Faculty Bibliography

BACKGROUND: Two studies assessed the effect of a low-estrogen-dose 21/7-day oral contraceptive containing ethinylestradiol and drospirenone (EE 20 mcg/drsp 3 mg) on ovarian activity in Japanese and Caucasian women. STUDY DESIGN: Study 1 was conducted in Japanese women (20-35 years), and Study 2 was conducted in Caucasian women (18-35 years). All women received EE 20 mcg/drsp 3 mg in a 21-day active pill regimen. The primary endpoint was the proportion of women with ovulation inhibition (Hoogland score <6; as assessed by transvaginal ultrasonography) during treatment cycle 2. RESULTS: Japanese (n=23) and Caucasian (n=30) women received two cycles of study treatment. During treatment cycle 2, ovulation was inhibited in 100% and 92.9% of Japanese and Caucasian women, respectively. CONCLUSIONS: EE 20 mcg/drsp 3 mg in a 21/7-day regimen provides comparable ovarian suppression in Japanese and Caucasian women, with normal ovarian function resuming shortly after treatment end in both populations.

OBJECTIVE: Some authors suggest a glucose challenge test (GCT) threshold of 150 mg/dL in Asian gravidas. The impact of such a policy on outcomes is unknown. STUDY DESIGN: A retrospective cohort of 1705 Asian gravidas. Subjects (n=95) had a GCT of 140-150 mg/dL and underwent a 3-h glucose tolerance test (GTT). Matched controls (n=190) had a GCT of <140 mg/dL. Birthweight was the primary outcome and the secondary outcomes were cesarean delivery (CD) rate and macrosomia. RESULTS: Eight subjects (11.9%) had gestational diabetes mellitus (GDM); none had GTT fasting values of >90 mg/dL. Mean birthweight was 3282 g in the subjects and 3238 g in the controls (P=0.39). There were no significant differences in the secondary outcomes. CONCLUSION: Compared with controls, study patients did not deliver significantly larger infants. However, raising the GCT threshold would have missed 8 subjects (11.9%) with GDM. Raising the GCT threshold to 150 mg/dL in Asian gravidas may unacceptably lower the sensitivity of the screening test.

PURPOSE: To analyze the patterns of local-regional recurrence in patients with head and neck cancer treated with parotid-sparing conformal and segmental intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: Fifty-eight patients with head and neck cancer were treated with bilateral neck radiation (RT) using conformal or segmental IMRT techniques, while sparing a substantial portion of one parotid gland. The targets for CT-based RT planning included the gross tumor volume (GTV) (primary tumor and lymph node metastases) and the clinical target volume (CTV) (postoperative tumor bed, expansions of the GTVs and lymph node groups at risk of subclinical disease). Lymph node targets at risk of subclinical disease included the bilateral jugulodigastric and lower jugular lymph nodes, bilateral retropharyngeal lymph nodes at risk, and high jugular nodes at the base of skull in the side of the neck at highest risk (containing clinical neck metastases and/or ipsilateral to the primary tumor). The CTVs were expanded by 5 mm to yield planning target volumes (PTVs). Planning goals included coverage of all PTVs (with a minimum of 95% of the prescribed dose) and sparing of a substantial portion of the parotid gland in the side of the neck at less risk. The median RT doses to the gross tumor, the operative bed, and the subclinical disease PTVs were 70.4 Gy, 61.2 Gy, and 50.4 Gy respectively. All recurrences were defined on CT scans obtained at the time of recurrence, transferred to the pretreatment CT dataset used for RT planning, and analyzed using dose-volume histograms. The recurrences were classified as 1) "in-field," in which 95% or more of the recurrence volume (V(recur)) was within the 95% isodose; 2) "marginal," in which 20% to 95% of V(recur) was within the 95% isodose; or 3) "outside," in which less than 20% of V(recur) was within the 95% isodose. RESULTS: With a median follow-up of 27 months (range 6 to 60 months), 10 regional recurrences, 5 local recurrences (including one noninvasive recurrence) and 1 stomal recurrence were seen in 12 patients, for a 2-year actuarial local-regional control rate of 79% (95% confidence interval 68-90%). Ten patients (80%) relapsed in-field (in areas of previous gross tumor in nine patients), and two patients developed marginal recurrences in the side of the neck at highest risk (one in the high retropharyngeal nodes/base of skull and one in the submandibular nodes). Four regional recurrences extended superior to the jugulodigastric node, in the high jugular and retropharyngeal nodes near the base of skull of the side of the neck at highest risk. Three of these were in-field, in areas that had received the dose intended for subclinical disease. No recurrences were seen in the nodes superior to the jugulodigastric nodes in the side of the neck at less risk, where RT was partially spared. CONCLUSIONS: The majority of local-regional recurrences after conformal and segmental IMRT were "in-field," in areas judged to be at high risk at the time of RT planning, including the GTV, the operative bed, and the first echelon nodes. These findings motivate studies of dose escalation to the highest risk regions.

PURPOSE: To develop techniques which facilitate sparing of the major salivary glands while adequately treating the targets in patients requiring comprehensive bilateral neck irradiation (RT). PATIENTS AND METHODS: Conformal and static, multisegmental intensity modulated (IMRT) techniques have been developed. The salivary flow rates before and periodically after RT have been measured selectively from each major salivary gland and the residual flows correlated with glands' dose volume histograms. Subjective xerostomia questionnaires have been developed and validated. The pattern of local-regional recurrences has been examined using CT scans at the time of recurrence, transferring the recurrence volumes to the planning CT scans and regenerating the dose distributions at the recurrence sites. RESULTS: Target coverage and dose homogeneity in IMRT treatment plans were found to be significantly better than standard RT plans. Significant parotid gland sparing was achieved. The relationships among dose, irradiated volume and saliva flow rates from the parotid glands were characterized by dose and volume thresholds. A mean dose of 26 Gy was found to be the threshold for stimulated saliva. Subjective xerostomia was significantly reduced in patients irradiated with parotid sparing techniques, compared to patients with similar tumors treated with standard RT. The large majority of recurrences occurred inside high-risk targets. CONCLUSIONS: Tangible gains in salivary gland sparing and target coverage are being achieved and an improvement in some measures of quality of life is suggested by our findings. A mean parotid gland dose of < or = 26 Gy should be a planning objective if significant parotid function preservation is desired. The pattern of recurrence suggests that careful escalation of the dose to targets judged to be at highest risk may improve tumor control.

The purpose of the study was to investigate the use of a dextran-coated ultrasmall superparamagnetic iron oxide (USPIO) as a blood pool contrast agent for thoracic and abdominal MR angiography. Abdominal and thoracic MR angiography was performed in six healthy volunteers using two-dimensional and three-dimensional spoiled gradient echo (SPGR) sequences before and after intravenous administration of USPIO. Doses ranged from 1.1 to 2.6 mg Fe/kg. Flip angle was varied from 20 to 60 degrees. Subjective image quality, analysis of signal-to-noise ratio (SNR), and blood T1 relaxation times were measured. USPIO significantly lowered the T1 of blood (from 1,210 ms precontrast to 159 ms postcontrast at a dose of 2.6 mg Fe/kg) (P < .01). Image quality on coronal fast three-dimensional breath-hold SPGR images of the abdomen increased with increasing dose and was maximum at the highest dose, producing an aortic SNR of 9.6 compared to 1.8 precontrast. Axial two-dimensional time-of-flight (TOF) aortic SNR was reduced significantly from 13 on precontrast to 6 on the postcontrast images at the highest dose (P < .05) due to T2* shortening effects. There was little flip angle dependence on image quality. Due to the T1 shortening effect and long intravascular half-life, USPIO improved visualization of vascular anatomy using three-dimensional fast SPGR imaging. The echo time must be minimized to minimize signal loss from T2* shortening effects. The blood pool distribution of USPIO is useful for equilibrium-phase MR angiography.

PURPOSE: To investigate the efficacy of magnetic resonance (MR) imaging with dextran-coated superparamagnetic iron oxide in the differentiation of metastatic and benign nodes in patients with head and neck cancer. MATERIALS AND METHODS: MR imaging was performed before and after intravenous administration of iron oxide in 12 patients. Ninety-one pathologically proved nodes were visually analyzed, and 66 lymph nodes were quantitatively analyzed by measuring signal intensity in visually selected regions of interest. RESULTS: Forty of 42 histologically proved metastatic nodes and 41 of 49 benign nodes were detected, yielding 95% sensitivity and 84% specificity. The signal intensity ratio of benign nodes was substantially lower than that of metastatic nodes, indicating better differentiation of metastatic and benign nodes. Furthermore, 13 of 14 normal-sized nodes were detected. CONCLUSION: MR imaging with iron oxide can enable specific differentiation of metastatic and benign nodes in patients with head and neck cancer. This agent may potentially enhance the detection of metastatic lymph nodes and deserves further investigation.

The effects of the transforming growth factor-beta 1 (TGF-beta 1) and epidermal growth factor (EGF) on the growth of cells from 2 endometrial cancer lines, Ishikawa and HEC-50 were evaluated by measuring rates of DNA synthesis and changes in cell numbers during culture. EGF at 17 and 1.7 nM concentrations consistently enhanced HEC-50 cell proliferation. TGF-beta 1 inhibited Ishikawa cell proliferation but, unexpectedly for epithelium-derived cells, stimulated HEC-50 cell growth. This effect is of interest as it indicates that endometrial cells can acquire an altered responsiveness to a growth inhibitor during the process of malignant transformation. Northern blot analyses showed expression of TGF-alpha, TGF-beta 1 and EGF receptors mRNA in both cell lines. Neither estradiol (E2) nor 4-hydroxytamoxifen (OHTam) affected mRNA levels for either TGF-alpha or TGF-beta in HEC-50 cells, a line unresponsive to E2 for proliferation. In Ishikawa cells, previously shown to respond to both E2 and OHTam by increasing proliferation rates, E2 increased TGF-alpha mRNA and reduced TGF-beta mRNA levels. OHTam lowered the levels of both mRNA species, although the effect was greater on TGF-beta than TGF-alpha mRNA. These data are consistent with, but do not prove, the existence of a possible autocrine regulation by TGF-alpha and TGF-beta of human cancer cell proliferation, which might be under E2 influence in Ishikawa cells

Cu(2+)-Zn2+ superoxide dismutase (SOD-1) is a ubiquitously synthesized eukaryotic enzyme with a variety of important roles in mammalian development and physiology. With the goal of better understanding the structure and regulation of this gene, we have cloned and analyzed the genomic structure of the mouse SOD-1 gene. The murine sequence has an intron:exon organization very similar to that of the human gene, though significant diversion was observed in the promoter and 3' regions. These differences account for the observation that only a single transcript for SOD-1 is seen in mouse cells, while two transcripts are derived from the human gene. The cloning of mouse SOD-1 should allow elucidation of the regulatory characteristics of this element, as well as new and informative genetic engineering experiments

Studies of hormonal growth regulation in cultured human endometrial cancer cells are limited by the requirement of exogenous growth factors, usually supplied by addition of serum. The present report provides evidence that estradiol can stimulate proliferation of endometrial cancer cells of the Ishikawa line in the absence of serum or added growth factors. Mitogenic effects of estrogen were demonstrated in two different experimental systems, in cells attached to the substratum of mammalian tissue culture dishes, and in cells forming colonies in soft agar under anchorage-independent conditions. Addition of estradiol to a mixture of serum-free, phenol red-free Dulbecco's minimal essential medium and Ham's F-12 medium, supplemented with L-glutamine and 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid [basal medium: (BM)] significantly increased the proliferation of cells attached to culture dishes. Dose-response experiments revealed maximal estradiol stimulation at 10 nM; significant responses were also observed at 1 nM and at 100 nM concentrations. The mitogenic effect of 10 nM estradiol was comparable to that of 1% charcoal-treated fetal bovine serum and the two effects were additive. The presence of estradiol in serum-free BM resulted in a shortening of the doubling time of exponentially proliferating cells from 38 to 29 h. From the labeling index, measured after exposure to a pulse of [3H]thymidine, and from the mitotic index, both determined in exponentially proliferating cells, the lengths of the S and M phases were calculated to be 11 and 1 h, respectively. From these data it was estimated that estradiol shortened the G1 phase by approximately 40%, from 22 to 13 h. Estradiol doubled the colony formation efficiency of cells plated in BM containing 0.3% agar in the absence of serum as well as in the presence of 1% charcoal-treated fetal bovine serum. The stimulation of colony formation by estradiol was influenced by medium components, since no effects were observed in minimal essential medium. The colony formation efficiency was positively related to the serum concentrations and remained significantly lower in minimal essential medium than in BM at comparable serum levels. The observed positive relationship between colony formation efficiency and cell densities at plating suggests a cooperative mitogenic effect, likely due to autocrine and paracrine action of secreted growth factors. These results define a model to evaluate hormonal growth regulation mediated by autocrine mitogens in human endometrial cancer cells in the absence of interfering exogenous growth factors.(ABSTRACT TRUNCATED AT 400 WORDS)