Hand eczema in children referred for patch testing: North American Contact Dermatitis Group Data, 2000-2016.

BACKGROUND: Little is known about the aetiologies and relevant allergens in paediatric patients with hand eczema (HE). OBJECTIVES: To characterize the aetiologies and determine the proportion of positive and currently relevant allergens in children/adolescents (age < 18 years) with HE referred for patch testing. METHODS: A retrospective analysis (2000-2016) of North American Contact Dermatitis Group data was performed. RESULTS: Of 1634 paediatric patients, 237 (14·5%) had involvement of the hands. Final physician diagnoses included allergic contact dermatitis (49·4%), atopic dermatitis (37·1%) and irritant contact dermatitis (16·9%). In multivariable logistic regression models, employment was the only association with increased odds of any HE or primary HE. Children with HE vs. those without HE had similar proportions of positive patch tests (56·1% vs. 61·7%; χ2 -test, P = 0·11). The five most common currently relevant allergens were nickel, methylisothiazolinone, propylene glycol, decyl glucoside and lanolin. In multivariable logistic regression models of the top 20 relevant allergens, HE was associated with significantly higher odds of currently relevant reactions to lanolin, quaternium-15, Compositae mix, thiuram mix, 2-mercaptobenzathiazole and colophony. The allergens with the highest mean significance-prevalence index number were methylisothiazolinone, carba mix, thiuram mix, nickel and methylchloroisothiazolinone/methylisothiazolinone. CONCLUSIONS: Children with HE who were referred for patch testing had a high proportion of positive patch tests, which was similar to the proportion found in children without HE. Children with HE had a distinct and fairly narrow profile of currently relevant allergens.

Phase III randomized study of the proposed adalimumab biosimilar GP2017 in psoriasis: impact of multiple switches.

BACKGROUND: Adalimumab is used to treat several inflammatory diseases, including plaque psoriasis. GP2017 is a proposed adalimumab biosimilar. OBJECTIVES: To assess the impact of multiple switches between GP2017 and reference adalimumab (ref-ADMB) following the demonstration of equivalent efficacy and similar safety and immunogenicity, in adult patients with active, clinically stable, moderate-to-severe plaque psoriasis. METHODS: This 51-week double-blinded, phase III study randomly assigned patients to GP2017 (n = 231) or ref-ADMB (n = 234) 80 mg subcutaneously at week 0, then 40 mg biweekly from week 1. At week 17, patients were rerandomized to switch (n = 126) or continue (n = 253) treatment. The primary end point was patients achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) at week 16, with equivalence confirmed if the 95% confidence interval (CI) for the difference in PASI 75 between treatments was ± 18%. The key secondary end point was the change from baseline to week 16 in continuous PASI. Other end points were PASI over time; PASI 50, 75, 90 and100; pharmacokinetics; safety; tolerability and immunogenicity for the switched and continued treatment groups. RESULTS: Equivalent efficacy between GP2017 and ref-ADMB was confirmed for the primary (66·8% and 65·0%, respectively; 95% CI -7·46 to 11·15) and key secondary end points (-60·7% and -61·5%, respectively; 95% CI -3·15 to 4·84). PASI improved over time and was similar between treatment groups at week 16, and the switched and continued groups from weeks 17 to 51. There were no relevant safety or immunogenicity differences between GP2017 and ref-ADMB at week 16, or the switched and continued groups from weeks 17 to 51. No hypersensitivity to adalimumab was reported upon switching. CONCLUSIONS: Following the demonstration of GP2017 biosimilarity to ref-ADMB, switching up to four times between GP2017 and ref-ADMB had no detectable impact on efficacy, safety or immunogenicity.

Apremilast for the treatment of moderate-to-severe palmoplantar psoriasis: results from a double-blind, placebo-controlled, randomized study.

BACKGROUND: Palmoplantar psoriasis is a variant of psoriasis vulgaris which can severely impair quality of life. OBJECTIVES: The main objectives of this double-blind, placebo-controlled, randomized study were to assess the efficacy and impact on quality of life and work productivity of apremilast for the treatment of moderate-to-severe palmoplantar psoriasis. METHODS: A total of 100 patients with moderate-to-severe palmoplantar psoriasis were randomized to either apremilast 30 mg bid or placebo for 16 weeks. At Week 16, all patients received apremilast 30 mg bid until Week 32. The primary endpoint was the proportion of patients who achieved a Palmoplantar Psoriasis Physician Global Assessment (PPPGA) of 0/1 at Week 16. RESULTS: There was no significant difference in the proportion of patients who achieved a PPPGA of 0/1 at Week 16 between patients randomized to apremilast (14%) and placebo (4%; P = 0.1595). After 32 weeks of treatment with apremilast, 24% of patients achieved a PPGA of 0/1. In addition, apremilast was superior to placebo in achieving Palmoplantar Psoriasis Area Severity Index (PPPASI) 75 (apremilast: 22%; placebo: 8%; P = 0.0499), in improving PPPASI (apremilast: -7.4 ± 7.1; placebo: -3.6 ± 5.9; P = 0.0167), Dermatology Life Quality Index score (apremilast: -4.3 ± 5.1; placebo: -0.8 ± 4.5; P = 0.0004) and in reducing activity impairment (apremilast: -11.0 ± 22.3; placebo: 2.5 ± 25.5; P = 0.0063). CONCLUSION: Despite the absence of a significant difference between apremilast and placebo in proportion of patients achieving a PPPGA of 0/1, the presence of significant differences observed for several secondary endpoints suggests that apremilast may have a role in the treatment of moderate-to-severe palmoplantar psoriasis.

The effect of multiple small doses of X rays on skin reactions in the mouse and a basic interpretation. 1976.

Multiple-fraction experiments have been carried out to determine the response to repeated small doses of 240 kV X rays down to 45 rad per fraction, using the mouse skin reaction system. A method of irradiating without anesthetic was developed so that up to 64 fractions could be given within 8 days; over this time, proliferation was negligible. It was found that the total dose required to produce a given reaction continued to rise with the number of fractions above 30 fractions, in contradiction to the recent conclusions of Dutreix and colleagues. The plot of reciprocal total dose against size of each fraction was shown to be linear. This finding led to an analysis in terms of a function F(e), which is proportional to the slope of the chord of the appropriate cell survival curve from the origin to the dose per fraction used. The cell survival curve derived here was well fitted by an equation of the form (s = e(-(αD+ßD(2)). The initial slope was 1/690 rad and the slope at 2340 rad was 1/126 rad. Thus, 1 rad at a dose approaching 0 rad has 18% of the effect of 1 rad at a single dose of 2340 rad for mouse skin reactions. A cell survival theory based on Neary's theory of chromosome aberrations is presented and the current results are consistent with the postulate that cell death results from the formation of chromosome aberrations.

21 years of biologically effective dose.

In 1989 the British Journal of Radiology published a review proposing the term biologically effective dose (BED), based on linear quadratic cell survival in radiobiology. It aimed to indicate quantitatively the biological effect of any radiotherapy treatment, taking account of changes in dose-per-fraction or dose rate, total dose and (the new factor) overall time. How has it done so far? Acceptable clinical results have been generally reported using BED, and it is in increasing use, although sometimes mistaken for "biologically equivalent dose", from which it differs by large factors, as explained here. The continuously bending nature of the linear quadratic curve has been questioned but BED has worked well for comparing treatments in many modalities, including some with large fractions. Two important improvements occurred in the BED formula. First, in 1999, high linear energy transfer (LET) radiation was included; second, in 2003, when time parameters for acute mucosal tolerance were proposed, optimum overall times could then be "triangulated" to optimise tumour BED and cell kill. This occurs only when both early and late BEDs meet their full constraints simultaneously. New methods of dose delivery (intensity modulated radiation therapy, stereotactic body radiation therapy, protons, tomotherapy, rapid arc and cyberknife) use a few large fractions and obviously oppose well-known fractionation schedules. Careful biological modelling is required to balance the differing trends of fraction size and local dose gradient, as explained in the discussion "How Fractionation Really Works". BED is now used for dose escalation studies, radiochemotherapy, brachytherapy, high-LET particle beams, radionuclide-targeted therapy, and for quantifying any treatments using ionising radiation.

Sustained progression-free survival with weekly paclitaxel and bevacizumab in recurrent ovarian cancer.

OBJECTIVE: To determine efficacy, toxicity, and survival in patients with recurrent epithelial ovarian cancer (EOC) receiving combination of weekly paclitaxel and biweekly bevacizumab (PB). METHODS: We reviewed chemotherapy logs identifying all patients receiving combination PB. Toxicities were graded using CTCAEv3.0 criteria. Response rates (RR) were measured using RECIST criteria or by CA-125 levels per modified Rustin criteria. RR and progression-free survival (PFS) were determined and plotted using Kaplan-Meier survival analysis. RESULTS: Fifty-one patients receiving at least two cycles of chemotherapy were evaluable for survival and 55 patients receiving one cycle of PB were evaluable in toxicity analysis. The mean number of previous regimens was four. The overall median PFS was 7 months and median OS was 12 months. The overall response rate (ORR) was 60% (CR 25% and PR 35%). Median PFS for complete and partial responders were 14 and 5 months respectively. Stable disease was seen in 26% with median PFS of 6 months. Thirteen experienced treatment delays for a variety of factors. The most G3/4 toxicities were fatigue (16%), hematologic (9%) and neurotoxicity (7%). Three patients (5%) experienced bowel perforations. CONCLUSIONS: Combination of paclitaxel and bevacizumab is feasible and demonstrates an acceptable toxicity profile and a high response rate. These observations should be useful in planning future clinical trials with this combination therapy.

Application of robotic stereotactic radiotherapy to peripheral stage I non-small cell lung cancer with curative intent.

AIMS: To determine the effectiveness of robotic stereotactic radiotherapy with image guidance and real-time respiratory tracking against early stage peripheral lung cancer. MATERIALS AND METHODS: We treated patients with stage I non-small cell lung cancer (NSCLC) with CyberKnife and analysed their clinical characteristics and outcomes. All patients had co-morbid conditions that precluded lobectomy. The clinical target volume (CTV) included the gross tumour volume (GTV) and a 6mm margin in all directions to account for microscopic extension. The planning target volume (PTV) equalled CTV+2mm in all directions for uncertainty. Tumour motion was tracked using a combination of Synchrony and Xsight Spine tracking methods with the aid of a single gold marker implanted in the centre of the tumour, or using the newer Xsight Lung method without markers for selected tumours. A 60-67.5 Gy dose was prescribed to the 60-80% isodose line (median 65%) and given in three to five fractions. Patients were followed every 3 months for a median of 27.5 months (range 24-53 months). RESULTS: Of the 67 patients with NSCLC stage IA or IB treated between January 2004 and December 2008, we report the results of a cohort of 31 with peripheral stage I tumours of 0.6-71 cm(3) volume treated between January 2004 and December 2007 with total doses between 60 and 67.5 Gy in three to five fractions. The median D(max) was 88.2 Gy and the median V(95) of the PTV was 99.6% or 27.9 cm(3). No grade 3 or above toxicity was encountered. Four cases of radiation pneumonitis and one case of oesophagitis were observed. In those patients whose pre- and post-treatment results were available, no change in pulmonary function tests was observed. Actuarial local control was 93.2% for 1 year and 85.8% for up to 4.5 years. One-year overall survival was 93.6% and 83.5% for up to 4.5 years, as projected by Kaplan-Meier analyses. CONCLUSIONS: In this small cohort of patients with stage I peripheral NSCLC, robotic stereotactic radiotherapy seems to be a safe and obviously superior alternative to conventionally fractionated radiotherapy, with results that may be approaching those obtained with lobectomy without the associated morbidity.

Optimum overall times II: Extended modelling for head and neck radiotherapy.

AIMS: A previous paper in this journal (part I) concluded that there was no pronounced optimum overall time, at least up to 70 fractions of 1.15 Gy at two fractions/day in 50 days. The maximum tolerable tumour doses increased only 2% from the best short schedules of 21 or 23 days to those of 50 days. Only this range was modelled in part I because it covered the fewest and the most fractions, and the longest overall times that will probably be used in practice. Most UK schedules, typically using five fractions a week, yield tumour effective doses about 10% less than the best schedules in other developed countries. The present paper covers a much wider range of fraction numbers from one to 115, and from 1 to 80 days. Some numerical errors in the Tables in part I are also corrected in the present appendix. These made no difference to the main conclusions just described. MATERIALS AND METHODS: Standard linear quadratic modelling was used, assuming at first alpha/beta=10 Gy, alpha=0.35 ln/Gy, Tk=21 days, Tp=3 days for tumours, but with Tk=7 days, Tp=2.5 Gy for acute mucosal reactions, as before. A late complications constraint of 70 Gy was accepted, and an acute constraint of 51 Gy (both at 2 Gy fractions). Alternative values of more rapid or slower repopulation were also explored (Tp=2 days or Tp=5 days, respectively). RESULTS: Optimal values were shown at 22-32 days for one fraction/day five times a week, and at 42-49 days for two fractions/day at 10 fractions/week. Repopulation caused a rapid fall in tumour dose after 30 days with one fraction/day, but not until after 50 days with two fractions/day, and so was not seen in part I with its too-practical end time. CONCLUSIONS: Biological modelling can extrapolate calculations outside the borders of published treatment schedules to clarify borderline situations. Optimum schedules in radiotherapy can reliably give more tumour control if two fractions/day are used. The potential gains are equivalent to about two fractions of 2 Gy as given by this modelling. However, the late complications will be less with some nearly tumour equivalent shorter schedules if optimally designed.

Is there an optimum overall time for head and neck radiotherapy? A review, with new modelling.

AIMS: To test by modelling whether a non-standard fractionated schedule giving optimum log cell kill could be expected, between short (accelerated) and longer multiple fraction/day schedules. MATERIALS AND METHODS: Linear quadratic modelling was carried out for many schedules, with biologically effective doses converted to normalised total doses (NTDs; in 2 Gy fractions). Late complication and acute mucosal NTDs were calculated as constraint doses for each schedule, and the highest tumour NTDs and log cell kill values within both constraints were calculated. This modelling is robust and agrees with conclusions in a very recent meta-analysis (Bourhis J, Overgaard J, Audry H, et al. Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. www.thelancet.com. Published online August 17, 2006). RESULTS: The six schedules that gave the highest tumour log cell kill deliver a narrow range of 11.1-11.2 log10 cell kill in the present parameters. Other regularly used schedules give closer to 10 log10. Using one fraction/day fails to achieve the highest therapeutic ratios. Suggestions are made for escalating certain UK schedules. Fractionated radiotherapy results in a nearly constant tumour cell kill if the acute mucosal NTD is held constant. However, a small (3%) gain in tumour cell kill occurs from 3 weeks to 73 fractions of 1.15 Gy in 7 weeks. That is how fractionation works, within both acute and late constraints. Short accelerated schedules enable fewer late complications, but do not do as well for the minority of head and neck tumours that repopulate slowly. CONCLUSIONS: Schedules of 4-6 weeks overall time could be chosen to give at least 11 log10 cell kill, which are safe. Most tumours would require two fractions/day, until routine monitoring of repopulation rates becomes feasible to select individual tumours. There is no 'optimum schedule', but each chosen schedule can be balanced against its own risk of excessive acute or late complications, as shown in these examples.

Biologically effective doses in radiotherapy of cervical carcinoma*.

Presented study evaluates biologically effective dose (BED) in patients receiving low-medium dose-rate (LDR/MDR) brachytherapy (BRT) plus external beam radiotherapy (XRT) based on tumor cell proliferation values in cancer of the cervix patients. This study includes 229 patients treated entirely by radiotherapy at the Centre Oncology in Krakow. Doses to Point A were estimated for total treatment for each brachytherapy insertion. BED3 were calculated for reference points in the rectum. The linear quadratic equation was used to calculate BED, which is proportional to log cell kill, and the normalized total dose (NTD), that is, equivalent to a 2 Gy fraction schedule. In BEDs 10 calculation overall treatment time for each patient. Tumor proliferation rate was based on Bromodeoxyuridine labeling index (BrdUrdLI) assessed on biopsy material before beginning the radiotherapy. Total BED at those points was summed for each patient. The medium overall treatment time was 90 days (range 30--210). The mean calculated total BED for point A for tumour and "early reactions" was equal to 104.0 Gy10 and 229.0 Gy3 for the rectum, equivalent to NTD=86.6 Gy and 137.4 Gy in 2 Gy fractions, respectively. Kaplan-Meier analysis revealed that age >50 years, higher than mean BRBEDs and totBEDs doses, gaps in treatments shorter than 40 days and disease free survival (DFS) was significant prognostic factor for overall survival. In the multivariate Cox anaysis age >50 years, BRBED10 >77 Gy and gaps ?40 days appeared to be significant for overall survival. None of the examined parameters was significant for tumor control. However, patients age and shorter gaps in the treatment were predictive for DFS.

What can we expect from dose escalation using proton beams?

It has been demonstrated without doubt in the literature, including elsewhere in this issue, that much better conformal dose distributions in radiation therapy can be obtained with proton beams than with photons (X-rays) or electrons. It is also clear that this remains entirely true--for the fundamental reason of particle range--even after the latest and projected developments in computer-generated IMRT (intensity-modulated radiation therapy) photon dose escalation are fully considered. We consider several examples of tumour dose-response curves that illustrate the quite large gains to be obtained when dose escalation can be achieved, if normal tissue complications can also be avoided. Two contrasting types of tumour are considered in detail, prostate tumours and non-small-cell lung carcinomas. There is a considerable way to go yet to achieve really high non-recurrence rates, especially in the lung tumours. Proton beams would make this progress much safer and more effective than any variants with photons.

A skin moisturizing cream containing Quaternium-18-Bentonite effectively improves chronic hand dermatitis.

BACKGROUND: Irritant and allergic hand dermatitis is difficult to control in individuals who are unable to avoid causative exposures. Effectiveness of "protective" creams has been poor. OBJECTIVE: To determine if hand dermatitis, primarily of an occupational nature, could be improved by the use of a newly developed moisturizing cream containing Quaternium-18-Bentonite. METHODS: Adult male and female subjects with chronic hand dermatitis felt to be either allergic, irritant, or combined in nature, after a 2-week observation period, were given the study cream for routine application. At 2, 4, and 8 weeks, the investigator and the subject evaluated the skin parameters, including redness, scaling, fissuring, blistering, and pruritus, on a numerical scale. A global evaluation was also performed. Photographs were taken at each visit. Use of topical corticosteroids was recorded. No systemic therapies other than antihistamines were allowed. RESULTS: Thirty-seven subjects were enrolled in the study and 33 completed it. The physician's and the subject's initial global evaluations averaged 6.0 and 5.8, respectively (0-10 scale). The final scores were 2.9 and 2.8, respectively, an improvement of 50% (p < 0.001). Topical corticosteroid usage was reduced in 29 of 33 subjects. Fifteen of 35 had a final score of 0-2, indicating complete or almost complete clearing. Only 10, including 2 of the dropouts, failed to show improvement. No adverse effects were noted. COMMENT: This moisturizing cream significantly improved chronic hand dermatitis in a majority of individuals with previously uncontrolled dermatitis despite continuing in their regular occupation.

Balsam-related systemic contact dermatitis.

BACKGROUND: Positive patch tests to balsam of Peru (BOP) or fragrance mix (FM) suggest the possibility of systemic contact dermatitis from balsam-related foods and spices. OBJECTIVE: This was a retrospective study to determine whether avoidance of balsam-related foods results in an improvement of dermatitis in these patients. METHODS: A review of the records of all patients seen from July 1 to Dec 31, 1998 with positive patch tests to BOP, FM, cinnamic aldehyde, and balsam of tolu was performed 9 to 14 months after their evaluation in a tertiary dermatology center. All patients were contacted via telephone to assess the status of their dermatitis and whether they were able to note any specific balsam-related food allergies. RESULTS: A total of 75 patients were identified, and 71 could be contacted. Fourteen were only allergic to BOP or FM on testing; 31 were positive to BOP/FM and other allergens with presumed relevance to BOP/FM; 26 were positive to BOP/FM and others with other allergens felt to be responsible for the dermatitis and were not placed on a BOP diet. Excluding this last group, 21 of 45 (47%) had complete or significant improvement that they related to dietary modification. Ten did not modify their diet, with 8 reporting no improvement. Eight improved with fragrance or other allergen avoidance only, and 6 modified their diet unsuccessfully. Most commonly implicated foods included tomatoes, citrus, and spices. CONCLUSION: Almost half of the subjects with positive patch tests to BOP or FM who followed a BOP reduction diet reported significant to complete improvement of their dermatitis.

Dental metal allergy in patients with oral, cutaneous, and genital lichenoid reactions.

BACKGROUND: The subject of lichen planus (LP) and dental metal allergy long has been debated. An overwhelming majority of the existing literature focuses on mercury and gold salts in relation to oral lichen planus. OBJECTIVE: Our objective was to expand current knowledge regarding LP and lichenoid lesions (LL) and dental metal allergy by investigating more metals and investigating cutaneous and genital disease in addition to oral disease. METHODS: Fifty-one patients with known LP or LL were patch tested to a series of dental metals. Patients chose to replace their dental metals or make no revision. A telephone survey was conducted after 1 year to determine disease state. RESULTS: Thirty-eight of 51 patients (74.5%) had at least 1 positive reaction. Twenty-five of 51 patients (49.0%) showed sensitivity to at least 1 mercurial allergen. Prevalence data for patients patch tested by the North American Contact Dermatitis Group (NACDG) from 1996 to 1998 was available for chromate, cobalt, gold, nickel, and thimerosal. The prevalence of positive reactions was higher in our group than in the NACDG group for all 5 of these allergens, and statistical significance was achieved for chromate (P = .028), gold (P = .041), and thimerosal (P = .005). Of patients who had a positive patch test reaction to 1 or more metals, 100% (9 of 9) reported improvement after metal replacement, whereas 62.5% (15 of 24) reported improvement without metal replacement. CONCLUSION: Sensitization to dental metals is more common among LP and LL patients than in routinely tested patients, and might be an etiologic or triggering factor in the disease.

Patch testing discordance alert: false-negative findings with rubber additives and fragrances.

From July 1996 through June 1998, the North American Contact Dermatitis Group evaluated 318 patients for suspected contact dermatitis by patch testing simultaneously with Finn Chambers and the T.R.U.E. Test allergen system. Discrepancies between the two systems were found in some of the results, particularly with fragrance and rubber allergens. These results suggest that positive reactions to fragrance, thiuram, and carba mix allergens may be missed if the T.R.U.E. Test is used alone.

Advanced head and neck carcinoma in women: treatment outcomes may not improve with accelerated hyperfractionated radiotherapy.

BACKGROUND: The authors undertook a retrospective study on local tumor control, survival, and complications of conventional irradiation compared with accelerated hyperfractionated irradiation in women with selected head and neck tumor sites. METHODS: One hundred eight consecutive women who were treated with radiation alone for cure during 1974-1998 were analyzed. Patients were excluded who had T1 tumors of the vocal cord and those who were treated with brachytherapy implants. Fifty-nine patients were treated with conventional fractionation once daily (QD) during 1974-1998 with a median dose of 2.1 grays (Gy) per fraction up to a total median dose of 69 Gy in a median overall time of 54 days. Forty-nine patients were treated with accelerated hyperfractionation twice daily (BID) during 1987-1998 at a median dose of 1.6 Gy per fraction BID, with an interfraction interval of 4-6 hours, for a total median dose of 66 Gy in 35 days. Patients were not randomized into the QD group or the BID group. RESULTS: The 7-year actuarial local control (LC) rates for T1-T2 tumors in QD-treated and BID-treated patients were 79% and 87%, respectively (P = not significant [NS]). For T3-T4 tumors, the LC rates at 7 years were 59% and 56% for the QD and BID groups, respectively (P = NS). A Cox regression analysis for LC showed that the significant variables were T classification and overall time. Schedule (QD or BID), total dose, dose per fraction, and patient age were not significant variables. For the QD and BID groups, the 7-year actuarial cause specific survival rates for patients with Stage I-II disease were 100% and 65%, respectively (P = 0.004), and, for patients with Stages III-IVA,IVB disease, the rates were 39% and 56%, respectively (P = NS), respectively. Acute morbidity was higher with the BID schedule: In the BID group, 8% of patients required tube or parenteral feeding, and 0% of patients in the QD group required such feeding (P = 0.04). The 5-year actuarial probability of Grade 3-5 late effects (according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer grading system) was 4% for the BID group and 0% for the QD group (P = NS). CONCLUSIONS: This study suggests that accelerated hyperfractionated irradiation for women with advanced carcinoma of the head and neck does not provide significantly better local tumor control or cause specific disease free survival compared with conventional fractionation. Women with these malignancies appear to have a better prognosis compared with men.