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Biomedical subjects

J L Mansi

Publications and source records attributed to J L Mansi.

At least 19 recordsLinked to original sources
PubMed2004

A novel continuous infusional 5-fluorouracil-based chemotherapy regimen compared with conventional chemotherapy in the neo-adjuvant treatment of early breast cancer: 5 year results of the TOPIC trial.

BACKGROUND: To compare the efficacy of continuous infusional 5-fluorouracil (5-FU)-based chemotherapy against conventional bolus chemotherapy in the preoperative treatment of patients with large operable early breast cancer. PATIENTS AND METHODS: Four hundred and twenty-six women with histologically proven 3 cm invasive early breast cancer were randomised to receive pre-operative infusional 5-FU 200 mg/m(2) by daily 24 h continuous infusion via a Hickman line for 18 weeks with epirubicin 60 mg/m(2) intravenous (i.v.) bolus on day 1 and cisplatin 60 mg/m(2) i.v. bolus on day 1, both repeating 3-weekly (infusional ECisF), or conventional bolus doxorubicin 60 mg/m(2) i.v. on day 1 and cyclophosphamide 600 mg/m(2) i.v. on day 1, both repeating 3-weekly (AC), both schedules for six courses. Patients subsequently had local therapy (surgery or radiotherapy or both) and tamoxifen 20 mg orally daily as appropriate. RESULTS: The 5 year results for AC and infusional ECisF, respectively, were as follows: overall response, 75% and 77%; complete clinical remission, 31% and 34%; pathological complete remission (pathCR), 16% for both; and pathCR with residual ductal carcinoma in situ (DCIS), 25% and 24%. Mastectomy rates were 37% and 34%, respectively. Five-year overall survival was 74% for AC and 82% for infusional ECisF (hazard ratio 0.76, 95% confidence interval 0.51-1.13; P = 0.18). Both treatments were well tolerated. Grade III/IV lethargy, vomiting, alopecia and plantar-palmar erythema were significantly greater for infusional ECisF; grade III/IV leucopenia was significantly greater for AC. CONCLUSIONS: Preoperative continuous infusional 5-FU-based chemotherapy is no more active than conventional AC for early breast cancer; with a median 5 year follow-up, the infusion-based schedule shows a non-significant trend towards improved survival.

Adult↗
PubMed2002

The bisphosphonate zoledronic acid impairs Ras membrane [correction of impairs membrane] localisation and induces cytochrome c release in breast cancer cells.

Bisphosphonates are well established in the management of cancer-induced bone disease. Recent studies have indicated that these compounds have direct inhibitory effects on cultured human breast cancer cells. Nitrogen-containing bisphosphonates including zoledronic acid have been shown to induce apoptosis associated with PARP cleavage and DNA fragmentation. The aim of this study was to identify the signalling pathways involved. Forced expression of the anti-apoptotic protein bcl-2 attenuated bisphosphonate-induced loss of cell viability and induction of DNA fragmentation in MDA-MB-231 cells. Zoledronic acid-mediated apoptosis was associated with a time and dose-related release of mitochondrial cytochrome c into the cytosol in two cell lines. Rescue of cells by preincubation with a caspase-3 selective inhibitor and demonstration of pro-caspase-3 cleavage products by immunoblotting suggests that at least one of the caspases activated in response to zoledronic acid treatment is caspase-3. In both MDA-MB-231 and MCF-7 breast cancer cells, zoledronic acid impaired membrane localisation of Ras indicating reduced prenylation of this protein. These observations demonstrate that zoledronic acid-mediated apoptosis is associated with cytochrome c release and consequent caspase activation. This process may be initiated by inhibition of the enzymes in the mevalonate pathway leading to impaired prenylation of key intracellular proteins including Ras.

Apoptosis↗
PubMed2002

A phase II trial of the vitamin D analogue Seocalcitol (EB1089) in patients with inoperable pancreatic cancer.

Inoperable cancer of the exocrine pancreas responds poorly to most conventional anti-cancer agents, and new agents are required to palliate this disease. Seocalcitol (EB1089), a vitamin D analogue, can inhibit growth, induce differentiation and induce apoptosis of cancer cell lines in vitro and can also inhibit growth of pancreatic cancer xenografts in vivo. Thirty-six patients with advanced pancreatic cancer received once daily oral treatment with seocalcitol with dose escalation every 2 weeks until hypercalcaemia occurred, following which patients continued with maintenance therapy. The most frequent toxicity was the anticipated dose-dependent hypercalcaemia, with most patients tolerating a dose of 10-15 microg per day in chronic administration. Fourteen patients completed at least 8 weeks of treatment and were evaluable for efficacy, whereas 22 patients were withdrawn prior to completing 8 weeks' treatment and in 20 of these patients withdrawal was due to clinical deterioration as a result of disease progression. No objective responses were observed, with five of 14 patients having stable disease in whom the duration of stable disease was 82-532 days (median=168 days). The time to treatment failure (n=36) ranged from 22 to 847 days, and with a median survival of approximately 100 days. Seocalcitol is well tolerated in pancreatic cancer but has no objective anti-tumour activity in advanced disease. Further studies are necessary to determine if this agent has any cytostatic activity in this malignancy in minimal disease states.

Administration, Oral↗
PubMed2002

The role of bisphosphonates in breast cancer management: review article.

Bone metastases are a common problem in the management of breast cancer and are associated with considerable morbidity. Bone pain, hypercalcaemia, fractures and cord compression all occur requiring interventions such as analgesia, radiotherapy and surgery. Bisphosphonates are drugs that are active in the bone microenvironment. Their effects on osteoclasts are well described: they potently inhibit osteoclast mediated bone resorption by delaying the maturation of immature osteoclasts and by directly inducing osteoclast apoptosis. It has been known for some time that bisphosphonates, in combination with intravenous rehydration, effectively treat hypercalcaemia associated with solid malignancies. It has now been demonstrated In clinical trials in breast cancer patients that regular bisphosphonate administration reduces the morbidity associated with osteolytic skeletal metastases. There is an emerging suggestion from clinical trial work that bisphosphonates may be able to reduce or delay the development of skeletal metastases although this remains controversial as the three published trials present conflicting results. The more potent third-generation bisphosphonates, such as zoledronate, are now being tested for each of these indications with promising results and may replace other bisphosphonates in the future. Laboratory studies have recently demonstrated that bisphosphonates have direct cytotoxic effects against breast cancer cells in vitro, inducing apoptosis and preventing adhesion to bone. This adds support to the hypothesis that bisphosphonates may have a genuine beneficial effect in the adjuvant setting.

Bone Density↗
PubMed2001

Vitamin D receptor gene polymorphisms are associated with breast cancer risk in a UK Caucasian population.

There is increasing evidence that vitamin D can protect against breast cancer. The actions of vitamin D are mediated via the vitamin D receptor (VDR). We have investigated whether polymorphisms in the VDR gene are associated with altered breast cancer risk in a UK Caucasian population. We recruited 241 women following a negative screening mammogram and 181 women with known breast cancer. The VDR polymorphism Bsm I, an intronic 3' gene variant, was significantly associated with increased breast cancer risk: odds ratio bb vs BB genotype = 2.32 (95% CI, 1.23-4.39). The Bsm I polymorphism was in linkage disequilibrium with a candidate translational control site, the variable length poly (A) sequence in the 3' untranslated region. Thus, the 'L' poly (A) variant was also associated with a similar breast cancer risk. A 5' VDR gene variant, Fok I, was not associated with breast cancer risk. Further investigations into the mechanisms of interactions of the VDR with other environmental and/or genetic influences to alter breast cancer risk may lead to a new understanding of the role of vitamin D in the control of cellular and developmental pathways.

Adult↗
PubMed2001

Duration of chemotherapy in advanced non-small-cell lung cancer: a randomized trial of three versus six courses of mitomycin, vinblastine, and cisplatin.

PURPOSE: So far there are no published data on optimal duration of chemotherapy for advanced non-small-cell lung cancer (NSCLC); six or more courses are usually recommended. We have carried out a multicenter randomized trial comparing three versus six courses of chemotherapy. PATIENTS AND METHODS: Patients with stage IIIb or IV NSCLC were randomized at start of treatment to receive either three or six courses of mitomycin 8 mg/m(2) (courses 1, 2, 4, and 6), vinblastine 6 mg/m(2), and cisplatin 50 mg/m(2) (MVP) every 21 days. Treatment was stopped early in both arms for progressive disease or unacceptable toxicity. Key end points were overall survival, duration of symptom relief, and quality-of-life assessment using the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30 with lung cancer-specific module QLQ-LC13. RESULTS: Three hundred eight patients were randomized. Seventy-two percent of the 155 patients randomized to three courses completed treatment. In the 153 patients randomized to six courses, 73% completed three courses and 31% six courses. Median survival was 6 versus 7 months, respectively, and 1-year survival 22% versus 25% (P =.2). Median duration of symptom relief was 4.5 months (both arms), and 8% versus 18% had continuing symptom relief (P =.4). Quality-of-life parameters were the same or improved for patients randomized to only three courses, including significantly decreased fatigue (P =.03) and a trend toward decreased nausea and vomiting (P =.06). CONCLUSION: Our findings show no evidence for additional clinical benefit by continuing MVP chemotherapy beyond three courses. This challenges current orthodoxy of six courses or more. Further trials addressing duration of chemotherapy are now warranted, particularly with newer chemotherapy schedules.

Adult↗
PubMed2000

Bisphosphonates induce apoptosis in human breast cancer cell lines.

Breast cancer has a prodigious capacity to metastasize to bone. In women with advanced breast cancer and bone metastases, bisphosphonates reduce the incidence of hypercalcaemia and skeletal morbidity. Recent clinical findings suggest that some bisphosphonates reduce the tumour burden in bone with a consequent increase in survival, raising the possibility that bisphosphonates may have a direct effect on breast cancer cells. We have investigated the in vitro effects of bisphosphonates zoledronate, pamidronate, clodronate and EB 1053 on growth, viability and induction of apoptosis in three human breast cancer cell lines (MDA-MB-231, Hs 578T and MCF-7). Cell growth was monitored by crystal violet dye assay, and cell viability was quantitated by MTS dye reduction. Induction of apoptosis was determined by identification of morphological features of apoptosis using time-lapse videomicroscopy, identifying morphological changes in nucleis using Hoechst staining, quantitation of DNA fragmentation, level of expression of bcl-2 and bax proteins and identification of the proteolytic cleavage of Poly (ADP)-ribose polymerase (PARP). All four bisphosphonates significantly reduced cell viability in all three cell lines. Zoledronate was the most potent bisphosphonate with IC50 values of 15, 20 and 3 microM respectively in MDA-MB-231, MCF-7 and Hs 578T cells. Corresponding values for pamidronate were 40, 35 and 25 microM, whereas clodronate and EB 1053 were more than two orders of magnitude less potent. An increase in the proportion of cells having morphological features characteristic of apoptosis, characteristic apoptotic changes in the nucleus, time-dependent increase in the percentage of fragmented chromosomal DNA, down-regulation in bcl-2 protein and proteolytic cleavage of PARP, all indicate that bisphosphonates have direct anti-tumour effects on human breast cancer cells.

Antineoplastic Agents↗
PubMed1999

Outcome of primary-breast-cancer patients with micrometastases: a long-term follow-up study.

BACKGROUND: Bone-marrow micrometastases have been found in patients with primary breast cancer. We report long-term follow-up of women with primary breast cancer, diagnosed between 1981 and 1986, who had multiple aspirates taken at the time of initial surgery. METHODS: 350 women with primary breast cancer were examined immunocytochemically with antibody to epithelial membrane antigen. We investigated associations with various prognostic factors as well as the effect of micrometastases on relapse-free survival and overall survival. FINDINGS: At median follow-up of 12.5 years, 151 patients had metastatic disease and 136 patients had died from breast cancer. 10-year relapse-free and overall survival were 43.9% (95% CI 33.4-54.7) and 44.9% (34.2-55.9) in patients with micrometastases, and 62.7% (56.5-68.6) and 65.7% (59.4-71.5) in patients without micrometastases at presentation (p<0.001). For relapse-free survival and overall survival, allowing for tumour size, lymph-node status, and vascular invasion, the effect of micrometastases decreased and was no longer significant, with a hazard ratio of 1.09 (0.74-1.61) for relapse-free survival and 1.21 (0.84-1.75) for overall survival. INTERPRETATION: The presence of bone-marrow micrometastases in patients with primary breast cancer is associated with a shorter relapse-free survival and overall survival, but is not an independent prognostic factor. This immunocytochemical technique may be of value in patients for whom pathological tumour size and lymph-node status are unavailable (ie, patients receiving primary medical treatment).

Adult↗
PubMed1999

Management of adenocarcinoma of unknown primary with a 5-fluorouracil-cisplatin chemotherapy regimen (CFTam).

BACKGROUND: Adenocarcinoma of unknown primary comprises up to 10% of metastatic malignant disease. With few exceptions this diagnosis carries a very poor prognosis of a few months with minimal survival advantage to chemotherapy. However there is the possibility that chemotherapy can improve symptom control and quality of life. PATIENTS AND METHODS: Forty-four patients with adenocarcinoma of unknown primary received CFTam chemotherapy regimen (5-FU 750 mg/m2/day by protracted infusion for five days, cisplatin 60 mg/m2 once and tamoxifen 20 mg daily on a 21-day cycle). Disease response and toxicity were collected and survival compared to patients who were not treated or who received different chemotherapy regimens. RESULTS: Overall response to CFTam was 27% with a median duration of 10 months (range 4-26 months). The chemotherapy was well tolerated with no grade 4 non-haematological toxicity and only three patients (7%) grade 4 neutropaenia with only two (5%) patients developing sepsis. There were no toxic deaths. Performance status was maintained or improved in responders. CONCLUSIONS: CFTam is a well tolerated chemotherapy regimen with similar efficacy to other regimens described in the treatment of adenocarcinoma of unknown primary. In the absence of a significant survival advantage there is a need to conduct randomised trials of chemotherapy versus best supportive care to quantify any improvement in quality of life or symptom control.

Adenocarcinoma↗
PubMed1999

Marimastat in recurrent colorectal cancer: exploratory evaluation of biological activity by measurement of carcinoembryonic antigen.

Marimastat is a specific inhibitor of matrix metalloproteinases that has been shown to be effective in cancer models. A pilot, escalating-dose study of oral marimastat was performed in patients with recurrent colorectal cancer, in whom evaluation of serological response was made by measurement of carcinoembryonic antigen (CEA) levels. The study assessed the safety and tolerability of 4 weeks administration of marimastat, and determined a dose range producing detectable serological effects. Patients were recruited with a serum CEA level greater than 5 ng ml(-1), and rising by more than 25% over a 4-week screening period. Patients were treated for 28 days and entered into a continuation protocol if a serological response or clinical benefit was observed. Pharmacokinetic and safety data determined that groups of patients were recruited sequentially at 25 mg and 50 mg twice daily, and, thereafter, 10 mg twice daily, 10 mg once daily, 5 mg once daily and 20 mg once daily. A biological effect (BE) was defined as a CEA value on day 28 no greater than on day 0; a partial biological effect (PBE) was defined as a rise in CEA over the 28-day treatment period of less than 25%. Of 70 patients recruited, 63 completed the 28-day treatment period, and 55 were eligible for cancer antigen analysis. Examination of the dose-effect relationships provides evidence for a causal relationship between marimastat and biological effects: the proportion of patients with BE or PBE was higher with twice daily dosing (16 out of 25, 64%) than with once daily dosing (11 out of 30, 37%) (P = 0.043, chi2 test). Furthermore, the median rates of rise of CEA fell markedly during treatment compared with the screening period for patients receiving twice daily marimastat (P<0.0001), but not for patients receiving marimastat once daily (P = 0.25). Musculoskeletal adverse events emerged as the principal drug-related toxicity of marimastat, occurring in a dose- and time-dependent fashion. It was concluded that marimastat was associated with dose-dependent biological effects in cancer patients. The occurrence of musculoskeletal side-effects define 25 mg twice daily as the upper limit of the dose range for continuous use in further studies. Therefore, a dose range of 20 mg once daily to 25 mg twice daily seems appropriate for further studies, which should aim to demonstrate the efficacy of the drug in terms of conventional clinical end points and describe the long-term tolerability of this novel agent.

Administration, Oral↗
PubMed1998

Are serial measurements of CA19-9 useful in predicting response to chemotherapy in patients with inoperable adenocarcinoma of the pancreas?

Thirty-nine patients with inoperable adenocarcinoma of the pancreas were studied (27 male, 12 female; median age 60 years, range 39-75 years). All patients received chemotherapy with continuous infusion 5-fluorouracil with intravenous bolus epirubicin followed by cisplatin, repeated every 21 days for a total of six cycles and were evaluable for response. Serum CA19-9 concentrations were obtained at baseline and before each cycle. A rise or fall in the tumour marker was defined as a greater than 15% increase or decrease in the marker on two consecutive occasions 3 weeks apart. A plateau in the tumour marker was defined as a less than 15% decrease or increase on two occasions. Changes in marker expression were compared with serial computerized tomography scanning before treatment and after the third and sixth cycle of chemotherapy. Thirty-five of 39 patients had an elevated CA19-9 (87.9%). Thirteen (36.2%) exhibited a decrease, seven (19.4%) a plateau and 16 (44.4%) patients had a progressive rise in serum CA19-9. The sensitivity of CA19-9 was 67% for predicting a partial response and 86% for progressive disease. The median survival for the 13 patients exhibiting a reduction was 333 days, for the seven patients exhibiting a plateau 253 days and for those who had a progressive rise 185 days. The difference in median survival between the group of patients with > 15% decrease and those with > 15% increase of CA19-9 was significant (P = 0.001). In the cohort of patients who exhibited a reduction in CA19-9, no tumour progression was seen, and the reduction occurred during the first three cycles of treatment. Thus, interval scanning may be avoided in this group of patients.

Adenocarcinoma↗
PubMed1997

Association of tumor angiogenesis with bone marrow micrometastases in breast cancer patients.

BACKGROUND AND PURPOSE: The microscopic detection of tumor cells (micrometastases) in bone marrow and the extent of blood vessel formation (angiogenesis) in primary tumor specimens are recognized as independent prognostic markers in patients with breast cancer. Since micrometastases occur as a consequence of interaction between the neoplastic cells and the tumor neovasculature, we have examined the relationship between these markers to determine whether the degree of angiogenesis is related to the presence of micrometastases. METHODS: Micrometastases were identified in bone marrow aspirates collected from multiple sites in 214 breast cancer patients prior to surgery (mastectomy or lumpectomy). Tumor cells were detected through an examination of epithelial membrane antigen expression and an analysis of cell morphology. Tumor vascularity was graded semiquantitatively or quantitatively (Chalkley point count) after immunohistochemical staining of the CD31 antigen expressed by the endothelial cells. The reproducibility and accuracy of the vascular grading were validated by use of kappa statistics. Associations between micrometastases and clinicopathologic characteristics, including angiogenesis, were examined using chi-squared and logistic regression techniques. All tests of statistical significance were two-sided. RESULTS: Of the 214 patients, 42 (20%) were positive for bone marrow micrometastases and 75 (35%) had tumors of high vascular grade. There was 86% agreement between vascular grades assessed twice for 35 tumors (kappa statistic = 0.66); for 22 evaluated tumors, there was absolute concordance between vascular grade and Chalkley point count. There were significant positive associations between tumor angiogenesis and micrometastasis (P = .01), tumor grade (P = .003), and estrogen receptor expression (P = .007); however, no significant associations were observed with tumor size (P = .9), lymph node status (P = .33), vascular invasion (peritumoral blood or lymph vessels) (P = .9), menopausal status (P = .17), or age (P = .12). Adjusting for confounding factors, multivariate analysis showed that only tumor angiogenesis (odds ratio = 2.7; P = .016) and vascular invasion (odds ratio = 2.7; P = .012) were significant determinants for the presence of micrometastases. CONCLUSIONS: This study suggests that an assessment of tumor angiogenesis and vascular invasion gives a reliable indication of the likelihood of the presence of bone marrow micrometastases in patients with breast cancer and that both processes contribute to metastases.

Aged↗
PubMed1997

Bile duct stents: is there an increased rate of complications in patients receiving chemotherapy?

The aim of this study was to determine whether palliative chemotherapy accelerates the rate of biliary stent occlusion, in patients with a malignant biliary obstruction. Such treatment can induce neutropenia and increase the risk of bacterial sepsis. Overgrowth of bacteria within the bile of patients receiving chemotherapy could accelerate the rate of stent occlusion. Retrospective analysis of treatment records for 80 consecutive patients with a diagnosis of adenocarcinoma arising from the pancreas, bile ducts or gall bladder was conducted. Two groups were identified, those with a biliary stent in situ (primary stent group: 47/80; 59%) at the time of referral and those without (no stent group: 33/80; 41%). The majority of patients went on to receive chemotherapy, 64% and 70% in the primary stent group and no stent group, respectively. The rate of febrile neutropenia was similar in the two groups (5% versus 7% of all chemotherapy cycles in the primary stent group and no stent group, respectively). The rate of stent occlusion was not significantly different between those exposed to chemotherapy (37%; 95% CI 20-54%) and those unexposed (39%; 95% CI 19-59%). Similarly, the mean duration of patency was not shortened by chemotherapy (105 days in the chemotherapy group versus 119 days in the non-chemotherapy group; P = 0.97, Mann-Whitney U-test). We conclude that there is no evidence of increased rate of bile duct-related complications in patients receiving chemotherapy. In particular, we find no indication for the use of prophylactic antibiotics.

Adult↗
PubMed1997

Outpatient treatment with epirubicin and oral etoposide in patients with small-cell lung cancer.

To assess the efficacy and toxicity of an outpatient combination chemotherapy in small-cell lung cancer (SCLC), we treated 70 consecutive patients with epirubicin 80 mg m(-2) i.v. on day 1 and etoposide 200 mg o.d. p.o. on days 1-4 (EE) at 3-weekly intervals. The median age of patients was 64 years (range 39-84). The male-female ratio was 42:28 and 35 (50%) had metastatic disease. Fifty-seven patients were evaluable for response. The overall response rate was 64.4%, including 14 (23.7%) complete responses and 24 (40.7%) partial responses. Median time to progression was 7 months in responders and 8 months in patients with limited disease. The median survival in patients with limited disease was 10.5 months (range 0.5-70 +) and 7 months (range 0.5-24) in those with extensive disease. Improvement of symptoms occurred in 79% of patients with shortness of breath, 80% with cough, 81% with haemoptysis and 68% with pain. In 19 patients an increase in body weight was noted. Major (WHO grade 3/4) toxicities were neutropenia in 13 (18.5%) patients, alopecia in 33 (47.1%) patients, mucositis in 15 (21.4%) patients, anorexia in eight patients (11.4%), nausea and vomiting in six patients (8.5%) and diarrhoea in 4 (5.7%) patients. In conclusion, EE is an active and well-tolerated outpatient regimen in the treatment of SCLC. The survival data in this unselected group of patients were disappointing and the possible explanations for this are discussed.

Administration, Oral↗
PubMed1996

Trousseau's syndrome in association with ovarian carcinoma.

BACKGROUND: The association of neoplastic disease and thromboembolic disorders was first recognized by Trousseau in 1865. Abnormalities of blood coagulation tests have been reported in the majority of patients with cancer, including ovarian carcinoma. However, Trousseau's syndrome has rarely been reported in women with ovarian carcinoma. METHODS: A literature search for cases of Trousseau's syndrome in association with ovarian carcinoma was performed using the MEDLINE database. Case notes of patients with ovarian carcinoma treated at St. George's Hospital were reviewed and cases of Trousseau's syndrome identified. RESULTS: We report a series of 4 cases of Trousseau's syndrome in association with ovarian carcinoma occurring over a 3- to 4-year period, and highlight the particular difficulties associated with the management of these thromboembolic effects. CONCLUSIONS: Trousseau's syndrome can impair quality of life in patients with advanced ovarian carcinoma and enhanced anticoagulation regimens may be required for effective palliation.

Female↗