Malignant Small Tumor Research Articles

Abstract P4-06-09: Genetic Signature Discriminating Metastatic from Non-Metastatic Small Tumors

Abstract Background: The widespread use of mammographic screening resulted in increased diagnosis of small (<2 cm; T1) tumors. Small tumors are associated with better prognosis, including a lower likelihood of developing metastasis, than larger tumors. Although this lower propensity to metastasize suggests that less aggressive treatments may be warranted in patients with T1 tumors, a subset of patients with small tumors (10-20%) will be diagnosed with lymph node metastasis. Methods: Frozen breast specimens were collected from women with T1 tumors and either negative (n=29) or positive (n=15) lymph node status. RNA was isolated from pure tumor cell populations after laser microdissection. Gene expression data was generated using HG U133A 2.0 arrays (Affymetrix). Differential expression was determined using Mann-Whitney testing using a P-value < 0.001 to define significance. Results for ESR1 were validated by immunohistochemistry. Results: Tumor characteristics did not differ significantly between groups in terms of age at diagnosis, grade, HER2 or PR status; however, tumors from patients with positive lymph nodes (47%) were significantly (P<0.05) more frequently ER negative compared to node negative (14%) patients. Gene expression analysis revealed 17 genes that were differentially expressed between node negative and node positive tumors: 6 with higher expression in node positive, including AURKA, and 11 with higher expression in node negative patients, including ESR1 and EPHX2. Of note, ESR1 was expressed at >4X higher levels in tumors without metastasis, in agreement with IHC findings. Conclusions: Small metastatic tumors differ in gene expression from those without metastasis. EPHX2 has been implicated as a metastasis suppressor while AURKA has been implicated as a metastasis promoter. These results suggest that small tumors have different propensities to metastasize and the genetic signature may serve as a new molecular tool to discriminate metastatic and non-metastatic small tumors, allowing appropriate treatment and risk assessment to be performed. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-06-09.

Histological progression of small intrapulmonary metastatic tumor from primary lung adenocarcinoma

The histopathology of small metastases is thought to reflect the early metastatic process. To clarify the morphological features of early metastatic tumor progression, we analyzed the histological heterogeneity of many small intrapulmonary metastases. Histological typing based on the World Health Organization classification (bronchioloalveolar carcinoma, acinar, papillary, and solid subtype) was used to evaluate 234 metastases from the primary lung adenocarcinomas of 139 patients. The predominant subtype of metastasis 3 mm or less in diameter was bronchioloalveolar carcinoma when the primary lesion was diagnosed as predominant bronchioloalveolar carcinoma, acinar, and papillary subtype. When the histology of the primary tumor was predominantly a solid subtype, the predominant subtype of metastatic tumor was also a solid subtype. However, analysis of metastases that were more than 3 mm showed that the predominant subtype of the metastasis reflected the predominant subtype of the primary tumor. Furthermore, we evaluated the number of subtypes in primary and metastatic tumors. As the metastasis grew larger, the number of subtypes in the metastatic lesion increased and came close to the number composed in the primary lesion. These findings suggest that implanted cancer cells display lepidic growth in the early metastatic phase and recapitulate the morphological heterogeneity of the original tumor as the metastasis enlarges.

Application of local flaps in repair of nasal defects after excision of small cutaneous malignant tumors

Objective To investigate the methods for repairing skin defects after excision of small cutaneous malignant tumors at the lower one third part of nose and their clinical effects.Methods Lesions of small cutaneous malignant tumors at lower one third part of the nose were removed in 54 patients.Intraoperative pathology was performed to confirm the absence of survival carcinoma tissues after resection.According to the site,size,shape and neighborous skin status of defects,bilobed flaps,two-side rotation flaps and nasolabial flaps were selected to repair nasal skin tissue defects.Results There were 39(72.22%) cases of basal cell carcinoma, 9(16.67%) squamous cell carcinoma, 6(11.11%) keratoacanthoma.Skin defects after tumor removal were situated at the lower one third part of nose in all cases with less than 2.0 cm in diameter.Bilobed flaps were used to repair skin defects in 20 cases.rotation flaps in 2 cases,and nasolabial flap in 32 cases.As a result,all flaps survived and no obvious deformation of nose was observed in these cases.No recurrence occurred in a 5-year follow-up.Conclusion A satisfactory repair of skin defects at the lower one third part of nose with a diameter of less than 2.0 cm is achieved with bilobed flaps,two-side rotation flaps and nasolabial flaps. Key words: Nose; Skin neoplasms; Surgical flaps

The calcified lung nodule: What does it mean?

The aim of this review is to present a pictorial essay emphasizing the various patterns of calcification in pulmonary nodules (PN) to aid diagnosis and to discuss the differential diagnosis and the pathogenesis where it is known. The imaging evaluation of PN is based on clinical history, size, distribution and the gross appearance of the nodule as well as feasibility of obtaining a tissue diagnosis. Imaging is instrumental in the management of PN and one should strive not only to identify small malignant tumors with high survival rates but to spare patients with benign PN from undergoing unnecessary surgery. The review emphasizes how to achieve these goals. One of the most reliable imaging features of a benign lesion is a benign pattern of calcification and periodic follow-up with computed tomography showing no growth for 2 years. Calcification in PN is generally considered as a pointer toward a possible benign disease. However, as we show here, calcification in PN as a criterion to determine benign nature is fallacious and can be misleading. The differential considerations of a calcified lesion include calcified granuloma, hamartoma, carcinoid, osteosarcoma, chondrosarcoma and lung metastases or a primary bronchogenic carcinoma among others. We describe and illustrate different patterns of calcification as seen in PN on imaging.

Merkel Cell Carcinoma

Merkel cell carcinoma (MCC) is synonymous with primary cutaneous neuroendocrine carcinoma. It tends to affects elderly whites, but there is also an increased incidence among immunosuppressed patients. The recent identification of a novel polyomavirus associated with the tumor has stimulated renewed interest in its pathogenesis. MCC tends to show classic histologic features of a neuroendocrine carcinoma and is often positive for CK20, but nonclassic cytologic findings and unusual immunophenotypes may be observed and can lead to a diagnostic confusion. MCC needs to be distinguished from other primary cutaneous tumors with a small cell appearance and metastatic tumors. Surgical excision is the treatment of choice, but radiation therapy has also found to be effective. Sentinel lymph node biopsy has become an integral part of the staging of patients with MCC.

Application of digital subtraction angiography and interventional treatment in gastrointestinal arterial hemorrhage

To investigate the clinical value of digital subtraction angiography (DSA) and interventional treatment in gastrointestinal arterial hemorrhage. DSA data and experiences of interventional treatment of 78 cases with gastrointestinal arterial hemorrhage were retrospectively analyzed. The positive rate of DSA diagnosis was 74%(58/78). Contrast media overflow direct sign was found in 33%(26/78) patients. Contrast media overflow direct sign of postoperative anastomotic stoma was found in 83%(15/18) patients. Hemorrhage causes of 15 cases were duodenal ulcer, 5 stomach ulcer, 2 gastric cancer, 1 Dieulafoy disease, 9 vascular malformation and dysplasia, 8 in anastomotic stoma bleeding after gastrointestinal operation, 10 hepatic artery blow out and bleeding after operation of liver disease, 5 Crohn disease, 6 intestinal tract diverticulum hemorrhage, 6 enteritis or ulcer and 3 polyp of small intestine, 1 midrange malignant small intestinal interstitial tumor, 2 well differentiated small intestine leiomyosarcoma, 5 colon and rectal cancer. Fifteen cases received arterial drug infusion and 36 received arterial embolization. Twenty-seven cases underwent operation after DSA and interventional treatment, whose coincidence with pathology was 78%(21/27). Technical success rate of arterial embolization was 86%(31/36) and clinical success rate was 72%(26/36). Technical success rate of arterial drug perfusion was 60%(9/15) and clinical success rate was 40%(6/15). Rebleeding rate was 16%(8/51) after intervention treatment. During follow-up for 2-36 months, 1 rebleeding patient received gastroscope treatment after embolization, but failed and died later. There were no severe complications,such as ischemic necrosis,in all the cases. DSA is very important for the location and qualitation of gastrointestinal arterial hemorrhage. Transarterial drug infusion and embolization are safe and effective, and available to selective operation and complication handling.

Early incorporated endothelial cells as origin of metastatic tumor vasculogenesis

Vascularization of solid tumors is thought to occur by sprouting or intussusceptive angiogenesis, co-option of existing vessels, and vasculogenic mimicry after the onset of tumor hypoxia, when the tumor radius exceeds the oxygen diffusion distance. In contrast, here we show that individual endothelial cells that are incorporated into pre-hypoxic tumors give rise to tumor blood vessels via vasculogenesis. Small metastatic lung tumor sections obtained after tail-vein injection of a syngeneic breast cancer cell line in the nude mice were labeled with antibodies against endothelial cell markers. Immunofluorescence showed the incorporation and mixed growth of CD31-, Tie-2-, and CD105-positive endothelial cells in tumors with radii less than oxygen diffusion distance and subsequent development of blood vessels from these early-incorporated endothelial cells. This observation lays the foundation of a novel vasculogenic paradigm of tumor vascularization, where incorporation of endothelial cells and their growth among tumor cells occur before the onset of core hypoxia in lung metastatic tumors.

Imaging After Radiofrequency Ablation of Hepatic Tumors

Radiofrequency ablation (RFA) is now increasingly used as a first-line therapeutic modality for small malignant hepatic tumors in many parts of the world. The importance of radiological imaging at follow-up to assess therapeutic effectiveness, presence of complications, and recurrences cannot be overemphasized, as RFA treatment is minimally invasive and locally applied. A broad spectrum of imaging findings obtained by the use of various modalities has been reported by many investigators. In this review, we describe findings, including chronologic changes of the ablation zones, both local and remote recurrences, and complications that occur after RFA of the liver as well as the advantages and disadvantages of the use of each imaging modality for a specific situation.

In Vivo Factors Influencing the Freezing Cycle During Cryoablation of Small Renal Masses

The aim of this study is to present a procedural analysis of the cryoablations performed in our department for small renal tumors and to try to identify clinical parameters or factors that influence the freezing rate during the procedure. We collected all data from the procedures performed in our department until August 2007. Based on the intraoperative biopsy result, we grouped the cases in two groups: renal-cell carcinoma (RCC) and benign. We calculated the freezing rate in both groups and compared them. Finally, we performed a univariate and multivariate analysis to identify clinical parameters that significantly influence the freezing rate. A total of 70 cryoablations of small renal tumors in 67 patients were performed during this period. From these, 56 procedures met the inclusion criteria and were analyzed further. The RCC group consisted of 48 cases (39 RCC and 9 lesions with a nondiagnostic biopsy) while 8 formed the benign group. There was no difference in the freezing rate between these two groups. Preoperative creatinine levels above 120 IU, diabetes mellitus, American Society of Anesthesiologists score 3, and location of the tumor at the lower pole were found to increase the freezing rate. The only factor that significantly decreased the freezing rate was the presence of chronic obstructive pulmonary disease. The multivariate analysis showed that the location of the tumor and diabetes mellitus influence more significantly the temperature v time graph. The freezing rate during cryotherapy of small renal tumors is significantly influenced by various clinical factors, while there are no differences in the freezing rate of those proven small malignant tumors and the small benign lesions.

Quasi-Multistatic MIST Beamforming for the Early Detection of Breast Cancer

Microwave imaging via space-time (MIST) beamforming has been shown to be one of the most promising imaging modalities for detecting small malignant breast tumors. This paper outlines two modifications to the MIST system developed by Hagness for the early detection of breast cancer, resulting in a quasi-multistatic MIST beamformer (multi-MIST). Multistatic MIST beamforming involves illuminating the breast with an ultrawideband (UWB) signal from one antenna while collecting the reflections at an array of antennas, as opposed to traditional monostatic MIST beamforming where only the transmitting antenna records the reflections from the breast. In order to process the multistatic data, traditional data-adaptive artifact removal algorithms have to be modified to accommodate signals from all antennas. Also, the MIST beamforming algorithm, which spatially focuses the signal and compensates for frequency-dependent propagation effects, has to be modified. The algorithms are tested on a 2-D anatomically accurate finite-difference time-domain model of the breast. The multi-MIST beamformer described here is shown to offer an improved signal to clutter ratio when compared to the traditional monostatic MIST beamformer.

Fluorine-18 labeling and biodistribution studies on peroxisome proliferator-activated receptor-γ ligands: potential positron emission tomography imaging agents

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is an important regulator of lipid metabolism; it controls the differentiation of preadipocytes and is also found at high levels in small metastatic tumors. In this report, we describe the radiochemical synthesis and evaluation of two (18)F-labeled analogs of the potent and selective PPARgamma agonist farglitazar. The isomeric aromatic fluorine-substituted target compounds [(2S)-(2-benzoylphenylamino)-3-(4-(2-[2-(4-[(18)F]fluorophenyl)-5-methyloxazol-4-yl]ethoxy)-phenyl)propionic acid ([(18)F]-1) and (2S)-[2-(4-fluorobenzoyl)phenylamino]-3-(4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-phenyl)propionic acid ([(18)F]-2)] were prepared in fluorine-18-labeled form, respectively, by radiofluorination of an iodonium salt precursor or by Ullmann-type condensation with 2-iodo-4'-[(18)F]fluorobenzophenone after nucleophilic aromatic substitution with [(18)F]fluoride ion. Each compound was obtained in high specific activity and good radiochemical yield. (18)F-1 and (18)F-2 have high and selective PPARgamma binding affinities comparable to that of the parent molecule farglitazar, and they were found to have good metabolic stability. Tissue biodistribution studies of (18)F-1 and (18)F-2 were conducted, but PPARgamma-mediated uptake of both agents was minimal. This study completes our first look at an important class of PPARgamma ligands as potential positron emission tomography (PET) imaging agents for breast cancer and vascular disease. Although (18)F-1 and (18)F-2 have high affinities for PPARgamma and good metabolic stability, their poor target-tissue distribution properties, which likely reflect their high lipophilicity combined with the low titer of PPARgamma in target tissues, indicate that they have limited potential as PPARgamma PET imaging agents.

Capsule endoscopy for the diagnostics of small intestine tumours

Three to six percent of all gastrointestinal tumours and one to two percent of all malignant gastrointestinal tumours develop in the small intestine. These occur more frequently in men than in women and the peak of occurrence is at the age of 50 to 60 years. According to epidemiological investigations to date the most frequently developing primary tumours in the small intestine are adenocarcinomas, carcinoid tumours, lymphomas and small bowel gastrointestinal stromal tumours. Clinical appearance of the tumours is the same, independent of their histological type. Fifty percent of the benign tumours is asymptomatic and is only discovered incidentally at autopsy. In comparison, 80% of malignant tumours is symptomatic. The prognosis of small intestine malignant tumours is very poor as at the time of diagnosis they have already formed metastases in 45-75% and at the time of surgery they are in 20-50% irresectable. The reason for the late diagnosis is on the one hand the non-specific nature of the symptoms, on the other hand, the limited visualisation of the entire small intestine via traditional radiological and endoscopic methods. Capsule endoscopy (CE) revolutionised the diagnostics of the small intestine by enabling non-invasive, pain-free investigation of the entire small intestine. The timely application of CE may replace a range of expensive assays with limited diagnostic value. Initial results indicate a higher prevalence of small intestine tumours than it had been estimated based on earlier epidemiological investigations. The new method provides an early diagnosis, enabling a definitive therapy, eventually significantly improving patient survival.

Preoperative evaluation of pancreatic adenocarcinoma

The preoperative evaluation of resectability for pancreatic cancer fails to identify up to 25% of patients who are unfortunately found to be unresectable at surgical exploration. Inoperative findings in this circumstance is usually due to either small volume metastatic disease or regional tumor invasion. While advances in computed tomography (CT) technology has increased accuracy of local tumor extent, occult metastatic disease remains a common problem. Although 2-[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) has been demonstrated to be useful in the staging of many malignancies (e.g. esophageal cancer, recurrent colorectal cancer, lung cancer), it has not been found to significantly increase the accuracy of determining resectability preoperatively in pancreatic cancer, especially with regard to detection of small volume metastatic disease. There are a variety of pancreatic cancer-specific antigens which are being developed as a method for targeted molecular imaging; we provide preliminary data targeting the integrin alpha(v)beta(6) to demonstrate the potential feasibility of this approach. Further developments may allow the accurate determination of patients with resectable pancreatic cancer, and more importantly, those with unresectable disease that may forego unnecessary surgery, the associated morbidity, and the subsequent delay of appropriate therapy.

Early Experiences of Robotic-assisted Laparoscopic Liver Resection

PurposeThe surgical robotic system is superior to traditional laparoscopy in regards to 3-dimensional images and better instrumentations. Robotic surgery for hepatic resection has not yet been extensively reported.Patients and MethodsBetween March and May 2007, we performed 3 robot-assisted left lateral sectionectomies of the liver. Case 1 had a hepatocellular carcinoma (HCC), case 2 had colon cancer with liver metastasis, and case 3 had intrahepatic duct stones.ResultsAll patients had successful operation and recovered without complications. Shorter length of hospital stays, earlier start of oral feeding and less amount of ascites were found. However, case 1 had recurrent HCC at 3 months after operation.ConclusionRobotic-assisted liver surgery is still a new field in its developing stage. In patients with small malignant tumors and benign liver diseases, robotic-assisted laparoscopic resection is feasible and safe. Through experience, the use of robotics is expected to increase in the treatment of benign diseases and malignant neoplsms. However, careful patient selection is important and long-term outcomes need to be evaluated.

Myxoma Virus Oncolysis of Primary and Metastatic B16F10 Mouse Tumors In Vivo

Myxoma virus (MV) is a rabbit-specific poxvirus, whose unexpected tropism to human cancer cells has led to studies exploring its potential use in oncolytic therapy. MV infects a wide range of human cancer cells in vitro, in a manner intricately linked to the cellular activation of Akt kinase. MV has also been successfully used for treating human glioma xenografts in immunodeficient mice. This study examines the effectiveness of MV in treating primary and metastatic mouse tumors in immunocompetent C57BL6 mice. We have found that several mouse tumor cell lines, including B16 melanomas, are permissive to MV infection. B16F10 cells were used for assessing MV replication and efficacy in syngeneic primary tumor and metastatic models in vivo. Multiple intratumoral injections of MV resulted in dramatic inhibition of tumor growth. Systemic administration of MV in a lung metastasis model with B16F10LacZ cells was dramatically effective in reducing lung tumor burden. Combination therapy of MV with rapamycin reduced both size and number of lung metastases, and also reduced the induced antiviral neutralizing antibody titres, but did not affect tumor tropism. These results show MV to be a promising virotherapeutic agent in immunocompetent animal tumor models, with good efficacy in combination with rapamycin.

Small Malignant Hepatic Tumor Detection in Gadolinium- and Ferucarbotran-Enhanced Magnetic Resonance Imaging: does Combining Ferucarbotran-Enhanced T2*-Weighted Gradient Echo and T2-Weighted Turbo Spin Echo Images have Additive Efficacy?

ObjectiveTo determine if a combination of ferucarbotran-enhanced T2*weighted-gradient echo (T2*W-GRE) and T2-weighted turbo spin echo (T2W-TSE) images in gadolinium- and ferucarbotran-enhanced MRI has additive efficacy compared to each image alone for detecting small (≤ 2.0 cm) hepatocellular carcinoma (HCC) lesions in a group of cirrhotic patients and metastases in a group of non-cirrhotic patients.Materials and MethodsTwo readers retrospectively analyzed gadolinium- and ferucarbotran-enhanced T2*W-GRE, T2W-TSE, and combined T2*W-GRE/T2W-TSE images of 119 patients with 157 HCCs and 32 patients with 98 metastases. The diagnostic accuracy and sensitivity for each image set and the combined set were evaluated using the alternative-free response receiver operating characteristic method.ResultsThe mean area under the curve value of the combined set (0.966) tended to be better than that for each individual image set (T2W-TSE [0.910], T2*W-GRE [0.892]). Sensitivities in the combined set were higher than those in each individual image set for detecting HCC (mean, 93.0% versus 81.6% and 86.7%, respectively, p < 0.01). Sensitivities in the combined set and the T2W-TSE set were the same for detecting metastases, and both were higher than the sensitivity seen in the T2*W-GRE set (mean, 97.5% versus 85.2%, p < 0.01).ConclusionCombining ferucarbotran-enhanced T2*W-GRE and T2W-TSE has additive efficacy for detecting HCC in cirrhotic patients, but T2W-TSE is preferred for detecting metastases in non-cirrhotic patients.

Correlation between ultrasonographic tumor data and peritumoral subretinal fluid findings with OCT for the early detection of small malignant melanocytic tumors

Correlation between ultrasonographic tumor data and peritumoral subretinal fluid findings with OCT for the early detection of small malignant melanocytic tumors

The Effect of Meloxicam, a Selective COX-2 Inhibitor, on the Microvasculature of Small Metastatic Liver Tumors in Rats

COX-2 is involved in tumor angiogenesis and modulation of the production of angiogenetic factors by colorectal carcinoma cells. It has been shown that COX-2 inhibitors have inhibitory activities against various types of tumor, including colorectal carcinoma. In this study, we investigated the tumor vessels of small metastatic liver tumors in rats and the effect of meloxicam, a selective COX-2 inhibitor, on their growth and microvasculature. The metastatic liver tumors were produced by intraportal inoculation of RCN-H4 cells in male F344/DuCrj rats (n = 40). The microvasculature was examined by scanning electron microscopy and stereomicroscopy. Microvascular casts were produced by perfusion via the abdominal aorta 14 days after tumor inoculation. Four groups (control, groups 1-3) of rats were treated with meloxicam 0, 0.6, 1.0 and 3.0 mg/kg/day, respectively, by oral gavage 5 days/week for two weeks from the day of inoculation of RCN-H4 cells. The mean number of tumors was significantly decreased in groups 1-3 (5.6+/-0.8 standard deviation, SD; 3.6+/-1.1; and 5.5+/-1.1, respectively) compared with control (11.2+/-2.7; P = 0.0002, each). Meloxicam also significantly reduced the mean diameter of the tumor: 730+/-254, 685+/-212 and 644+/-139 in groups 1-3, respectively, in comparison with 870+/-276 in control (P = 0.0025, 0.0011 and <0.0001, respectively). Meloxicam's anti-angiogenic activity interferes with the growth of metastatic liver tumors. Meloxicam might have therapeutic potential for liver metastasis of colorectal carcinoma.

The Solitary Pulmonary Nodule

The imaging evaluation of a solitary pulmonary nodule is complex. Management decisions are based on clinical history, size and appearance of the nodule, and feasibility of obtaining a tissue diagnosis. The most reliable imaging features are those that are indicative of benignancy, such as a benign pattern of calcification and periodic follow-up with computed tomography for 2 years showing no growth. Fine-needle aspiration biopsy and core biopsy are important procedures that may obviate surgery if there is a specific benign diagnosis from the procedure. In using the various imaging and diagnostic modalities described in this review, one should strive to not only identify small malignant tumors--where resection results in high survival rates--but also spare patients with benign disease from undergoing unnecessary surgery.

Radical excision of malignant sacral tumors using a modified threadwire saw

Surgical treatment of malignant sacral tumors is difficult, and has a high rate of recurrence. The aim of this study was to examine the wide margin of large and small malignant sacral tumors using a threadwire saw (T-saw). We devised a flexible silver guide probe connected to a modified threadwire saw by a suture thread to perform osteotomies. We operated on 10 patients with sacral tumors using this device. The sacral excisions were performed via a posterior approach by four surgeons (two on each side) working simultaneously. We obtained a wide margin in all cases and no recurrence, after a mean follow-up of 4 years 2 months (range, 1 year 8 months-7 years 8 months). In one case, one nerve root on the right side was injured. Our new method is easier and faster than the conventional method in cases in which bilateral sacral nerve root canals require sectioning, and it produces a wide tumor margin.