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Cassini Ion Neutral Mass Spectrometer (INMS) measurements from roughly a hundred Titan encounters over the Cassini mission yield neutral and ion densities systematically lower, by factors approximately 2 to 3, than estimates from several other spacecraft systems, including the Attitude and Articulation Control System, and Navigation system. In this paper we present a new INMS instrument sensitivity model, obtained by re-analyzing (1) the capture and transmission of neutral gas through the instrument, and (2) the detector gain reduction during pre-launch testing. By correcting for an under-estimation of gas leakage out of the instrument into space by the original calibration model, and adjusting for the gain change, the new model brings INMS densities into much closer agreement with the other Cassini systems. Accordingly, the INMS ion densities are revised upward by a constant detector sensitivity correction factor of 1.55±21 %, while the neutral sensitivities have a complex instrument pointing direction dependence, due (mostly) to the effect of the INMS vent and antechamber-to-closed source tube. In the special case of on-ram pointing the neutral densities are revised upward by a constant factor of 2.2±23 %. The corrected neutral and ion sensitivities given here are applicable to all previously published INMS results at Titan, Enceladus and elsewhere in the Saturn system. The new model gives reliable densities at high ram angles, in some cases above 90 degrees, thereby expanding the list of Titan flybys from which INMS densities may be extracted. We apply the model to obtain accurate densities from several off-ram Titan flybys which gave unusual neutral density vs. altitude profiles, or unreasonably high densities, with the original calibration.

Multiple Titan encounters by the Cassini spacecraft have shown that ion chemistry in Titan's upper atmosphere is much more complex than previously thought. As well as showing a great variety of species present below 100 amu, they also include the detection of negative ions and of large abundances of ions above 100 amu. Here, we use data from two Cassini instruments, the Cassini plasma spectrometer's ion beam sensor (CAPS/IBS) and the ion and neutral mass spectrometer (INMS) during fourteen Cassini encounters with Titan's upper atmosphere. By simultaneous analysis of the combined data, we are able to determine the ion temperature, one component of the wind speed and spacecraft potential. Using these derived quantities, we are also able to extend the analysis of CAPS/IBS data to quantify the abundance of ions above 100 amu and to statistically estimate their composition.

Aims To investigate intensity-modulated radiotherapy (IMRT) plans for women with carcinoma of the breast, using a small number of Sim-CT slices, thus avoiding changing the patient's position and potential problems with CT capacity. Materials and methods Ten CT scans of women with breast cancer were obtained for use in the study. IMRT plans based on an open tangent pair and additional top-up segment fields were created using the full CT scan, and represented the gold standard treatment plan for comparison purposes. Five-slice CT simulator scans were artificially created by omitting intermediate slices from the full CT scans. Additionally, the intermediate CT slices were recreated via interpolation of the five slices using a standard interpolation algorithm. IMRT plans were created in the same way as for the full CT scans. To allow a suitable plan comparison to be made, the beam segments and monitor units were transferred to the full CT scans, and the dose distribution calculated. Results The interpolated five-slice plans showed no significant difference in the volume of tissue receiving dose outside the range 95–105%, compared with the IMRT plans created using the full CT data set (1.3±2.2%, P =0.092). In contrast, the discrete slice CT simulator plans increased by 6.3±5.4%, P =0.0054, showing a statistically significant difference in the dose distribution produced and a clinically inferior plan. Conclusions Plans created using five discrete slice CT scans were inferior to full CT-derived IMRT treatment plans, and are therefore not acceptable for IMRT. However, interpolating five CT simulator slices provides adequate anatomical information to produce comparable IMRT plans to those created by full CT scans of the patient. This allows the introduction of IMRT for this patient group without the need to change treatment position to accommodate CT scanning.

Local recurrence of cancer in the treated breast following breast-conserving surgery and radiotherapy occurs in a minority of patients, but can represent a significant clinical problem. The impact of local relapse on the subsequent course of the disease is disputed. The aim of this retrospective review was to identify the rate and prognostic factors for breast recurrence and to determine the subsequent outcome. The case notes of 2159 patients treated between 1989 and 1992 were reviewed. Actuarial local relapse rate was 6.3% at 5 years. Factors predictive for recurrence on multivariate analysis were age (P0.001), status of excision margins (P=0.019), and pathological UICC stage (P=0.01). One hundred and sixty-one patients developed local recurrence in the treated breast of whom 101 were treated with further surgery. The 5-year cancer-specific survival of this group was comparable with that of the patients who remained free of breast relapse (82 vs. 88%) but subsequently fell to 61 vs. 80% at 8 years (P0.001). Sixty patients were unable to have salvage surgery; their cancer-specific survival was much worse than that of patients with operable recurrences at 33% at 5 years and 13% at 8 years. Eighty-three patients (4% of the original 2159 patients) had uncontrolled local disease at time of death or last follow-up. The prognosis of patients who developed recurrence within 2 years of their initial treatment was inferior to those who developed recurrences after 4 years (cancer-specific survival 5 years post-recurrence 23 vs. 57% P=0.008). Systemic therapy should be considered for patients with early breast recurrence in view of their inferior survival.

Background and purpose : Using pulsed field gel electrophoresis (PFGE) a significant correlation was demonstrated between residual DNA double-strand breaks (dsbs) and the development of late radiation fibrosis in a group of 39 breast cancer patients studied retrospectively. This group formed a training cohort generating a hypothesis that there is a relationship between residual radiation-induced DNA dsbs in cultured fibroblasts and late radiotherapy reactions in breast cancer patients. The aim of this study was to retest and validate the hypothesis. Materials and methods : The study was retrospective. Skin biopsies were taken from a validation cohort of 50 breast cancer patients and PFGE was used to examine residual radiation-induced dsbs in cultured fibroblasts. Late morbidity was measured clinically as fibrosis and using the late effects on normal tissues scales that incorporate subjective, objective management and analytic data (LENT SOMA). Results : PFGE data were obtained for 49 biopsies. In the 49 patients there was no correlation between residual DNA damage and either fibrosis ( r =−0.027, P =0.85) or LENT SOMA ( r =−0.10, P =0.48) scores. There was no significant relationship between residual damage and fibrosis for the combined training and validation cohorts of 88 patients ( r =0.20, P =0.063). Conclusions : This study did not validate the hypothesis that there is a relationship between fibroblast residual DNA damage and late morbidity in breast cancer patients. The PFGE assay on fibroblasts is not a suitable test of the degree of late radiation-induced fibrosis in the breast.

A regional workgroup comprised of individuals from regulatory agencies, uni versities, and consulting companies was formed to develop an approach for incor porating information on chemical availability in soils into risk assessment and risk based decision making. The approach consists of the following decision framework for including information on chemical availability: (1) Determine the usefulness of incorporating information on bioavailability; (2) Identify information needs from a conceptual model of exposure for the site and from exposure pathways judged critical to the assessment; (3) Identify soil factors that affect bioavailability; (4) Determine the type or form of information (measures and/or models) that can be used within the risk assessment and risk management process; (5) Select methods (measures and/or models) based on the “weight of evidence” or strength of the bioavailability information they will provide and how that information will be used for risk assessment and risk based decision ma...

Purpose: To study the relationship between the severity of late reactions to radiotherapy in breast cancer patients, and the extent of residual radiation-induced DNA damage, using a rapid assay of keratinocytes obtained directly from skin biopsies. Methods and Materials: A review was made of 32 patients with breast cancer, treated uniformly by radiotherapy between 1983 and 1988, following breast-conserving surgery. Their late radiotherapy reactions were scored (9–14 years post-radiotherapy) using a modified LENT SOMA scale, and a 5-mm buttock skin punch biopsy was obtained. Intact skin was irradiated at room temperature, and after allowing 24 h for repair, the tissue was disaggregated and the cells processed for pulsed field gel electrophoresis (PFGE). Residual DNA damage was expressed as the fraction of DNA released (FDR) following 150 Gy. Results: Studies using flow cytometry on disaggregated breast skin showed that over 90% of the cells were keratinocytes. The PFGE assay was robust with low background FDRs in unirradiated skin samples (mean 3.2%) and a wide range of FDRs following irradiation from 11.5% to 26.6%. No correlation was found between the FDR at 150 Gy (FDR 150) and any of the late reaction scores or retrospective acute reaction scores. There was, however, a borderline significant correlation for family history and FDR 150 ( p = 0.059). Conclusion: Rapid measurement of residual DNA damage in irradiated differentiated keratinocytes, the predominant cell population in skin biopsies, showed no correlation with the severity of symptomatic early or documented late reactions in a retrospectively studied group of 32 breast cancer patients.

The treatment outcomes were reviewed for all the patients at this institute who underwent breast irradiation after breast conserving surgery in 1991. Of a total of 643 patients treated, 194 (30%) had presented with tumours detected by screening mammography. The breast was irradiated with a tangential pair of fields, giving a dose of 40 Gy in 15 fractions over 3 weeks in 97% of these patients. A boost was not used. With a median follow-up of 4.7 years, there was better cancer related survival in patients with screen detected cancers compared with those that were non-screen detected (94% versus 84% at 5 years; P = 0.002). The breast recurrence rate at 5 years was 1% for screen detected cancers compared with 6% for those that were non-screen detected (P = 0.01). Factors additional to screen detected status that were found to be significant for cancer survival were pathological stage (P = 0.03) and histological grade (P = 0.01). In a Cox multivariate analysis, only two factors were significant for breast recurrence: screen detected status (P = 0.023) and histological grade (P = 0.016) This study suggests that breast irradiation with 40 Gy given over 3 weeks after breast conserving surgery for screen detected breast cancer gives a high level of local control out to 5 years.

In 1990, we published the results of a clinical trial involving 708 patients with breast carcinoma of 4 cm or less in diameter, who, following lumpectomy, were randomized to have radiotherapy to the tumour bed only (limited field, LF group) or to the whole breast and regional nodes (wide field, WF group). No adjuvant systemic therapy was prescribed. At the time the median follow-up was 37 months. We present the updated results after an extended median follow-up of 65 months. The overall survival is 72.7% and 71.2% for the LF and WF groups respectively. The actuarial breast recurrence rate (first event) is 15% (LF) versus 11% (WF) for infiltrating ductal carcinoma, whereas, for infiltrating lobular carcinoma, the recurrence rate was 34% (LF) versus 8% (WF). A high actual recurrence rate of 21% (LF) and 14% (WF) was also found for extensive ductal carcinoma in situ. It was extremely rare for medullary, mucoid or tubular carcinomas to recur. Salvage surgery was possible in 86% (LF) and 90% (WF) respectively. The recurrence rate in the breast following lumpectomy and wide field irradiation is comparable with others reported in the literature. This trial also shows the lumpectomy with limited field irradiation is feasible, albeit with a higher breast recurrence rate; the latter could be reduced by improved selection and refinement of the technique.

Since 1982, the standard method of post-mastectomy regional radiotherapy at the Christie Hospital has been to use a single electron field of fixed energy (8 MeV) to irradiate the chest wall, matched to a single megavoltage field (4 or 8 MV) irradiating the nodal areas in the axilla and supraclavicular fossa. (A separate parasternal field was not used.) All 500 cases treated in 1982 and 1983 with this method were reviewed (median follow-up 59 months). Four hundred and twenty-two were referred directly post-mastectomy and 78 for local recurrence after previous mastectomy. Of these, 42 were treated palliatively and 458 with radical intent. In radical cases the given dose in both fields was 40 Gy in 15 fractions in 3 weeks. The overall survival (n=458) was 51% (actuarial) at 5 years. At 5 years the local recurrence rate by site and UICC stage were as follows: chest wall — all Stages 17%, Stage I 4%, Stage II 13%, Stage III 26%, recurrent cases 21%; axillary recurrence — all Stages 20%, Stage I 4%, Stage II 10%, Stage III 22%, recurrent cases 39%; supraclavicular recurrences — all Stages 9%. Only one patient of the 500 treated had a parasternal recurrence. Late effects included mild telangiectasia in the electron field and asymptomatic apical lung fibrosis in the photon field. There was no match line fibrosis.

Transrectal ultrasound (TRUS) was used to measure tumour size in patients with carcinoma of the cervix and to assess its prognostic significance. Clinical staging was conducted and at the time of examination under anaesthesia, TRUS was used to assess maximum transverse diameter of the tumour. Eighty-one patients were studied. FIGO stages were 1B 34 patients, IIA seven patients, IIB 31 patients, IIIA two patients and IIIB seven patients. Mean tumour diameters by stage were IB 37 mm, IIA 37 mm, IIB 49 mm, IIIA 42 mm and IIIB 50 mm. There was a significant correlation between size and stage (p = 0.001). With a median follow-up of 18 months, 16 relapses have occurred. The actuarial relapse rates at median follow-up by stage were IB 10%, IIA 17%, IIB 22%, IIIA 0% and IIIB 35%. The actuarial relapse rates by size grouping at median follow-up were less than 30 mm 0%, greater than 30 and less than 40 mm 11%, greater than 40 and less than 50 mm 22%, and greater than 50 mm 38%. There was a significant difference between the mean recorded size of the tumours in the relapsed group and the relapse-free group (p = 0.02). Despite the small number of patients and short follow-up, tumour size as measured by TRUS appears to predict relapse.

Background and purpose Intensity-modulated radiotherapy (IMRT) can improve dose homogeneity within the breast planned target volume (PTV), but may be more susceptible to patient/organ motion than standard tangential radiotherapy (RT). We used daily cone-beam CT (CBCT) imaging to assess inter-fraction motion during breast IMRT and its subsequent impact on IMRT and standard RT dose homogeneity. Materials and methods Ten breast cancer patients selected for IMRT were studied. CBCT images were acquired immediately after daily treatment. Automatic image co-registration was used to determine patient positioning variations. Daily PTV contours were used to calculate PTV variations and daily delivered IMRT and theoretically planned tangential RT dose. Results Group systematic (and random) setup errors detected by CBCT were 5.7 (3.9) mm laterally, 2.8 (3.5) mm vertically and 2.3 (3.2) mm longitudinally. Rotations >2° in any axis occurred on 53/106 (50%) occasions. Daily PTV volume varied up to 23%. IMRT dose homogeneity was superior at planning and throughout the treatment compared with standard RT (1.8% vs. 15.8% PTV received >105% planned mean dose), despite increased motion sensitivity. Conclusions CBCT revealed inadequacies of current patient positioning and verification procedures during breast RT and confirmed improved dose homogeneity using IMRT for the patients studied.

An audit was performed to assess the frequency of cardiac irradiation in patients receiving radiotherapy for left-sided breast cancer. Images from an 'online' electronic portal imaging device were reviewed in patients who were treated with a tangential pair of megavoltage fields. In 169 consecutive patients treated on a Philips SL25 6 MV linear accelerator equipped with an SRI 100 imaging device, the cardiac apex was included in the radiotherapy field in 15 patients (9%). The long term sequelae of such cardiac irradiation is uncertain. The results of this audit suggest that careful treatment technique and quality control with portal imaging can minimize unnecessary cardiac irradiation in the majority of patients.

Background and purpose Evaluation of effect of timing of external beam radiation therapy (EBRT) following surgery for craniopharyngioma. Materials and methods Between 1976 and 2002, 87 patients (28 children) received EBRT in a regional referral centre. Forty-four patients received EBRT adjuvantly and 43 on relapse. The median total dose was 42.5Gy (range 34.7–52.5Gy) in 2.25–2.83Gy fractions over a median of 20 days (range 17–32). Effect of EBRT timing, type of original surgery, age on survival, progression-free survival (PFS) and quality of life (QOL) was studied. Results Survival from diagnosis was 86 and 76% and PFS was 78 and 66% at 10 and 20 years, respectively, with no significant difference seen between those treated adjuvantly or at relapse or according to age. QOL deteriorated significantly from diagnosis to last follow-up. Excluding patients who relapsed following EBRT, QOL did not deteriorate significantly overall ( P =0.35). Children had worse QOL and greater morbidity at all timepoints compared to adults. Conclusions EBRT is effective both adjuvantly and at relapse. QOL deteriorates over time-relapse following EBRT was the only significant factor. Children have greater morbidity compared to adults, but no evidence for greater EBRT-induced toxicity was seen.

Curative radiotherapy for cancer patients requires the use of radiation doses that are limited by the tolerance of the surrounding normal tissues. Unfortunately, these tolerance doses vary not only between tissues but also between individuals. In a small proportion of sensitive patients, exposure to radiation can lead to severe irreversible morbidity and even death several months to years after treatment. At present these radiosensitive patients can be identified only retrospectively. Here we describe a cytokine microarray technique that was used to identify differentially expressed gene transcripts in fibroblasts obtained from a small group of patients who suffered either negligible or severe normal damage to tissues after radiotherapy. If our preliminary findings can be confirmed, the availability of such markers may eventually allow the prediction of outcome prior to commencement of radiotherapy, and thus allow modification of radiotherapy protocols to minimize adverse late effects, without compromising tumor control.

At the institute, since the late 1980s, there has been a uniform treatment protocol for the management of the regional lymph nodes in patients referred for radiotherapy following breast-conserving surgery. An analysis of 2277 consecutive patients referred for radiotherapy between 1989 and 1992, with particular reference to regional lymph node management, has been undertaken. Axillary surgery alone was used in 517 patients (23%); 1191 (52%) patients had no axillary surgery but had radiotherapy to the axilla, and infraclavicular and supraclavicular fossae by a single anterior field, delivering 40 Gy in 15 daily fractions over 3 weeks; and 474 patients (21%) had axillary surgery followed by radiotherapy. Ninety-five patients (4%) underwent no axillary treatment. There was a total of 155 axillary recurrences with a median follow-up of 5.9 years, giving an actuarial nodal control rate of 94% at 5 years (95% confidence interval (CI) 93.1–95.1). The overall survival at 5 years was 86% (95% CI 84.6–87.5). There was a trend towards improved axillary control with surgery alone compared with radiotherapy alone (4.5% versus 5.9% actuarial axillary failure rate at 5 years). An extremely low incidence of brachial plexus neuropathy secondary to radiotherapy was reported. The multidisciplinary treatment protocol used gave a high rate of regional node control, with minimal recorded morbidity.

AIM: To evaluate the sensitivity and specificity of axillary magnetic resonance imaging (MRI) in symptomatic patients, who had previously been treated for breast cancer, compared with clinical outcome after a minimum of 1 year. METHODS: One hundred and five patients underwent axillary MRI examinations and were diagnosed as axillary tumour, metastatic tumour, treatment effect or normal. RESULTS: At MRI, 48 patients had axillary tumour, 51 had metastatic tumour (37 had both), 27 had treatment effect and 22 were normal. At outcome (median follow-up, 484 days), 54 patients were positive for axillary tumour, 59 for metastatic disease (40 had both), 21 had treatment effect alone and 18 were clear. Magnetic resonance imaging showed 89% sensitivity, 100% specificity and 94% accuracy for recurrent axillary tumour, and 85% sensitivity, 98% specificity and 90% accuracy for metastatic tumour. Soft tissue plaques were the commonest axillary disease pattern seen (37). Small volume soft tissue plaques gave the most diagnostic difficulty. Non-dynamic enhancement with intravenous Gadopentetate dimeglumine (Gd-DTPA) in a subset of 34 patients improved sensitivity for axillary tumour from 40 to 74%, and improved diagnostic confidence in 11 patients (32%). Magnetic resonance imaging had a positive management impact leading to treatment alteration in 45 patients, 43 of whom had recurrent axillary and/or metastatic tumour. CONCLUSIONS: Tumour plaques were the commonest pattern of recurrent axillary disease. Forty-eight percent of the patients had metastatic deposits identified by MRI. Magnetic resonance imaging had excellent specificity (100%) and good sensitivity (89%) for recurrent axillary tumour compared with outcome at 1 year, which was improved by non-dynamic administration of Gd-DTPA in 32% of the subset who received it.

Background and purpose : Prediction of late normal tissue reactions to radiotherapy would permit tailoring of dosage to each patient. Measurement of residual DNA double strand breaks using pulsed field gel electrophoresis (PFGE) shows promise in this field. The aim of this study was to test the predictive potential of PFGE in a group of retrospectively studied breast cancer patients. Materials and methods : Thirty nine patients, treated uniformly for breast cancer 9–15 years previously, with excision of the tumour and radiotherapy to the breast and drainage areas, were assessed clinically using the LENT SOMA scale, and a 5-mm punch biopsy taken from the buttock. Fibroblast cell strains were established and used to study residual DNA double strand breaks, using PFGE. Results : There were significant correlations between the DNA assay results and the fibrosis score ( r s =0.46; P =0.003), the combined fibrosis and retraction score ( r s =0.45, P =0.004) and the overall LENT score ( r s =0.43; P =0.006). Using polychotomous logistic regression, the fibroblast DNA assay result was an independent prognostic factor for fibrosis severity. Conclusions : There is a relationship between residual radiation-induced DNA damage in fibroblasts and the severity of the late normal tissue damage seen in the patients from whom the cells were cultured.

Prognostic factors predicting for breast recurrence following breast conserving surgery and radiotherapy have been identified in a prospective randomised trial comparing two different radiotherapy techniques. The first used megavoltage radiation to encompass the whole breast and regional nodes (WF group). The second used an electron field directed to the tumour bed only (LF group). With a median follow up of 8 years survival in both groups was the same (72%). There was an increased rate of breast recurrence in the LF group: 25%, compared to the WF group: 13% (P = 0.00008), expressed in actuarial terms at 8 years. In a multivariate analysis of factors predicting for breast recurrence, once the difference in treatment technique is allowed for, only two factors were found to be significant: histological grade (P = 0.013) and lymphovascular invasion in the histological specimen (P = 0.037).

An audit was carried out of post-operative radiotherapy given for carcinoma of the endometrium at the Christie Hospital between the years of 1984-86. 139 patients were treated following total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO). 54 patients were treated with vaginal brachytherapy alone, 55 had pelvic brick external beam irradiation and 30 patients had both external beam irradiation and vaginal brachytherapy. Overall survival was 84% at 5 years, with a 5.8% local recurrence rate. Histological grade was a prognostic factor for survival (p=0.023) and relapse (p=0.002). Tumour stage was a significant prognostic factor for survival (p=0.011), but not relapse. Survival for stage IB disease was 100% at 5 years with no local recurrence. Major treatment related morbidity was 1.4%, overall; for vaginal brachytherapy alone 0%; for external beam therapy 2%; and combined therapy 3%. Given their good prognosis, and the small but definite risk of major morbidity, patients with stage IB disease may not need postoperative external beam irradiation.

Radiotherapy-induced emesis is poorly controlled with existing antiemetics. 5-Hydroxytryptamine (5HT3) receptor antagonists are a new class of antiemetics which have been demonstrated to be effective in controlling cytotoxic-induced emesis. We have prospectively studied the antiemetic efficacy of the 5HT3 receptor antagonist granisetron in an open non-randomized efficacy and toxicity study, at two dose levels, in patients receiving lower hemibody radiotherapy for multiple bone metastases. Of the 22 patients studied, 13 patients received 20 micrograms/kg and nine patients 40 micrograms/kg of granisetron, administered as an intravenous infusion 1 h before radiotherapy. Radiotherapy was administered as a single exposure to the lower half body to a midline dose of 8 Gy. A complete response (no nausea or vomiting) was observed in 9/13 patients at the lower dose level and 6/9 patients at the higher level. No major adverse events were recorded. We conclude that granisetron is a well-tolerated and effective antiemetic agent in radiotherapy-induced emesis. Formal comparison with conventional antiemetic agents in this situation is required.

Between 1979 and 1984 thirty-seven patients were treated with combination chemotherapy for metastatic seminoma; 27 of these had relapsed following initial radiotherapy for stage I and IIA disease and 10 patients with stage IIB-IV disease received chemotherapy de novo followed by radiotherapy to sites of bulk disease. Treatment consisted of either a cis-platinum containing combination (25 patients), or cyclophosphamide and etoposide (12 patients). The overall survival of all patients at 5 years was 49%, 34 patients were assessable for response; a CR was obtained in 8 (24%) and a GPR in 19 (56%), the 5 year survival of this group being 66% at 5 years. No difference in survival was seen in relation to age, previous irradiation, serum HCG or LDH; bulk disease however, was an adverse prognostic factor. Survival was similar for both chemotherapy schedules but neutropenia and life-threatening sepsis was less with the cyclophosphamide etoposide combination.

This study describes 26 patients with histologically proven malignant epithelial thymic tumours seen at one radiotherapy centre between 1965 and 1980. Twenty-three patients had mediastinal radiotherapy and the overall 5-year survival rate (corrected for intercurrent death) of this group was 35%. Those patients in which there was complete surgical removal of the tumour had a good prognosis. Where this was not achieved, the prognosis was poor.

e12003 Background: A number of cytotoxic agents are used for the treatment of advanced breast cancer. Benefit beyond 2 lines of palliative chemotherapy remains poor. Eribulin is a new IV cytotoxic ...