Despite the increase of serum CA 19-9, complete metabolic response and tumoral calcifications in PET/CT: Could it be a tumor stunning after chemotherapy?

A 74-year-old male patient with a history of nausea, vomiting, and loss of appetite revealed thickening of the antrum and pylorus in gastroscopy and non-mucinous adenocarcinoma was diagnosed in the biopsy. The patient underwent 18F-FDG PET/CT for staging. PET/CT showed intense FDG uptakes in the primary lesion, locoregional lymph nodes and liver metastases. After 5-fluorouracil based chemotherapy, a complete metabolic response in metastatic liver lesions, lymph nodes, and the primary tumor was detected. Furthermore, tumor calcifications were observed in the liver and locoregional lymph node metastases. Although a complete response, there was a 40 percent serum CA 19-9 level increase. During the follow-up, intense FDG uptake was observed in the calcified metastatic liver lesions and some lymph nodes, similar to the continuous increase in serum CA 19-9 levels. Ascites, multiple metastatic lung nodules and metabolic progression in liver lesions were observed on PET/CT in the patient who continued to receive chemotherapy.     

A specific vaccine effective against stage I and stage II malignant disease in guinea pigs effect of variations in preparations and storage

Summary Guinea pigs, each with an established, syngeneic dermal line 10 tumor and lymph node metastases, were immunized by intradermal injection of a mixture of irradiated line 10 cells and an emulsion containing heat-killed BCG. Immunization eradicated 7- or 10-day-old dermal tumors (about 10 or 12 mm in diameter, respectively) and prevented growth of microscopic lymph node metastases. Fourteen-day-old dermal tumors (about 15 mm in diameter) were not rejected by immunization.Guinea pigs with stage II disease (21-day-old dermal tumors and palpable metastases in the first draining lymph node) were treated by excision of the dermal tumor and the first draining lymph node, and by specific immunization. This treatment eliminated tumor cells remaining in the second draining lymph nodes. The surgical treatment alone was not curative, palpable metastases in the second draining lymph nodes progressed and the animals died (some with visible lung metastases).Emulsions containing killed BCG were good adjuvants even after prolonged storage at 4° C, but lost most of their adjuvant activity after autoclaving or freezing.     

Sampling of sentinel lymph nodes: a simulation study

OBJECTIVE: To analyze the effects of various slicing schemes on the detection of metastases in lymph nodes. STUDY DESIGN: Use of an advanced computer simulation tool. RESULTS: Bisectioning along the longitudinal axis is an inadequate approach. Slicing ellipsoid lymph nodes along their longitudinal axis also results in a lower rate of detecting metastases since metastatic deposits have a predilection to localize subcapsularly. CONCLUSION: Ellipsoid lymph nodes must be sliced perpendicular to the longest axis to increase the rate of detecting metastases.     

Adjacent thoracic lymph node metastases originating from two separate primary cancers: case report

Reported is an unusual case of adjacent thoracic lymph nodes demonstrating metastases from two different primary malignancies. A 51 year-old woman with a previous history of bilateral breast cancer underwent a radical gastro-oesophagectomy for adenocarcinoma of the lower third of the oesophagus. The resection specimen demonstrated breast and oesophageal metastases in adjacent thoracic lymph nodes. Mechanisms for this phenomenon, including the known local immune suppression on lymphoid cells by oesophageal carcinoma cells, are discussed.     

Tumor lymphangiogenesis and melanoma metastasis

Malignant melanomas of the skin primarily metastasize to lymph nodes, and the detection of sentinel lymph node metastases serves as an important prognostic parameter. There is now compelling evidence that melanomas can induce lymphangiogenesis (growth of lymphatic vessels), mainly at the tumor-stroma interface, and that the level of tumor lymphangiogenesis is correlated with the incidence of sentinel lymph node metastases and with disease-free survival. Thus, tumor lymphangiogenesis can serve as a novel prognostic predictor in melanoma. Vascular endothelial growth factor (VEGF)-C, released by melanoma cells and by tumor-associated macrophages, likely represents the major lymphangiogenic factor in melanoma, although other members of the VEGF family might also be involved. The recent discovery that tumors can induce a premetastatic niche, by inducing lymphatic vessel growth in sentinel lymph nodes even before metastasis, and that lymph node lymphangiogenesis enhances metastatic spread, indicates that activated lymphatic vessels represent novel targets for the detection and/or therapy of melanoma metastases.     

磁共振靶向对比剂在淋巴结成像中的研究进展

准确评价淋巴结转移与否关系到对肿瘤患者的分期和预后的判断。目前对淋巴结良恶性诊断的主要依据为淋巴结的大小和形态,正常大小的转移性淋巴结很可能被遗漏,增大的淋巴结是良性增生还是恶性转移也很难鉴别。近年来随着MR特异性对比剂,特别是MR靶向淋巴结对比剂的发展,MR淋巴成像（MR Lymphography,MRL）显示了极为诱人的前景。该文主要介绍MR淋巴靶向对比剂的研究进展。     

Lymph node metastases of papillary thyroid cancer in immunohistochemical and molecular examination--preliminary report

BACKGROUND: Total thyroidectomy with lymphadenectomy is the most typical operation in a case of papillary thyroid cancer. Range of lymph node resection still remains a matter of controversy. In some publications treatment of lymph node metastases doesn't affect survival, so only selective lymph node resection is the extended enough operation. The others remark that, local relapse- the worst prognostic factor, appears the most often in the lymph nodes, so they suggest more aggressive treatment. To solve that problem we try to find more sensitive methods to examine lymph nodes. AIM: To compare the results of detection lymph node metastases of papillary thyroid cancer by immunohistochemistry with the results of RT- PCR for thyroglobulin (Tg) mRNA. MATERIAL AND METHODS: Each of one hundred eighty four cervical lymph nodes obtained from 24 patients, operated in our Department was divided into 2 halves: one was used for conventional histopathology and immunohistochemistry, the other part was investigated by RT- PCR for Tg mRNA. Immunohistochemical staining for Tg was performed on formalin-fixed, paraffin-embedded sections with anti-Tg antibodies. RESULTS: According to routine, histopathological examination 8 (33.5%) patients had involved lymph nodes. One hundred correspondence of the results of immunohistochemistry and histopathology was observed. We obtained different results of examination of the lymph nodes in 6 (25%) patients. In four patients (16.7%) RT-PCR was more sensitive in detection of positive lymph nodes, in two patients (8.3%) it revealed less metastasized lymph nodes than immunohistochemistry. The remaining 18 patients didn't have any differences, fourteen (58.3%) of them had the negative lymph nodes and four (16.7%) had positive, the same lymph nodes in all examinations. Finally, according to RT-PCR 10 (41.7%) of the patients had metastasized lymph nodes. COCLUSION: Tg RT-PCR is a sensitive method of detection of papillary thyroid cancer cells and may help to detect the metastases of papillary thyroid cancer in regional lymph nodes.     

Lower expression of CXCR4 in lymph node metastases than in primary breast cancers: potential regulation by ligand-dependent degradation and HIF-1alpha

Stromal-derived factor-1 (SDF-1) is a unique ligand of the CXC chemokine receptor 4 (CXCR4), which is critically involved in the metastasis of breast cancer. High levels of SDF-1 in the common destination organs of metastasis, such as the lymph nodes, lungs, liver, and bones, attract CXCR4-positive tumor cells. The interaction between SDF-1 and CXCR4 leads to the activation of specific signaling pathways, allowing for homing and metastatic progression. However, regulation of CXCR4 expression at the metastatic organ site is not well-documented. We detected the expression of CXCR4 and hypoxia inducible factor (HIF)-1alpha in breast tumor tissues by immunohistochemical staining and analyzed SDF-1 in primary tumors and lymph nodes using real-time RT-PCR. Compared to the corresponding metastasized tumors in the lymph nodes, primary invasive carcinomas showed more intense staining for CXCR4, particularly on the cellular membrane. Both primary tumors and lymph node metastases exhibited higher levels of CXCR4 expression compared to non-neoplastic breast tissues. Therefore, we hypothesized that the tumor environment in the lymph nodes may cause the reduction of CXCR4 levels in the metastatic tumor cells because of: (1) high SDF-1 levels and (2) lower levels of HIF-1alpha. Our in vitro data demonstrated that high levels of SDF-1 can induce the internalization and degradation of CXCR4 through the lysosome pathway. In addition, lower levels of HIF-1alpha in the lymph node metastases, probably induced by the less hypoxic environment, further lowered CXCR4 levels. These results indicate that ligand-dependent degradation and lower HIF-1alpha levels may be potential causes of lowered levels of CXCR4 in the lymph nodes compared to the primary tumors. Our study suggests that CXCR4 levels in tumor cells are regulated by its microenvironment. These findings may enhance our ability to understand the biological behavior of breast cancers.     

Tumour-induced immune modulation of sentinel lymph nodes

Sentinel lymph nodes (SLNs), being the first nodes to receive lymph from a primary tumour and the preferential site of initial tumour metastases, are intensively exposed to the bioactive products of tumour cells and other associated cells. This makes them ideal for studies of the factors that determine selective tissue susceptibility to metastases. We postulate that tumour-induced immune modulation of SLNs facilitates lymph-node metastases by inhibiting the generation of tumour-specific cytotoxic T cells that are active against tumour cells of primary and metastatic melanomas. Immune modulation of the lymph nodes can be reversed by granulocyte/macrophage colony-stimulating factor (GM-CSF), a finding that has implications for the future therapy of lymph-node metastases.     

Cervical lymph node metastases of thyroid carcinoma - an alternative of the "lateral aberrant thyroid"

The neoplastic thyroid tissue found in the laterocervical lymph nodes of euthyroid patients is associated with an intrathyroid carcinoma identified in the subsequently operated gland, asserting its metastic origin. Eighty percent of the thyroid carcinomas present cervical metastases in a variable number of lymph nodes belonging to more than one topographic group.     

Evidence that treatment with vaccinia melanoma cell lysates (VMCL) may improve survival of patients with stage II melanoma

Summary A total of 80 patients with melanoma metastases in regional lymph nodes were treated by i.d. injections with a vaccine prepared from a vaccinia virus-infected allogeneic melanoma cell line; 39 patients have been followed for a 2-year period. Interim results from comparison of the treated group with 151 historical controls treated without the vaccine from September 1978 to December 1981 at the same institution and 56 non-randomized concurrent controls suggest that survival was significantly prolonged in the vaccinated group. At the 2-year period overall survival was 75% in the treated compared to 57% in the historical control group. Subset analysis showed a greater apparent benefit of vaccine therapy among patients who had metastases detected at the time of treatment of the primary melanoma (synchronous metastases), while therapy appeared less effective in patients with metastases detected at some time after treatment of the primary (delayed metastases). In the latter only those with one lymph node appeared to benefit from the treatment whereas in patients with synchronous metastases patients with three or more nodes as well as one node appeared to have improved survival. The survival rates at 2 years for treated patients with synchronous metastases in one, two, three or more lymph nodes was 100%, 83% and 79% respectively compared with that of 82%, 86% and 47% respectively in the equivalent control groups. Survival rates in treated patients with delayed metastases in one, two, three or more lymph nodes was 70%, 70% and 65% compared with 47%, 42% and 35% in the equivalent control groups. Treatment and control groups appeared well matched for a number of known prognostic features, including number and size of involved nodes, sex and thickness of primary tumor. Multivariate analysis indicated the effect of treatment was independent of these factors. Despite the empiricism of this approach the present results suggest that this form of therapy warrants further evaluation in a randomized controlled trial.     

Distinct Ezrin Truncations Differentiate Metastases in Sentinel Lymph Nodes from Unaffected Lymph Node Tissues,from Primary Breast Tumors,and from Healthy Glandular Breast Tissues

BACKGROUND: Lymph node metastasis status is a prognostic factor for further lymph node involvement and for patient survival in breast cancer patients. Frozen section analysis of lymph nodes is a reliable method for detection of macro-metastases. However, this method is far less effective in detecting micro-metastases, requesting improved diagnostic procedures. METHODS: We investigated expression and truncation of ezrin in (i) sentinel lymph node metastases, (ii) unaffected axillary lymph nodes, (iii) primary breast tumors, and (iv) healthy glandular breast tissues using 2D gel electrophoresis, SDS-PAGE, and mass spectrometry in addition to Western blotting. RESULTS: Full-length ezrin (E1; amino acids 1–586) is present in all four investigated tissues. Two truncated ezrin forms, one missing about the first hundred amino acids (E2a) and the other lacking about 150 C-terminal amino acids (E2b) were detectable in primary tumor tissues and in sentinel lymph node metastases but not in glandular tissues. Strikingly, an ezrin truncation (E3) which consists approximately of amino acids 238–586 was found strongly expressed in all sentinel lymph node metastases. Moreover, an N-terminal ezrin fragment (E4) that consists approximately of amino acids 1–273 was identified in sentinel lymph node metastases as well. CONCLUSIONS: We show for the first time the existence of tissue-dependent specific ezrin truncations. The distinguished strong Western blot staining of ezrin E3 in sentinel lymph node metastases underlines its capability to substantiate the occurrence of lymph node (micro)metastases in breast cancer patients.     

Diagnostic value of intraoperative histopathological examination of the sentinel nodes in breast cancer and skin melanoma—Preliminary results of single centre retrospective study

Objective

Intraoperative histopatological examination of the sentinel nodes enables selection of patients who need dissection of the regional lymphatic system during the same operation. The aim of this study is to evaluate the diagnostic value of intraoperative histopathological examination of the sentinel nodes in breast cancer and skin melanoma. Intraoperative histopathology of the sentinel nodes as a diagnostic method is used in patients with melanoma and breast cancer. Recent studies have proved it to be an effective method for evaluating the nodes in the final histopathology. Intraoperative histopathological examination of the sentinel nodes is not performed routinely and there is no clear position on this issue. In this paper we try to prove that intraoperative test gives patients the simultaneous benefits of removal of regional lymph nodes metastases and earlier initiation of adjuvant therapy.

Methods

The study comprises 137 patients with breast cancer and 35 patients with malignant skin melanoma. Sentinel nodes were intraoperatively sectioned and examined by means of the imprint method and frozen section evaluation. The patients with positive sentinel nodes underwent immediate dissection of regional lymph nodes. Those with negative sentinel nodes diagnosed in the intraoperative examination, but positive in final pathologic results, underwent subsequent dissection of regional lymph nodes.

Results

60 sentinel lymph nodes were found in 35 patients with skin melanoma. In 3 patients, 3 sentinel lymph nodes were false negative in the intraoperative histopathological examination. No false positive sentinel lymph nodes were found. 249 sentinel lymph nodes were found in the intraoperative histopathological examination in 137 patients with breast cancer. There were no false positive sentinel nodes, but there were 7 false negative sentinel nodes. In this study, only 5 (3.6%) patients with breast cancer and 3 (8.5%) patients with skin melanoma required another regional operation.

Conclusion

The method of intraoperative histopathological evaluation of the sentinel nodes enables identification of metastases in these lymph nodes and gives a possibility to carry out a one-step regional lymphadenectomy and start the adjuvant therapy earlier.     

Dynamics of aberrant methylation of functional groups of genes in progression of breast cancer

For the first time, the epigenetic status of breast benign proliferative processes, malignant breast tumors, and metastases to regional lymph nodes has been studied using the GoldenGate Cancer Panel I DNA methylation microarray (Illumina, United States). The functional groups of differentially methylated genes were identified in each set of samples. The aberrant methylation of genes that regulate cell proliferation and mobility was found in the samples of benign proliferative breast processes. The aberrant methylation of genes responsible for cell differentiation and proliferation, as well as protein phosphorylation and cell mobility, was observed in the samples of malignant breast tumors. The differential methylation of the genes that regulate cell adhesion, the formation of anatomical structures, angiogenesis, immune response, signal transduction, and protein phosphorylation were found in samples with metastases to regional lymph nodes compared to the unaltered breast epithelium. It was found that tissues that range from benign proliferative processes and metastases to regional lymph nodes were generally characterized by a relatively lower level of epigenetic variability compared to the tissues of the primary tumor.     

Metallic tin-induced lymphadenopathy in rat strains and hybrids

Metallic tin powder, injected into Lewis rats obtained from three different sources, caused enlargement of the regional draining lymph nodes. The histopathology featured epithelioid cell granulomas around phagocytosed particles of tin and an intense hyperplasia of plasma cells. The same material injected into August rats enlarged the lymph nodes but the enlargement was caused by granulomas without a major concomitant plasma cell response. In most other strains, tin produced less lymph node enlargement and the plasma cell response was minimal. However, F1 hybrids of Lewis rats with either the August, Brown-Norway (BN), or Dark Agouti (DA) strains developed plasma cell hyperplasia similar to that seen in the parental Lewis strain. The response to tin was the same whether the tin was injected into the feet or into the peritoneal cavity. Thus, the lymph node response to metallic tin varied from a slight, banal response to insoluble foreign particles, to an exuberant granulomatous hyperplasia, to an intense plasmacellular hyperplasia, depending on the genetic characteristics of the subjects.     

MAGE-A3/4 and NY-ESO-1 antigens expression in metastatic esophageal squamous cell carcinoma

In the present study we analyzed immunohistochemical expression of MAGE-A 3/4 and NY-ESO-1 in 55 samples of esophageal squamous cell carcinomas (ESCC) and their respective lymph node metastases. To our knowledge this is the first study to assess and compare the expression of these antigens in ESCC lymph node metastases. Fifty (90.9%) primary ESCC were positive for MAGE-A 3/4 and 53 (96.6%) were positive for NY-ESO-1. MAGE-A 3/4 was expressed in all lymph node metastases and the intensity of expression was high in a majority of cases. NY-ESO-1 was negative in 2 (7.1%) lymph nodes metastases, while the reaction was predominantly moderate in the positive group. In primary tumors MAGE-A 3/4 showed a significantly higher intensity of expression compared to NY-ESO-1 (P=0.047), while in lymph node metastases the intensity of expression was not significantly different (P=0.387). Primary tumors with and without lymph node metastases showed no significant differences in MAGE-A 3/4 (P=0.672) and NY-ESO-1 (P=0.444) expression. Intensity of MAGE-A 3/4 (P=0.461) and NY-ESO-1 (P=0.414) expression in primary tumors was not significantly different compared to the expression in their respective lymph nodes metastases. Expression of MAGE-A 3/4 in primary tumors showed significant positive correlation with primary tumor expression of NY-ESO-1 (P=0.021) but no significant correlation with the expression of MAGE-A 3/4 in lymph node metastases (P=0.056). Expression of NY-ESO-1 in primary tumors showed significant positive correlation with the expression of NY-ESO-1 in lymph node metastases (P=0.001) and significant negative correlation with patients’ age (P<0.001). Expression of MAGE-A 3/4 and NY-ESO-1 in primary tumors and lymph node metastases showed no significant correlation with prognostic parameters such as tumor grade and TNM stage (P>0.05). We have shown different levels of MAGE-A 3/4 and NY-ESO-1 expression in almost all specimens of primary tumor and lymph node metastases, suggesting that ESCC may be possible target of immunotherapy and anti-tumor vaccination. High levels of expression in lymph node metastases indicate possible clinical benefit of postoperative vaccine with MAGE-A3 and NY-ESO-1 in advanced stage of disease.     

Inhibition of the development of metastases by dietary vitamin C:K3 combination

The tumor growth-inhibiting and chemo-potentiating effects of vitamin C and K(3)combinations have been demonstrated both in vitro and in vivo. The purpose of this study was to investigate the influence of orally administered vitamin C and K(3) on the metastasis of mouse liver tumor (T.L.T.) cells implanted in C3H mice. Adult male C3H mice were given water containing vitamin C and K3 (15 g/0.15 g dissolved in 1000 ml) beginning 2 weeks before tumor transplantation until the end of the experiment. T.L.T. cells (106) were implanted intramuscularly in the right thigh of mice. All mice were sacrificed 42 days after tumor transplantation. Primary tumor, lungs, lymph nodes and other organs or tissues suspected of harboring metastases were macroscopically examined. Samples of primary tumors, their local lymph nodes, lungs and main organs such as liver, kidneys, spleen were taken for histological examination. Forty-two percent of control mice exhibited lung metastases and 27% possessed metastases in local lymph nodes whereas 24% of vitamin-treated mice exhibited lung metastases and 10% possessed local lymph nodes metastases. The total number of lung metastases was 19 in control group and 10 in vitamin C and K(3)-treated mice. Histopathological examination of the metastatic tumors from the vitamin-treated mice revealed the presence of many tumor cells undergoing autoschizic cell death. These results demonstrate that oral vitamin C and K(3) significantly inhibited the metastases of T.L.T. tumors in C3H mice. At least a portion of this inhibition was due to tumor cell death by autoschizis.     

Pulmonary metastases in guinea pigs as a consequence of dermal implantation of line-10 tumor cells

Summary Metastases to the lungs of guinea pigs occurred at high frequency as a consequence of intradermal implantation of tumor cells derived from the syngeneic hepatocellular carcinoma line-10. Surgery had a major influence on the proportion of guinea pigs found to have pulmonary metastases at necropsy. Without surgery all guinea pigs died with extensive lymph node metastases; macroscopic pulmonary metastases were present in a minority of the animals. Animals treated by excision of dermal tumors survived longer than untreated animals, and macroscopic pulmonary metastases were present in the majority of the animals. Animals treated by excision of dermal tumor and regional lymph nodes were rendered tumor-free. The data suggest that lymph node metastases were the most likely source of the tumor cells that spread to the lungs in animals from whom the dermal tumor transplant had been removed.