Feasibility of using interpolated contours of targets and organs at risk in intensity‐modulated radiation therapy treatment planning for advanced‐stage nasopharyngeal carcinoma

To assess the dosimetric effect of using interpolated contours in planning intensity‐modulated radiation therapy (IMRT) for advanced T‐stage nasopharyngeal carcinoma. The present study focused on T3–T4 tumours where the proximity of targets to neurological organs poses a stringent test on the feasibility of such an approach. Contours of targets and organs were delineated on CT images of 2.5‐mm interval and a reference IMRT plan was generated. An investigative (INV) IMRT plan was then generated with the same planning protocol, but based on interpolated contours that replaced deleted contours on alternate slices. The reference and INV plans were compared. Regarding target coverage, all targets in the INV plans met the acceptance criteria except for the PTV in one case. Regarding organs, the mean dose to 1% volume of the brainstem and spinal cord in the INV plans were kept below their dose limits. No significant differences in the mean doses to others organs were found. Satisfactory target coverage and protection of critical organs to a degree similar to full‐scale contouring could be achieved with use of interpolated contours. The saving in manpower time for contouring is expected to significantly improve the throughput of the IMRT planning process.     

Maternal and neonatal effects of outlet forceps delivery compared with spontaneous vaginal delivery in term pregnancies

Previous retrospective studies have suggested that the prophylactic use of outlet forceps has a beneficial impact on the neonate because it shortens the second stage of labor and decreases the incidence of neonatal hypoxia. The purpose of this study was to compare the immediate maternal and neonatal effects of outlet forceps delivery (N = 165) with spontaneous vaginal delivery (N = 168) in term parturients. Subjects were randomized to the study or control group immediately before delivery. There were 88 nulliparas and 77 multiparas in the forceps delivery group and 90 and 78, respectively, who delivered spontaneously, a nonsignificant difference. There were no significant differences in gestational age, parity, infant birth weight, length of the first and second stages of labor, use of conduction (continuous epidural) anesthesia, decrease in hematocrit values, Apgar scores, or umbilical arterial pH values between the forceps and spontaneous delivery groups. Seventeen infants in the forceps group and 16 in the control group had cephalhematoma, facial bruising, subconjunctival hemorrhage, or scalp abrasion (not significant). No neonate had fractures, nerve palsies, or intracranial hemorrhage (determined by cranial ultrasound). In the nulliparous population, significant differences were found in the use of episiotomy (93 versus 78%) and the incidence of deep perineal lacerations (24 versus 10%) with forceps compared with spontaneous delivery, respectively (P less than .05). No significant differences between the groups were found in multiparas. We conclude that the use of outlet forceps in patients with uncomplicated labor has no immediate effect on the neonate. Furthermore, outlet forceps delivery does not significantly shorten the second stage of labor and is associated with an increased incidence of maternal perineal trauma.     

Serum lipids and lipoproteins in continuous or cyclic medroxyprogesterone acetate treatment in postmenopausal women treated with conjugated estrogens

This study evaluates effects on serum lipids of continuous or sequential progestogens for hormonal replacement in women. Subjects received either a cyclic regimen of replacement (0.625 mg/d of conjugated equine estrogens (Es) for 25 days/month and 10 mg medroxyprogesterone acetate [MPA] for the last 13 days of E) or 0.625 mg/d E along with either 5 or 10 mg MPA (Provera, Upjohn Company, Kalamazoo, MI). Study parameters were measured over a 24-week period. No differences in total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, apolipoproteins I and II, sex hormone-binding globulin, or serum MPA levels were noted between the sequential and 5 mg continuous group. The 10 mg MPA group did not have an increase in HDL or decrease in low-density lipoprotein as did the other groups.     

Comparison of anterior colporrhaphy and retropubic urethropexy for patients with genuine stress urinary incontinence

OBJECTIVE: Our purpose was to compare the efficacy of anterior colporrhaphy and retropubic urethropexy performed for genuine stress urinary incontinence.STUDY DESIGN: A retrospective analysis was performed on women who underwent either anterior colporrhaphy or retropubic urethropexy for genuine stress urinary incontinence. Patients were identified by a computer-assisted search, and these women were contacted by telephone. The interview was used to assess current continence status. Variables reviewed included demographic data, medications, hormonal status, current smoking history, significant medical and surgical history, and time to recurrence of incontinence. Operative procedure, prior or concomitant hysterectomy, history of previous incontinence procedures, concomitant surgery for repair of other pelvic floor defects, experience level of the primary surgeon, and duration of postoperative catheterization were also documented.RESULTS: Seventy-six women who had undergone surgery for genuine stress incontinence during a 4-year period were identified and evaluated by telephone interview. Fifty-six had undergone anterior colporrhaphy and 20 retropubic urethropexy. Both groups of patients were comparable in age, social status, race, parity, and weight. The duration of follow-up (mean ± SD) was 66.6 ± 14.2 months (range 48 to 96 months). Concurrent surgery to repair other pelvic floor defects was more common in patients undergoing anterior colporrhaphy than in patients undergoing retropubic urethropexy (p < 0.05). Of the 56 patients treated with anterior colporrhaphy, 26 (46%) were continent at the time of interview versus 15 of 20 (75%) treated with retropubic urethropexy (p < 0.05). Times to recurrence for anterior colporrhaphy and retropubic urethropexy were not significantly different. History of previous incontinence procedures, concomitant hysterectomy, previous hysterectomy, duration of postoperative catheterization, obesity, chronic lung disease, and smoking were not correlated with success for either procedure. Experience of the primary surgeon did have a significant effect on success, with attending staff having a better cure rate than resident surgeons (p < 0.05).CONCLUSION: Retropubic urethropexy was significantly more effective than anterior colporrhaphy for long-term cure of genuine stress urinary incontinence. We believe these conclusions should be tempered because of the complex nature of genuine stress incontinence. Patients having anterior colporrhaphy may represent a high-risk group because nearly all of them had associated pelvic floor defects. Experience of the surgeon seems to enhance the liklihood of success and may reflect subtle modifications of technique.     

Design and synthesis of dipeptide nitriles as reversible and potent Cathepsin S inhibitors

The specificity of the immune response relies on processing of foreign proteins and presentation of antigenic peptides at the cell surface. Inhibition of antigen presentation, and the subsequent activation of T-cells, should, in theory, modulate the immune response. The cysteine protease Cathepsin S performs a fundamental step in antigen presentation and therefore represents an attractive target for inhibition. Herein, we report a series of potent and reversible Cathepsin S inhibitors based on dipeptide nitriles. These inhibitors show nanomolar inhibition of the target enzyme as well as cellular potency in a human B cell line. The first X-ray crystal structure of a reversible inhibitor cocrystallized with Cathepsin S is also reported.     

Heterogeneity of health disparities among African American, Hispanic, and Asian American women: unrecognized influences of sexual orientation

OBJECTIVES: This study compared health indicators among self-identified lesbians/bisexual women and heterosexual women residing in Los Angeles County. METHODS: Respondents were English-speaking Hispanic, African American, and Asian American women. Health status, behavioral risks, access barriers, and indicators of health care were assessed. RESULTS: Prevalence rates of chronic health conditions were similar among women in the 3 racial/ethnic groups. However, lesbians and bisexual women evidenced higher behavioral risks and lower rates of preventive care than heterosexual women. CONCLUSIONS: Among racial/ethnic minority women, minority sexual orientation is associated with increased health risks. The effects of sexual minority status need to be considered in addressing health disparities affecting this population.     

Human cytomegalovirus infection and expression in human malignant glioma

Malignant gliomas are the most common primary brain tumors in adults, have no known etiology, and are generally rapidly fatal despite current therapies. Human cytomegalovirus (HCMV) is beta-herpesvirus trophic for glial cells that persistently infects 50-90% of the adult human population. HCMV can be reactivated under conditions of inflammation and immunosuppression, and HCMV gene products can dysregulate multiple cellular pathways involved in oncogenesis. Here we show that a high percentage of malignant gliomas are infected by HCMV and multiple HCMV gene products are expressed in these tumors. These data are the first to show an association between HCMV and malignant gliomas and suggest that HCMV may play an active role in glioma pathogenesis.     

Focal adhesion kinase enhances signaling through the Shc/extracellular signal-regulated kinase pathway in anaplastic astrocytoma tumor biopsy samples

Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that on activation generates signals that can modulate crucial cell functions, including cell proliferation, migration, and survival. In vitro, overexpression of FAK has been shown to promote cell proliferation by signaling through the Ras/mitogen-activated protein kinase cascade in several cell types. We have shown previously that overexpression of exogenous FAK lacking alternative splicing in malignant astrocytoma clones injected intracerebrally into SCID mouse brains promotes tumor cell proliferation. Here, we show that in anaplastic astrocytoma biopsy samples, FAK is expressed as an unspliced variant and migrates with a faster mobility similar to that observed in embryonic brain. Compared with nonneoplastic adult brain biopsies, the levels of FAK protein are elevated as are its levels of activation as assessed by autophosphorylation and overall tyrosine phosphorylation. The activity of Src kinase in these tumors is also elevated, as well as the activity of Src kinase associated with FAK; the latter may result in enhanced Src kinase phosphorylation of FAK. Phosphorylated Shc is associated with FAK in the anaplastic astrocytoma biopsy samples and in astrocytoma cells overexpressing FAK in vitro but not in nonneoplastic brain biopsy samples. Elevated extracellular signal-regulated kinase-2 activation and elevated expression of cyclins D and E are also found in anaplastic astrocytoma biopsy samples. These data provide evidence that the increased FAK activity in these tumors contributes to phosphorylation of Shc and likely to the promotion of Ras activity, extracellular signal-regulated kinase-2 activation, and cell proliferation in vivo.     

Intratumoral 5-fluorouracil produced by cytosine deaminase/5-fluorocytosine gene therapy is effective for experimental human glioblastomas

5-Fluorouracil (5-FU) is a potent antimetabolite used for chemotherapy of gastrointestinal (GI), breast, and head and neck malignancies. Although clinical trials have been conducted, the poor therapeutic index of 5-FU has precluded its clinical use for a number of other tumor types. It is unclear whether this lack of utility is due to problems with drug delivery or inherent insensitivity. Adenovirus (Ad) vector-mediated cytosine deaminase (CD)/5-fluorocytosine (5-FC) gene therapy has the potential to overcome pharmacokinetic issues associated with systemic 5-FU and is particularly well suited to use with tumors in which local control is paramount, such as recurrent, localized prostate cancer and malignant gliomas. In this study, the in vitro response by a panel of human tumor cell lines derived from both GI (colon, pancreas) and non-GI (prostate, glioma) tumors to 5-FU and to AdCMVCD (an Ad encoding Escherichia coli CD)/5-FC was examined. Whereas the sensitivity (IC(50)) of individual cell lines to these agents varied, no significant difference in median IC(50) for either 5-FU or AdCMVCD/5-FC was evident for the four tumor types tested (P > 0.1). The relevant contributions of Ad gene transfer efficiency and inherent 5-FU sensitivity in determining response to AdCMVCD/5-FC were then assessed. Multiple linear regression analysis revealed that whereas both factors significantly contribute to the response, inherent 5-FU sensitivity was substantially more important (beta= 0.78 versus 0.48; P < 0.001). Finally, the therapeutic efficacy of a single intratumoral injection of AdCMVCD followed by systemic 5-FC was assessed in three intracranial C.B17 severe combined immunodeficient mouse models of human glioma. AdCMVCD/5-FC efficacy was specific, virus dose-dependent, and closely paralleled in vitro 5-FU and CD/5-FC sensitivity in two of three models tested. These results reveal that glioma cells are as sensitive as GI tumor cells to the antineoplastic effects of 5-FU, identify inherent 5-FU sensitivity as an important factor in determining CD/5-FC efficacy, and confirm previous findings in rat models that demonstrate the potential clinical utility of AdCMVCD/5-FC gene therapy for gliomas.     

Use of topical misoprostol to reduce radiation‐induced mucositis: Results of a randomized,double‐blind,placebo‐controlled trial

Radiation‐induced mucositis is an acute reaction of the mucosa of patients undergoing head and neck radiotherapy. It can have debilitating and dose‐limiting consequences. There is no consensus on an accepted intervention that significantly reduces its severity. Misoprostol is a synthetic prostaglandin E₁ analogue, with properties of a mucosal cytoprotectant. We designed a randomized, double‐blind, placebo‐controlled trial of misoprostol in patients with head and neck cancer. The aim of this study was to determine if topical misoprostol was effective in reducing the severity of radiation‐induced mucositis in patients receiving radical dose radiotherapy. The effect of this intervention on a patient’s general well‐being was also investigated. The primary end‐point of the study was the incidence of Radiation Therapy Oncology Group grade 3 mucositis. Between 1999 and 2002, 83 patients were recruited into the study at Westmead and Nepean Hospitals, Sydney. Forty‐two patients were randomized to receive misoprostol and 41 to receive a placebo. Most patients received radiotherapy in the adjuvant setting (52 of the 83) and had either an oral cavity (42 of the 83) or an oropharyngeal (16 of the 83) cancer. We could not identify any significant difference in the incidence of severe mucositis based on whether patients were allocated to receive misoprostol or placebo. There was no significant difference in the mean area under the mucositis curve (13.2 vs 16.6; P = 0.1). Patients allocated to misoprostol did report slightly increased soreness (7.6 vs 6.9; P = 0.04) and a greater use of analgesics. However, this difference did not translate into a worse feeling of general well‐being as measured by a simple visual analogue scale (5.8 vs 5.2; P = 0.3). In conclusion, we were unable to identify a reduction in radiation‐induced mucositis in patients receiving misoprostol. There is a paucity of high‐level evidence on potentially useful interventions and a continued need for new and innovative research, incorporating quality‐of‐life measurements, in patients experiencing radiation‐induced mucositis.