rare in overall incidence (2-3% of thyroid cancer), ATC accounts for 50% of thyroid cancer related mortality. The rapid rate of growth and metastasis makes optimization of treatment algorithms challenging and development of novel therapeutic strategies difficult. Our group has developed an integrated preclinical model of ATC using validated human cell lines and a xenograft mouse model which recapitulates disease characteristics and closely mimics response to treatment including chemotherapy and ionizing radiation (IR). Experimental procedures: Validated human ATC cell lines were either injected into the right thyroid lobe of athymic nude mice in an orthotopic tumor model or intravenously (tail-vein) to generate pulmonary metastases. Tumors were exposed to varying doses of ionizing radiation (IR) and monitored using both anatomic magnetic resonance imaging (MRI) sequences as well as hyperpolarized (HP) [1-13C]-pyruvate (PYR). HP-MR data was acquired using either temporal or spatial acquisition sequences depending on the experimental aims. At the completion of intended experiments, primary thyroid tumors and pulmonary metastases were harvested and analyzed using standard histologic and immunohistochemical techniques. Results: We have employed HP-MR using labeled [1-13C]-pyruvate to measure tumor metabolic activity in real-time. We have translated this capability into precise measurements of tumor viability at the primary site, which when combined with anatomic MRI sequences provides enhanced visualization and identification of critical cervical structure invasion. HP-MR has allowed us to identify sub-centimeter pulmonary metastases and differentiate tumor from normal lung parenchyma based on the inherently higher rate of conversion of labeled pyruvate (PYR) into lactate (LAC). We had previously demonstrated that pharmacologic perturbations in tumor reducing potential can be detected in real time using HP-MR. In these studies we extended these initial experiments to demonstrate that HP-MR can detect parallel and opposing changes in tumor reactive oxygen species (ROS) levels following irradiation. Using the ATC xenograft mouse model we were able to measure acute (2hr) changes in tumor reducing potential following irradiation compared to control tumor (p=0.004). Furthermore, HP-MR allowed us to identify areas of ATC tumors which display enhanced reducing potential, potentially driving ATC radio-resistance. Conclusion: Utilization of HP-MR metabolic imaging has allowed us to further develop our preclinical model of ATC and improve our ability to develop novel translational applications. Specifically, we believe HP-MR can improve the ability to monitor loco-regional tumor growth and invasion, as well as the development of pulmonary metastases. Furthermore, the development of a quantifiable imaging-based biomarker of radiation effect may permit adaptive IR plans based upon tumor response that would optimize disease treatment and improve clinical outcomes. Citation Format: Vlad Sandulache, Yunyun Chen, Jaehyuk Lee, Marc Ramirez, Heath Skinner, Laurence Court, Jim Bankson, Stephen Lai. Using magnetic resonance and hyperpolarized tracers to monitor solid tumor progression, metastasis, and response to treatment. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B07.

Sphingosine kinase 1 mediates head & neck squamous cell carcinoma invasion through sphingosine 1-phosphate receptor 1.

BackgroundHead and neck squamous cell carcinoma (HNSCC) is characterized by aggressive loco-regional invasion. Sphingosine kinase1 (SphK1), an enzyme in sphingolipid metabolism, is emerging as a key player in HNSCC pathology. The observation that SphK1 is overexpressed in all HNSCC stages and is associated with depth of tumor invasion, metastasis and clinical failure underscores the importance of SphK1 in HNSCC pathology. Still, the mechanisms underlying SphK1 regulation of invasion have not been delineated. Therefore, we sought to mechanistically describe how SphK1 regulates invasion in HNSCC.MethodsInvasion assays were used to measure invasive ability of SphK1 overexpressing human tongue squamous cell carcinoma (SCC-25 cells). Western blotting, quantitative qPCR, ELISA and zymography were used to measure the effect of SphK1 and sphingosine 1-phoshate receptor 1 (S1P1) on invasion measures, MMP-2/9, E-cadherin, EGFR, IL-6/STAT3, in SCC-25 cells.ResultsSphK1 expression is elevated in cells with an invasive phenotype as compared to non-invasive phenotype. We show SphK1 overexpression increased EGF-induced EGFR/ERK and AKT activity, increased matrix metalloproteinase (MMP)-2/9 mRNA and reduced E-cadherin. SphK1 overexpression also increased IL-6 concentration and EGF-induced STAT3 phosphorylation, exemplifying that SphK1 modulates IL-6/STAT3 signaling. Notably, we show that S1P1 knockdown reduced IL-6/STAT3 signaling, representing another pathway by which SphK1/S1P regulates invasion.ConclusionsTaken together, our data suggest that SphK1 sits at the hub of multiple key signaling cascades, all which have been implicated in the regulation of invasiveness, making SphK1 an attractive target for the development of HNSCC therapies.

Cancer du testicule: particularités cliniques et limites thérapeutiques en milieu hospitalier urologique au Sénégal

ObjectiveTo investigate the clinical features and limitations of therapeutic management of testicular cancer in Senegal. Patients and methodsThis is a retrospective study over 15 years period between January 1997 and January 2012. Twenty-two cases were collected but only 17 had complete data for analysis. ResultsThe average annual incidence was 1.13 cases per year, with a mean age of 27±9.5 years. The most affected age group was between 21 and 40 years.Clinical diagnosis was suspected by the presence of a scrotal swelling in10 cases and by empty scrotum associated with abdominal or pelvic mass in the remaining 7 cases. Orchiectomy was the main treatment option, done either by high inguinal approach in 8 patients or by trans- peritoneal route in other 7 patients. Histologically, a predominance of embryonic non seminomatous germ cell carcinoma was noted in 10 cases including infantile type in one case. Seven cases developed disease progression:3 cases of peritoneal carcinmatosis, 3 other cases of locoregional invasion with retroperitoneal lymphadenopathy and one case of pulmonary metastasis. At a mean follow up of six months, nine patients died, four were lost to follow up while the remaining four cases were still alive. ConclusionTesticular cancer is a rare tumor in Senegal and usually involves young people. Clinical diagnosis is always done at very advanced stage with a very high mortality rate.