Circulating breast-derived DNA allows universal detection and monitoring of localized breast cancer.

BACKGROUND: Tumor-derived circulating cell-free DNA (cfDNA) is present in the plasma of individuals with cancer. Assays aimed at detecting common cancer mutations in cfDNA are being developed for the detection of several cancer types. In breast cancer, however, such assays have failed to detect the disease at a sensitivity relevant for clinical use, in part due to the absence of multiple common mutations that can be co-detected in plasma. Unlike individual mutations that exist only in a subset of tumors, unique DNA methylation patterns are universally present in cells of a common type and therefore may be ideal biomarkers. Here we describe the detection and quantification of breast-derived cfDNA using a breast-specific DNA methylation signature. PATIENTS AND METHODS: We collected plasma from patients with localized breast cancer before and throughout treatment with neoadjuvant chemotherapy and surgery (N = 235 samples). RESULTS: Pretreatment breast cfDNA was detected in patients with localized disease with a sensitivity of 80% at 97% specificity. High breast cfDNA levels were associated with aggressive molecular tumor profiles and metabolic activity of the disease. During neoadjuvant chemotherapy, breast cfDNA levels decreased dramatically. Importantly, the presence of breast cfDNA towards the end of the chemotherapy regimen reflected the existence of residual disease. CONCLUSION: We propose that breast-specific cfDNA is a universal and powerful marker for the detection and monitoring of breast cancer.

Protease-activated receptors (PARs) in cancer: Novel biased signaling and targets for therapy.

Despite the fact that G protein-coupled receptors (GPCRs) mediate numerous physiological processes and represent targets for therapeutics for a vast array of diseases, their role in tumor biology is under appreciated. Protease-activated receptors (PARs) form a family which belongs to GPCR class A. PAR1&2 emerge with a central role in epithelial malignancies. Although the part of PAR1&2 in cancer is on the rise, their underlying signaling events are poorly understood. We review hereby past, present, and future cancer-associated PAR biology. Mainly, their role in physiological (placenta-cytotophobalst) and patho-physiological invasion processes. The identification and characterization of signal pleckstrin homology (PH)-domain-binding motifs established critical sites for breast cancer growth in PAR1&2. Among the proteins found to harbor important PH-domains and are involved in PAR biology are Akt/PKB as also Etk/Bmx and Vav3. A point mutation in PAR2, H349A, but not R352A, abrogated PH-protein association and is sufficient to markedly reduce PAR2-instigated breast tumor growth in vivo as also placental extravillous trophoblast (EVT) invasion in vitro is markedly reduced. Similarly, the PAR1 mutant hPar1-7A, which is unable to bind PH-domain, inhibits mammary tumors and EVT invasion, endowing these motifs with physiological significance and underscoring the importance of these previously unknown PAR1 and PAR2 PH-domain-binding motifs in both pathological and physiological invasion processes.

PH motifs in PAR1&2 endow breast cancer growth.

Although emerging roles of protease-activated receptor1&2 (PAR1&2) in cancer are recognized, their underlying signalling events are poorly understood. Here we show signal-binding motifs in PAR1&2 that are critical for breast cancer growth. This occurs via the association of the pleckstrin homology (PH) domain with Akt/PKB as a key signalling event of PARs. Other PH-domain signal-proteins such as Etk/Bmx and Vav3 also associate with PAR1 and PAR2 through their PH domains. PAR1 and PAR2 bind with priority to Etk/Bmx. A point mutation in PAR2, H349A, but not in R352A, abrogates PH-protein association and is sufficient to markedly reduce PAR2-instigated breast tumour growth in vivo and placental extravillous trophoblast (EVT) invasion in vitro. Similarly, the PAR1 mutant hPar1-7A, which is unable to bind the PH domain, reduces mammary tumours and EVT invasion, endowing these motifs with physiological significance and underscoring the importance of these previously unknown PAR1 and PAR2 PH-domain-binding motifs in both pathological and physiological invasion processes.

Changes in psychological distress of women in long-term remission from breast cancer in two different geographical settings: a randomized study.

GOALS OF WORK: Psychological distress and coping styles in women diagnosed with stages I and II breast cancer have attracted substantial clinical and research attention over the last several decades. The contradictory and, at times, controversial findings stimulated the present randomized research whose purpose was to explore the possibility and probability of predicting which variables affect the psychological distress level of women with breast cancer 1 to 5 years after diagnosis (time period 1) and 6 to 8 months after period 1 (time period 2). PATIENTS AND METHODS: The study was conducted in two large oncology centers in Graz, Austria, and Jerusalem, Israel, with a sample population comprising 424 patients. MAIN RESULTS: The only variables that significantly predicted change in the psychological distress levels (Grand Severity Index, GSI; except for the GSI level during period 1) were Fighting Spirit (Mental Adjustment to Cancer, MAC) in the Graz sample and Perceived Family Support (PFS) in the Jerusalem sample. These results are discussed in relation to other findings. CONCLUSIONS: In light of these findings, it is highly important to preliminarily identify women with less adaptive psychological coping mechanisms and to provide them with efficacy tools for behavioral and cognitive changes within their own network of social and health resources.

Do different cultural settings affect the psychological distress of women with breast cancer? A randomized study.

Breast cancer is the most common malignant disease among women in developed countries. In Austria and Israel, it accounts for 15% and 18%, respectively, of all cancers and 30% of all cancers in women. The purpose of this study, conducted in Graz, Austria, and Jerusalem, Israel, was to determine whether different geographical and cultural settings differentially affect the psychological distress of women who have survived breast cancer and why. The dependence of psychological distress on psychosocial variables such as quality of life, body image, impact of cancer and coping styles was examined at time 1 in a randomized sample of 424 breast cancer women who were disease-free at the time of the study and were surveyed 1-5 years after diagnosis. The most contributing variables to the level of psychological distress in both populations were: the number of stressful life events during last year, financial problems and feeling uncomfortable with the body. Regarding coping styles, mental adjustment to cancer was the principal contributor to psychological distress level [determined by the Grand Severity Index (GSI) scores] in the Graz group, while intrusion was the principal contributor to the GSI level in the Jerusalem group.

Effects of age on coping and psychological distress in women diagnosed with breast cancer: review of literature and analysis of two different geographical settings.

Age-related differences in emotional distress were examined by studying two random samples (N=424) of women diagnosed with early stages of breast cancer in Graz, Austria and Jerusalem, Israel. We found that psychological distress, coping abilities, and different perceptions of illness are attributable to socialization differences of age experience according to young (49 or younger), intermediate (50-64) and old (65 and older) age groups. Patients were interviewed at home to obtain sociodemographic and medical background data. They also completed five standardized instruments (Brief Symptom Inventory, Psychological Adjustment to Illness Scale, Impact of Events Scale, Mental Adjustment to Cancer, and Perceived Family Support). A two-way MANOVA for all the demographic variables yielded significant main group (Graz vs. Jerusalem) effect (P<0.0001), significant main age effect (P<0.0001) and significant interaction (group by age) effect (P<0.001). Examination of the contribution of the age category to the level of the coping variables showed a different pattern in each group. The psychological distress variables revealed that, in the Jerusalem sample, there is a tendency toward decreasing distress levels with age and, in the Graz sample, elevated scores for the intermediate-age group. Age was found to be related to the level of Global Severity Index (GSI) and to the variables correlated to the GSI level. Psychological intervention should be guided to the different age groups.

Recombinant thyroid-stimulating hormone in differentiated thyroid cancer.

Recombinant TSH is effective in providing exogenous TSH stimulation for patients with differentiated thyroid cancer on thyroid hormone-suppressive therapy. It allows for detection of thyroid remnant and metastases by radioiodine scan and by serum thyroglobulin determination. The sensitivity and image quality of the WBS are similar after rTSH and after THSH withdrawal in the majority of patients. The equivalent 100% sensitivity of rTSH- and withdrawal-stimulated serum thyroglobulin measurement alone in identifying patients with radioiodine uptake outside the thyroid bed [38] may eventually lead to more extensive use of serum thyroglobulin testing after rTSH, with more selective application of radioiodine WBS [39]. Currently, a phase IV trial is in progress to evaluate the efficacy of rTSH-stimulated thyroglobulin levels as the primary modality for long-term follow-up of low risk thyroid cancer patients. The use of rTSH prevents the morbidity, metabolic impairment and the risk of tumor progression associated with THST withdrawal, because of shorter exposure time to elevated TSH [38]. Furthermore, it decreases the radiation exposure of healthy tissues due to faster iodine clearance in euthyroidism. rTSH is well tolerated, with transient nausea in 10.5% and headache in 7.3% of patients. No antibodies specific to rTSH were documented, even after multiple courses of the drug. Currently, rTSH is suggested for patients who do not respond to hormone withdrawal or cannot tolerate hypothyroidism. For patients with low risk of tumor recurrence, rTSH-stimulated testing may be used at 6-12 months after postoperative I-131 ablation and with a repeat cycle of rTSH one year later, followed by testing every 3-5 years. In high risk patients, one set of negative I-131 scan and thyroglobulin test results after hormone withdrawal are recommended before using rTSH testing, because of a greater sensitivity of the withdrawal scan and because rTSH is not currently approved for subsequent I-131 therapy often indicated in these patients [24]. Subsequently, two cycles of rTSH testing are recommended at 6-12 month intervals, followed by testing every 1-3 years for at least the first decade after initial diagnosis. The cost of this commercially available form of rTSH has been considered a major impediment to its common use; however, this should be weighed against the loss of productivity of working hours related to withdrawal [40]. In the therapeutic setting, rTSH is the only acceptable option in a subgroup of patients with hypopituitarism, ischemic heart disease, a history of "myxedema madness," debilitation due to advanced disease, or inability to elicit TSH elevation due to continued production of thyroxine by thyroid remnant or metastatic tumor [33,38]. In conclusion, recombinant TSH facilitates the management of patients with differentiated thyroid carcinoma. It increases the sensitivity of thyroglobulin testing during thyroid hormone suppression therapy and enables radioiodine uptake for whole-body scan and occasionally for radioiodine therapy, without the need for prolonged THST withdrawal and its associated hypothyroidism, reduced quality of life and risk of tumor progression.

Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma.

BACKGROUND: Doxil (ALZA Corp., Mountain View, CA) is a formulation of doxorubicin in polyethylene-glycol coated liposomes with a prolonged circulation time and unique toxicity profile. As yet, the effect of the dose schedule on toxicity and the correlation of toxicity with pharmacokinetics have not been directly addressed. METHODS: The objectives of this study were to examine the toxicity profile and pharmacokinetics of various dose schedules of Doxil in a group of patients with metastatic breast carcinoma (MBC) previously treated with chemotherapy. Forty-five patients received a total of 268 courses of Doxil (median per patient, 5; range, 1-19). Six dose schedules were investigated: 35 mg/m2 every 3 weeks (11 patients), 45 mg/m(2) every 3 weeks (5 patients), 50 mg/m(2) every 4 weeks (5 patients), 60 mg/m(2) every 4 weeks (6 patients), 65 mg/m(2) every 5 weeks (6 patients), and 70 mg/m(2) every 6 weeks (12 patients). Doxil pharmacokinetics was examined in 24 of these patients at the dose levels of 35, 45, 60, and 70 mg/m(2). RESULTS: Stomatitis was dose related, with higher incidence and severity at doses of 60-70 mg/m(2). Skin toxicity in the form of palmar-plantar erythrodysesthesia (PPE) developed usually after two or more courses of treatment and was schedule dependent with shorter dosing intervals leading to increased frequency and severity of skin manifestations. Myelosuppression, mainly as leukopenia/neutropenia, was dose dependent but mild and uncomplicated in most cases. Hair loss was infrequent (< 7%) and always of limited extent. Despite high cumulative doses up to 1500 mg/m(2), cardiac toxicity was observed in only 1 patient who received prior mitoxantrone and mediastinal radiotherapy. Objective responses, improvements, and durable stabilizations were observed in 9, 6, and 14 patients, respectively, indicating significant antitumor activity of Doxil in previously treated MBC patients. Doxil pharmacokinetics was well described by a monoexponential elimination curve with a long T(1/2) (median, 79 hours), a slow clearance (median, 40 mL/hour), and a small volume of distribution (median, 3.9 L). Cmax (peak plasma concentration) and AUC (area under the concentration*time curve) increased linearly with dose with a statistically significant correlation. Correlation analysis of dose and pharmacokinetic parameters with Doxil toxicites revealed that stomatitis grade and leukocyte nadir were correlated strongly with dose and Cmax, and weakly with AUC, whereas PPE grade was correlated significantly with only 1 parameter, T(1/2). CONCLUSIONS: The toxicity of Doxil is dose and schedule dependent and well correlated with pharmacokinetic parameters. Pharmacokinetic guidance of Doxil dosing may be a useful tool.

Genetic testing of breast and ovarian cancer patients: clinical characteristics and hormonal risk modifiers.

OBJECTIVES: Carriers of the mutations 185delAG and 5382insC in the BRCA1 gene and 6174delT in the BRCA2 gene have a substantial life-time risk for breast and ovarian cancers (BC and OC). The aim of the study was to identify the clinical features and the hormonal risk modifiers in mutation carriers and the implication in suggested guidelines for treatment decisions in BRCA1/2 carrier patients. STUDY DESIGN: Breast and/or ovarian cancer patients from the Oncology and Cancer Genetic clinics were tested for the three Ashkenazi founder mutations: 87 patients were identified as carriers of one of these mutations. Clinical presentation and age at onset were correlated with the mutations, in patients with bilateral BC or BC and OC, the length of time that elapsed between the diagnosis of the two cancers was recorded. We compared BC and OC patients with regard to ages at menarche, first pregnancy and menopause, number of pregnancies and deliveries, the use of oral contraceptives, hormonal replacement therapy and fertility treatments. RESULTS: The carriers of the three BRCA1/2 Ashkenazi founder mutations did not differ in clinical presentation nor age at onset. Forty-three patients (74.1%) of 58 BC patients were diagnosed between the ages 30 and 50, only four (6.9%) patients were diagnosed after age 60. Of BC patients diagnosed before age 35, 63.6% developed second BC as compared to 25.5% of those diagnosed after age 35. Ovarian cancer was diagnosed after age 45 in 89.7% of the patients, only one patient was diagnosed under the age of 40. Oral contraceptives use was documented in 61.3% of BC patients as compared to 11.8% of OC patients. Other hormonal factors did not differ between the two groups. CONCLUSIONS: The carriers of the three Ashkenazi founder mutations should be considered at the same risk for BC and for OC and treatment options should be the same. Mutation carriers diagnosed with BC before the age of 35 are at a very high risk for developing second breast cancer. Most ovarian cancers in carriers were diagnosed after age 45, and prophylactic oophorectomy should be postponed to the age of 45. Oral contraceptives might elevate the risk of BC in mutation carriers.

MDR1 gene expression in primary and advanced breast cancer.

P-glycoprotein (Pgp)-associated multidrug resistance (MDR) is related to intrinsic and acquired cross resistance to anthracyclines, vinca alkaloids, and other antineoplastic antibiotics. Expression of MDR1 is widely considered to play an important role in conferring resistance to adjuvant chemotherapy in women with breast tumor cells in women with disseminated disease, although data supporting this view is, at best, conflicting. The expression of MDR1 gene and its gene product, P-glycoprotein, was investigated in primary and advanced breast cancers (both previously untreated and previously treated on specific treatment protocols) to assess the role of P-glycoprotein in determining responsiveness to adjuvant chemotherapy. Expression was assessed by immunohistochemistry, reverse transcription-PCR (RT-PCR), Northern Blot and Western Blot. MDR1 mRNA was detected in 40% of the breast cancers tested by RT-PCR with 40 cycles of PCR amplification. When reducing the PCR amplification cycles to 28, the MDR1 gene expression signal disappeared from breast cancers of the highest expressers; however, known MDR1 positive control normal tissues, such as adrenal, kidney, and liver continued to show an expression product. Western and Northern blots failed to demonstrate the MDR1 gene product, P-glycoprotein, in these breast cancers. In contrast, physiologic levels of P-glycoprotein was clearly detected in normal adrenal, kidney, and liver by these techniques. Immunohistochemistry confirmed that breast carcinoma cells lacked P-glycoprotein expression; however, interstitial mononuclear cells, morphologically consistent with lymphocytes or macrophages did show immunostaining in some of these breast tumors. MDR1 gene expression identified by RT-PCR was not correlated either with response to paclitaxel therapy (29 patients able to be evaluated, p = 0.34, Fisher Exact Test) or overall survival (32 breast cancer patients with clinical follow-up information, p = 0.336, log rank). In conclusion, P-glycoprotein was not expressed in breast carcinoma cells at significant levels, although it was expressed in stomal lymphocytes or macrophages. These results suggest that P-glycoprotein does not play a significant role in multidrug resistance of breast cancer.

Thrombin receptor overexpression in malignant and physiological invasion processes.

Although the involvement of soluble and matrix-immobilized proteases in tumor cell invasion and metastasis is well recognized, the role of proteolytically activated cell surface receptors has not been elucidated. We report here that thrombin receptor, a member of the protease-activated receptor family, is preferentially expressed in highly metastatic human breast carcinoma cell lines and breast carcinoma biopsy specimens. Introduction of thrombin receptor antisense cDNA considerably inhibited the invasion of metastatic breast carcinoma cells in culture through a reconstituted basement membrane. During placental implantation of the human embryo, thrombin receptor is transiently expressed in the invading cytotrophoblasts. These results emphasize the involvement of thrombin receptor in cell invasion associated with tumor progression and normal embryonic development.

Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation.

PURPOSE: A phase II study of liposomal doxorubicin was conducted in patients with ovarian cancer who failed to respond to platinum- and paclitaxel-based regimens. Liposomal doxorubicin was selected as a result of its superior activity against ovarian cancer xenografts relative to free doxorubicin and activity in refractory ovarian cancer patients that was noted during the phase I study. PATIENTS AND METHODS: Thirty-five consecutive patients were accrued in two institutions (22 in one and 13 in the other). All had progressive disease after either cisplatin or carboplatin and paclitaxel, or at least one platinum-based and one paclitaxel-based regimen. Patients received intravenous (I.V.) liposomal doxorubicin 50 mg/m2 every 3 weeks with a dose reduction to 40 mg/m2 in the event of grade 3 or 4 toxicities, or a lengthening of the interval to 4 weeks (and occasionally to 5 weeks) with persistence of grade 1 or 2 toxicities beyond 3 weeks. RESULTS: Nine clinical responses (one complete response [CR], eight partial responses [PRs]) were observed in 35 patients (25.7%), with seven of these having been confirmed by two consecutive computed tomographic (CT) measurements. The median progression-free survival was 5.7 months with an overall survival of 1.5 to 24+ months (median, 11 months). Although 13 patients experienced grade 3 or 4 nonhematologic skin and mucosal toxicities (either hand-foot syndrome or stomatitis), with dose modifications, the treatment was very well tolerated. Nausea that was clearly attributable to the drug, hair loss, extravasation necrosis, or decreases in ejection fraction did not occur. CONCLUSION: Liposomal doxorubicin has substantial activity against ovarian cancer refractory to platinum and paclitaxel. The responses achieved with liposomal doxorubicin were durable and maintained with minimal toxicity. This liposomal formulation should be evaluated further in combination with other drugs in less refractory patients.

The role of psychological variables in a group of melanoma patients. An Israeli sample.

This study examined whether there is a difference in the psychological distress and/or coping modes of patients with early localized malignant melanoma. The authors compared the patients diagnosed at stages IA and B of the disease with those diagnosed at stages IIA and B. The population consisted of 100 melanoma patients who agreed to take part in a study of adjustment to chronic disease. The patients were individually interviewed at home and completed six self-reports. Three of the reports assessed psychological outcome, two assessed coping, and one assessed support systems. No substantial differences were found between the patients treated at stages I and II on any of the psychological measures, despite the fact that those with greatest thickness and depth (stage IIB) are at higher risk of recurrence. The women showed greater distress than the men, confirming earlier observations made in patients with colon cancer.

Ovarian cysts in premenopausal and postmenopausal tamoxifen-treated women with breast cancer.

OBJECTIVE: Our purpose was to investigate the frequency of ovarian cysts in tamoxifen-treated breast cancer patients. STUDY DESIGN: The study population included 95 consecutive tamoxifen-treated premenopausal and postmenopausal women with breast cancer who were followed up by the outpatient clinic at the Hadassah University Hospital between September 1990 and June 1992. Tamoxifen was administered orally (20 mg/day). All patients underwent a pelvic examination and vaginal ultrasonography with a 5 MHz vaginal probe. RESULTS: During the study 11 of 95 tamoxifen-treated breast cancer patients (11%) had ovarian cysts. Five cysts were detected in postmenopausal women (6.3% of the postmenopausal women) and six in premenopausal women (37.5% of the premenopausal women). In postmenopausal and premenopausal women the mean tamoxifen treatment interval was 19.4 +/- 7.8 months (range 4 to 48 months) and 28 +/- 6.1 months (range 12 to 54 months), respectively (p = 0.41). In 8 of the 11 patients the ovarian cystic enlargement disappeared after cessation of tamoxifen treatment. Two patients underwent laparotomy because of persistent cysts and the third because of a rapidly growing myoma. The three cysts were found to be benign. CONCLUSION: Ovarian cysts are a common side effect of tamoxifen treatment. The ovarian cysts can develop in tamoxifen-treated premenopausal as well as postmenopausal women with breast cancer. Most of the tamoxifen-associated cysts disappear after tamoxifen treatment is abandoned.

Liposomal doxorubicin: antitumor activity and unique toxicities during two complementary phase I studies.

PURPOSE: The purpose of our studies was to define the maximal-tolerated dose of liposomal doxorubicin (DOX-SL; Liposome Technology Inc, Menlo Park, CA), a doxorubicin formulation of polyethyleneglycol-coated liposomes, characterize the toxicities associated with this formulation, and evaluate any indication of antitumor activity within a phase I setting. PATIENTS AND METHODS: Two separate phase I studies were conducted following the initial human pharmacokinetic testing at one of the sites (Hadassah). The starting dose of 20 mg/m2 at the University of Southern California was just below the dose without toxicity in the pharmacokinetic study. At Hadassah, the phase I starting dose was just above their earlier safe single doses, 60 mg/m2. Both studies involved cohorts of at least three patients and redosing every 3 to 4 weeks. To determine the recommended dose for phase II trials, an additional level of 50 mg/m2 every 3 weeks was explored, and the level of 60 mg/m2 every 4 weeks was expanded. RESULTS: A total of 56 patients receiving 281 courses of DOX-SL was accrued and evaluated for toxicity. Hand-foot (H-F) syndrome and stomatitis are the two main dose-limiting factors of DOX-SL. Stomatitis was dose-limiting for high single doses of DOX-SL greater than 70 mg/m2. Skin toxicity manifested primarily as H-F syndrome was dose-limiting for repetitive dosing, but acceptable at either 50 mg/m2 every 3 weeks or 60 mg/m2 every 4 weeks. Attenuation of acute subjective symptoms and lack of alopecia were generally observed. Patients with carcinomas of the breast, ovary, prostate, and head and neck were among those showing objective antitumor responses or improvement based, in part, on blood levels of tumor markers. CONCLUSION: The toxicity profile of DOX-SL differs prominently from that of the free drug administered by bolus or rapid infusion and with some differences, resembles that of prolonged continuous infusion. This finding, as well as the antitumor activity observed, supports wide phase II testing of DOX-SL in solid tumors.

Paclitaxel (Taxol) in heavily pretreated ovarian cancer: antitumor activity and complications.

OBJECTIVE: To analyze the efficacy and toxicity of Taxol in patients with ovarian cancer who had failed at least two previous chemotherapy treatment regimens. PATIENTS AND METHODS: Sixty-eight patients with advanced pretreated ovarian cancer, with either measurable or evaluable disease who were shown to have disease progression were entered on a National Cancer Institute sponsored 'compassionate' treatment referral center protocol and received intravenous infusion of Taxol over 24 hours 135 mg/m2, (after steroid-containing premedication) repeated every 3 weeks and continued while showing no evidence of progression. RESULTS: Of the 68 patients enrolled, 10 patients (15%) had a partial response and one assessable by marker only had improvement of disease. In addition, 27 others (40%) were stable on continued Taxol for a median time of 6.4 months and CA-125 decreased in 20 patients out of 59 patients with elevated baseline CA-125s. Twenty-seven patients progressed while receiving 1-6 cycles of treatment. Three patients were not evaluable for response. Neutropenia and its complications occurred primarily during the first two cycles of Taxol treatment. Febrile episodes requiring antibiotic treatment occurred in 44% of patients which is a higher incidence than in prior series. CONCLUSIONS: Taxol as a single agent has modest activity in heavily pretreated ovarian cancer patients but appears to be useful and is subjectively well tolerated by many. The high incidence of infection in comparison with other series of patients with ovarian cancer treated with chemotherapy suggests this pretreated patient population has enhanced susceptibility to develop complications from neutropenia. Safer treatment in this advanced setting should include more aggressive use of cytokines and/or less myelosuppressive regimens (e.g. shorter Taxol infusions).

Progressive muscle relaxation and guided imagery in cancer patients.

The aim of this study was to gather information on the immediate and long-term effects of six sessions of group Progressive Muscle Relaxation with Guided Imagery on the psychological distress of self-referred cancer patients. Patients' psychological distress and coping with cancer were assessed by three self-reports: the Multiple Locus of Control, the Impact of Events Scale (IES), and the Brief Symptom Inventory (BSI). Of the 123 patients who started group therapy, 37 dropped out during its course. The 86 patients who completed the intervention showed marked improvement on both BSI and IES, an improvement maintained over the next 6 months in 58 patients who continued assessment through the followup period.