Presence Of Distal Metastasis Research Articles

Atypical teratoid rhabdoid tumours (ATRTs)-a 21-year institutional experience.

Atypical teratoid/rhabdoid tumours (ATRTs) are malignant embryonal tumours of childhood that affect the central nervous system (CNS). We aim to determine which factors, including patient age, extent of resection (EOR), presence of distal metastasis and use of adjuvant therapies, affect overall survival in children with atypical teratoid/rhabdoid tumours (ATRTs) treated at this single centre. Retrospective cohort review of patients with histological diagnosis of ATRT treated over 21years (1999-2020) was conducted. Data on demographics, tumour location, presence of metastasis, use of adjuvant therapy, extent of resection (EOR), complications, neurological outcome post-surgery, and overall survival were collected. Kaplan-Meier survival analysis was performed. A total of 45 children (mean age 2 years) underwent 64 operations. 25 patients were <1year of age. Gross-total resection (GTR) pre-adjuvant therapy was achieved in 15, near-total resection (NTR) in 15, subtotal resection (STR) in 9, and biopsy in 6 children. Most children had good neurological outcomes post-operatively (28/45 with GOS 5). Fourteen patients survived longer than 4 years. Survival analysis showed a significant difference in median survival in favour of GTR and localised disease. There was no significant difference in median survival between patients <1year vs >1year of age (p=0.84). We find that presence of metastasis was an important factor in poor survival inpatients with ATRT. GTR, where possible, may confer significant survival benefit in ATRT. Children aged <1year appear to have performed as well as those >1year and therefore should stillbe considered for radical surgery.

Abstract 2407: Transmembrane chloride intracellular channel 1 (tmCLIC1) protein is a key regulator of colorectal cancers' metastasis

Abstract Colorectal cancer (CRC) is the third most common tumor worldwide and the fourth cause of cancer-related death. The presence of distal metastasis at the time of the first diagnosis represents a worst prognosis factor for patients’ long-term survival. Therefore, finding new targets to arrest the metastatic process is a main challenge for successful CRC therapy. Our laboratory focused its attention on the Chloride Intracellular Channel 1 (CLIC1), a metamorphic protein able to switch from a cytoplasmic to a transmembrane form associated to ion channel activity. Previous experiments demonstrate that tmCLIC1 functional activity is negligible in normal colon cells, while increases proportionally to CRC cells’ aggressiveness. Moreover, we also reveal that tmCLIC1 supports CRC cells abnormal proliferation rate. Here, we show that tmCLIC1 pharmacological inhibition or its stable downregulation led to a significative reduction of CRC cells migrative and invasive potential, in vitro. To further confirm our hypothesis, we analysed downregulation of metalloproteinase-7 (MMP-7) protein and p38 mitogen-activated protein kinase (MAPK) signalling, both involved in migration and metastatic processes. Moreover, we demonstrate in murine model that CLIC1 knock-down impairs tumor growth and limits cancer cells dissemination. We tried to investigate the alteration of metastatic pathways after CLIC1 silencing. We obtained that many different genes are downregulated when CLIC1 protein is absent; in particular, genes regulated by Reactive Species of Oxygen (ROS) levels. In this scenario, we tried to define the mechanism of action in which CLIC1 is involved. Altogether, all the results obtained in the present work could be considered a starting point to design a new therapeutic strategy to counteract against metastatic colorectal cancer. Citation Format: Francesca Cianci, Ivan Verduci, Valentina Carlini, Carlotta Tacconi, Matteo Ranucci, Alessandro Fantin, Tullio Florio, Michele Mazzanti. Transmembrane chloride intracellular channel 1 (tmCLIC1) protein is a key regulator of colorectal cancers' metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2407.

Comparison of colorectal cancer outcomes in young adults and octogenarians

BackgroundThis study aimed to characterise the outcomes associated with colorectal cancer (CRC), comparing young adults (<50 years), patients of screening age (50–79 years), and octogenarians (>80 years). MethodsAll consecutive CRC resections with curative intent were recruited into this study from a prospectively maintained CRC database at a tertiary academic centre. ResultsA total of 745 eligible cases were identified. Five-year survival in young adults was poorer than that of patients of screening age. Young adults had the highest incidence of rectal cancer resections, and presented with the most advanced tumour stages. Independent associations for poorer survival in young adults were increased nodal stage, the presence of distal metastases, and loss of MLH1/PMS2 staining on immunohistochemistry. Young adults had similar survival to octogenarians, when comparing patients treated with curative intent, regardless of oncological treatment.

Abstract 2893: Transmembrane Chloride Intracellular Channel 1 (tmCLIC1) protein as a potential target for colorectal cancer metastasis

Abstract Colorectal cancer (CRC) is the third most common tumor worldwide and the fourth cause of cancer-related death. The presence of distal metastasis at the time of the first diagnosis represents a worst prognosis factor for patients' long-term survival. Therefore, finding new targets to arrest the metastatic process is a main challenge for successful CRC therapy. Our laboratory focused its attention on the Chloride Intracellular Channel 1 (CLIC1), a metamorphic protein able to switch from a cytoplasmic to a transmembrane form associated to ion channel activity. Previous experiments demonstrated that transmembrane CLIC1 (tmCLIC1) functional activity is negligible in normal colon cells, while increases proportionally to CRC cells' aggressiveness. Moreover, we also revealed that tmCLIC1 supports CRC cells abnormal proliferation rate. Here, we show that tmCLIC1 pharmacological inhibition or its stable knock-down by gene silencing led to a significative reduction of CRC cells migrative and invasive potential, in vitro. To further confirm our hypothesis, we assessed in CLIC1 knock-down cells the downregulation of metalloproteinase-7 (MMP-7) protein and p38 mitogen-activated protein kinase (MAPK) signaling, both involved in migration and metastatic processes. Moreover, by injecting subcutaneously transfected cell lines in nude mice, we demonstrate that CLIC1 knock-down impairs tumor growth and limits cancer cells dissemination to lung. Our results suggest a role for tmCLIC1 in promoting CRC metastasis, making this protein a promising pharmacological target to arrest or slow-down CRC metastasis development. Moreover, thanks to its functional expression exclusively associated with malignant progression, tmCLIC1 could allow to limit side effects on healthy cell population. Citation Format: Francesca Cianci, Valentina Carlini, Ivan Verduci, Matteo Ranucci, Michele Mazzanti. Transmembrane Chloride Intracellular Channel 1 (tmCLIC1) protein as a potential target for colorectal cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2893.

English

BACKGROUND Solid pseudopapillary neoplasm (SPN) of pancreas is a rare epithelial tumour of low malignant potential. SPN accounts for less than 1 to 2 % of exocrine pancreatic tumours. It mainly affects women between the second and third decade of life, and its management is not well defined. The aim of this study was to report clinicopathological characteristics of SPN and its outcome. METHODS A retrospective study was conducted in a tertiary care centre from January 2015 to December 2019. All patients who were diagnosed and treated as SPN of pancreas in our institute were retrospectively reviewed. A data of the characteristics of these patients was developed, including age, gender, size, location of tumour, treatment, histopathological and immunohistochemical features. RESULTS Six patients were diagnosed as having SPN of pancreas, during the 5-year period. All 6 patients were female. Youngest age of occurrence was 15 years. Maximum age was 41 years. Average age was 25 years. All patients were symptomatic and the most common symptom was dull aching upper abdominal pain. Contrast enhanced computed tomography (CECT) was done for all patients. 3 patients had typical features of SPN. Endoscopic ultrasound (EUS) was done for 4 patients and EUS fine needle aspiration cytology (FNAC) was done for 3 patients. Patients were provided with procedure details and informed consent was taken. All patients were subjected to surgical treatment. Out of six patients, two underwent laparoscopic spleen preserving distal pancreatectomy, two patients underwent classical Whipple’s procedure and two patients had undergone median pancreatectomy. CONCLUSIONS SPN are rare neoplasms, typically affecting young females without clear histogenesis and with a malignant potential. Appearance from imaging studies can be adequate to guide surgical resection without pre-operative pathological assessment. But in unclear cases, EUS-FNAC with immunohistochemistry helps in establishing a pre-operative diagnosis. Surgical resection should be offered when feasible. Prognosis of SPN of the pancreas is good due to its favourable biological features, even in the presence of distal metastasis. KEYWORDS Solid Pseudopapillary Neoplasm (SPN)

Regional lymph node involvement is associated with poorer survivorship in patients with upper extremity osteosarcoma than with lower extremity osteosarcoma: a SEER analysis.

BackgroundAlthough the upper limb is the second most common site of osteosarcoma, investigations into clinical manifestation differences between upper and lower limb patients are still sporadic. We retrospectively investigated the characteristics of these patients to gain a better understanding of the differences between upper and lower limb osteosarcoma patients.MethodsThis retrospective study involved patients diagnosed with extremity osteosarcoma between 1997 and 2016 collected from the Surveillance, Epidemiology, and End Results (SEER) database. Patient characteristics were analyzed with t-tests, rank sum tests and chi-square tests. Log-rank tests were applied to evaluate univariate significance, and Cox hazards models were performed in multivariate analysis. A binary logistics regression model was used to screen the risk factors related to lymph node involvement.ResultsIn total, 1,882 patients, 1,588 (84.4%) with lower limb lesions and 294 (15.6%) with upper limb lesions were enrolled in our study. The patients with upper limb osteosarcoma exhibited poorer 5-year overall survival (OS) than patients with lower limb osteosarcoma (54.8% vs. 63.2%, P=0.02). The upper limb patients had more lymph node involvement (5.6% vs. 2.7%, P=0.03), which was found to be an independent prognostic factor (P=0.000). Tumors located in the upper limbs and the presence of distal metastasis were risk factors related to lymph node involvement in the extremity (P<0.05). The upper limb patients were tended to suffer greater risk of being affected by both metastasis and lymph node involvement (15.7% vs. 9.4%, P=0.18).ConclusionsUpper limb osteosarcoma patients are characterized by more lymph node involvement than lower limb patients, leading to poorer OS. In addition, upper limb patients are at greater risk for both lymph node involvement and distal metastasis. Our results suggest that upper limb patients should be screened more thoroughly for regional lymph node involvement.

Solid Pseudopapillary Tumor of the Pancreas: A Single-center Experience and Review of the Literature.

Solid pseudopapillary tumors (SPTs) of the pancreas are a rare occurrence, not exceeding 1-2% of all exocrine pancreatic tumors. SPT was first described in 1959 as "papillary tumor of the pancreas, benign or malignant" and affects mainly young women, in their second or third decade of age. These tumors are of low malignant potential, unclear pathogenesis, grow gradually and become considerably large before causing symptoms. A typical clinical presentation is often described by affected patients and, in some cases, an SPT is an incidental finding during the time the patient undergoes medical imaging studies for other health issues. SPT is frequently located at the head or tail of the pancreas. Metastases are rare but, when present, affect predominantly the liver. We report a series of five SPT cases in female patients 13-47 years old, presenting with almost identical symptoms of upper abdominal discomfort and non-tender palpable mass. Two out of five patients also reported vomiting, nausea and poor appetite as co-existing non-diagnostic symptoms. Only one patient presented without any symptoms. Tumor location and dimensions varied. One patient underwent a pancreatoduodenectomy (Whipple's procedure), while the remaining patients underwent distal pancreatectomy with concomitant splenectomy. Perioperative morbidity and mortality was zero. All five patients are disease-free at a follow-up from 3 months to 13 years. Histopathology reports supported the diagnosis of SPT and no metastatic disease was present in any of the patients. The overall prognosis of SPT of the pancreas is excellent due to its favorable biological features, even in the presence of distal metastasis. Although surgical resection is often curative, a close follow-up is advised in order to diagnose a possible local recurrence or distal metastasis and choose the proper therapeutic option for the patients.

A tumour score with multidetector spiral CT for venous infiltration in pancreatic cancer: influence on borderline resectable

A tumour score for venous invasion in patients with pancreatic adenocarcinoma was evaluated by means of computed tomography (CT), in order to improve the assessment of medical treatment and clinical outcome with special attention to borderline resectable disease. Fifty-six consecutive patients who underwent curative surgical resection for pancreatic cancer were analysed. On the basis of CT criteria, tumour involvement of the portal vein (PV) and superior mesenteric vein (SMV) was graded according to an adapted 4-point scale: score 1, definite absence of invasion; score 2, probable absence of invasion; score 3, probable presence of invasion; score 4, definite presence of invasion. Correlations between the venous infiltration scores and the patients' clinical features were also evaluated. After radiological evaluation of PV and SMV grades of infiltration, 21/56 (37%) and 37/56 (66%) patients, respectively, were found to have borderline resectable disease. The 4-point scale achieved a sensitivity of 80%, a specificity of 96% and an accuracy of 93% in the evaluation of the PV, and a sensitivity of 100%, a specificity of 94% and an accuracy of 95% in the evaluation of the SMV. Analysis of the distribution of clinical characteristics by PV and SMV infiltration showed that both scores correlated with the presence of distal metastasis (p=0.016 and p=0.028, respectively), and resection margins status (p=0.015 and p=0.006, respectively). This adapted tumour score is reliable for assessing venous invasion and might improve preoperative staging in patients with borderline resectable pancreatic cancer.

Expression of carbonic anhydrase IX, PAX2 and PAX8 and their association with clinicopathologic characteristics in renal epithelial tumors

To study the expression of carbonic anhydrase IX (CAIX), PAX2 and PAX8 in different types of renal epithelial tumor and their association with clinicopathologic characteristics. Immunohistochemical study by EnVision method was performed in order to assess the expression of CAIX, PAX2 and PAX8 in 155 cases of renal cell carcinoma and 4 cases of metastatic clear cell renal cell carcinoma (CCRCC). Ninety-six cases of non-neoplastic renal parenchymal tissue adjacent to CCRCC, 8 cases of clear cell hepatocellular carcinoma and 2 cases of clear cell hidradenoma were used as controls. CAIX was commonly expressed in CCRCC (94.0%, 63/67), of which 77.8% (49/63) showed strong positivity. CAIX was focally positive in papillary renal cell carcinoma, collecting duct carcinoma and urothelial carcinoma of renal pelvis. It was negative in chromophobe renal cell carcinoma, oncocytoma and adjacent non-neoplastic renal tissue. CAIX was also strongly expressed in the 4 cases of metastatic CCRCC. Focal expression of CAIX was demonstrated in the 8 cases of clear cell hepatocellular carcinoma and 2 cases of clear cell hidradenoma. The expression of CAIX in CCRCC did not correlate with tumor grading, clinical staging and presence of distal metastasis. On the other hand, PAX2 showed positive expression in different types of renal epithelial tumor, clear cell hepatocellular carcinoma and clear cell hidradenoma in various degrees. In contrast, PAX8 was commonly expressed in all types of renal epithelial tumor, with the exception of urothelial carcinoma of renal pelvis. PAX8 was not expressed in clear cell hepatocellular carcinoma and clear cell hidradenoma. Regarding diagnosis of CCRCC, CAIX demonstrated high sensitivity and specificity. PAX2 showed high specificity but low sensitivity. PAX8 was sensitive and specific in the diagnosis of renal epithelial tumor. CAIX is a useful immunohistochemical marker with high specificity and sensitivity in distinguishing CCRCC from other types of renal epithelial tumor and clear cell tumors of non-renal origin. PAX2 is a marker with high sensitivity and low specificity for diagnosis of renal epithelial tumors. PAX8 is typically expressed in renal epithelial tumors. The combined detection of CAIX, PAX2 and PAX8 is useful in the diagnosis and differential diagnosis of renal epithelial tumors.

Abstract 3375: Phase 1 pharmacodyamic activity of multiple-dose PEGylated hyaluronidase PH20 (PEGPH20) in patients with solid tumors.

Abstract Enzymatic degradation of hyaluronan (HA), a key component of the extracellular matrix (ECM), can enhance tumor perfusion, improve delivery of chemotherapeutics, and enhance the effects of anti-tumor agents. HA accumulation has been correlated with local invasion, the presence of distal metastasis, higher tumor grade, and poorer overall survival. PEGPH20, a pegylated form of recombinant human hyaluronidase PH20, is an investigational therapeutic agent under clinical development for the treatment of patients with solid tumors that may accumulate HA. Preclinical studies have demonstrated that sustained HA removal, accomplished with PEGPH20, inhibits tumor growth and enhances chemotherapeutic activity in HA-rich xenografts and genetically engineered mouse tumor models. Twenty-six patients with advanced solid tumors were enrolled in a Phase 1 multi-center trial. Patients received weekly or twice weekly doses of IV PEGPH20 (0.5 - 5 μg/kg) for the first 4-week cycle, followed by once-weekly dosing for the subsequent 4-week cycles. Serial blood samples were drawn from each patient, and plasma concentrations were measured by an ultrasensitive hyaluronidase activity assay to assess PEGPH20 pharmacokinetics (PK). Plasma levels of HA catabolites were measured using a quantitative HPLC method to characterize PEGPH20 pharmacodynamics (PD). Other measures of PD activity were evaluated in selected patients, including DCE-MRI, DW-MRI, 18FDG-PET, textural analysis on CT, and histochemical staining of HA in tumor biopsies collected both before and after PEGPH20 treatment. Peak plasma PEGPH20 concentrations increased with dose, and plasma pharmacokinetics (PK) were well described by a linear PK model. Pre-treatment plasma HA levels were typically &amp;lt;1 μg/mL and increased in a dose-dependent fashion after PEGPH20 treatment. Increased plasma HA corresponded with decreased HA staining in patients with available tumor biopsies. DCE-MRI analysis indicated early (24-48 hr) and rapid increase in tumor perfusion compared to baseline in 4 patients with serial MRI assessments. Pharmacodynamic activity was also demonstrated when pre-treatment 18FDG-PET scans were compared with images collected at scheduled times after PEGPH20 dosing. Reduction in FDG uptake exceeding 25% was demonstrated in 3 of 4 patients after one cycle of treatment, consistent with a partial metabolic response. These data are consistent with the mechanism of action reported in preclinical models, and results support continued evaluation of PEGPH20 in combination with anti-tumor agents via modification of the ECM. Citation Format: Ping Jiang, Daniel C. Maneval, Ramesh K. Ramanathan, Jeffrey R. Infante, Mitesh Borad, Alberto Bessudo, Patricia LoRusso, Barry J. Sugarman, Deborah Carson, Marie A. Printz, Curtis B. Thompson, Paneer Selvam, Joy Zhu, Ronald Korn, H Michael Shepard, Gregory I. Frost. Phase 1 pharmacodyamic activity of multiple-dose PEGylated hyaluronidase PH20 (PEGPH20) in patients with solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3375. doi:10.1158/1538-7445.AM2013-3375

Abstract 4955: Pegylated recombinant human hyaluronidase PH20 (PEGPH20) increases tumor perfusion in mouse xenografts and phase 1 cancer patients.

Abstract Pegylated recombinant human hyaluronidase PH20 (PEGPH20) is an investigational therapeutic agent under clinical development for use alone or in combination with other cancer therapies for the treatment of patients with non-hematologic malignancies that may accumulate hyaluronan (HA), a glycosaminoglycan that is a significant component of the extracellular matrix of many solid tumors. HA accumulation has been correlated with local invasion, the presence of distal metastasis, higher tumor grade, and poorer overall survival. Preclinical studies have demonstrated that sustained HA removal, accomplished with PEGPH20, decreases tumor interstitial pressure, increases vascular area, inhibits tumor growth and enhances chemotherapeutic activity in HA-rich xenografts and genetically engineered mouse tumor models. As dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a clinically translatable MRI perfusion protocol, we used DCE-MRI imaging to evaluate the effects of PEGPH20 treatment on tumor vascular permeability, vascular surface area and/or blood flow. In mice, prostate cancer PC3 cells were implanted adjacent to the right tibial periosteum. When tumors reached ∼500 mg, animals were staged into vehicle or PEGPH20 (4.5 mg/kg) treatment groups. Utilizing gadopentetate dimeglumine (Gd-DTPA) as a contrast agent, pre-treatment baseline DCE scans of the tumors were acquired. Animals were subsequently IV dosed with test article and post-treatment scans were acquired at 24 h. Initial area under the curve (IAUC) and Ktrans were calculated voxel-by-voxel using a 2-compartment PK model. Although vehicle alone did not increase or decrease Ktrans or IAUC, PEGPH20 treatment increased Ktrans (1/sec) and IAUC (mmol.s) by 74% and 78.7%, respectively. Concurrent to preclinical studies, DCE-MRI imaging was conducted pre- and post- PEGPH20 in 9 patients in a Phase 1 dose-escalation, safety, tolerability, PK/PD study of PEGPH20 treatment in patients with advanced solid tumors. Patients were treated with 1.6, 3 or 5 μg/kg PEGPH20 1-2/weekly. Baseline, day 1, day 2-5 and end-of-cycle (EOC) scans were acquired (w/ Gd-DTPA) in 3 patients. Images were fit on a pixel-by-pixel basis to a 2-compartment, 3-parameter, PK model and Ktrans and extracellular volume (Ve) calculated. Results suggest an early and rapid increase in tumor perfusion in target lesions, compared to baseline (mean ΔKtrans = 428%; N=3; Day 2-5 scans), as well as an expansion of the extracellular space with a reduction of these parameters towards baseline by EOC (mean ΔKtrans = 28% above baseline). Taken together, these studies suggest that PEGPH20 increases vessel permeability, blood flow and/or vessel surface area in HA-rich solid tumors. Additional preclinical and clinical studies, complete with DCE-MRI imaging, are ongoing to further evaluate PEGPH20 in the treatment HA-rich malignancies. Citation Format: Curtis B. Thompson, Patrick McConville, Ron Korn, Jenifer Baranski, Meridith Baugher, Deanne Lister, Erin Trachet, Jacob Y. Hesterman, Jack Hoppin, Joy Zhu, Daniel C. Maneval. Pegylated recombinant human hyaluronidase PH20 (PEGPH20) increases tumor perfusion in mouse xenografts and phase 1 cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4955. doi:10.1158/1538-7445.AM2013-4955

Abstract 3915: Tumor-targeted hyaluronan (HA) imaging with a recombinant HA binding protein: TSG6dHep-Fc.

Abstract A new investigational therapeutic agent, pegylated recombinant human hyaluronidase PH20 (PEGPH20) is a currently under clinical development for the treatment of tumors that accumulate hyaluronan (HA), a nonsulfated glycosaminoglycan and a major constituent of the extracellular matrix (ECM) of many solid tumors. HA accumulation has been correlated with local invasion, the presence of distal metastasis, higher tumor grade, and poorer overall survival in multiple malignancies. Preclinical studies have demonstrated that sustained HA removal, accomplished with PEGPH20, inhibits tumor growth and enhances chemotherapeutic activity in HA-rich xenografts and genetically engineered mouse tumor models. To facilitate non-invasive clinical selection of patients with HA-rich malignancies, and confirm PEGPH20 enzymatic targeting of these malignancies, we have developed a soluble recombinant HA binding protein by fusing a tumor necrosis factor-stimulated gene-6 protein (TSG6) fragment, mutated at the heparin-binding site, with human IgG1 Fc (TSG6dHep-Fc). In preclinical proof-of-concept studies, recombinant TSG6dHep-Fc was labeled with the near-infrared fluorophore DyLight755 (TSG6dHep-FcDL755) and administered IV to the following xenograft peritibial athymic mouse models: HA-rich pancreatic BxPC3, HA-poor prostate Du145 and HA-rich prostate Du145/HAS2. TSG6dHep-FcDL755 HA binding was imaged via fluorescence (IVIS Lumina II, Caliper Life Sciences, Inc.). Systemic/dermal HA binding was weakly present, but easily removed via background subtraction to allow tumor intensity quantification. In the HA-rich xenograft models, pancreatic BxPC3 and prostate Du145/HAS2, TSG6dHep-FcDL755 strongly labeled the peritibial tumors, peaking at 2 days post administration and was completely absent at day 10 post administration. In contrast, the HA-poor prostate Du145 tumors were very weakly labeled, making background subtraction of systemic/dermal HA binding difficult. In separate experiments, mice were treated with a single dose of PEGPH20 (4.5 mg/kg, IV) or vehicle prior to TSG6dHep-FcDL755 imaging. In all groups dosed with PEGPH20, TSG6dHep-FcDL755 signal intensity was extremely low and appeared to be limited to non-specific, whole body labeling. These results suggest that imaging with labeled TSG6dHep-Fc could be a useful tool for selecting patients with HA-rich malignancies, thereby enabling clinicians to noninvasively identify patients who might benefit from therapies that target HA and the ECM. Citation Format: Xiaoming Li, Lei Huang, Ge Wei, Ryan J. Osgood, Qiping Zhao, Ping Jiang, H. Michael Shepard, Daniel C. Maneval, Curtis B. Thompson. Tumor-targeted hyaluronan (HA) imaging with a recombinant HA binding protein: TSG6dHep-Fc. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3915. doi:10.1158/1538-7445.AM2013-3915

Tumor length assessed by miniprobe endosonography can predict the survival of the advanced esophageal squamous cell carcinoma with stricture receiving concurrent chemoradiation

There were tumor strictures commonly encountered in the esophageal squamous cell carcinoma (ESCC) to limit the conventional echoendoscope for exact tumor staging and size measurements. This study evaluated the role of miniprobe endosonography (EUS) to predict the survival of ESCC patients after concurrent chemoradiation therapy (CCRT). This study prospectively enrolled ESCC patients to receive high-frequency miniprobe EUS for the assessments of the tumor size and tumor-node-metastasis (TNM) stage. For the patients defined with advanced stages to receive CCRT as initial therapy, the tumor size parameters assessed by EUS were analyzed for their correlation with the treatment response and the patients' survivals. Fifty-four patients, >96% with advanced TNM stage III or IV, were enrolled with a medium follow-up of 320.5 days. Almost all of the 54 cases had partial or complete stricture of the esophageal lumens due to the tumor obstructions at enrollment. The overall median survival was 18.6 months, and the 1- and the 2-year survival rates were 64.9 and 45.2%, respectively. Patients with initial tumor length <6 cm assessed by the pre-CCRT EUS had a better survival than those with length ≥6 cm (median survival: >56.5 months vs. 11.5 months, P= 0.006). The patients with initial tumor length <6 cm had a higher rate of downstage than those with tumor length ≥6 cm after the first course of CCRT (80.0% vs. 16.7%, P= 0.035). Multivariate Cox regression confirmed the initial tumor length (hazard ratio [HR]= 1.21, P= 0.034) as well as the presence of distal metastasis are both independent predictors of the survival in ESCC patients receiving CCRT. For the ESCC patients, commonly with tumor stricture, the miniprobe EUS to assess tumor length before CCRT can predict the treatment response and the survivals.

Abstract 442: Treatment of tumor xenografts in vivo with PEGylated human recombinant hyaluronidase PH20 (PEGPH20) does not increase the metastatic behavior of malignant cells

Abstract Hyaluronan (HA), a nonsulfated glycosaminoglycan, is a significant component of the extracellular matrix of many solid tumors. HA accumulation has been correlated with local invasion, the presence of distal metastasis, higher tumor grade, and poorer overall survival. We have previously demonstrated that sustained HA removal, accomplished with a novel pegylated human recombinant hyaluronidase PH20 (PEGPH20), inhibited tumor growth and enhanced chemotherapeutic activity in HA-rich xenografts (Thompson et al, 2010). As endogenous lysosomal hyaluronidase expression has been implicated as a tumor promoter (Kovar et al, 2006), and exogenous hyaluronidase has been shown to act as a tumor suppressor (Shuster et al, 2002), we aimed to determine whether exogenous PEGPH20 administration alters the metastatic behavior of malignant cells in solid tumors. In a first set of experimental metastasis studies, HA-rich prostate PC3 (2e5) or breast MDA-MB-231 (1e5) cells were intracardially injected (IC) into nude mice (NCR nu/nu). Mice were subsequently treated (&amp;gt;20 min) with a single dose of PEGPH20 (4.5 mg/kg, IV) or vehicle and tumor seeding into organs tracked via bioluminescent imaging over time (n=8/group). In a second set of spontaneous metastasis experiments, prostate PC3 (2e6) or breast MDA-MB-231-Has2 (2e6) cells were injected into either the tibia periosteum or mammary fad pad of nude mice, respectively. MDA-MB-231-Has2 cells are a MDA-MB-231 Has 2 synthase overexpressing clone, shown to overexpress HA both in vitro and in vivo. When PC3 tumors reached ∼375 mm3 (n=11/group), and MDA-MB-231-Has2 reached ∼400 mm3 (n=6/group), mice received PEGPH20 (4.5 mg/kg, IV) or vehicle, q3d × 8 or q3d × 5, respectively. Mice were subsequently sacrificed and lymph node metastasis assessed histologically. Following the initial set of IC experiments, no significant difference in the number or frequency of metastatic nodules, as assessed by bioluminescence, was observed following PEGPH20 treatment versus control in either cell line (PC3, p=0.49; MDA-MB-231, p=0.89). In the second set of experiments, no difference in lymph node metastasis in either cell line was detected (PC3, p=0.68; MDA-MB-231, p=0.55). Finally, no histological evidence of increased metastases was observed in any organs examined (liver, kidney, heart, spleen or lung) following PEGPH20 administration in either study. Taken together, these results suggest exogenous PEGPH20 administration does not impact metastatic behavior in the PC3 prostate, MDA-MB-231 breast or MDA-MB-231-Has2 breast preclinical models. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 442. doi:10.1158/1538-7445.AM2011-442

Quantitative analysis of BCL2 mRNA expression in nasopharyngeal carcinoma: an unfavorable and independent prognostic factor

Programmed cell death plays a vital role in a wide variety of physiological processes. Defects in apoptotic cell death contribute to neoplastic diseases by preventing or delaying normal cell death. BCL2 (Bcl-2) is an anti-apoptotic gene with marked up-regulation in various malignancies, such as breast cancer, in which expression of the BCL2 protein has been proposed as a prognostic tumor biomarker. The purpose of the current study was to investigate mRNA expression of the BCL2 gene in nasopharyngeal carcinoma (NPC) biopsies and assess its prognostic value. For this purpose, total RNA was isolated from 89 malignant and hyperplastic nasopharyngeal biopsies from Tunisian patients. After testing the quality of the extracted RNA, cDNA was prepared by reverse transcription. A highly sensitive real-time PCR methodology for BCL2 mRNA quantification was developed using SYBR® Green chemistry. GAPDH served as an endogenous control gene. Relative quantification analysis was performed using the comparative C (T) (2(-∆∆CT)) method. High BCL2 mRNA levels were detected in advanced-stage nasopharyngeal tumors (p = 0.030). Furthermore, BCL2 mRNA expression was strongly associated with lymph node involvement (p = 0.009) and presence of distal metastases (p = 0.013). Survival analysis demonstrated that patients with BCL2-positive nasopharyngeal tumors have significantly shorter disease-free and overall survival (p = 0.011 and p = 0.028, respectively). The major contribution of the current study is the quantification and evaluation, for the first time, of the prognostic significance of the BCL2 mRNA expression in nasopharyngeal carcinoma (NPC) patients. Our results suggest that mRNA expression levels of BCL2 may represent a novel unfavorable and independent tumor biomarker for nasopharyngeal carcinoma.

Surgery for renal carcinoma metastases

During the last few years, the increasing use of diagnostic imaging (especially ultrasound) has allowed a remarkable rise in the detection of asymptomatic, early-stage renal neoplasms, possibly treatable by radical surgery. Renal cell carcinoma, however, is still the renal neoplastic condition with the highest mortality rate, due in most cases to the presence of distal metastases. Because of a lack of agreement on an efficient systemic therapeutic approach, surgery is generally considered to be the most suitable option to remove metastases: it is technically easy to perform, it can increase survival and the patient's psychological compliance, though metastasectomy is unlikely to cure the metastatic patient. In our experience, we studied 1475 patients who underwent surgery for renal cell carcinoma from 1983 on. 304 (20%) developed a metastasis; 4 subjects only (5.4%) out of the 74 having multiple metastatic anatomical sites were long-surviving. 39 subjects (16.9%) out of the 230 having single-site metastases are currently disease-free (mean follow-up: 80 months from diagnosis): 33 out of the 111 patients who underwent metastasectomy, 4 out of the 57 who received a medical therapy, 1 out of the 14 being administered radiotherapy, and 1 out of the 48 who were cared under palliative purposes only. Therefore we concluded that, in case of single-site (lung or adrenal) metastases, surgery is the most suitable and advisable therapeutic approach, being the only option able to achieve survival even for a small amount of patients. New biologic drugs are currently under investigation, which can interfere with tumor proliferation and angiogenesis: the study results are still preliminary, nevertheless these drugs open the way to a multimodal medical option of treatment for metastatic renal cell carcinoma.

Has Improvement in Endoscopic Ultrasounds' Technology Over the Last 20 Years Enhanced It's Ability to Diagnose Distal Metastasis of Esophageal Cancers?: A Meta-Analysis and Systematic Review

Background: Presence of distal metastasis in esophageal Ca carries a poor prognosis and limits therapeutic options. It is hoped that better technology will result in better detection rates and improvement in therapy. The affect of technological advancements on Endoscopic Ultrasounds (EUS) ability to diagnose distal mets from esophageal Ca is not known. Aim: To evaluate the affect of technologic advancement on the the accuracy of EUS in diagnosing distal mets of esophageal ca. Methods: Study Selection Criteria: Distal metastasis was defined as mets to peritoneum, liver, cervical LN, celiac axis LN, or abdominal lymph nodes.

Epidermal growth factor receptor, c-MET, beta-catenin, and p53 expression as prognostic indicators in stage II colon cancer: a tissue microarray study.

Through the use of molecular markers, it may be possible to identify aggressive tumor phenotypes and tailor therapies to treat them. This approach would be particularly useful for stage II colon cancer. The purpose of this study was to define the prognostic value of epidermal growth factor receptor (EGFR), c-MET, beta-catenin, and p53 protein expression in TNM stage II colon cancer using tissue microarray technology. In this study, we retrospectively analyzed, resected, and otherwise untreated paraffin-embedded specimens from 134 consecutive patients with Tumor-Node-Metastasis stage II colonic carcinomas for EGFR, c-MET, beta-catenin, and p53 protein expression by immunohistochemistry. Thirty-five percent, 77, and 65% of tumors exhibited strong (+2 and +3 immunopositivity) expression of EGFR, c-MET, and beta-catenin, respectively. Fifty-four percent exhibited nuclear staining for p53 in >10% of the tumor cells. Univariate analysis revealed that increased nuclear p53 expression (P = 0.001), strong membranous EGFR expression (P = 0.04), and lymphovascular invasion (P = 0.01) were significantly related to disease recurrence and that p53 (P = 0.02) and EGFR (P = 0.05) expression were associated with decreased survival. Increased nuclear p53 expression also correlated with the presence of distal metastasis (P = 0.027). No significant association was seen between c-MET expression and prognosis, whereas a strong trend was detected between loss of beta-catenin (P = 0.065) expression and poor outcome. Multivariate analysis indicated that p53 (P = 0.04), EGFR (P = 0.05), and lymphovascular invasion (P = 0.03) were independent predictors of recurrence and that p53 (P = 0.02) and EGFR (P = 0.01) expression were both associated with poor survival. This retrospective tumor microarray study, restricted to Tumor-Node-Metastasis stage II colon cancer patients who did not undergo adjuvant therapy, supports the use of EGFR and p53 as biological markers, which may assist in predicting disease recurrence and survival.

CD44 expression patterns in breast and colon tumors: a PCR-based study of splice variants.

CD44 cell-surface receptor expresses multiple isoforms, some of which are believed to play a role in tumor growth and metastasis. The CD44 gene is composed of 19 exons, of which 9 (exons 6 to 14) are alternatively spliced to form inclusions in the intervening membrane proximal region. Sequences present in the shortest metastatic variant cloned from a rat metastatic cell line have been shown to correspond to human exons 10 and 11, also called exons v6 and v7. Using RT-PCR, we have addressed in detail the CD44 isoforms produced in human breast and colon tumors. We analyzed 53 breast-tumor- and 58 colon-tumor-related samples as well as 1 benign mastopathy, 1 normal breast, 4 non-invaded lymph nodes and 8 normal colon tissues. All tumors analyzed expressed the hemopoietic CD44 (CD44H) isoform (no alternatively spliced exons added), whereas 81% expressed the CD44E form (addition exons 12, 13 and 14). Furthermore, 85% of tumors presented complex patterns of expression, with an average number of 5 to 6 bands detected. In view of their implication in the metastatic process, we investigated in greater detail the isoforms containing exons 10 and 11 (v6 and v7). Exon 10 was more frequently expressed than exon 11, 80% and 57% of the samples respectively. The great majority of cases showed ladder-like patterns starting from the shortest forms (exons 5-10 or 5-10-11) and larger-molecular-weight bands corresponding predominantly to sequential inclusions of exons from 3' to 5'. Exon-10 and exon-11 variants were also found in one benign mastopathy. The majority of normal tissues (1 breast and 6/8 colon) expressed only the CD44H isoform. These data indicate that expression of metastatic variants is common in human breast and colon tumors and can occur early during cancer progression, as testified by their presence in a benign breast tumor. While expression of exon-10 variants were correlated with presence of distal metastases in colon tumors, exon-11 variants were not (metastatic events were too rare in our breast-tumor series to reach significance). This suggest that exon 10 may correspond to the minimal sequences required to favor metastatic events.

Outcome of 249 patients attending a nuclear medicine department with well differentiated thyroid cancer; a 23 year review.

249 patients with well differentiated thyroid cancer attended the Nuclear Medicine Department of the Royal Liverpool Hospital (formerly housed at the Liverpool Clinic) from 1967 to 1990. Papillary carcinoma was histologically evident in 68% of patients and follicular carcinoma in 32%. Fifteen percent of all patients died of their cancer. The extent of initial surgery did not appear to influence the recurrence of disease, nor the patient survival. Univariate analysis showed that males had a worse survival rate than females during the 5 years after diagnosis but thereafter survival rates were similar. Multivariate analysis indicated that unfavourable survival factors were "age over 45 years at diagnosis" and "presence of distal metastases". Survival was not significantly different with or without 131I ablation where there were no distal metastases. Outcome of pregnancy after 131I ablation gave no cause for concern. No serious complications were observed following 131I therapy. Serum thyroglobulin tests were introduced only half way through the review period and were helpful in predicting the presence of tumour recurrence but these data are to be discussed in another communication.