Showing papers in "Journal of Cancer Research and Clinical Oncology in 2004"
TL;DR: The finding indicated that biannual screening reduced HCC mortality by 37%.
Abstract: Screening for hepatocellular carcinoma (HCC) has been conducted for over 20 years, but there is no conclusive evidence that screening may reduce HCC mortality. The aim of this study was to assess the effect of screening on HCC mortality in people at increased risk. This study included 18,816 people, aged 35–59 years with hepatitis B virus infection or a history of chronic hepatitis in urban Shanghai, China. Participants were randomly allocated to a screening (9,373) or control (9,443) group. Controls received no screening and continued to use health-care facilities. Screening group participants were invited to have an AFP test and ultrasonography examination every 6 months. Screening was stopped in December 1997; by that time screening group participants had been offered five to ten times. All participants were followed up until December 1998. The primary outcome measure was HCC mortality. The screened group completed 58.2 percent of the screening offered. When the screening group was compared to the control group, the number of HCC was 86 versus 67; subclinical HCC being 52 (60.5%) versus 0; small HCC 39 (45.3%) versus 0; resection achieved 40 (46.5%) versus 5 (7.5%); 1-, 3,-, and 5-year survival rate 65.9%, 52.6%, 46.4% versus 31.2%, 7.2%, 0, respectively. Thirty-two people died from HCC in the screened group versus 54 in the control group, and the HCC mortality rate was significantly lower in the screened group than in controls, being 83.2/100,000 and 131.5/100,000, respectively, with a mortality rate ratio of 0.63 (95%CI 0.41–0.98). Our finding indicated that biannual screening reduced HCC mortality by 37%.
1,258 citations
TL;DR: A molecular signature that can classify metastatic HCC patients is generated, osteopontin is identified as a lead gene in the signature, and it is found that genes favoring metastasis progression were initiated in the primary tumors.
Abstract: Metastasis remains one of the major challenges before hepatocellular carcinoma (HCC) is finally conquered. This paper summarized a decade’s studies on HCC metastasis at the Liver Cancer Institute of Fudan University. We have established a stepwise metastatic human HCC model system, which included a metastatic HCC model in nude mice (LCI-D20), a HCC cell line with high metastatic potential (MHCC97), a relatively low metastatic potential cell clone (MHCC97L) and several stepwise high metastatic potential cell clones (MHCC97H, HCCLM3, and HCCLM6) from their parent MHCC97 cell. Endeavors have been made for searching human HCC metastasis-related chromosomes/proteins/genes. Monogene-based studies revealed that HCC invasion/metastasis was similar to that of other solid tumors, and the biological characteristics of small HCC were only slightly better than that of large HCC. Using comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), genotyping, cDNA microarray, and 2-dimensional gel electrophoresis, we obtained some interesting results. In particular, in collaboration with the National Institute of Health (NIH) in the United States, we generated a molecular signature that can classify metastatic HCC patients, identified osteopontin as a lead gene in the signature, and found that genes favoring metastasis progression were initiated in the primary tumors. We also found that chromosome 8p deletion, particularly in the region of 8p23, was associated with HCC metastasis. Cytokeratin 19 was identified as one of the proteins, which was found in MHCC97H, but not in MHCC97L cells. Experimental interventions using the high metastatic nude mice model have provided clues for the prevention of HCC metastasis. Translation from workbench to bedside demonstrated that serum VEGF, microvessel density, and p53 scoring may be of value for the prediction of postoperative metastatic recurrence. Interferon alpha proved effective for the prevention of recurrence both experimentally and clinically. In conclusion, HCC metastasis that probably initiated in the primary tumor is a multigene-involved, multistep, and changing process. The further elucidation of the mechanism underlying HCC metastasis will provide a more solid basis for the prediction and prevention of the metastatic recurrence of HCC.
419 citations
TL;DR: The establishment of this new cell line has completed the stepwise metastatic HCC cell mode system, which was characterized by a similar genetic background but with significant differences in spontaneous metastasis behavior and supports the theory that cancer metastasis is a highly selective dynamic process.
Abstract: To establish a “stepwise metastatic human hepatocellular carcinoma (HCC) cell model system” for in-depth study of the underlying mechanisms of HCC metastasis. Using MHCC97— a metastatic human hepatocellular carcinoma (HCC) cell line reported in 1999—as the parent cells, we subsequently established three cell lines (MHCC97-L, HMCC97-H, and HCCLM3) with increasing spontaneous metastatic potential. Now, the fourth cell line with unique multiple metastatic characteristics has been established by six rounds of in vivo selection. This cell line, designated as HCCLM6, is a polygonal epithelial cell with hypotriploid karyotype, the modal chromosomes are 55-58, and marker chromosomal abnormalities include i(1) (q10), i(8)(q10), der (4) t(4;8)(q31;q22), i(X)(q10). The cell population doubling time was 32 h. Fluorescent PCR showed HBV DNA integration in the cellular genome. Thirty-five days after HCCLM6 was injected subcutaneously into BALB/c nude mice, prominent lung metastases occurred in 100% of the recipient animals. When tumor tissue was orthotopically implanted into the liver of nude mouse, widespread loco-regional and pulmonary metastases occurred. Inoculation of this cell into the footpad of nude mice also produced 75% regional lymph node metastasis. Compared with MHCC97-L which was not metastastatic via subcutaneous or footpad inoculation and 40% metastatic via orthotopic inoculation, HCCLM6 had increased expression of matrix metalloproteinase (MMP-2 and MMP-9) and cytokeratin 19 (CK19), and decreased expression of Rb2/p130. The establishment of this new cell line has completed our stepwise metastatic HCC cell mode system, which was characterized by a similar genetic background but with significant differences in spontaneous metastasis behavior. The study supports the theory that cancer metastasis is a highly selective dynamic process and the cell model system could be a useful platform for the study of HCC metastasis.
201 citations
TL;DR: Molecular markers (biomarkers) for hepatocellular carcinoma (HCC) metastasis and recurrence could provide additional information to that gained from traditional histopathological features, as understanding of tumor biology deepens.
Abstract: Molecular markers (biomarkers) for hepatocellular carcinoma (HCC) metastasis and recurrence could provide additional information to that gained from traditional histopathological features. A large number of biomarkers have been shown to have potential predictive significance. One important aspect of this is to detect the transcripts of tumor-associated antigens (such as AFP, MAGEs, and CK19), which are proposed as predictive markers of HCC cells disseminated into the circulation and for metastatic recurrence. Another important aspect is to analyze the molecular markers for cellular malignancy phenotype, including DNA ploidy, cellular proliferation index, cell cycle regulators, oncogenes, and tumor suppressors (especially p53 gene), as well as telomerase activity. Molecular factors involved in the process of HCC invasion and metastasis, including adhesion molecules (E-cadherin, catenins, ICAM-1, laminin-5, CD44 variants, osteopontin), proteinases responsible for the degradation of extracellular matrix (MMPs, uPA system), as well as angiogenesis regulators (such as VEGF, intratumor MVD), have also been shown to be potential predictors for HCC metastatic recurrence and clinical outcomes. One important new trend is to widely delineate biomarkers with genomic and proteomic expression with reference to predicting metastatic recurrence, molecular diagnosis, and classification, which has been drawing more attention recently. Body fluid (particularly blood and urine) testing for biomarkers is easily accessible and more useful in clinical patients. The prognostic significance of circulating DNA in plasma or serum and its genetic alterations is another important direction. More attention should be paid to these areas in the future. As understanding of tumor biology deepens, more and more new biomarkers with high sensitivity and specificity for HCC metastatic recurrence could be found and routinely used in clinical assays. However, the combination of the pathological features and some of the biomarkers mentioned above seems to be more practical up to now.
199 citations
TL;DR: Molecular modifications made novel anticancer compounds accessible with strongly improved CDK inhibitory potential and with broad spectrum antitumour activity and this novel family of compounds holds strong promise for clinical anticancer activity.
Abstract: Indirubin, a 3, 2' bisindole isomer of indigo, has originally been identified as the active principle of a traditional Chinese preparation and has been proven to exhibit antileukemic effectiveness in chronic myelocytic leukemia. Indirubin was detected to represent a novel lead structure with potent inhibitory potential towards cyclin-dependent kinases (CDKs) resulting from high affinity binding into the enzymes ATP binding site. This seminal finding triggered our research to improve the pharmacological activities of the parent molecule within comprehensive structure-activity studies. Molecular modifications made novel anticancer compounds accessible with strongly improved CDK inhibitory potential and with broad spectrum antitumour activity. This novel family of compounds holds strong promise for clinical anticancer activity and might be useful also in several important noncancer indications, including Alzheimer's disease or diabetes.
180 citations
TL;DR: The views of an expert meeting of cardiologists and oncologists on the use of dexrazoxane in anthracycline-based chemotherapy are summarized to help to identify those patients who are at particular risk of cardiotoxicity and who would benefit the most from dexraz oxane.
Abstract: This article summarizes the views of an expert meeting of cardiologists and oncologists on the use of dexrazoxane in anthracycline-based chemotherapy. Anthracycline-induced cardiotoxicity remains a major concern and new trends in treatment (e.g., combination of an anthracycline with other agents) will ensure that it remains a problem. Dexrazoxane reduces this cardiotoxicity in adults and children with a range of tumor types. Further research may help to identify those patients who are at particular risk of cardiotoxicity and who would benefit the most from dexrazoxane. There are also numerous possibilities for dexrazoxane in other clinical situations, which must be addressed in future trials.
151 citations
TL;DR: Down-regulation of Sox2, a human homolog of a chicken gastric transcription factor, may be important factors for the development of IM.
Abstract: The molecular mechanisms underlying the development of intestinal metaplasia (IM) of the human stomach have yet to be clarified in detail. Besides ectopic expression of intestinal transcription factors, Cdx1 and Cdx2, little information is available regarding other regulatory factors. Hence, we here analyzed Sox2, a human homolog of a chicken gastric transcription factor, with reference to our new classification for gastric/intestinal (GI)-mixed type IM. Twenty specimens of surgically resected antral mucosa were subjected to a gland isolation technique. Isolated glands were classified into gastric (G), GI-mixed, and solely intestinal (I) types according to Alcian blue and paradoxical concanavalin A staining and were quantified for mRNA levels of gastrointestinal markers. MUC5AC and MUC6 transcripts decreased with the progression of IM, while MUC2 and villin-1 were inversely correlated. Sox2 showed a gradual decrease from G, through GI, to the I type (G vs GI and GI vs I, P<0.01 and P<0.005, respectively). On the other hand, Cdx1 (G vs GI and GI vs I, P<0.0001 and P=0.337, respectively) and Cdx2 (G vs GI and GI vs I, P<0.0001 and P<0.05, respectively) appeared in IM. Immunohistochemical study confirmed decreased expression of Sox2 and ectopic emergence of Cdx2 protein in IM glands. Down-regulation of Sox2, besides ectopic expression of Cdx genes, may be important factors for the development of IM.
139 citations
TL;DR: Overexpression of MMP-2 and M MP-9 in dysplasia as well as SCC suggests that these alterations occur in early stages of esophageal tumorigenesis.
Abstract: Purpose
Matrix metalloproteinases (MMPs) are known to play an important role in extracellular matrix remodeling during the process of tumor invasion and metastasis. However, little is known about their role in preinvasive lesions and early esophageal carcinomas.
115 citations
TL;DR: The S100 gene family is closely associated with ESCC and the deregulation of some S100 genes was closely correlated with histological differentiation of ESCC.
Abstract: Purpose
To study the differential expression of the S100 gene family at the RNA level in human esophageal squamous cell carcinoma (ESCC), and to find the relationship of the S100 gene family with ESCC.
110 citations
TL;DR: This is the first study demonstrating that PRL-3 is a potential marker for liver metastasis of colorectal cancer and negatively influences the prognosis of colorean cancer patients.
Abstract: To investigate PRL-3 protein expression in normal colorectal epithelia and colorectal cancers with monoclonal antibody (MAb) against PRL-3. MAb against PRL-3 was prepared with the hybridoma technique, and its specificity was confirmed with ELISA and Western blotting assays. The expression of PRL-3 protein in normal colorectal epithelia and colorectal cancers was examined by immunohistochemistry assay. Logistic regression and survival analysis were performed to determine the clinical significance of PRL-3 expression. MAb 3B6 against PRL-3 was obtained and showed high specificity. PRL-3 protein was expressed in two of 28 (7.1%) normal colorectal epithelia, 21 of 88 (23.9%) primary colorectal cancers, 22 of 41 (53.7%) metastatic lymph nodes and eight of 12 (66.7%) liver metastases, respectively. The PRL-3 expression rates of metastases were significantly higher than those of primary colorectal cancers and normal colorectal epithelia (P <0.05). PRL-3 expression was significantly associated with the liver metastasis of colorectal cancer (P = 0.004) and tended to shorten survival time (P = 0.0145). This is the first study demonstrating that PRL-3 is a potential marker for liver metastasis of colorectal cancer and negatively influences the prognosis of colorectal cancer patients.
103 citations
TL;DR: It is expected that the indication of neoadjuvant chemotherapy can be decided more precisely by the preoperative evaluation of patient prognosis with FDG-PET due to a possible elimination of overtreatment for those who have good prognosis and, thus, need not to be treated with chemotherapy.
Abstract: [18F]2-Deoxy-2-fluoro-D-glucose (FDG)-positron emission tomography (PET) was applied to breast cancer patients for the purpose of preoperative evaluation of patient prognosis with more accuracy than conventional TNM staging. FDG-PET was performed preoperatively in 81 patients with breast cancer, and the maximum standardized uptake value (SUVmax) of tumors as well as the focal accumulation of FDG in the axillary region (PET-N status) were investigated in their association with patient prognosis. The SUVmax high group (n=40) showed a significantly (P=0.011) poorer prognosis than the SUVmax low group (n=41) (5-year disease-free survival (DFS) rates; 75.0% vs 95.1%). FDG-PET was more accurate in the diagnosis of axillary lymph node status than physical examination, i.e., diagnostic accuracy was 80% and 70% for FDG-PET and physical examination, respectively. The combination of high SUVmax and positive PET-N (+) was shown to be a highly significant risk factor being independent of the clinical T and N factors, i.e., patients with high SUVmax and positive PET-N (+) showed a significantly (P<0.001) poorer prognosis than the other patients (5-year DFS rates; 44.4% vs 96.8%). These results suggest that FDG-PET is useful in the preoperative evaluation of prognosis in breast cancer patients with more accuracy than conventional TNM staging. It is expected that the indication of neoadjuvant chemotherapy can be decided more precisely by the preoperative evaluation of patient prognosis with FDG-PET due to a possible elimination of overtreatment for those who have good prognosis and, thus, need not to be treated with chemotherapy.
TL;DR: Fatigue 2.5 years after adjuvant radiation therapy (RT) in patients with localized breast cancer did not increase above baseline levels before RT in conservatively operated breast cancer patients.
Abstract: The aim of this study was to evaluate fatigue 2.5 years after adjuvant radiation therapy (RT) in patients with localized breast cancer and to assess its relation to pre- and immediate post-treatment fatigue values. The association of fatigue with psychological distress and functional impairment was analyzed as well as pretreatment predictors for chronic fatigue. Of a set of 41 patients whose fatigue was evaluated during adjuvant radiation therapy, 38 patients alive and free of cancer at 2.5 years (t2) after RT were assessed in this study. Patients received the Fatigue Assessment Questionnaire (FAQ), a visual analog scale on fatigue intensity (VAS-F) as well as on cancer-related distress (VAS-D), the Hospital Anxiety and Depression Scale (HADS), and three questions of the Short-Form 36-Item Health Survey (SF-36) per mail. All 38 patients returned their questionnaires. The values were compared to pretreatment (t0) and immediate post-treatment levels (2 months after RT, t1). There was no significant difference between chronic fatigue levels at 2.5 years after RT and pretreatment values. When compared to immediate post-treatment levels the FAQ global score and the HADS anxiety score displayed a significant increase. Cancer-related distress correlated closely with fatigue scores. Patients with functional impairment had slightly higher fatigue values. Age or hormonal therapy were not associated with chronic fatigue levels. Pretreatment fatigue and pretreatment HADS anxiety and depression scores were good predictors of fatigue at 2.5 years after RT explaining 60% (FAQ) and 49% (VAS-F) of its variance. Fatigue 2.5 years after RT did not increase above baseline levels before RT in conservatively operated breast cancer patients. Chronic fatigue correlated closely with psychological distress. Patients with pretreatment elevated fatigue, anxiety or depression levels are at risk for chronic fatigue.
TL;DR: This paper summarizes the latest findings, especially regarding the clinical significance of endothelial cell markers and angiogenic factors in HCC, and experimental and clinical anti-angiogenesis therapies.
Abstract: Hepatocellular carcinoma (HCC) is a typical hypervascular tumor. Many angiogenic factors have been studied in HCC, and several anti-angiogenic therapies have been tested in animal models and patients. This paper summarizes the latest findings, especially regarding the clinical significance of endothelial cell markers and angiogenic factors in HCC, and experimental and clinical anti-angiogenesis therapies. Further developments in this area, such as endothelial cell-oriented research and better experimental and clinical designs in the evaluation of anti-angiogenic therapies are discussed.
TL;DR: Data show that caspase-8 and -9 are involved in the apoptotic effect of celecoxib in cervical cancer cells, which requires the FADD-dependent pathway in a cell type-specific manner and NF-κB may play a key role in Celecoxib-induced apoptosis.
Abstract: Recently, many studies have shown that celecoxib induces apoptosis in various cancer cells by different mechanisms depending on the cell type. This study examined the apoptotic effect of celecoxib in cervical cancer cells and its mechanism. Cell viability was measured by MTT assay and apoptosis was examined by DNA fragmentation and flow cytometry. Western blotting and immunoprecipitation were used to explore various mechanisms of celecoxib-induced apoptosis. The activation of NF-κB was confirmed by EMSA. Celecoxib induced apoptosis independent of COX-2 activity. This event accompanied the activation of caspase-8 and -9 with Bid cleavage and the loss of mitochondrial membrane potential. The protective effect of caspase-8 and -9 inhibitors on celecoxib-induced apoptosis suggests the importance of caspase-8 and -9 activation in this apoptotic pathway. Fas/FADD-mediated apoptotic pathway was detected only in C33A cells, demonstrated by the immunoprecipitation of Fas-FADD in celecoxib-treated cells and the protective effect of FADD dominant negative mutant. Finally, NF-κB appeared to be involved in celecoxib-induced apoptosis, as revealed by increased NF-kB DNA binding activity in a time-dependent manner and attenuation of its proapoptotic effect by N-tosyl-L-phenylalanyl-chloromethyl ketone, an NF-kB blocker. These data show that caspase-8 and -9 are involved in the apoptotic effect of celecoxib in cervical cancer cells. This requires the FADD-dependent pathway in a cell type-specific manner. In addition, NF-κB may play a key role in celecoxib-induced apoptosis.
TL;DR: It is concluded that the PI3K-Akt pathway plays an important role in preventing Fas-mediated apoptosis; and a PI3 K inhibitor, such as LY294002, might be a useful anti-tumoral agent for gastric carcinoma.
Abstract: It is well known that Fas ligand and anti-Fas antibodies can induce apoptosis, although some cancer cells are resistant to their stimuli. On the other hand, phosphatidylinositol 3’-kinase (PI3 K) and Akt mediate the survival signal and allow the cells to escape from apoptosis in various human cancers. Thus, we postulated that LY294002, a PI3 K inhibitor, should inactivate Akt, consequently inhibiting cell proliferation and increase apoptosis in the human gastric carcinoma cell line, MKN-45. Previously, we reported that MKN-45 was resistant against the anti-Fas antibody, CH-11, without interferon-gamma pretreatment in vitro. LY294002 caused a decrease of phosphorylated-Akt and an inhibition of cell proliferation via cell cycle arrest in the G0/G1 phase by P27/Kip1 accumulation, but there was no obvious induction of apoptosis. The simultaneous treatment of LY294002 and CH-11 significantly induced apoptosis confirmed by morphology and DNA ladder formation. Decreased phosphorylated-Akt by LY294002 treatment led to a down-regulation of Mcl-2 and phosphorylated Bad proteins, which are anti-apoptotic factors and belong to the Bcl-2 family. On the other hand, expression levels of the other anti-apoptotic factors, such as FLICE-inhibitory protein (FLIP), Bcl-2 and Bcl-XL, which are associated with the Fas-mediated apoptotic signal pathway, did not change after LY294002 treatment. We concluded that: 1) the PI3K-Akt pathway plays an important role in preventing Fas-mediated apoptosis; and 2) a PI3 K inhibitor, such as LY294002, might be a useful anti-tumoral agent for gastric carcinoma.
TL;DR: It is concluded that overexpression of antiapoptotic proteins B cl-2 and Bcl-XL and down-regulation of caspase-3 activity may be associated with cisplatin resistance in human ovarian cancer.
Abstract: Resistance to cisplatin is the main reason for treatment failure in ovarian cancer. Apoptosis is the main mechanism of action of most cancer chemotherapeutic agents. The apoptosis-associated proteins expressed in cisplatin-sensitive (A2780, COC1) and -resistant (A2780/DDP, COC1/DDP) ovarian cancer cell lines, as well as their effects on caspase-3 activity in these cells, were studied by reverse transcriptase polymerase chain reaction and Western blot analysis. The apoptotic ratios of A2780, COC1, A2780/DDP, and COC1/DDP cells after treatment with cisplatin were measured by flow cytometry. Expression of Bcl-2 and Bcl-XL in A2780/DDP and COC1/DDP cells was significantly higher than that in A2780 and COC1 cells, respectively. Expression of Bax and Bcl-Xs did not differ in cisplatin-resistant and -sensitive cells. Caspase-3 activity was reduced markedly and apoptotic ratios were significantly lower in A2780/DDP and COC1/DDP cells than in A2780 and COC1 cells after treatment with cisplatin. We conclude that overexpression of antiapoptotic proteins Bcl-2 and Bcl-XL and down-regulation of caspase-3 activity may be associated with cisplatin resistance in human ovarian cancer.
TL;DR: Good sensitivity and specificity for the detection of primary and secondary liver lesions which is superior to ultrasound and CT scan but not to MRI scan is demonstrated.
Abstract: Outcome of patients with metastatic disease mainly depends on accurate preoperative tumor staging. 18[F]fluorodeoxyglucose positron emission tomography (18F-PET) has been proven to be a valuable diagnostic tool in a number of different tumors but its direct influence on liver surgery has not been thoroughly investigated. Between July 1999 and March 2000, 50 consecutive patients with 174 suspected liver lesions were admitted to the University Hospital Jena. All 50 patients underwent abdominal ultrasound, CT-scan, and 18-FDG positron emission tomography scanning. In 23 patients the diagnostic work-up was completed by MRI scan. Altogether there were a total of 174 histologically proven intrahepatic lesions, nine of which were benign. The sensitivity, specificity, and positive predictive value of PET for all hepatic lesions was 82%, 25%, and 96% compared with 63%, 50%, and 96% for abdominal ultrasound, 71%, 50%, and 97% for CT-scan, and 83%, 57%, and 97% for MRI-scan. In 23 of 50 patients 24 extrahepatic lesions were identified. In these patients the sensitivity and specificity of PET—compared to abdominal ultrasound, CT-scan, and MRI-scan for all extrahepatic lesions—was 63% and 60%, 29% and 25%, 47% and 50% and 40% and 50%, respectively. The findings on PET scan had a direct impact on operative management in nine patients (18%). Our series demonstrates good sensitivity and specificity for the detection of primary and secondary liver lesions which is superior to ultrasound and CT scan but not to MRI scan. The main value of PET scan consists in the detection of extrahepatic tumor (64%). Due to better detection of extrahepatic tumor, FDG-PET is a very useful addition to the currently used anatomically-based images in all cases of advanced tumor spread with high risk of extrahepatic tumor.
TL;DR: Interestingly there is diversity seen in VEGF expression amongst the various histologic subtypes of STS, and LMS, CS, and MFH are more likely to reveal overexpression of V EGF than the other histologicSubtypes, except LMS.
Abstract: To evaluate the prevalence and role of vascular endothelial growth factor (VEGF) overexpression in soft tissue sarcoma (STS). VEGF expression was detected by the avidin-biotin-complex method using Santa Cruz biotechnology (SC 7629). The expression of VEGF was assessed according to the percentage of immunoreactive cells: more than 10% of the cells staining were graded as positive. No detectable staining or <10% (of cells) staining was graded as negative. Two hundred and seventy-three patients (164 females and 109 males) with a mean age of 56 years (range: 1–93 years) were included in the study. Sixty-eight of the 273 (24.91%) patients diagnosed with STS between 1986 and 2001 revealed VEGF overexpression. VEGF overexpression was predominantly seen in 30% (15/50) of patients with malignant fibrous histiocytoma (MFH), 20.45% (9/44) of dermatofibrosarcomas (DFS), 25% (9/36) of leiomyosarcomas (LMS), and 30% (6/20) of patients with carcinosarcomas (CS). Despite overexpression being seen in about a quarter of patients with STS, VEGF overexpression was of prognostic value in only those patients with the LMS histologic type, as VEGF overexpression was associated with a shorter survival in this subgroup(P=0.01, by log-rank sum test). Twenty-four point nine per centof STS overexpress VEGF and interestingly there is diversity seen in VEGF expression amongst the various histologic subtypes of STS. LMS, CS, and MFH are more likely to reveal overexpression of VEGF than the other histologic subtypes. There was no relationship between survival and VEGF status in any subtype of STS, except LMS. There is an urgent need for larger studies to validate our findings. In addition, randomized clinical trials evaluating the efficacy of angiogenesis inhibitors in soft tissue sarcomas, especially LMS, are warranted.
TL;DR: An EGFR negative/c-KIT positive staining pattern is typical of thymic carcinoma, whereas thymomas are generally EGFR positive/c -KIT negative.
Abstract: Purpose
Promising new therapies for neoplasia include tyrosine kinase receptor antagonists. Tyrosine kinase oncogenes present an appealing anti-tumor drug target since they play an integral role in a variety of cellular responses including cell proliferation and differentiation. We previously demonstrated a high rate of epidermal growth factor receptor (EGFR) expression in advanced-stage thymic epithelial tumors. More recently, we have examined c-KIT (CD117) expression in a similar series of tumors.
TL;DR: The findings suggest that perindopril has no direct cytotoxicity against tumor cells, but has a potential to inhibit tumor growth due to suppression of VEGF-induced angiogenesis in vivo.
Abstract: Recently, it has been reported that angiotensin-I converting enzyme (ACE) inhibitors have anticancer activity. In particular, the ACE inhibitor, perindopril, significantly inhibits tumor growth and angiogenesis in hepatocellular carcinoma cells along with suppression of the VEGF level. However, the mechanisms of suppression of the VEGF level are still unclear, and there are no previous reports on this subject related to head and neck squamous cell carcinoma (HNSCC). In some previous studies, angiotensin II, which is produced from angiotensin I by ACE, directly stimulates VEGF expression. In the present study, we focused upon angiotensin II, and investigated the effect of perindopril on VEGF expression, angiogenesis, and tumor development of HNSCC with in vitro and in vivo studies. In the in vitro cell proliferation assays, there was no significant difference between the perindopril-treated group and the control group. However, the perindoprilat-treated group showed a significant reduction in mRNA expression of VEGF and inhibited the induction activity of the VEGF promoter in comparison to the control group. Perindoprilat treatment also significantly suppressed angiotensin II production in vitro. In the in vivo studies, perindopril had a significant inhibitory effect on tumor growth, and reduced blood vessel formation surrounding the tumors. Our findings suggest that perindopril has no direct cytotoxicity against tumor cells, but has a potential to inhibit tumor growth due to suppression of VEGF-induced angiogenesis in vivo. Angiotensin II might have an important role in carcinogenesis, and the antiangiogenic activity of perindopril is at least partly mediated by angiotensin II inhibition. The ACE inhibitor perindopril has clinical potential as a useful antitumor agent.
TL;DR: Results suggest that PPARγ levels are not correlated with the rates of cell proliferation, and it is suggested that differentiation induction by TGZ was only observed in the cell lines with enhancedPPARγ expression.
Abstract: We investigated the relationship between the effects of troglitazone (TGZ) on cellular growth, differentiation and apoptosis induction, and the induction of peroxisome proliferator-activated receptor (PPAR) γ in three human colon cancer cell lines, HCT-15, DLD-1and LoVo. Viable cell number was evaluated by the Alamar blue assay and apoptotic cell death by TUNEL methods. Expression of PPARγ mRNA and protein was examined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot, respectively. The differentiation markers of colonic mucosa, villin and MUC2 mRNAs, were analyzed by real-time RT-PCR. HCT-15 and DLD-1 cells proliferated rapidly while LoVo cells grew slowly. TGZ dose-dependently inhibited the proliferation of all the cell lines, and also induced apoptotic cell death. High expression of PPARγ mRNA and protein was demonstrated in DLD-1 and LoVo cells before TGZ treatment. After the treatment, PPARγ mRNA and protein levels were increased in HCT-15 and LoVo cells. Villin and MUC2 mRNAs were increased by TGZ treatment in HCT-15 cells while villin mRNA was repressed in LoVo cells. Changes in expression of PPARγ, villin or MUC2 mRNAs were not observed in DLD-1 cells. These results suggest that PPARγ levels are not correlated with the rates of cell proliferation. Differentiation induction by TGZ was only observed in the cell lines with enhanced PPARγ expression.
TL;DR: Insulin resistance/hyperinsulinemia is associated with a more aggressive course of the disease in certain groups of the patients but—in contrast to excessive estrogenic stimulation—does not result in increased genotoxic damage in tumor and normal tissues.
Abstract: To study the frequency of insulin resistance (IR) in endometrial cancer patients, its relation to the clinical course of the disease and DNA damage, and to evaluate possible approaches to the pharmacological correction of IR in the patients studied. The signs of insulin resistance syndrome and its association with the clinical and pathological features of the disease and DNA damage in somatic cells (micronucleus frequency in peripheral blood lymphocytes) and endometrial normal and tumor tissue (alkaline unwinding) were determined in 99 endometrial cancer patients. The frequency of insulin resistance syndrome counted on the basis of fasting plasma glucose and insulin concentrations according to Duncan et al. is equal to 0.35 (95% CI 0.24–0.46), or 35%, in endometrial cancer patients who do not have a history of diabetes mellitus. Patients with well- or moderately differentiated endometrial adenocarcinomas (mostly type I) had statistically significantly higher basal and stimulated plasma insulin and C-peptide concentrations than patients with poorly differentiated endometrial adenocarcinomas or rarely encountered tumors of the endometrium (primarily type II). Interestingly, the level of fasting insulinemia positively correlates with disease stage and with local and regional tumor dissemination only in the group of patients with well- or moderately differentiated endometrial adenocarcinomas. On the other hand, hyperinsulinemia and other hormonal-metabolic disturbances typical of insulin resistance syndrome do not increase the probability of DNA damage of somatic cells (according to the data of micronucleus test). In addition, no association between hormonal-metabolic disturbances and the degree of DNA unwinding in tumor and visually unchanged endometrium was found. Thus, insulin resistance/hyperinsulinemia is associated with a more aggressive course of the disease in certain groups of the patients but—in contrast to excessive estrogenic stimulation—does not result in increased genotoxic damage in tumor and normal tissues. The data obtained once more confirm the need for treatment and prevention measures aimed at correcting hormonal-metabolic disturbances in endometrial cancer patients and groups at risk of this disease. Such an approach might include use of antidiabetic biguanides, thiazolidinediones (glitazones), and statins.
TL;DR: The progressive decline in ERβ expression paralleled the increase in tumor grade, suggesting its decreased expression may play an important role in astrocytic tumor initiation and in the potential response of glial neoplasms to tamoxifen.
Abstract: Estrogen receptor β (ERβ) is the second identified receptor mediating the effects of estrogen on target tissues. The role of ERβ in cancer pathobiology is largely unknown, because specific antibodies have not been available until recently. Initial studies have shown that ERβ expression declines in breast, ovarian, prostatic, and colon carcinomas. Tamoxifen, a synthetic anti-estrogen compound that is a mixed agonist/antagonist of estrogen receptor α (ERα) and a pure antagonist of ERβ, has moderate beneficial effects in human astrocytic neoplasms. However, most published studies agree that glial tumors do not express ERα. The purpose of this study was to explore the expression of ERβ in astrocytic neoplasms. ERβ expression was monitored immunohistochemically in 56 cases of astrocytomas of all grades (grade I–IV) and in adjacent non-neoplastic brain tissue. Moderate or strong nuclear immunopositivity was obtained in non-neoplastic astrocytes and in low-grade astrocytomas, whereas the majority of high-grade tumors were immunonegative or displayed weak immunoreactivity. The progressive decline in ERβ expression paralleled the increase in tumor grade. In as much as ERβ is possibly the only ER expressed in astrocytes, its decreased expression may play an important role in astrocytic tumor initiation and in the potential response of glial neoplasms to tamoxifen.
TL;DR: The level of comorbidity has an influence on the 3-year survival of postmenopausal women with breast cancer and long-term follow-up is required to appraise these findings in relation to treatment strategies.
Abstract: The aim was to assess the impact of comorbidity on survival of postmenopausal women with breast cancer diagnosis in the period 1995–1997. The level of comorbidity was described by the methods suggested by Satariano and Charlson. Cox’s proportional hazard models were used to explore the impact of comorbidity on all-cause mortality. After a median follow-up time of 52 months, an increasing level of comorbidity was associated with a higher all-cause mortality. Compared to patients without comorbid conditions, the hazard ratio of death (HR) was 1.2 (95% CI: 0.8–1.7) for Satariano index 1 and HR 2.3 (95% CI: 1.5–3.5) for Satariano index ≥2, and HR 1.6 and 2.1 for the Charlson comorbidity index, respectively. Independent of comorbidity, the treatment pattern had a strong impact on survival. The level of comorbidity has an influence on the 3-year survival of postmenopausal women with breast cancer. Long-term follow-up is required to appraise these findings in relation to treatment strategies.
TL;DR: It is demonstrated that gefitinib is able to suppress invasion and proliferation of AI-PC cells by suppressing EGF-stimulated activation of the PI3 K/AKT pathway and support a possible use of the drug in the treatment of advanced PC to limit not only proliferation but also invasion to other districts.
Abstract: Androgen-independent prostate cancer (AI-PC) is characterized by a higher invasive potential compared to hormone-responsive prostate cancer. A therapeutic option for AI-PC should thus be targeted to suppress not only cell proliferation, but also the invasive ability of the cells. Here, we investigated the effect of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib (‘IRESSA’, ZD1839) on EGF-stimulated invasion and proliferation in two androgen-independent prostate cancer cell lines PC3 and DU145. In addition, we determined the effect of the compound on EGF-stimulated PI3 K/AKT pathway activation, in view of the key role exerted by this pathway in carcinoma cell invasion. Cell proliferation was determined by thymidine incorporation in the nuclei. Cell cycle analysis was performed by flow cytometry. Invasion through matrigel in vitro was measured by using Boyden chambers. PI3 K activity was measured by immunokinase assay and AKT phosphorylation was evaluated by Western blot analysis. Gefitinib inhibits invasion through matrigel and collagen in response to EGF in both cell lines. In addition, we confirm the inhibitory effect of the compound on basal and EGF-induced cell proliferation. Such an effect was accompanied by accumulation of the cells in the G0/G1 phase of the cell cycle. The effect of the compound is due, as expected, to suppression of EGF-induced autotransphosphorylation of EGFR. In addition, we demonstrate here that gefitinib inhibits EGF-induced activation of PI3 K/AKT pathway in both cell lines. Overall, our results demonstrate that gefitinib is able to suppress invasion and proliferation of AI-PC cells by suppressing EGF-stimulated activation of the PI3 K/AKT pathway and support a possible use of the drug in the treatment of advanced PC to limit not only proliferation but also invasion to other districts.
TL;DR: Most eye metastases of breast cancer are located in the choroidea, while an extrabulbar localization within the orbit is rare, with only 3–10% of all ocular metastases.
Abstract: Intraorbital metastases of solid tumors are a rarely diagnosed clinical condition, even though pathological reports suggest an incidence of up to 30% in cancer patients. We report two cases of intraorbital, extraocular metastases in breast cancer. The first patient was a 45-year-old man who presented with diplopia, upward divergence of the left bulb, and local pain. In the standard cerebral magnetic resonance imaging (MRI) no cerebral or ocular tumor was detectable. A subsequent T1-weighted, contrast-enhanced orbital MRI with fat suppression revealed an infrabulbar mass of 18×13 mm in size. The second patient, a 59-year-old woman, complained of slight diplopia when looking to the left. Cerebral MRI with fat suppression showed a retrobulbar mass with 17×13 mm. In both patients metastatic breast cancer was known for several years, and both had been in a stable disease situation. Both patients were treated with stereotactic radiation, applying a cumulative dose of 35 and 45 Gy, respectively, which resulted in marked improvement of local symptoms. Most eye metastases of breast cancer are located in the choroidea, while an extrabulbar localization within the orbit is rare, with only 3–10% of all ocular metastases. Autopsy reports reveal that an estimated 10–30% of breast cancer patients develop this form of metastasis. This is in strong contrast to rare clinical case reports, suggesting frequently absent to mild clinical signs and difficult diagnosis. If breast cancer patients complain of ophthalmological symptoms such as local pain, impaired vision, or diplopia, it is important to consider ocular or orbital metastatic disease.
TL;DR: In this preliminary report of a limited patient population, the ability to safely deliver a platinum agent to individuals with either documented carboplatin hypersensitivity, or a high risk for this potentially serious toxicity ofcarboplatin is demonstrated.
Abstract: Carboplatin hypersensitivity is an increasingly recognized toxicity in individuals receiving >6 cumulative courses of this important antineoplastic agent. We wished to determine if a novel multi-pronged approach to re-treating patients with a high risk for this potentially serious side effect could permit the safe delivery of this class of cytotoxic drugs. Five patients with gynecologic malignancies who had either experienced a documented carboplatin hypersensitivity reaction (n =4) or had a “positive” carboplatin skin test (n =1), received a multi-drug oral regimen administered over several days which was designed to block known mediators of anaphylaxis. Four of these individuals subsequently underwent treatment with either cisplatin or carboplatin employing a “dose escalation” desensitization schema. Four patients underwent successful treatment with either cisplatin or carboplatin (3, 4, 5, 6+ total additional courses) without any further evidence of hypersensitivity. In this preliminary report of a limited patient population, we have demonstrated the ability to safely deliver a platinum agent to individuals with either documented carboplatin hypersensitivity, or a high risk for this potentially serious toxicity of carboplatin. Further exploration of this novel management strategy in a larger group of patients is indicated.
TL;DR: Work of the past decade has clearly established Cox-2 and a subset of prostanoids and their receptors as crucial players in oncogenesis that regulate, and are regulated by, pathways with essential functions inoncogenesis.
Abstract: The cyclooxygenases Cox-1 and Cox-2 are the ratelimiting enzymes in the synthesis of all prostanoids from arachidonic acid (Smith et al. 2000). While Cox-1 is expressed constitutively in a subset of cell types, Cox-2 is highly regulated by transcriptional and post-translational mechanisms in response to a plethora of stimuli. Induction of Cox-2 triggers the synthesis of different prostanoids that play essential roles in many physiological processes and responses, such as inflammation, pain, fever, and platelet aggregation. Cyclooxygenases catalyze a two-step reaction that converts arachidonic acid to prostaglandin H2 (PGH2) which in turn serves as the precursor for the synthesis of all biologically active prostanoids: PGD2, PGE2, PGF2, prostacyclin (PGI2), 15-deoxy-D-PGJ2, and thromboxane A2 (Fig. 1). Work of the past decade has clearly established Cox-2 and a subset of prostanoids and their receptors as crucial players in oncogenesis that regulate, and are regulated by, pathways with essential functions in oncogenesis. This article will provide a review of the literature covering this area of research.
TL;DR: Identification of AR-positive gastric carcinomas in gastric biopsies may warrant a more aggressive therapeutic approach and anti-androgen or AR-targeted agents may represent a novel strategy in tackling this devastating malignancy.
Abstract: To investigate the expression of sex steroid receptors in gastric cancer and to correlate their tumor expression profile with the clinicopathological parameters and overall survival of the patients. Immunohistochemical methodology was employed in formalin-fixed paraffin-embedded sections from 86 patients with gastric carcinoma. Monoclonal antibodies against androgen (AR), estrogen (ER), and progesterone (PR) receptors were used. Survival rates were estimated by the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis was performed by the Cox proportional hazards model. Fifteen (17.4%) cases of gastric adenocarcinomas were positive for AR, two (2.3%) were positive for PR and three (3.5%) were positive for ER. Significantly higher AR expression was found in tumors with metastases to lymph nodes (P = 0.03). Patients with AR-positive tumors (AR+) had worse prognosis than (AR-) patients (median survival 9 months vs 24 months, P = 0.03). Patients with AR- and heat shock protein 27 (HSP27)-positive tumors (AR+/HSP27+) had a median survival of 6 months, whereas (AR-/HSP27-) patients had a median survival of 42 months (P = 0.017). Multivariate analysis revealed that AR expression and UICC stage were independent factors of unfavorable prognosis (P = 0.037 and P = 0.0055, respectively). Identification of AR-positive gastric carcinomas in gastric biopsies may warrant a more aggressive therapeutic approach and anti-androgen or AR-targeted agents may represent a novel strategy in tackling this devastating malignancy.
TL;DR: The β-glucuronidase inhibitor SAL is able to significantly reduce CPT-11-induced mucosal damage in the small intestine of rats, and might soon have a clinical impact for the treatment of patients with C PT-11.
Abstract: Purpose
To evaluate the ability of D-saccharic acid 1.4-lactone (SAL), a β-glucuronidase inhibitor, to prevent irinotecan hydrochloride (CPT-11) from inducing mucosal damage as a cause of diarrhea in rats.