Biomedical subjects
Publications and source records attributed to B Arun.
We report a case of angioleiomyoma of the spermatic cord. Tumours arising from the spermatic cord are rare and most of them are benign. The commonest are lipomas with sarcomas being the predominant malignant variety. This is the first reported case of angioleiomyoma of the spermatic cord.
The pathogenesis of breast cancers that do not express estrogen receptors or Her-2/neu receptors (ER-/HER2- phenotype) is incompletely understood. We had observed markedly elevated gene expression of gamma-aminobutyric acid type A (GABA(A)) receptor subunit pi (GABApi, GABRP) in some breast cancers with ER-/HER2- phenotype. In this study, transcriptional profiles (TxPs) were obtained from 82 primary invasive breast cancers by oligonucleotide microarrays. Real-time reverse transcription-polymerase chain reaction (RT-PCR) was used to measure GABApi gene expression in a separate cohort of 121 invasive breast cancers. GABApi gene expression values from TxP and RT-PCR were standardized and compared with clinicopathologic characteristics in the 203 patients. GABApi gene expression was increased in 16% of breast cancers (13/82 TxP, 20/ 121 RT-PCR), particularly in breast cancers with ER-/HER2- phenotype (60%), and breast cancers with basal-like genomic profile (60%). The profile of genes coexpressed with GABApi in these tumors was consistent with an immature cell type. In multivariate linear regression analysis, the level of GABApi gene expression was associated with ER-/HER2- phenotype (P < 0.0001), younger age at diagnosis (P = 0.0003), and shorter lifetime duration of breastfeeding (< or = 6 months) in all women (P = 0.017) and specifically in parous women (P = 0.013). GABApi gene expression was also associated with combinations of high grade with ER-/HER2- phenotype (P = 0.002), and with Hispanic ethnicity (P = 0.036). GABApi gene expression is increased in breast cancers of immature (undifferentiated) cell type and is significantly associated with shorter lifetime history of breastfeeding and with high-grade breast cancer in Hispanic women.
Studies have shown that COX-2 is up-regulated in several epithelial carcinomas. In this study, we wish to elucidate if endometrial cyclooxygenase-2 (COX-2) expression in endometrial adenocarcinoma is increased relative to normal endometrium. Thirty-six deparaffinized tissue sections from patients with endometrial adenocarcinoma were analyzed by immunohistochemistry for the presence of COX-2. A control group consisted of 13 age-matched patients without malignancy, who underwent surgery for uterine prolapse. Statistical analysis was performed using the Kruskal-Wallis test; differences between groups were evaluated using the Fisher's Exact Test. We found that COX-2 expression was markedly increased in 13 of 36 patients (36.1%) with endometrial adenocarcinoma: in contrast only one of 13 (7.7%) control patients demonstrated increased COX-2 expression (p < or = 0.05). Eight of the 13 COX-2 positive patients in the study had well differentiated adenocarcinoma; the remaining five COX-2 positive patients had moderately and poorly differentiated adenocarcinoma (4 and 1, respectively). In conclusion, COX-2 expression in the endometrium is associated with endometrial adenocarcinoma, especially of the well differentiated type. This may provide an avenue for chemoprevention of endometrial adenocarcinoma. In addition, with new selective inhibitory drugs being developed, inhibition of COX-2 may play an adjunctive role approach to standard therapy, especially for well-differentiated endometrial carcinoma. Further studies are required to investigate the role of COX-2 expression in carcinogenesis.
PURPOSE: The goal of this study was to examine the feasibility of developing a multigene predictor of pathologic complete response (pCR) to sequential weekly paclitaxel and fluorouracil + doxorubicin + cyclophosphamide (T/FAC) neoadjuvant chemotherapy regimen for breast cancer. PATIENTS AND METHODS: All patients underwent one-time pretreatment fine-needle aspiration to obtain RNA from the cancer for transcriptional profiling using cDNA arrays containing 30721 human sequence clones. Analysis was performed after profiling, and 42 patients' clinical results were available, 24 of which were used for predictive marker discovery; 18 patients' results were used as an independent validation set. RESULTS: Thirty-one percent of patients had pCR (six discovery and seven validation), defined as disappearance of all invasive cancer in the breast after completion of chemotherapy. We could identify no single marker that was sufficiently associated with pCR to be used as an individual predictor. A multigene model with 74 markers (P <or=.09) was built using data from the discovery samples and tested on the validation samples. Overall, a 78% (14 of 18) predictive accuracy was observed, with a 100% (three of three) positive predictive value for pCR, a 73% (11 of 15) negative predictive value, a sensitivity of 43% (three of seven), and a specificity of 100% (11 of 11). The expected response rate to T/FAC neoadjuvant therapy in unselected patients is 28%. CONCLUSION: Our results suggest that transcriptional profiling has the potential to identify a gene expression pattern in breast cancer that may lead to clinically useful predictors of pCR to T/FAC neoadjuvant therapy.
Breast cancer is a significant global health problem. It is the most common malignancy in women. Mammographic screening is recommended for women older than 40 yr for early detection of breast cancer. The aim of this study is to evaluate the role of screening mammography in ovarian cancer independent of age. Eighty-four patients with ovarian cancer were evaluated with bilateral mammography. Two hundred asymptomatic healthy controls with a similar age distribution were also imaged with screening mammography. Mammography results were classified according to the American College of Radiology criteria in five groups. The median age of the study group was 51.4 (range, 27-77) and 49.3 (range, 30-75) in the control group. Screening mammography detected four cases of malignancy (4.8%) in patients with ovarian cancer; two were the primary breast carcinomas(2.5%) and two were metastatic cancers from the ovary. Five subjects (2.5%) among healthy controls were also found to have breast cancer. Although the incidence of primary breast carcinoma was found to be similar in the two groups (2.5%), mammographic imaging detected metastatic disease to the breast from the ovaries. Mammography should therefore be considered in patients with ovarian cancer independent of age.
Over the past years there have been significant advances in breast cancer treatment and early detection. For the first time, a decrease in cancer mortality has been observed. Recently, much progress has been made in the understanding of carcinogenesis partly due to available new technologies to detect early molecular changes in the tissue. The knowledge of breast cancer carcinogenesis has provided possible opportunities to prevent breast cancer. Currently, several clinical breast cancer prevention trials are ongoing. This paper reviews issues related to breast cancer chemoprevention including identification of high risk cohorts, endpoint biomarkers, current and new chemopreventive agents as well as models to evaluate these agents.
Endothelin-1 (ET-1) is a potent mitogen in various precursor tumor cells, including endometrial adenocarcinoma. It is proposed that ET-1 produced by endometrial adenocarcinoma may participate in the angiogenesis of this carcinoma in vivo. Endothelin converting enzyme-1 (ECE-1) is the key enzyme that synthesizes ET-1. In this study, we tried to demonstrate the expression of ECE-1 in endometrial carcinomas. Deparaffinized tissue sections from patients with endometrial adenocarcinoma were analyzed by immunohistochemistry for the presence of ECE-1. Our study showed that the expression of ECE-1 was markedly increased in 9 of 15 (60%) well-differentiated endometrial adenocarcinomas; in contrast, only 2 out of 10 (20%) control specimens showed a mild labeling. With new selective inhibitory molecules emerging, research is currently evaluating the possible inhibition of ECE-1 as an alternative approach for the treatment of endometrial as well as other carcinomas.
Topoisomerase I (topo-I) inhibitors are a new class of anticancer agents with a mechanism of action aimed at interrupting DNA replication in cancer cells, the result of which is cell death. Most, if not all, topo-I inhibitors are derivatives of the plant extract camptothecin. Topotecan is a derivative of camptothecin which has been structurally modified to increase water solubility. The pharmacokinetic profile of topotecan is usually characterised by a two-compartment model and is linear in the dose range of 0.5 - 3.5 mg/m(2). Current clinical trials suggest antitumour activity against a variety of human tumour types, including ovarian cancer, non-small cell lung cancer (NSCLC) and non-lymphocytic haematologic malignancies. The main dose-limiting toxicity (DLT) is non-cumulative myelosuppression. Non-haematologic toxicities are usually mild. Based on several Phase I studies, the recommended Phase II dose was 1.5 mg/m(2)/day iv. for 5 days. Current Phase I and Phase II trials are evaluating the combination of topotecan with other chemotherapeutic agents to increase the therapeutic benefits of topotecan. The DLT in these trials is mainly myelosuppression.
Anemia is a frequent complication of cancer and its treatment. A defect in erythropoietin production has been advocated as being the main cause of anemia in cancer patients. We studied serum erythropoietin levels in 74 patients with solid tumors and in a control group consisting of 20 otherwise healthy individuals without any malignancy, who have only iron deficiency anemia. Serum erythropoietin levels were measured by enzyme immunoassay in cancer patients without anemia (n=34), and in anemic cancer patients (n=40); either receiving chemotherapy (n=21) or not (n=19). Anemic cancer patients were found to have decreased response of erythropoietin for a given hemoglobin level (mean, 40.1+/-34.7 u/ml), compared with the patients having only iron deficiency anemia (mean, 69.7+/-68.6 u/ml) (P<0.05). In patients with iron deficiency anemia having no malignancy, erythropoietin response was remarkably high and inversely correlated with the level of hemoglobin (r=-0.69; P=0. 05). Although there was no correlation between hemoglobin and erythropoietin response in cancer anemia (r=-0.07), serum levels of erythropoietin were found to be higher in anemic cancer patients (mean, 40.1+/-34.7 u/ml), compared with cancer patients with normal hemoglobin values (mean, 19.96+/-18.4 u/ml). There was not any statistically significant difference between erythropoietin levels in anemic cancer patients with or without chemotherapy (mean, 43. 7+/-37.7 u/ml and 41.9+/-30.08 u/ml respectively; P>0.05). No difference in serum erythropoietin levels were noted in patients treated with cisplatin or non-cisplatin containing regimens (mean, 48.36+/-33.12 u/ml and 38.55+/-43.52 u/ml, respectively; P>0.05). In this study, we demonstrated that anemia in cancer patients was caused by blunted erythropoietin response, rather than its quantitative deficiency. Serial measurements, however, should be considered in patients receiving chemotherapy.
BACKGROUND: The authors retrospectively determined the clinical outcome of patients with inflammatory breast carcinoma (IBC) treated with high dose chemotherapy (HDC) and autologous bone marrow (ABM) or peripheral blood stem cell (PBSC) support. METHODS: Twenty-four consecutive patients with IBC received HDC, including escalating doses of carboplatin (range, 1.2-1.8 g/m2) and cyclophosphamide (range, 4.8-6.0 g/m2) over 3 days followed by ABM (n=5) or PBSC infusion (n=19). Restaging evaluation was performed 100 days after transplant, every 6 months for 2 years, and then yearly thereafter. After transplantation, fifteen patients received immunotherapy with interleukin-2 (IL-2) or IL-2 and interferon-alpha. RESULTS: The 2-year estimated disease free survival (DFS) and overall survival (OS) for these patients were 71% (90% confidence interval [CI], 55-87%) and 73% (90% CI, 53-93%), respectively. The median follow-up of surviving patients was 19 months (range, 8-68 months). Six patients developed disease recurrence at a median of 10 months (range, 4-16 months) after transplantation. Four of these 6 patients died from metastatic disease at a median of 18 months (range, 14-21 months). Using the generalized Wilcoxon test and the Cox proportional hazards regression model, patients with tumors that demonstrated estrogen receptors had an improved DFS (P=0.03). CONCLUSIONS: Combining HDC and ABM or PBSC for patients with IBC may yield an improved OS and DFS.
We previously demonstrated findings suggestive of autologous GVHD in patients receiving IL-2-activated peripheral blood stem cells (PBSC) with IL-2 after transplantation. A pilot study was designed to test tolerability, feasibility and frequency of autologous GVHD and engraftment using IL-2 and alpha-IFN post-transplantation. After cyclophosphamide (6 g/m2) and carboplatin (1800 mg/m2), patients with high-risk stage II or III breast cancer received chemotherapy and rhG-CSF mobilized autologous PBSC that had been cultured in IL-2 for 24 h. Subcutaneous administration of IL-2 began on day 0 at 6 x 10(5) IU/m2/day for 5 of 7 days each week and continued for 4 weeks. Once engraftment occurred, alpha-IFN was initiated at a dose of 1 x 10(6)/m2/day subcutaneously for 30 days. Thirty-four consecutive patients with stage II (n=20), IIIA (n=6) and IIIB (n=8) disease were treated. All patients were without evidence of disease at the time of transplantation. The average time required for the ANC to reach 500/mm3 was 10 days (range: 8-11 days) and for platelets to reach 20000/mm3 was 10.7 days (range: 6-21 days). Forty-seven percent of patients (n=16) completed the full course of immunotherapy; the remaining patients received attenuated doses due to patient's request (n=6), development of temperature >38 degrees C (n=3), development of neutropenia (n=3), serious infection (n=1) and miscellaneous reasons (n=5). Four patients experienced transient moderate toxicities (level 3) including elevated liver function tests, nausea, rash and capillary leak syndrome. Pathological findings suggestive of skin GVHD developed in 43% of patients (12/28 patients) when skin biopsies were evaluated in a blinded fashion. At 13 months post-transplant (median; range: 5-24 months), 28 patients (82%) remain disease-free. These results demonstrate the feasibility and toxicity of this regimen along with pathological findings compatible with autologous GVHD of the skin.
Antiphospholipid antibodies are strongly associated with thrombosis and appear to be the most common of the acquired blood protein defects causing thrombosis. Based upon our experience, approximately 25% of patients with unexplained venous thrombosis, approximately 60% of patients with cerebrovascular thrombosis, approximately 37% of patients with transient ischemic attacks, approximately 18% with premature coronary artery thrombosis and approximately 60% of patients with recurrent fetal loss (recurrent miscarriage syndrome) harbor antiphospholipid antibodies. Although the precise mechanism(s) whereby antiphospholipid antibodies alter hemostasis to induce a hypercoagulable state remain unclear, several theories have been advanced. Since the aPTT is unreliable in patients with lupus anticoagulant and is not usually prolonged in patients with anticardiolipin antibodies, definitive tests, ELISA for IgG, IgA and IgM anticardiolipin antibodies and the dilute Russel's viper venom time (followed by cephalin correction for confirmation) for lupus anticoagulant should be immediately ordered when suspecting the antiphospholipid syndrome in individuals with otherwise unexplained thrombotic or thromboembolic events or recurrent fetal loss. However, if one strongly suspects antiphospholipid thrombosis syndrome clinically and assays for lupus anticoagulants and anticardiolipin antibodies are negative, specific assays for all three idiotypes of phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, phosphatidylinositol and phosphatidylglycerol are available and should be considered. These may clearly be indicated for difficult diagnostic cases of fetal wastage syndrome, and cerebrovascular events, but their significance in other types of thrombosis, particularly venous, remains unclear at present. Since about 65% of patients with antiphospholipid antibodies will fail warfarin therapy (rethrombose), it is important to define this common defect and institute appropriate antithrombotic therapy for appropriate time periods.
Disseminated intravascular coagulation (DIC) is a complex disorder, with pathophysiology being variable and highly dependent upon the triggering event(s), host response(s) and comorbid conditions. As a result of these complicated interactions, the clinical expression and laboratory findings are varied, thereby affecting the specifics of diagnosis and therapeutic approaches. The highly complex and variable pathophysiology of DIC often results in a lack of uniformity in clinical manifestations, a lack of consensus in the specific appropriate laboratory criteria of diagnosis, and a lack of specific therapeutic modalities. Indeed, recommendations for therapy are often difficult because the morbidity and survival is more dependent on the specific cause of DIC and because the generally used specific therapeutic approaches, which include for example heparin, low-molecular-weight-heparin antithrombin concentrate and protein C concentrate, have never been subjected to objective prospective randomized trials, except antithrombin concentrates. An analysis of the complex and varied pathophysiological events in DIC provide objective guidelines and criteria for the clinical diagnosis, the laboratory diagnosis, and the definition of severity. These data compounded by an understanding of complex and varied pathophysiology can be used for objective evaluation of therapeutic responses and results. DIC is an intermediary mechanism of disease usually seen in association with well-defined clinical disorders. The pathophysiology of DIC serves as an intermediary mechanism in many disease processes, which sometimes remain organ specific. This catastrophic syndrome spans all areas of medicine and presents a broad clinical spectrum that is confusing to many. Most physicians consider DIC to be a systemic hemorrhagic syndrome; however, this is only because hemorrhage is evident and often impressive. Less commonly appreciated is the profound microvascular thrombosis and sometimes, large vessel thrombosis. The hemorrhage is often simple to contend with in patients with fulminant DIC, but it is the small- and large-vessel thrombosis, with impairment in blood flow, ischemia, and associated end-organ damage that usually leads to irreversible morbidity and mortality. In conclusion, the pathophysiological mechanisms, clinical, and laboratory manifestations of DIC are complex in part due to interrelationships within the hemostasis system. Only by clearly understanding these extraordinarily complex pathophysiological interrelationships can the clinician and laboratory scientist appreciate the divergent and wide spectrum of often confusing clinical and laboratory findings in patients with DIC. Many therapeutic decisions to be made are controversial and lack validation. Nevertheless, newer antithrombotic agents, and agents which can block, blunt or modify cytokine activity and the activity of vasoactive substances appear to be of value. The complexity and variable degree of clinical expression suggests that therapy should be individualized depending on the nature of DIC, age, etiology of DIC, site and severity of hemorrhage or thrombosis and hemodynamics and other appropriate clinical parameters.
This study was undertaken to investigate a possible association of anticardiolipin antibodies (ACLAs) in cancer patients with thromboembolic events. Twenty-five patients with solid tumors complicated with acute thrombosis, 36 cancer patients without any thrombotic events, and a group of 20 healthy volunteers without thrombosis or malignancy were included. The mean age of the cancer patients with and without thrombosis and healthy subjects were 50 years (range 20-75), 45 years (range 23-66), and 40 years (range 20-68), respectively. Deep venous thrombosis (n = 16) and thrombosis of the central venous port-catheter systems (n = 9) were confirmed by Doppler sonography in all patients. IgG and IgM isotypes of ACLAs were quantitated by enzyme-linked immunosorbent assay with normal levels of < 23 GPL and < 11 MPL, respectively. Mean values of IgG ACLAs were found similar in cancer patients with acute thrombosis (13.8 +/- 4.9 GPL), without thrombosis (12.8 +/- 5.4 GPL) or in healthy subjects (14.8 +/- 5.5 GPL). Although the mean values of IgM ACLAs were within normal limits in all groups, cancer patients with thrombotic events had higher levels of IgM ACLAs (mean = 10.5 +/- 2.2 MPL) than cancer patients without thrombosis (mean = 4.6 +/- 2.4 MPL) (p = .01). Healthy subjects also had lower levels of IgM ACLAs (mean = 7.1 +/- 3.2 MPL) than cancer patients with thrombosis (p = .16). In addition, a higher percentage of cancer patients with or without thrombosis had IgM and IgG ACLA levels above normal limits compared with healthy controls. In conclusion, our study suggests an association between ACLAs or IgG and particularly IgM isotypes and venous thrombosis in malignancy. Identification of cancer patients who are at higher risk for developing thromboembolic events might lead to a better selection of patients for prophylactic anticoagulant therapy.
Tumor suppressor genes p53 and Rb are important in cell cycle control. Necessity of wild type p53 is implicated in irradiation-induced apoptosis. Numerous tumor cells carry p53 mutations and yet are sensitive to irradiation or chemotherapeutic agents. Therefore p53-and Rb-independent pathways must exist to account for irradiation-induced apoptosis. We evaluated the apoptotic response of a p53- and Rb-mutated, Human Papilloma Virus (HPV) negative cervical cancer cell line (C33a), and C33a cell lines infected with HPV 18 oncoproteins E6, E7, and E6&7 using recombinant retrovirus to various apoptosis-inducing agents including gamma irradiation, mitomycin C (MMC), and staurosporine (SSP). Apoptosis was measured by avidinebiotin tunnel staining method. Our results showed significant apoptosis in C33a cell lines in response to gamma-irradiation, MMC, and SSP. Moreover, apoptosis was enhanced when HPV 18 E6, and E6&7 infected C33a cell lines were treated with irradiation, MMC, and SSP. HPV 18 E7 infected C33a cell lines enhanced the apoptotic response to irradiation and to MMC, but not to SSP. In conclusion, our results imply the presence of a p53- and Rb-independent pathway in irradiation-induced apoptosis in cervical cancer cell lines: this effect is even more evident in HPV oncoprotein infected cell lines. The radiosensitizing effects of HPV oncoproteins may lead to new perspectives in the treatment of cervical cancer.
Loss of heterozygosity (LOH) at the mannose 6-phosphate/insulin-like growth factor 2 receptor gene locus (M6P/IGF2R) on 6q26-27 has recently been demonstrated in approximately 30% of both invasive and in situ breast cancers. LOH was coupled with somatic point mutations in the remaining allele in several instances, leading to the proposition that M6P/IGF2R is a tumor suppressor gene. Somatic mutations in M6P/IGF2R have also been described in hepatoma and gastrointestinal cancers with the replication error positive (RER+) phenotype. These data indicate that M6P/IGF2R loss of function mutations may be involved in the pathogenesis of a wide spectrum of malignancies. Extensive data on the normal function of the M6P/IGF2R suggest that loss of M6P/IGF2R activity may contribute to multiple aspects of tumor pathophysiology, including deregulated growth, apoptosis, angiogenesis and invasion.
A 46 year old male with acute promyelocytic leukemia treated with all-trans retinoic acid (ATRA), developed fever, bilateral erythematous nodules in his axillary area, lower abdomen and inguinal region. Histopathologic examination of the skin biopsy revealed dense neutrophil infiltration in the dermis without vasculitis. The diagnosis of Sweet's syndrome was made. High dose methylprednisolone was administered and the lesions started to improve within 24 hours.
An 'air pouch' technique of inducing highly localized, transplantable, estrogen-dependent adenocarcinomas of the mammary gland in Wistar rats with 7,12-dimethylbenzanthracene (DMBA) is described. The induction time was 67-80 days compared to 150-180 days by the conventional technique. Using this model estrogen receptor status, transplantation and effect of exogenous hormones on tumour growth have been studied. It is felt that this model might be a useful one for studying the biochemical mechanisms involved in hormone-dependent experimental mammary cancers.