Aggressive fibromatosis: clinical aspects

The clinical picture of desmoids is unpredictable, which is a feature of different tumor specific associations. Anatomic location, age, sex, association with FAP as well as other factors determine biological behavior of the tumor. Negative prognosis is linked with the intraabdominal area and as many as 80% of desmoids are associated with FAP. Currently, biological targeting therapy is used in the treatment of many cancer diseases. It is only the question of time when and by which of these therapies we will be able to treat the patients with aggressive fibromatosis as well. A disadvantage is heterogenity and rare occurrence of desmoids. The efficacy of tailoring treatment still depends on knowledge and study of particular disease biological markers, which is currently the most important issue. .     

Aggressive fibromatosis in children and adolescents

BACKGROUND:

Aggressive fibromatosis (AF) is a rare tumor of intermediate malignancy that has a strong potential for local invasiveness and recurrence. To date, there are no general recommendations for the clinical management of pediatric AF.

METHODS:

The authors retrospectively analyzed 94 patients aged ≤21 years, including 23 patients who underwent complete surgery (Group I), 42 patients who underwent incomplete surgery with microscopic residual tumor (Group II), and 29 patients who underwent either biopsy or macroscopically incomplete surgery (Group III).

RESULTS:

The 5‐year event‐free survival (EFS) and overall survival rates were 44% and 99%, respectively. Local recurrences developed in 22% of patients in Group I, in 76% of patients in Group II, and in 76% of patients in Group III. Two of 7 patients with abdominal disease died of tumor progression, whereas none of the patients with extra‐abdominal AF died of their disease. Systemic treatment was given to 15 patients as first‐line treatment and to 34 patients at time the time they developed recurrent disease: The response rate was 47% in the former patients and 50% in the latter patients. Objective responses were observed in 11 of 19 patients who received combined methotrexate plus vinblastine/vinorelbine, in 7 of 15 patients who received alkylating‐agent chemotherapy, and in 4 of 11 patients who received other therapies (tamoxifen, sulindac, interferon alfa).

CONCLUSIONS:

The current analysis suggested that the clinical course of AF in children may resemble that of AF in adults. Local recurrences did not affect the chance of responding to systemic therapy or the survival rate. The completeness of initial resection was the main factor that influenced EFS, whereas disease control after marginal resection was much the same as that achieved after intralesional surgery/biopsy. Good responses to systemic treatments, and particularly to low‐dose chemotherapy, were observed as reported previously in adults. Cancer 2010. © 2010 American Cancer Society.     

Aggressive fibromatosis: evidence for a stable phase

Purpose. Aggressive fibromatosis (AF) is an uncommon locally infiltrating benign disease of soft tissue for which treatment comprises complete surgical resection. Radiotherapy can be given postoperatively if the margin is incompletely resected. If the tumour is inoperable radiotherapy provides an alternative treatment. Hormone therapy and cytotoxic chemotherapy have also been used for unresectable or recurrent disease. All treatment modalities carry an associated morbidity. We believe that the natural history of aggressive fibromatosis may include a period of stable disease without progression, during which time, treatment is not always necessary.Patients and methods. We present a retrospective review of 42 patients referred to the Royal Marsden Hospital between 1988 and 1995 with aggressive fibromatosis. Evidence of periods of stable disease and the relationship to delivered treatment was obtained from the case notes, including the natural history prior to referral to our institution. Stable disease was defined as a period of no objective progression for 6 months or longer.Results. Seventeen patients could be assessed for stable disease and all (100%) experienced at least one episode of stable disease, eight of whom whilst receiving hormonal or cytotoxic therapy. Of the 23 patients who could not be assessed for stable disease, as they underwent surgery at presentation or recurrence of disease, only 2 had persisting disease at last follow-up. Both of these patients had had positive surgical resection margins.Discussion. This study demonstrates the variable natural history of AF, which can include a substantial period of stable disease in a significant number of patients. A less aggressive approach to the management of AF may therefore be appropriate, particularly if a subgroup of patients who are likely to experience a period of stable disease can be identified.     

CYP2D6与他莫昔芬疗效相关性的研究进展

CYP2D6是一种重要的P450系氧化代谢酶,是他莫昔芬在体内代谢成更强抗雌激素作用代谢产物endoxifen的重要代谢酶,因此,强代谢乳腺癌患者服用他莫昔芬后引起明显的潮热症状,而潮热症状的发生与他莫昔芬疗效正相关。除了CYP2D6基因多态性可能影响他莫昔芬体内的代谢外,帕罗西汀（paroxetine）可竞争性抑制CYP2D6对他莫昔芬的代谢,使乳腺癌患者对他莫昔芬疗效明显降低。     

Extra-abdominal primary fibromatosis: Aggressive management could be avoided in a subgroup of patients

Objective

To evaluate the impact of surgery as first-line treatment on event-free survival (EFS) of primary aggressive fibromatosis.

Patients and methods

Treatments were categorized into: surgery with or without radiotherapy and nonsurgical strategies with systemic treatment alone or wait and see policy. Eighty-nine patients had initial resection of their primary tumour followed by postoperative radiotherapy in 13 cases. Twenty-three did not undergo surgery but received systemic treatment or watch and wait policy.

Results

Median follow-up was 76 months. Overall 3 years EFS was 49%. In the univariate analysis, patients with microscopically complete surgery had a similar outcome to patients in the no-surgery group (3 years EFS of 65% and 68%, respectively). Gender, age, tumour size, treatment period and strategy (surgery versus no-surgery) were not statistically significant. Quality of resection according to margins and the tumour site were the only prognostic factors. There was a significant correlation between tumour site and quality of surgery (p = 0.0002).

Conclusions

A subset of patients with extra-abdominal fibromatosis could be managed with a nonaggressive policy, as growth arrest concerned 2/3 of nonoperated patients. When surgery is finally necessary, it should be performed with the aim of achieving negative margins.     

Expression of tumor-associated 90k-antigen in human breast cancer: No correlation with prognosis and response to first-line therapy with tamoxifen

It has been shown that a 90-kDa protein (90K), with an as yet unknown function, is expressed in the majority of human breast-cancer tissues. In addition, the serum level of this 90K antigen is elevated in a certain proportion of breast-cancer patients, and high serum levels are associated with a poor overall survival. It was therefore of interest to determine whether levels of 90K in tumor tissues could be used as a prognostic variable in breast cancer. In the present study, the levels of 90K in primary breast tumor cytosols were studied with respect to the length of relapse-free or overall survival in 547 patients (median follow-up, 81.4 months), and the relationship with response to first-line tamoxifen therapy and the length of progression-free survival in 184 patients with recurrent disease (median follow-up, 59.8 months). 90K levels in tumor cytosols were determined with an immunoradiometric assay. The cytosolic contents of 90K were not significantly correlated with age, menopausal status, tumor size, nodal status or differentiation grade. On the other hand, the levels of 90K were positively correlated with those of cytosolic estrogen receptor, progesterone receptor, urokinase-type plasminogen activator, its inhibitor PAI-I, cathepsin D and PS2. The cytosolic tumor level of 90K was not associated with the rate of relapse or death in primary breast cancer, nor with response to first-line therapy with tamoxifen or the length of progression-free survival in recurrent disease. © 1995 Wiley-Liss, Inc.     

mdm2-p53 Interaction: lack of correlation with the response to 5-fluorouracil in advanced colorectal cancer

OBJECTIVE: We investigated the relevance of mdm2 and p53 primary tumour expression to the clinical outcome of a consecutive series of advanced colorectal cancer patients treated with a 5-fluorouracil-based chemotherapy. METHODS: The expression of p53 and mdm2 was analyzed by an immunohistochemical assay in 80 formalin-fixed paraffin embedded primary tumour samples and related to the clinical response to 5-fluorouracil therapy and to the prognosis of the patients. In a subgroup of 46 tumours, the apoptotic index (AI) as determined by the Tunel technique was also assessed. RESULTS: Nuclear immunostaining of p53 and mdm2 was present in 42 and 30% of the cases, respectively. No correlation was demonstrated between p53 and mdm2 expression (rs = -0.01; p > 0.05). With regard to the clinical outcome, no statistical association was demonstrated among p53 and mdm2 expression, AI, probability of clinical response to treatment, time to progression, or overall survival. The subgroup of patients with a p53-negative/mdm2-positive tumour showed a worse response rate (15%); however, mdm2-positive/AI-negative tumours showed a 0% (0/7) probability of a clinical response as compared with 30% (9/30) of the remaining tumour patient subgroups; this also translated in a significantly worse overall survival probability (p = 0.01 by log rank). CONCLUSIONS: The analysis of mdm2 expression does not add significant clinical information in colorectal cancers with a different p53 status. Conversely, further analysis of AI seems to give data of a promising prognostic-predictive value.     

Erectile dysfunction and radiation dose to penile base structures: a lack of correlation

PURPOSE: To evaluate the relationship between the dose and volume of radiation to proximal penile structures and the development of erectile dysfunction after external beam radiotherapy (RT) for localized prostate adenocarcinoma. METHODS AND MATERIALS: The study cohort comprised 28 patients who were enrolled our in-house three-dimensional conformal RT dose escalation protocol. The patients were treated to 78 Gy between 1995 and 1998. This protocol included a planned quality-of-life questionnaire to assess sexual function 2 years after completing RT. All the study patients were potent before RT. The median follow-up was 66 months (range 39-95). Penile base contents were outlined retrospectively in restored treatment plans. The dose-volume histograms (DVHs) for the corpus spongiosum (penile bulb), corpora cavernosum and crura, and total penile structure (corpus spongiosum plus corpora cavernosum and crura) were calculated. Statistical significance was defined as p < 0.05. The Bonferroni correction was used to adjust for multiple comparisons. Power calculations showed that our study sample would detect radiation- induced impotence with a very high power. We also estimated that a relatively small difference of 10-15% in the DVHs between the potent and impotent patients could be detected. RESULTS: At 2 years after RT, 10 patients (35.7%) reported new-onset erectile dysfunction and were unable to attain firm enough erections to have intercourse. Only hypertension was observed to affect erectile dysfunction after external beam RT. We found no statistically significant correlation among age, diabetes, or heavy alcohol consumption and post-RT potency. The mean radiation dose +/- standard deviation delivered to the corpus spongiosum, corpora cavernosa and crura, and total penile structure was, respectively, 42.2 +/- 8.4 Gy, 36.3 +/- 8.0 Gy, and 38.2 +/- 7.5 Gy. t test comparisons were performed between DVHs of post-RT potent and impotent patients on multiple cutpoints. No dose-volume effect was found. Analysis of the DVHs when the patients were subdivided into normotensive and hypertensive groups also showed no dose-volume response. CONCLUSION: Our analysis did not show statistically significant correlations between potency preservation and radiation dose to the proximal penis. The entire etiology of radiation- induced erectile dysfunction remains unclear and further research is needed.     

Acquired tamoxifen resistance: correlation with reduced breast tumor levels of tamoxifen and isomerization of trans-4-hydroxytamoxifen

Acquired tamoxifen resistance represents a major cause of treatment failure in breast cancer. We implanted estrogen receptor-positive MCF-7 human breast cancer cells in athymic nude BALB/c mice as a model to study in vivo acquired tamoxifen resistance. After 4-6 months of tumor growth suppression by trans-tamoxifen, tumor progression was observed despite continued tamoxifen administration. Acquired resistance was not due to loss of estrogen receptors, to alterations in serum or tumor estrogen levels, or to changes in tamoxifen or its major metabolites in serum. Tamoxifen-resistant tumors remained estrogen dependent in vivo. However, resistance was also associated with the ability of tamoxifen to stimulate tumor growth. Resistant tumors were characterized by markedly lower intracellular tamoxifen levels and by isomerization of the potent antiestrogenic metabolite trans-4-hydroxy-tamoxifen to the less potent cis isomer. Metabolic tolerance, as manifested by alterations in cellular concentrations of tamoxifen and its metabolites, may thus be one mechanism for acquired tamoxifen resistance in breast cancer.     

MRI of transgene expression: correlation to therapeutic gene expression

Magnetic resonance imaging (MRI) can provide high-resolution 3D maps of structural and functional information, yet its use of mapping in vivo gene expression has only recently been explored. A potential application for this technology is to noninvasively image transgene expression. The current study explores the latter using a nonregulatable internalizing engineered transferrin receptor (ETR) whose expression can be probed for with a superparamagnetic Tf-CLIO probe. Using an HSV-based amplicon vector system for transgene delivery, we demonstrate that: 1) ETR is a sensitive MR marker gene; 2) several transgenes can be efficiently expressed from a single amplicon; 3) expression of each transgene results in functional gene product; and 4) ETR gene expression correlates with expression of therapeutic genes when the latter are contained within the same amplicon. These data, taken together, suggest that MRI of ETR expression can serve as a surrogate for measuring therapeutic transgene expression.     

Thymidylate synthase protein expression in primary colorectal cancer: lack of correlation with outcome and response to fluorouracil in metastatic disease sites.

PURPOSE: The aim of this study was to investigate the utility of quantitating thymidylate synthase (TS) in the primary tumor as a surrogate for metastatic disease sites to predict the likelihood of response and outcome to fluorouracil (FU) treatment in patients with metastatic colorectal cancer. METHODS: TS protein expression was evaluated using the TS 106 antibody and the avidin biotin labeling immunohistochemical technique in primary tumor samples from 219 patients with metastatic colorectal cancer. The patients were a representative sample of those patients enrolled into the Eastern Cooperative Oncology Group E2290 protocol that evaluated five separate FU-containing regimens in patients with metastatic residual or recurrent colorectal carcinoma. RESULTS: Our retrospective analysis found that the level and extent of TS protein expression in the primary tumor did not correlate with overall survival in patients with metastatic or recurrent colorectal cancer. A trend toward a direct correlation between the level of TS protein expression and response was noted in tumors that expressed high TS levels. This response advantage for patients expressing high TS levels in the primary tumor was apparent regardless of what FU-based treatment the patient received but was most apparent in the subgroup treated with leucovorin, in which the level of TS expression and response to FU and leucovorin reached statistical significance (P =.034). No significant interaction could be detected between the addition of leucovorin to FU and the level of TS expression in the primary tumor. CONCLUSION: This study demonstrated that measurement of TS protein levels in the primary tumor tissue does not aid in predicting outcome or response to FU in a metastatic disease site. These assays must be performed on biopsy tissue from the metastatic disease site that is used to radiologically assess response and outcome to treatment.     

Celecoxib prevents tumor growth in vivo without toxicity to normal gut: lack of correlation between in vitro and in vivo models

Nonsteroidal anti-inflammatory drugs have potential for use in the prevention and/or treatment of colorectal cancer. We have studied the cytotoxic effect of a specific COX-2 inhibitor, celecoxib, against LLC, HCA-7, and HCT-15 cells grown in cell culture and have compared these results with its effect on HCA-7 cells grown as xenografts in nude mice. "High-dose" celecoxib (>20 microM) reduced the viability of all three cell lines in vitro as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Flow cytometric analysis demonstrated that this loss of viability was attributable to the induction of apoptosis. Significantly, concentrations of the drug <10 microM had no effect on cell viability in vitro. The cytotoxic effects of high-dose celecoxib were independent of COX-2 inhibition because similar effects were observed in cox-2 (+/+), cox-2 (+/-) and cox-2 (-/-) fibroblasts. A plasma concentration of 2.3+/-0.7 microM was achieved when celecoxib (1250 mg/kg of chow) was fed to animals ad libitum. Despite a lack of toxicity at 2-3 microM celecoxib in vitro, there was attenuation of HCA-7 xenograft growth in vivo. Celecoxib had no effect on apoptosis, cell division, or the epithelial architecture of the normal gut in treated mice. These results support the need for additional clinical evaluation of celecoxib for treatment and/or prevention of colorectal cancer in humans.     

Atrial septal aneurysm: MRI and echocardiography correlation

A case of a patient with atrial septal aneurysm with findings in echocardiography and MRI is described.     

Thymidine kinase and thymidylate synthase in advanced breast cancer: response to tamoxifen and chemotherapy

Thymidylate synthase (TS) is a crucial target for 5-fluorouracil (5-FU) in the de novo pathway of pyrimidine synthesis, which is necessary for DNA synthesis. Thymidine kinase (TK) plays a key role in the complementary or alternative salvage pathway of pyrimidine synthesis in acute or pathological tissue stress. In the present study, the activity levels of TS and TK were determined in 257 primary breast tumors of patients who received tamoxifen as first-line systemic therapy after diagnosis of advanced disease. In 155 (60%) responding patients, the median response duration was 23 months for tumors with low TK activity, 15 months for tumors with intermediate TK activity, and 13 months for tumors with high TK activity (P = 0.003). In Cox multivariate analysis corrected for classical predictive factors including estrogen receptor and progesterone receptor, patients with intermediate and high levels of TK activity in their tumors showed a rapid disease progression (P = 0.0002) and an early death (P = 0.002) after start of tamoxifen treatment. Tumor TS activity levels were not significantly associated with the efficacy of tamoxifen treatment. In 121 patients who became resistant to tamoxifen or additional endocrine treatments and who received 5-FU-containing polychemotherapy, tumor TK activity was not significantly related to the efficacy of chemotherapy. Of the 13 patients with low tumor TS activity, only 1 (8%) responded favorably, whereas 46% (43 of 93) of those with intermediate and 73% (11 of 15) of those with high TS activity responded (P = 0.001). In Cox multivariate regression analysis in which TS was the only significant variable, intermediate and high TS activities were associated with a slow disease progression (P = 0.005) and prolonged survival (P = 0.016) on chemotherapy. In conclusion, for patients with recurrent breast cancer, high tumor TK activity is a significant marker of poor clinical outcome on tamoxifen therapy. Elevated tumor TS activity predicts a favorable outcome for 5-FU-containing polychemotherapy when applied after tumor progression on endocrine therapy.     

New benzoic acid derivatives with retinoid activity: lack of direct correlation between biological activity and binding to cellular retinoic acid binding protein

In this paper the biological activity of several newly synthesized benzoic acid derivatives of the Am- and Ch- series, which are structurally different from retinoic acid and arotinoids, was examined. These compounds inhibit squamous cell differentiation of rabbit tracheal epithelial cells in vitro as indicated by the inhibition of transglutaminase Type I and cholesterol 3-sulfate levels. In contrast to the inhibition of differentiation in rabbit tracheal cells, these compounds induce differentiation of mouse embryonal carcinoma F9 and human promyelocytic leukemia HL60 cells. The Am- and Ch- series of compounds also affect several parameters of cell proliferation. These agents are very potent inhibitors of growth of melanoma S91 cells and inhibit the induction of ornithine decarboxylase activity by phorbol 12-myristate 13-acetate in 3T6 fibroblasts. These results show that the Am- and Ch- derivatives elicit in several cell systems the same cellular responses as retinoic acid. We propose, therefore, that they exhibit mechanism(s) of action similar to those of retinoids. Comparison of the biological response with the binding capacity to the cellular retinoic acid-binding protein shows a lack of a direct correlation.     

Cisplatin-DNA adduct formation in patients treated with cisplatin-based chemoradiation: lack of correlation between normal tissues and primary tumor

Purpose In this study, the formation of cisplatin-DNA adducts after concurrent cisplatin-radiation and the relationship between adduct-formation in primary tumor tissue and normal tissue were investigated. Methods Three intravenous cisplatin-regimens, given concurrently with radiation, were studied: daily low-dose (6 mg/m²) cisplatin, weekly 40 mg/m², three-weekly 100 mg/m². A ³²P-postlabeling technique was used to quantify adducts in normal tissue [white blood cells (WBC) and buccal cells] and tumor. Results Normal tissue samples for adduct determination were obtained from 63 patients and tumor biopsies from 23 of these patients. Linear relationships and high correlations were observed between the levels of two guanosine- and adenosine–guanosine-adducts in normal and tumor tissue. Adduct levels in tumors were two to five times higher than those in WBC (P < 0.001). No significant correlations were found between adduct levels in normal tissues and primary tumor biopsies, nor between WBC and buccal cells. Conclusions In concurrent chemoradiotherapy schedules, cisplatin adduct levels in tumors were significantly higher than in normal tissues (WBC). No evidence of a correlation was found between adduct levels in normal tissues and primary tumor biopsies. This lack of correlation may, to some extent, explain the inconsistencies in the literature regarding whether or not cisplatin-DNA adducts can be used as a predictive test in anticancer platinum therapy.