Combination therapy: intermittent sorafenib with bevacizumab yields activity and decreased toxicity.

BACKGROUND: We previously reported preliminary results of our phase I study of continuous daily sorafenib with bevacizumab every other week for solid tumours. Toxicity was moderate, leading to additional dose levels (DL) testing intermittent sorafenib dosing. METHODS: Seventeen patients with advanced solid tumours were treated on three additional DLs testing sorafenib days 1-5 per week. Dose level 4 was sorafenib 200 mg twice daily (b.i.d.) and bevacizumab 5 mg kg(-1). DL5 alternated between bevacizumab 10 mg kg(-1)-sorafenib 200 mg b.i.d. (A) and sorafenib 400 mg b.i.d. with bevacizumab 5 mg kg(-1) (B). Outcome and toxicity data from 19 epithelial ovarian cancer (EOC) patients from DL 1-5 were analysed. RESULTS: Fewer patients required sorafenib dose reduction with the intermittent schedule (41 vs 74% daily, P=0.01). Hand-foot skin reaction (HFSR) remained the primary cause of dose reduction (n=5). Partial responses (12%) or disease stabilisation > or =4 months (53%; median 6 (4-26)) occurred in most patients on the intermittent schedule. Partial response occurred in 47% EOC patients treated in pooled analysis of duration 4-37 months. CONCLUSION: Intermittent sorafenib dosing with bevacizumab has promising clinical activity and less sorafenib dose reduction and side effects, but does not ameliorate HFSR. We are conducting a phase II clinical trial with intermittent sorafenib and bevacizumab in patients with EOC.

[Synchronising school entry health examinations in Lower-Saxony, Germany]. / Synchronisierung von Schuleingangsuntersuchungen in Niedersachsen.

BACKGROUND: In the German federal state of Lower-Saxony the districts are responsible for conducting school entry health examinations. There exist two different standard protocols for diagnosis and documentation, denoted as Weser-Ems (WE) and SOPHIA. In order to analyse and improve the comparability between these two protocols, a working group was established in 2006. One of the objectives was to adjust the protocols in such a way that in the future the collected data will allow for joint health reporting. METHODS: Each variable was discussed individually by the working group, and if diagnosis or documentation differed between the two protocols, specific modifications were proposed. For certain variables external expert opinions were obtained. For those variables that had to be revised quite generally, specific sub-working groups were established. As prerequisite for implementation, the recommendations of the working group had to be accepted by the user groups through majority votes. RESULTS: Of 88 (WE) or, respectively, 66 (SOPHIA) variables, 39 (WE) or, respectively, 34 variables initially fulfilled the requirements for a joint analysis. As a result of the working group, for more than 20 other variables the requirements for a joint analysis could be achieved. As soon as the sub-working groups have completed their work, also the issues of physical coordination, cognitive abilities and psychological health will be available for joint analysis. DISCUSSION: The synchronisation of school entry health examinations in Lower-Saxony is an example of how different protocols of diagnosis and documentation can be adapted to each other to enable joint data analysis without loosing their individual characteristics.

An ERCC1 splicing variant involving the 5'-UTR of the mRNA may have a transcriptional modulatory function.

Human ovarian cancer cells and tissues were examined for the presence or absence of a 42-bp splicing variant of ERCC1 gene, and for a possible functional role of this 42-bp sequence. This specific sequence exists in exon I, the 5'-UTR of the gene. Loss of this 42-bp sequence was associated with increased ERCC1 mRNA expression, in an assessment of 121 ovarian cancer specimens (p2<10(-6)). In cells in tissue culture, the absence of the 42-bp segment was associated with a twofold increased ability to drive transcription in a Luciferase reporter system. Protein can be demonstrated in ovarian cancer cells based on EMSA analysis. Computer analysis shows that this 42-bp sequence contains several binding sites, including a core-binding domain for protein RFX1, transcriptional repressor. These preliminary results lay the groundwork in determination of potential roles for a negative regulatory element in NER repair pathway.

Endometrial cancer: stage at diagnosis and associated factors in black and white patients.

OBJECTIVE: This study examined the relationship of clinicopathologic, health status, medical system, and socioeconomic factors to differences in stage at diagnosis of endometrial cancer in black and white patients. STUDY DESIGN: A population-based study of 130 black and 329 white patients with invasive endometrial cancer was conducted as part of the National Cancer Institute's Black/White Cancer Survival Study. Logistic regression was used to determine the relative importance of factors thought to be related to stage at diagnosis after age and geographic location were adjusted for. RESULTS: High-grade (poorly differentiated) lesions increased the risk for stage III or IV disease (odds ratio 8.3, 95% confidence interval 3.4 to 20.3), as did serous histologic subtype (odds ratio 3.5, 95% confidence interval 1.4 to 8.8) and no usual source of care (odds ratio 5.5, 95% confidence interval 1.4 to 20.9). In the final statistical model these three factors also accounted for the majority of the excess risk of advanced stage for blacks. CONCLUSIONS: Black-white racial disparities in stage at diagnosis appear to be related to higher-grade lesions and more aggressive histologic subtypes occurring more frequently in black patients with endometrial cancer.

Racial differences in tumor grade among women with endometrial cancer.

Black women with endometrial cancer have more advanced disease and less favorable tumor grade than do white women. This study evaluated whether racial differences in tumor grade could be explained by hormone-related factors and other putative determinants of grade. Subjects included 207 white and 81 black postmenopausal women diagnosed with primary cancer of the uterine corpus between 1985 and 1987. Blacks had poorer tumor grade than whites (odds ratio for FIGO grade 2 versus grade 1 is 1.8; odds ratio for grade 3 versus grade 1 is 2.8). Over 75% of the excess of poorly differentiated tumors versus well-differentiated tumors among blacks could be explained by racial differences in use of replacement estrogens, age at first pregnancy, history of oophorectomy, poverty, stage of disease, use of screening, and access to health care. The most prominent factor was estrogen therapy, which was associated with favorable tumor grade and was used much less frequently by blacks. Although not statistically significant, a moderate racial difference in tumor grade remained after control of the potential explanatory explanatory variables. This may reflect true biologic variation between blacks and whites and may explain, in part, the observation that blacks with endometrial cancer have a worse prognosis.

Is Candida stellatoidea disappearing from the vaginal mucosa?

A total of 681 vaginal isolates of germ tube-positive or germ tube-untested white, yeastlike fungi obtained from patients in various cities of the United States were tested for the presence of Candida stellatoidea (type I). Only 1 of the 681 isolates was identified as C. stellatoidea.

The oral contraceptives and infertility.

PIP: This paper emphasized the syndrome of anovulation and infertility following oral contraceptive therapy in patients with previously regular menses. Case histories of 2 successfully treated patients are given. The first was 22-years-old, gravida 0, and had taken Enovid for almost a year following marriage. Physical and histological findings were normal. Withdrawal flow but not ovulation followed oral administration of 10 mg of 6-alpha methyl 17-acetoxyprogesterone daily for 5 days. Ovulation began after prednisone, 5 mg twice daily, was given for 1 month. Several months later she conceived and has had a normal delivery. The other patient, a 23-year-old gravida 0, used Enovid for 2 years. After cessation her previously regular menstrual periods became very irregular and complete amenorrhea had lasted 4 months. Prednisone, 5 mg twice a day, restored ovulation in 1 month. She conceived the following month. Relative frequency of anovulation following oral contraception is believed greater than suspected. Patients who have not yet completed their families should be warned of the risk and contraceptives should not be used to treat infertility to produce a "rebound" effect.^ieng