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PubMed2001

Integration of neoadjuvant chemotherapy and surgery in the treatment of patients with breast carcinoma.

The use of neoadjuvant chemotherapy has its origins in the management of inoperable locally advanced breast cancer. Several important recent trials have demonstrated that neoadjuvant chemotherapy can increase the resectability rate of primary breast cancer, can allow more patients to successfully undergo breast conservation surgery, and does not confer a survival disadvantage compared with standard, adjuvant chemotherapy. These findings indicate that neoadjuvant chemotherapy is the preferred initial treatment for patients with locally advanced or inflammatory breast carcinoma. Neoadjuvant chemotherapy may also be appropriate in some women with earlier-stage disease. If a patient is predicted to derive little advantage from chemotherapy in the adjuvant setting, it is equally unlikely that an advantage will be seen with neoadjuvant chemotherapy. However, if a woman desires conservative breast surgery and her primary tumor size precludes this approach, neoadjuvant chemotherapy should be offered regardless of clinical disease stage. Careful initial patient assessment and close monitoring of response to neoadjuvant chemotherapy through physical assessment and imaging studies of the primary tumor and nodal metastases are critical in planning breast conservation surgery and have been shown to minimize the risk of local-regional recurrence. The clinical and pathologic response of the primary breast tumor to neoadjuvant chemotherapy appears to be a surrogate marker for the response of occult micrometastases and therefore patient outcome. The most exciting aspect of neoadjuvant chemotherapy in the multidisciplinary management of breast cancer is that neoadjuvant chemotherapy allows for the potential rapid evaluation of promising novel cancer therapies in patients who are predicted to do poorly on the basis of their minimal response to standard cytotoxic regimens. This remains a fertile area for ongoing and future trials of neoadjuvant chemotherapy. By using neoadjuvant chemotherapy, not only can we advance the field of breast cancer research but we may also offer our individual patients an early chance for potentially curative therapy.

Journal Article↗

PubMed2004

Rationale for the use of gemcitabine in breast cancer (Review).

Many active cytotoxic drugs and several regimens exist for breast cancer therapy. However, these conventional treatments have not changed the outcome of patients with locally advanced and metastatic disease. As a consequence, the dynamic balance between chemotherapy-induced side effects and benefits attributable to relief of cancer-related symptoms must be carefully considered in this setting. Gemcitabine is a pyrimidine nucleoside antimetabolite that has shown activity in a variety of solid tumors, a good toxicity profile, and non-overlapping toxicity with other chemotherapeutic drugs. As a single agent, gemcitabine yields response rates ranging from 14 to 37% as first-line treatment for advanced breast cancer and 12-30% as salvage therapy for patients previously treated with anthracycline and/or taxane treatment. Combined with vinorelbine, platinum, anthracyclines, and taxanes as doublets or triplets, response rates of 50 to 80% have been reported in phase II clinical studies. Gemcitabine in combination with anthracyclines and taxanes has been evaluated in the neoadjuvant setting in patients with early-stage breast cancer with interesting clinical and pathological response rates. Preliminary results of gemcitabine in combination with the biologic agent, trastuzumab, are encouraging. Phase III trials of gemcitabine combinations compared to standard regimens are ongoing with the aim to assess the independent contribution of gemcitabine.

Antibodies, Monoclonal↗

PubMed1993

Preoperative chemotherapy and radiotherapy for cancer of the esophagus.

BACKGROUND: We wished to determine the role and significance of preoperative chemotherapy and radiotherapy in management of operable cancer of the esophagus. METHODS: Twenty-two patients with clinical stage I-II cancer of the esophagus were entered in a prospective study of preoperative chemotherapy (5-fluorouracil/cisplatin) and radiotherapy (3405 cGy) administered concomitantly during 21 days followed by restaging and total esophagectomy. RESULTS: Five patients did not complete the protocol (three had toxicity, one refused surgery, and one had interim distant metastasis). Seventeen patients underwent total esophagectomy with cervical anastomosis. Two postoperative deaths resulted from sepsis. Thirteen (76%) of 17 patients were considered to have complete clinical response (esophagoscopy and computed axial tomographic scanning) before surgery, but only 5 (29%) of 17 were free of cancer. The median survival was 18 months (median follow-up 57 months). No difference in survival was seen between complete and partial pathologic response. CONCLUSIONS: (1) Preoperative chemotherapy and radiotherapy did not result in increased survival compared with historic controls (surgery alone). (2) Preoperative chemotherapy and radiotherapy clinical staging overestimates the incidence of complete tumor response. (3) Combination chemotherapy is well tolerated, but until newly developed drugs show their efficacy for treatment, surgery should continue to be the major modality for local control and an integral part of clinical investigational trials.

Adult↗

PubMed2000

Gene therapy for head and neck cancer.

OBJECTIVES/HYPOTHESIS: New treatment methods are needed for head and neck cancer to improve survival without increasing morbidity. Gene therapy is a potential method of improving patient outcome. Progress in gene therapy for cancer is reviewed with emphasis on the limitations of vector technology and treatment strategies. Given the current technological vector limitations in transmitting the therapeutic genes, treatments that require the fewest number of cells to be altered by the new gene are optimal. Therefore an immune-based gene therapy strategy was selected in which the tumors were transfected with the gene for an alloantigen, human leukocyte antigen (HLA)-B7, a class I major histocompatibility complex (MHC). This would restore an antigen presentation mechanism in the tumor to induce an antitumor response. This gene therapy strategy was tested in patients with advanced, unresectable head and neck cancer. STUDY DESIGN: Prospective trial. METHODS: Twenty patients with advanced head and neck cancer who had failed conventional therapy and did not express HLA-B7 were treated with gene therapy using a lipid vector by direct intratumoral injection. The gene therapy product contained the HLA-B7 gene and the beta2-microglobulin gene, which permits complete expression of the class I MHC at the cell surface. Patients were assessed for any adverse effects, for changes in tumor size, for time to disease progression, and for survival. Biopsy specimens were assessed for pathological response, HLA-B7 expression, apoptosis, cellular proliferation, CD-8 cells, granzyme, and p53 status. RESULTS: There were no adverse effects from the gene therapy. At 16 weeks after beginning gene therapy, four patients had a partial response and two patients had stable disease. Two of the tumors completely responded clinically, but tumor was still seen on pathological examination. The time to disease progression in the responding patients was 20 to 80 weeks. The median survival in patients who completed gene therapy was 54 weeks, compared with 21 weeks in patients whose tumors progressed after the first cycle of treatment. One patient survived for 106 weeks without any additional therapy. HLA-B7 was demonstrated in the treated tumors, and increased apoptosis was seen in the responding tumors. CONCLUSION: Significant advances have been made in the field of gene therapy for cancer. Alloantigen gene therapy has had efficacy in the treatment of cancer and can induce tumor responses in head and neck tumors. Alloantigen gene therapy has significant potential as an adjunctive treatment of head and neck cancer.

Adult↗

PubMed2001

Biological and clinical effects of aromatase inhibitors in neoadjuvant therapy.

Postmenopausal women with large primary oestrogen receptor-rich (>20 fmol/mg protein or 80 histoscore) breast cancers have been treated neoadjuvantly with either letrozole (2.5 or 10 mg daily n=12 in each case) or anastrozole (1 or 10mg daily n=12 and 11, respectively). Tumour was available for analysis before treatment (wedge biopsy) and 3 months later at definitive surgery (wide local excision or mastectomy). Clinical response to treatment was assessed by sequential measurements of tumour volume based on caliper assessment, ultrasound and mammography. Results showed that in these selected groups of patients a reduction in tumour volume with treatment was observed in 43 of 47 cases (91%). Pathological responses, i.e. clear decrease in tumour cellularity or increased fibrosis was evident in 32 cases (68%). Furthermore, there was a decrease with therapy in immunohistochemical staining for Ki67 in all tumours. Staining for progesterone receptor (PgR) was reduced in all 21 PgR-positive cancers treated with letrozole and in 16 of 17 positive cancers treated with anastrozole. These effects are at least as great as those seen in a non-randomised group of patients treated with tamoxifen over the same time period (additionally tamoxifen treatment was often associated with an increase in PgR staining). The results suggest that potent specific aromatase inhibitors will be valuable in treating hormone-dependent cancers.

Anastrozole↗

PubMed1999

Toxicology of a boronated porphyrin in dogs.

Among the most important characteristics of any therapeutic agent are efficacy and an acceptable toxicity. Prior to human use, toxicity studies are performed in both small and large animal models. Our laboratory has developed a new binary therapy agent, a boronated porphyrin (BOPP), with excellent potential efficacy. The purpose of this study is to examine the toxicology of this compound in dogs. Sixteen dogs were given 35 mg/kg of BOPP intravenously and evaluated for up to 28 days following administration. Clinical and pathologic responses were measured. BOPP was clinically well tolerated with some cases of weight loss, vomiting and mild photosensitivity. Adverse effects were limited primarily to thrombosis at the administration site in several subjects and three cases of mild, possibly transient, liver injury. Clinical pathologic tests found reversible changes in white blood cell counts and platelets, with neither change being clinically significant. The low toxicity associated with BOPP as shown in this study provides valuable evidence supporting the use of BOPP in binary therapy.

Animals↗

PubMed1982

Occult dental infection causing fever in renal transplant patients.

Fever secondary to odontogenic infection following successful renal transplantation is reported in three patients. All three patients initially lacked signs or symptoms localizing to the oral cavity, and two of the three patients did not have x-ray evidence of abscess formation. Two patients received antibiotic therapy without any apparent clinical response, and all three patients responded promptly to surgical extractions. Our patients illustrate that fever can be the only sign of dental sepsis in renal transplant recipients, and tooth extraction as empiric therapy may be necessary. Most important, however, is that the dental pathology responsible for their fever could have been detected and treated prior to transplantation. We recommend pretransplant dental evaluation of all patients with extraction of partially impacted molars and treatment of all periodontal disease and dental caries.

Adolescent↗

PubMed1991

Increased lung copper-zinc-superoxide dismutase activity and absence of magnetic resonance imaging-detectable lung damage in copper-deficient rats exposed to hyperoxia.

The effects of hyperoxia on physiological responses, pathological lung lesions detected noninvasively by proton magnetic resonance imaging (MRI), and the oxygen free radical defense enzymes were measured in Cu-deficient rats. Exposure to 85% oxygen seemed to impose a stress on the whole animal as indicated by two physiological responses, decreased food intake and decreased body weight of ad libitum-fed rats. However, all rats exposed to 85% oxygen, including the Cu-deficient group, were able to survive 1 wk of hyperoxia exposure. The target organ specificity for hyperoxia exposure was in the lung as indicated by the increased lung:body weight ratio in all hyperoxia-exposed rats regardless of dietary treatment. All dietary treatment groups exposed to hyperoxia had a similar increase in lung:body weight ratio, but none of the hyperoxia-exposed rats had MRI-detectable lung damage. After 7 d of hyperoxia exposure, all dietary treatment groups, including the Cu-deficient rats, had increased activity of lung CuZn-superoxide dismutase (CuZnSOD), but changes in CuZnSOD activity were not related to lung Cu or Zn concentrations. We propose that the ability to increase CuZnSOD activity is the most important factor of the enzymatic oxygen free radical defense system for protection against hyperoxia-induced lung damage detected by MRI. Even though lung Cu concentration was decreased in Cu deficiency, it seems that Cu-deficient rats are still able to increase lung CuZnSOD activity in response to 85% oxygen exposure.

Animals↗

PubMed2005

Radiopaque coil insertion into breast cancers prior to neoadjuvant chemotherapy.

Between May 1998 and December 2002, neoadjuvant chemotherapy was given to 81 women aiming to reduce tumour size and avoid mastectomy. A coil was inserted under ultrasound guidance into the tumour before treatment started. The impact of coil placement on subsequent surgery was assessed prospectively. Clinical response was seen in 69 patients and breast conservation was achieved in 60 cases. In 19 cases (23%) mammography and ultrasound were normal and localization was achieved exclusively by use of the coil. Eight of these 19 (10% of the total) had a complete pathological response; however in the remaining 11 cases (13%) there was residual invasive cancer. This study suggests that in patients undergoing neoadjuvant chemotherapy surgery is still appropriate even when clinical response appears complete. The use of the coil identifies 13% of patients with otherwise undetectable residual disease and is a valuable guide in identifying the site for further surgery.

Adult↗

PubMed1993

Cell mediated events that control blood coagulation and vascular injury.

UNLABELLED: Recent studies suggest that the generation of thrombin and other clotting factors plays a major role in cellular regulation and probably a variety of disease processes. Many of these cellular responses occur at thrombin levels lower than those required for fibrin clot formation. The availability of more specific reagents to intervene in the coagulation process will likely provide a better understanding of the role of the coagulation cascade and its inhibitors in normal and pathologic responses. In the immediate future, improved understanding of the role of inflammation and cellular responses in the control of coagulation offers many new and potentially safer interventions to prevent thrombosis. DISCLAIMER: It was my intent in this chapter to provide some outlines of the role of membranes in the blood clotting process and the role of coagulation factors in cellular activation. The scope of the area is so extensive that many important contributions have been overlooked and space limitations forced citation of reviews rather than primary publications in many cases. I regret these oversights.

Blood Coagulation↗

PubMedDate not supplied

Molecular markers and prediction of response to chemoradiation in rectal cancer.

Preoperative chemotherapy and radiation (chemoradiation) are increasingly used in the treatment of advanced rectal carcinoma to downstage the tumor so that a sphincter sparing procedure is used. This treatment modality has also resulted in not only local disease control but also decreased metastasis and increased survival. It is well known that with standard chemoradiation some tumors show marked pathologic response, while others remain non-responsive. Identification of tumor markers that can predict responsiveness to chemoradiation is extremely useful to avoid unnecessary preoperative treatment. To understand the role of thymidylate synthase (TS), p53 and Bcl-2 proteins, if any, in tumor response/resistance to chemoradiation, we examined pretreatment biopsy material obtained from 12 responsive and 13 non-responsive patients by immunohistochemistry. TS was undetectable in 11 of 12 (92%) responsive tumors and overexpressed in only 1 tumor (8%); whereas, p53 or Bcl-2 was overexpressed in 8 tumors (66%). In the non-responsive group of 13 tumors, overexpression of TS, p53 and Bcl-2 was observed in 7, 5 and 6 tumors, respectively. In 6 non-responsive tumors in which TS was undetectable, 5 tumors contained high levels of p53 or Bcl-2. These results indicate that level of TS in tumors is the best predictor of sensitivity or resistance to chemoradiation. No such correlation between overexpression of p53 and Bcl-2 and response to chemoradiation is observed.

Adult↗

PubMed1997

Magnetisation transfer ratio measurement in the cervical spinal cord: a preliminary study in multiple sclerosis.

MRI readily detects the lesions of multiple sclerosis (MS) in the brain and spinal cord. Conventional MRI sequences do not, however, permit distinction between the various pathological characteristics (oedema, demyelination, axonal loss and gliosis) of lesions in MS. Magnetisation transfer (MT) imaging may be more specific in distinguishing the pathologies responsible for disability in MS, namely demyelination and axonal loss, and therefore may have a potential role in monitoring treatment. We have applied MT imaging to the cervical spinal cord to see if it is feasible to measure MT ratios (MTR) in this region where pathological changes may result in considerable disability. We studied 12 patients with MS and 12 age- and sex-matched normal controls using a sagittal T2-weighted fast spin-echo sequence with and without an MT pulse. The median value for cervical cord mean MTR measurement in normal controls was 19.30% units (interquartile range 19.05-19.55), whereas values were significantly lower in MS patients (median = 17.95% units, interquartile range 17.25-19.00, P = 0.0004). There was a low intrarater variability for repeated mean MTR measurements. We conclude that it is possible to measure MTR in the cervical spinal cord, that a significant reduction occurs in patients with MS, and that there may be a role for this measure in future MS treatment trials.

Adult↗

PubMed1994

The L-histidine-mediated enhancement of hydrogen peroxide-induced cytotoxicity is a general response in cultured mammalian cell lines and is always associated with the formation of DNA double strand breaks.

Micromolar concentrations of L-histidine increase the cytotoxicity of hydrogen peroxide in a number of cell lines including CHO (hamster), EAHY, McCoy's, U937 and CCRF-CEM (human), Vero (monkey) and SC-1 (mouse). Importantly, these cell lines displayed different degrees of sensitivity to H2O2 alone and the extent of enhancement elicited by the amino acid was more pronounced in resistant cell lines. The increased cytotoxicity was invariably associated with the formation of DNA DSBs and a remarkable correlation was found by plotting the level of DNA DSBs against the cytotoxic response. These results strongly support the hypothesis that the mechanism whereby L-histidine increases the toxicity elicited by H2O2 involves the formation of DNA DSBs and are consistent with the possibility that the amino acid might participate in the regulation of the physio-pathological response to oxidative stress in mammals.

Animals↗

PubMed2003

Enduring challenge in the treatment of nonsmall cell lung cancer with clinical stage IIIB: results of a trimodality approach.

BACKGROUND: Stage IIIb (T4/N3) non-small-cell lung cancer (NSCLC) is considered an inoperable disease and treatment is an enduring challenge. Surgery after induction therapy seems to improve locoregional control. We report the results of a phase II prospective trimodality trial (chemotherapy and concomitant radiotherapy plus surgery) in patients with stage IIIb NSCLC. METHODS: From November 1992 to June 2000, 39 patients (37 men and 2 women, mean age 65 years) with clinical stage IIIb (34 T4N0 to 2, 4 T2 to 3N3, 1 T4N3, excluding T4 for malignant pleural effusion) entered the study. They received intravenous infusions of cisplatin 20 mg/m(2) and 5-fluorouracil 1,000 mg/m(2) (days 1 to 4 and 25 to 28) combined with a total dose of 50.4 Gy radiotherapy delivered over 4 weeks (1.8 Gy daily). Upon clinical restaging responders underwent surgery. RESULTS: All patients were available for clinical restaging. No complete response was observed. Twenty-one patients had partial response (53.8%), 16 had stable disease (41%), and 2 had progressive disease (5.2%). Hematologic toxicity was moderate. Twenty-two patients (56.4%), 21 with partial response and 1 with stable disease, underwent surgery with no perioperative death. A radical resection was possible in 21 cases. Nine lobectomies, 3 bilobectomies, and 9 pneumonectomies were performed. Complications occurred in 5 patients (23.6%). Fourteen of the patients who underwent surgery (66.6%) showed a pathologic downstaging. A complete pathologic response was obtained in 9 cases (49%). Overall 5-year survival (Kaplan-Meier) was 23%. Resected versus non-resected patients showed a significant difference: 38% versus 5.6% (p = 0.028, log rank). CONCLUSIONS: This trimodal approach for stage IIIb NSCLC appears safe and effective. It provides good therapeutic results with acceptable morbidity in surgical cases.

Adult↗

PubMed1996

Sex role conflict, social desirability, and eating-disorder attitudes and behaviors.

The relationship of conflict between sex role ideology and sex role orientation with eating-disorder behaviors and attitudes was examined. American participants were 321 female college students who completed the Bem Sex Role Inventory (Bem, 1974), Sex Role Ideology Scale (Kalin & Tilby, 1978), and Eating Disorders Inventory (EDI; Garner, Olmsted, & Polivy, 1983). The results indicated that conflict between ideology and self-perception had little effect on responses to the Inventory. Instead, students with higher levels of self-rated social desirability and lower levels of masculinity reported higher prevalence of eating-disorder behaviors and attitudes. Analyses of sex role orientation data revealed that participants categorized as undifferentiated had the most pathological responses to the EDI. Overall, the results suggested that social desirability and masculinity, more than sex role orientation or conflict, are strongly related to eating-disorder behavior, perhaps because of a third mediating factor.

Adolescent↗

PubMed2005

[Evaluation of response to neoadjuvant chemotherapy using breast scintigraphy in breast cancer].

BACKGROUND AND OBJECTIVE: We sought to evaluate the usefulness of Tc-99m-sestamibi breast scintigraphy in predicting neoadjuvant chemotherapy response in patients with breast cancer. PATIENTS AND METHOD: In 50 consecutive patients with breast cancer stages II and III, physical examination, mammography and scintimammography were performed before and after the administration of neoadjuvant chemotherapy. The 3 assessments were compared for predictive value using a pathological response as reference. Values derived from visual assessment of the scintimammography, a quantitative tumor/background index, and isotope clearance were compared to the immunohistochemical expression of P-glycoprotein, vascular endothelial growth factor (VEGF) and microvessel density (CD31) in relation to neoadjuvant chemotherapy response. RESULTS: Macroscopic response was obtained in 10 cases (20%). Sensitivity was 86.5% (95% confidence interval [CI], 70.4-94.9) for the physical examination, 83.3% (95% CI, 68-92.5) for the mammography and 76.5% (95% CI, 58.4-88.6) for the scintimammography. Specificity was 38.5% (95% CI, 15.1-67.7) for the physical examination, 42.9% (95% CI, 11.8-79.8) for the mammography and 8.3% (95% CI, 0.4-40.2) for the scintimammography. There were no statistically significant differences in isotope uptake and clearance with regard to response nor in relation to levels of expression of P-glycoprotein, VEGF and microvessel density. CONCLUSIONS: Breast scintigraphy with Tc-99m-sestamibi is not useful in predicting the response to neoadjuvant chemotherapy in breast cancer. Traditional physical examination and mammography are more effective. Isotope uptake and clearance do not predict response and there is not an effective in vivo measurement of chemo-resistance or tumor angiogenesis.

Adult↗

PubMedDate not supplied

Serum levels of tumor necrosis factor alpha correlate with response to neoadjuvant chemotherapy in locally advanced breast cancer.

It has been shown that serum levels of tumor necrosis factor alpha (TNF-alpha) are increased in breast cancer patients. There are few data available on the reduction of serum levels of this cytokine following chemotherapy. The aim of this study was to determine the effect of neoadjuvant chemotherapy on serum concentrations of TNF-alpha and the relation to response rates in locally advanced breast cancer. Twenty consecutive patients with non-inflammatory stage III-B breast cancer achieving a partial or complete clinical response to three courses of neoadjuvant chemotherapy followed by modified radical mastectomy were prospectively included in the study and evaluated. Sera were collected before the start and after the termination of chemotherapy. Serum concentrations of TNF-alpha were measured by an ELISA method. The pathological response rates were also evaluated and recorded. The control group consisted of 12 healthy age-matched women. The mean pre-treatment TNF-alpha value of breast cancer patients was 15.9 +/- 0.9 pg/mL while it was 5.8 +/- 1.7 pg/mL in the control group; the difference was statistically significant (p < 0.0001). The serum levels of TNF-alpha were markedly decreased in patients with partial and complete responses compared to pre-treatment values (p < 0.0001). There was also a difference in TNF-alpha levels in patients with partial vs complete responses (p < 0.0001). The relative change between pre- and post-treatment values correlated significantly with the type of response (p = 0.004). These results suggest that the serum concentration of TNF-alpha can be an indicator of response and could be used in clinical decision-making for patients with locally advanced breast cancer.

Adult↗

PubMed1992

Prolonged chemotherapy for localised squamous carcinoma of the oesophagus.

We evaluated the feasibility of six courses of chemotherapy in 34 consecutive patients with localised squamous cell carcinoma of the oesophagus. All 32 evaluable patients first received at least two courses of chemotherapy. There were 18 patients with resectable carcinomas who underwent surgery and 14 patients with unresectable carcinomas who received definitive chemoradiotherapy. After two courses of 5-fluorouracil and cisplatin 21 (66%) of 32 patients had either a complete or major response. A median of five courses (range, 1-6 courses) was administered. 17 out of 18 (94%) patients with resectable carcinoma had a 'curative' resection (negative proximal, distal, and radial margins by histopathology in an en-block resection specimen) and 2 patients had a complete pathological response. The median survival duration of all patients was 28 months (range, 2-46+ months). The median survival duration of 14 patients with unresectable carcinoma was 23 months (range, 8-36+ months), and the median survival duration of 18 patients with resectable carcinoma has not been reached at a median follow-up of 24+ months (range, 10+ to 46+ months). No deaths occurred because of chemotherapy or chemoradiation therapy. Our data suggest that prolonged chemotherapy is feasible in patients with locoregional squamous carcinoma of the oesophagus. An ongoing controlled trial will determine the contribution of chemotherapy to patients' survival.

Antineoplastic Combined Chemotherapy Protocols↗