"It's the single best thing I've done in the last 10 years": a qualitative study exploring patient and dietitian experiences with, and perceptions of, a multi-component dietary weight loss program for knee osteoarthritis.

OBJECTIVE: Explore patient and dietitian experiences with a multi-component dietary weight loss program for knee osteoarthritis to understand enablers and challenges to success at 6-months. DESIGN: Qualitative study embedded within a randomised controlled trial. Semi-structured individual interviews with 24 patients with knee osteoarthritis who undertook, and five dietitians who supervised, a weight management program (involving a ketogenic very low calorie diet (VLCD), video consultations, educational resources) over 6 months. Data were thematically analysed. RESULTS: Five themes were developed: (1) ease and convenience of program facilitated adherence (structure and simplicity of the meal replacements; not feeling hungry on diet; convenience of consulting via video) (2) social and professional support crucial for success (encouragement from partner, family, and friends; guidance from, and accountability to, dietitian; anxiety around going at it alone) (3) program was engaging and motivating (determination to stick to program; rapid weight loss helped motivation) (4) holistic nature of program was important (suite of high-quality educational resources; exercise important to compliment weight loss) (5) rewarding experience and lifelong impact (improved knee pain and function; positive lifestyle change). CONCLUSIONS: Patients and dietitians described positive experiences with the weight management program, valuing its simplicity, effectiveness, and convenience. Support from dietitians and a comprehensive suite of educational resources, incorporated with an exercise program, were considered crucial for success. Findings suggest this multi-component dietary program is an acceptable weight loss method in people with knee osteoarthritis that may benefit symptoms. Strategies for supporting long-term independent weight management should be a focus of future research.

Prevalence of Traumatic Findings on Routine MRI in a Large Cohort of Professional Fighters.

BACKGROUND AND PURPOSE: Previous studies investigating MR imaging abnormalities among fighters have had small sample sizes. This investigation assessed a large number of fighters using the same conventional sequences on the same scanner. MATERIALS AND METHODS: Conventional 3T MR imaging was used to assess 499 fighters (boxers, mixed martial artists, and martial artists) and 62 controls for nonspecific WM changes, cerebral microhemorrhage, cavum septum pellucidum, and cavum vergae. The lengths of the cavum septum pellucidum and cavum vergae and the ratio of cavum septum pellucidum to the septum pellucidum lengths were assessed. RESULTS: The prevalence of nonspecific WM changes was similar between groups. Fighters had a prevalence of cerebral microhemorrhage (4.2% versus 0% for controls, P = .152). Fighters had a higher prevalence of cavum septum pellucidum versus controls (53.1% versus 17.7%, P < .001) and cavum vergae versus controls (14.4% versus 0%, P < .001). The lengths of the cavum septum pellucidum plus the cavum vergae (P < .001), cavum septum pellucidum (P = .025), and cavum septum pellucidum to the septum pellucidum length ratio (P = .009) were higher in fighters than in controls. The number of fights slightly correlated with cavum septum pellucidum plus cavum vergae length (R = 0.306, P < .001) and cavum septum pellucidum length (R = 0.278, P < .001). When fighters were subdivided into boxers, mixed martial artists, and martial artists, results were similar to those in the whole-group analysis. CONCLUSIONS: This study assessed MR imaging findings in a large cohort demonstrating a significantly increased prevalence of cavum septum pellucidum among fighters. Although cerebral microhemorrhages were higher in fighters than in controls, this finding was not statistically significant, possibly partially due to underpowering of the study.

The effect of auditory stimulation on the tensor tympani in patients following stapedectomy.

CONCLUSION: We believe that a tensor tympani reflex, in response to loud sound, is present in a minority of people, although its functional significance with regard to sound transmission is questionable. The absence of startle response in our stapedectomized subjects makes us question whether the tensor component of the startle response is large enough to be identified by manometry. OBJECTIVES: This study was organized to examine reflex activity to stimulation by loud sound or by startle in the tensor tympani. Although many previous studies have been carried out, results have been contradictory, and methodological flaws have rendered the interpretations questionable. PATIENTS AND METHODS: Stapedectomized patients were invited to take part in the study. Thirteen patients underwent testing by extratympanic manometry, using a standard tympanometer. Responses were observed during repeated stimuli with loud sound at 500, 1000, 2000 and 4000 Hz to the ipsilateral and contralateral ears, and with an air jet against the closed eye. A control group was also studied for the startle test. RESULTS: Three clear ipsilateral (23%) and two clear contralateral (14%) responses to auditory stimuli were seen in the 13 patients. We found responses to startle stimuli in none of our study group and eight (42%) of control ears.

Prescribed vitamin D and calcium preparations in patients treated with bone remodelling agents in primary care: a report of a pilot study.

BACKGROUND: Recent guidelines recommend that patients receiving treatment for osteoporosis should also receive supplementation with calcium and vitamin D unless they are calcium and vitamin D replete. Given that the majority of elderly patients have inadequate levels of vitamin D and that determining nutritional status is time-consuming and costly, it seems prudent to ensure that the majority of patients aged over 65 and receiving medication for osteoporosis should receive supplementation as a matter of course. OBJECTIVES: To determine the level of co-prescription of calcium and vitamin D in patients receiving treatment for osteoporosis with bisphosphonates, teriparatide, raloxifene or strontium. STUDY DESIGN AND METHODS: A pilot audit of nine general practices covering a population of 61 202. RESULTS: Overall, 1.1% (n = 662) of patients were receiving treatment for osteoporosis; of those, only 34.1% of patients were co-prescribed calcium or calcium and vitamin D. Levels of co-prescription varied considerably across practices from 74.0% to 12.2%. CONCLUSIONS: Despite national guidelines, co-prescription of calcium and vitamin D with treatment for osteoporosis remains sub-optimal with considerable variation between practices. Strategies should be adopted to increase physician awareness of widespread vitamin D inadequacy, the rationale for supplementation and poor compliance.

Hyperbaric oxygen as an adjuvant treatment for malignant otitis externa.

BACKGROUND: Malignant, or necrotising, otitis externa is a potentially fatal infection of the external ear canal and surrounding soft tissue and bone. It may be complicated by involvement of cranial nerves, principally the facial nerves and the contents of the jugular foramen. It is an uncommon condition mainly found in the elderly or in diabetics. OBJECTIVES: To assess the effectiveness of adjunctive hyperbaric oxygen treatment for malignant otitis externa. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2003), MEDLINE (January 1966 to April 2004) and EMBASE (January 1985 to April 2004) with pre-specified terms. The date of the last search was 5th April 2004. SELECTION CRITERIA: Randomised controlled trials, involving adults, undergoing hyperbaric oxygen therapy in malignant otitis externa. DATA COLLECTION AND ANALYSIS: No identified articles described randomised controlled trials of hyperbaric oxygen therapy in the treatment of malignant otitis externa. MAIN RESULTS: Due to the lack of data no results could be presented. AUTHORS' CONCLUSIONS: No clear evidence exists to demonstrate the efficacy of hyperbaric oxygen therapy when compared to treatment with antibiotics and/or surgery. No data were found to compare rates of complication between the different treatment modalities. Further research is required.

Annual patterns in bacterioplankton community variability in a humic lake.

Bacterioplankton community composition (BCC) was monitored in a shallow humic lake in northern Wisconsin, USA, over 3 years using automated ribosomal intergenic spacer analysis (ARISA). Comparison of ARISA profiles of bacterial communities over time indicated that BCC was highly variable on a seasonal and annual scale. Nonmetric multidimensional scaling (MDS) analysis indicated little similarity in BCC from year to year. Nevertheless, annual patterns in bacterioplankton community diversity were observed. Trends in bacterioplankton community diversity were correlated to annual patterns in community succession observed for phytoplankton and zooplankton populations, consistent with the notion that food web interactions affect bacterioplankton community structure in this humic lake. Bacterioplankton communities experience a dramatic drop in richness and abundance each year in early summer, concurrent with an increase in the abundance of both mixotrophic and heterotrophic flagellates. A second drop in richness, but not abundance, is observed each year in late summer, coinciding with an intense bloom of the nonphagotrophic dinoflagellate Peridinium limbatum. A relationship between bacterial community composition, size, and abundance and the population dynamics of Daphnia was also observed. The noted synchrony between these major population and species shifts suggests that linkages across trophic levels play a role in determining the annual time course of events for the microbial and metazoan components of the plankton.

A phase I and pharmacologic study of capecitabine and paclitaxel in breast cancer patients.

BACKGROUND: Based on preclinical studies demonstrating that treatment with paclitaxel upregulates intratumoral thymidine phosphorylase (dTHdPase), which catalyzes the final step in the conversion of the oral fluoropyrimidine capecitabine to 5-fluorouracil (5-FU), as well as the overlapping spectra of activity for these agents, particularly in metastatic breast cancer, this phase I study evaluated the feasibility of administering capecitabine on an intermittent schedule in combination with paclitaxel in previously-treated patients with locally advanced or metastatic breast cancer. The study also sought to recommend doses for subsequent disease-specific studies, identify clinically significant pharmacokinetic interactions, and detect preliminary antitumor activity. PATIENTS AND METHODS: Nineteen previously treated women with metastatic breast cancer whose prior treatment included neither paclitaxel or capecitabine received one hundred one courses of capecitabine and paclitaxel. Paclitaxel was administered as a three-hour intravenous (i.v.) infusion at a fixed dose of 175 mg/m2 and capecitabine was administered as 2 divided daily doses for 14 days followed by a seven-day rest period every 3 weeks. The dose of capecitabine was increased from a starting dose of 1650 mg/m2/d. The plasma sampling scheme in the first course permitted characterization of the pharmacokinetics of each agent given alone and concurrently to detect major pharmacokinetic interactions. RESULTS: Palmar plantar erythrodysesthesia (hand foot syndrome) and neutropenia were the principal dose-limiting toxicities (DLT). Other toxicities included diarrhea and transient hyperbilirubinemia. Three of eight new patients treated with capecitabine 2000 mg/m2/d and paclitaxel 175 mg/m2 experienced DLT in the first course, whereas none of eleven new patients treated with capecitabine 1650 mg/m2/d and paclitaxel 175 mg/m2 developed DLT. Pharmacokinetic studies indicated that capecitabine did not grossly affect the pharmacokinetics of paclitaxel, and there were no major effects of paclitaxel on the pharmacokinetics of capecitabine and capecitabine metabolites. However, AUC values for the major 5-FU catabolite, fluorobeta-alanine (FBAL), were significantly lower in the presence of paclitaxel. Two complete and seven partial responses (56% response rate) were observed in sixteen patients with measurable disease; four of six patients whose disease was previously treated with high-dose chemotherapy and hematopoietic stem-cell support had major responses. Seven of nineteen patients had stable disease as their best response. CONCLUSIONS: Recommended combination doses of capecitabine on an intermittent schedule and paclitaxel are capecitabine 1650 mg/m2/d orally for 14 days and paclitaxel 175 mg/m2 i.v. every 3 weeks. The favorable preclinical interactions between capecitabine and paclitaxel, as well as the acceptable toxicity profile and antitumor activity in patients with metastatic breast cancer, support further clinical evaluations to determine an optimal role for the combination of capecitabine and paclitaxel in breast cancer and other relevant malignancies.

Randomized double-blind prospective trial to evaluate the effects of sargramostim versus placebo in a moderate-dose fluorouracil, doxorubicin, and cyclophosphamide adjuvant chemotherapy program for stage II and III breast cancer.

PURPOSE: To determine the effects of sargramostim (recombinant human granulocyte-macrophage colony-stimulating factor [rhu GM-CSF]) on the incidence, duration, and complications of myelosuppression after moderate-dose fluorouracil, doxorubicin, cyclophosphamide (FAC) adjuvant chemotherapy in patients with node-positive breast cancer. PATIENTS AND METHODS: In this randomized, double-blind, placebo-controlled study, 142 women with stage II and III breast cancer were to receive four 21-day cycles of chemotherapy that consisted of fluorouracil 600 mg/ m2 intravenously (IV), doxorubicin 60 mg/m2 IV, and cyclophosphamide 750 mg/m2 IV on day 1, followed by placebo or GM-CSF 250 micrograms/m2/d daily subcutaneously (SC) on days 3 through 15. All patients received prophylactic ciprofloxacin by mouth when the absolute neutrophil count (ANC) was less than 1,000/microL. RESULTS: Eighty-six percent of GM-CSF patients (n = 62) and 96% of placebo patients (n = 69) completed four assessable cycles of treatment on study. Overall, the median duration of severe neutropenia (ANC < 500/microL) was 2.8 days with GM-CSF and 6.8 days with placebo (P < .001); the duration of ANC less than 1,000/microL was 6.0 versus 9.1 days, respectively (P < .001). Hospitalizations for febrile neutropenia were uncommon in either group: GM-CSF, six; placebo, eight. The only other difference in hematologic toxicity was grade 3/4 thrombocytopenia observed with greater frequency in GM-CSF patients than placebo patients in cycles 3 and 4. GM-CSF increased mean the FAC dose-intensity among patients who completed two or more cycles (P < .001). GM-CSF was generally well tolerated and associated with more injection-site reactions, but less mucositis than placebo. There were no deaths on study. CONCLUSION: GM-CSF significantly enhanced ANC recovery after FAC chemotherapy; it decreased the incidence and duration of associated neutropenia and moderately increased the dose-intensity of adjuvant chemotherapy. Whether these effects will ultimately translate into improved long-term outcome remains to be determined.

Paclitaxel with mitoxantrone, fluorouracil, and high-dose leucovorin in the treatment of metastatic breast cancer: a phase II trial.

PURPOSE: Paclitaxel is a highly active single agent in the treatment of breast cancer. However, its optimal incorporation into combination regimens awaits definition. In this phase II study, we added paclitaxel, administered by 1-hour infusion, to a previously described combination regimen that included mitoxantrone, fluorouracil (5-FU), and high-dose leucovorin (NFL). PATIENTS AND METHODS: Forty-six patients with metastatic breast cancer received the following regimen as first- or second-line treatment: paclitaxel 135 mg/m2 by 1-hour intravenous (i.v.) infusion on day 1, mitoxantrone 10 mg/m2 by i.v. bolus on day 1, 5-FU 350 mg2/m by i.v. bolus on days 1, 2, and 3, and leucovorin 300 mg i.v. over 30 to 60 minutes immediately preceding 5-FU on days 1, 2, and 3. Courses were administered at 3-week intervals for a total of eight courses in responding patients. RESULTS: Twenty-three of 45 assessable patients (51%) had major responses. Previous chemotherapy, and in particular previous treatment with doxorubicin, did not affect response rate. The median response duration was 7.5 months. Myelosuppression was moderately severe, with 76% of courses resulting in grade 3 or 4 leukopenia. Hospitalization for treatment of fever during neutropenia was required in 13% of courses, and two patients died as a result of sepsis. Two patients developed severe congestive heart failure after a large cumulative anthracycline dose. CONCLUSION: This combination regimen was active as first- or second-line therapy for metastatic breast cancer, although its activity compared with other combination regimens or with paclitaxel alone is unclear. Myelosuppression was more severe than anticipated based on previous results with the NFL regimen or with paclitaxel administered at this dose and schedule as a single agent. The infrequent development of cardiotoxicity in these patients suggests that the paclitaxel/mitoxantrone combination may not share the problems previously reported with the paclitaxel/doxorubicin combination.

Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer.

PURPOSE: To perform a randomized three-arm comparison of tamoxifen (TAM; 20 mg/d) and two separate doses of toremifene (TOR; 60 mg/d [TOR60] and 200 mg/d [TOR200]) in postmenopausal patients with hormone receptor-positive or -unknown metastatic breast cancer. MATERIALS AND METHODS: Six hundred forty-eight patients with hormone receptor-positive or -unknown metastatic breast cancer were randomly assigned to receive TAM (n = 215), TOR60 (n = 221), or TOR200 (n = 212). RESULTS: The combined response rates (by intent to treat) were as follows;: TAM, 44%; TOR60, 50%; and TOR200, 48%. Complete and partial response rates were as follows: TAM, 19%; TOR60, 21%, and TOR200, 23% (not statistically different). Median times to progression and overall survival were not significantly different. Adverse events (lethal, serious but nonlethal, and important but non-life-threatening) were similar in all three arms, except that patients in the TOR200 arm had a statistically significantly increased rate of nausea (37% v 26% and 26% for TOR200, TAM, and TOR60, respectively; P = .027). Quality-of-life assessments were not different among the three arms. CONCLUSION: The activity, toxicity, and side effects of TOR in postmenopausal women with hormone receptor-positive or -unknown metastatic breast cancer are similar if not equivalent to those of TAM. We detected no clear evidence of a dose-response effect for TOR. TOR60 is an effective and safe agent for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer and can be considered an alternative to TAM as first-line treatment for such patients.

PUVA and methotrexate therapy of psoriasis: how closely do dermatology departments follow treatment guidelines? Psoriasis Audit Workgroup of the British Association of Dermatologists.

Following publication of treatment guidelines for patients with psoriasis, a six-centre audit was undertaken to assess current therapeutic practice for two second-line treatments, PUVA and methotrexate. The audit consisted of random sampling of casenotes by external auditors from a paired dermatology department, and assessment by questionnaire. One hundred and eight PUVA and 118 methotrexate casenotes were audited. The commonest indications for treatment were: (a) failure of tropical therapy--PUVA (mean 81% of casenotes), methotrexate (84%); (b) repeated hospital admissions--PUVA (16%), methotrexate (25%). For both PUVA and methotrexate, some aspects of treatment were well documented: PUVA--psoralen dosage (91%), response to PUVA (89%), cumulative lifetime UVA dosage (81%); methotrexate--pretreatment assessment of full blood count (91%), urea and electrolytes (85%), liver function tests (84%). For other aspects documentation was less complete: PUVA--no documentation of presence/absence of skin cancer history (66%), note of photoactive drugs (32%); methotrexate--concurrent medication (69%), history of presence/absence of liver disease (36%). Another aspect which was poorly documented in both PUVA and methotrexate notes was whether advice on contraception/fertility had been given. There was no indication in 29 of 32 casenotes of females of child-bearing age receiving PUVA, and 52 of 63 case notes of relevant patients on methotrexate. This project has demonstrated that formal, multicentre audit based on published guidelines is a practical proposition.

Phase II study of mitoxantrone, leucovorin, and infusional fluorouracil for treatment of metastatic breast cancer.

A new combination of mitoxantrone, folinic acid (leucovorin), and infusional fluorouracil (5-FU) was administered to 57 previously treated patients with metastatic breast cancer to evaluate the response rate, response duration, and toxicity of this regimen. Fifty-three patients who received 313 courses of therapy were assessable for response and toxicity. Median age was 48 years (range, 33 to 80 years), and the patients had received an average of 1.5 chemotherapy regimens before this study. Of 53 assessable patients, 24 (45%, or 42% of all entered patients) experienced partial responses (PRs) with a median duration of 6 months (range, 2 to 13 months). Nine (69%) of 13 assessable patients without prior doxorubicin treatment responded, compared with 15 (38%) of 40 with prior doxorubicin (P less than .05). Toxicity was generally mild with dose reductions necessitated more often by mucositis and/or diarrhea than by myelosuppression. One patient with prior high-dose doxorubicin treatment developed congestive heart failure. The combination of mitoxantrone, leucovorin, and infusional 5-FU is an active and well-tolerated regimen for metastatic breast cancer and deserves further evaluation in patients without prior doxorubicin therapy.

Papaveretum infusions in infants under 6 months of age.

The effectiveness of a continuous low dose papaveretum infusion for the relief of postoperative pain was assessed in 29 infants aged 1-6 months nursed on the infant surgical ward following major abdominal surgery. Trained nursing staff were able to adjust the dosage within prescribed guidelines and satisfactory analgesia was obtained with a regimen which delivered up to 0.0375 mg/kg/hour, approximately half the dose recommended in children older than 12 months. There was one case of clinically significant respiratory depression.

Phase I trial of adjuvant chemotherapy with cyclophosphamide, epirubicin and 5-fluorouracil (CEF) for stage II breast cancer.

Epirubicin is a new anthracycline with a potentially more favorable toxicity profile than the parent compound, doxorubicin. Accordingly, the feasibility and toxicity of 6 courses of adjuvant chemotherapy with cyclophosphamide (C), epirubicin (E), and 5-fluorouracil (F) were assessed in 10 patients with Stage 2 (node positive) breast cancer. Doses of C and F were 600 mg/m2 and E was 75 mg/m2. Moderate granulocytopenia (median count = 610/mm3) occurred on day 14 of the first 21 day treatment course and was the main toxicity encountered with treatment, although there were no episodes of granulocytopenic fever. Grade 3 or 4 vomiting occurred in 40% and significant alopecia in 30% of patients. Four patients experienced transient asymptomatic decreases in calculated radionuclide cardiac ejection fraction of greater than or equal to 10% but no signs or symptoms of cardiac failure were observed. If epirubicin proves to be less cardiotoxic than doxorubicin, this combination would merit further evaluation as potential adjuvant therapy for early breast cancer.

The effect of prior adjuvant chemotherapy on survival in metastatic breast cancer.

Some adjuvantly treated patients develop recurrent breast cancer and little is known about the effect of prior adjuvant chemotherapy on subsequent response rates to systemic therapy or on overall survival. We describe our retrospective comparison of 179 patients who received doxorubicin containing adjuvant chemotherapy and developed recurrent breast cancer on University of Arizona Cancer Center clinical trials with 202 non-adjuvantly treated patients entered onto clinical protocols for recurrent or metastatic breast cancer during the same period. Adjuvant failures had a shorter median survival from the date of onset of recurrent disease (18 months versus 28 months, P less than 0.001), a lower response rate to initial combination chemotherapy (38% versus 69%, P = 0.001), and a high incidence of CNS involvement at the time of relapse (11%). In patients having recurrent or metastatic breast cancer, a history of prior adjuvant chemotherapy appears to identify a subgroup who will have a higher incidence of CNS involvement, a lower response rate to chemotherapy and a shorter survival with metastatic disease. These findings may help explain the failure of improved relapse free survival seen in many adjuvant chemotherapy trials to result in improved overall survival.

Comparison of different trials of adjuvant chemotherapy in stage II breast cancer using a natural history data base.

Prognostic factors and treatment were analyzed for 2,578 patients to assess the impact of various forms of adjuvant chemotherapy on the natural history of operable stage II (node-positive) breast cancer. The outcome after surgery alone (or with radiotherapy) was determined in 1,014 patients in the natural history data base (NHDB). Adjuvant chemotherapy consisted of L-phenylalanine mustard (L-PAM; 130 patients); cyclophosphamide, methotrexate, and 5-fluorouracil (CMF; 645 patients); doxorubicin and cyclophosphamide (AC; 241 patients); CMF plus vincristine and prednisone (CMFVP; 263 patients); and 5-fluorouracil plus AC (FAC; 285 patients). L-PAM had minimal effect on relapse-free survival (RFS) compared to the NHDB, but all combination chemotherapy programs significantly improved RFS and survival compared to the NHDB. In women with 1-3 positive nodes, all combination chemotherapy programs produced similar results. In women with 4-9 positive nodes, the FAC regimen appeared to be associated with superior RFS compared to other programs, but all were superior to the NHDB. In women with 10 or more positive nodes, FAC was the only regimen associated with improved RFS. The use of a NHDB and known pretreatment characteristics, such as nodal status and tumor size, permits comparison of patients at similar risk of recurrence of breast cancer who have received adjuvant chemotherapy and provides leads for evaluation in future prospective clinical trials.

Development and use of a natural history data base of breast cancer studies.

Pretreatment information, type of treatment, and longitudinal follow-up on 1,971 patients with operable breast cancer were used to establish a breast cancer natural history data base (NHDB). Data were available for 957 patients with stage I (node-negative) breast cancer and 1,014 stage II (node-positive) patients. In women with negative nodes, information was available on 759 patients treated at the Milan National Cancer Institute and 188 patients treated at the Royal Marsden Hospital. After adjustment for differences in the distribution of patient prognostic factors, relapse-free survival and overall survival were not significantly different. Of the 1,014 node-positive patients, 540 were treated at the Milan National Cancer Institute, 258 at the Royal Marsden, and 216 at the M. D. Anderson Hospital. Relapse-free survival and overall survival did not significantly differ between Milan patients and those treated at the Royal Marsden Hospital. However, M. D. Anderson Hospital patients did have significantly better relapse-free and overall survival. In each institution, outcome was consistently most dependent on the number of involved axillary lymph nodes and tumor size. Also, similar patterns of survival were observed for each of the institutions. The development of an NHDB can be of value in the identification and evaluation of consistency of prognostic factors, permitting improved comparisons between clinical trials. The development of such a natural history data base (NHDB) provides a reference for assessing the impact of different adjuvant chemotherapy programs, and aids in the design of new protocols.