Through-Solvent Tunneling in Donor-Bridge-Acceptor Molecules Containing a Molecular Cleft.

Photoinduced electron transfer is used to investigate the solvent-mediated electron tunneling between electron donor and acceptor groups in polar solvents. Bis-peptide scaffolds are used to control the spatial positioning of electron donor and acceptor groups and create a molecular cleft. The photoinduced electron transfer is studied for two different cleft sizes, and the electronic coupling is found to be controlled by the nature of the solvent and the ability of the molecular cleft to accommodate it, as well as interact directly with it. These studies demonstrate the importance of electron tunneling through nonbonded contacts and reveal a strategy for examining such tunneling pathways in polar solvents.

Conformational preferences in a benzodiazepine series of potent nonpeptide fibrinogen receptor antagonists.

Previously, we reported the direct design of highly potent nonpeptide 3-oxo-1,4-benzodiazepine fibrinogen receptor antagonists from a constrained, RGD-containing cyclic semipeptide. The critical features incorporated into the design of these nonpeptides were the exocyclic amide at the 8-position which overlaid the Arg carbonyl, the phenyl ring which maintained an extended Gly conformation, and the diazepine ring which mimicked the gamma-turn at Asp. In this paper, we investigate conformational preferences of the 8-substituted benzodiazepine analogues by examining structural modifications to both the exocyclic amide and the seven-membered diazepine ring and by studying the conformation of the benzodiazepine ring using molecular modeling, X-ray crystallography, and NMR. We found that the directionality of the amide at the 8-position had little effect on activity and the (E)-olefin analogue retained significant potency, indicating that the trans orientation of the amide, and not the carbonyl or NH groups, made the largest contribution to the observed activity. For the diazepine ring, with the exception of the closely analogous 3-oxo-2-benzazepine ring system described previously, all of the modifications led to a significant reduction in activity compared to the potent 3-oxo-1, 4-benzodiazepine parent ring system, implicating this particular type of ring system as a desirable structural feature for high potency. Energy minimizations of a number of the modified analogues revealed that none could adopt the same low-energy conformation as the one shared by the active (S)-isomer of the 3-oxo-1, 4-benzodiazepines and 3-oxo-2-benzazepines. The overall data suggest that the features contributing to the observed high potency in this series are the orientation of the 3-4 amide and the conformational constraint imposed by the seven-membered ring, both of which position the key acidic and basic groups in the proper spatial relationship.

Granulosa cell tumor of the ovary associated with antecedent tamoxifen use.

BACKGROUND: Increased attention has been focused recently on the estrogenic effects of tamoxifen. Review of the literature reveals an association between tamoxifen use and gynecologic tumors. CASE: A 52-year-old postmenopausal woman was treated with tamoxifen for stage II estrogen receptor-positive breast carcinoma. Her aspartate transaminase and alanine transaminase levels increase markedly after 6 months of tamoxifen use. After an additional 17 months of elevated serum transaminases, the patient was found to have a stage Ic granulosa cell tumor of the ovary. CONCLUSION: Patients with tamoxifen-induced liver dysfunction may be at increased risk for granulosa cell tumors because of alterations in tamoxifen metabolism.

Default from colposcopy and loop excision electrocautery procedure appointments in a military clinic.

OBJECTIVE: To determine the extent of nonadherence and impediments to care in a military colposcopy and loop excision electrocautery procedure (LEEP) clinic. MATERIALS AND METHODS: The nonadherence rate for colposcopy and LEEP appointments was determined for a 6-month period at Walter Reed Army Medical Center. Nonadherence was defined as failure to keep an appointment or cancellation within 24 hours of the scheduled time. A nurse coordinator telephoned all nonadherent women. Women who agreed to participate were administered a structured survey to elicit their reasons for default from their appointments. RESULT: Sixty-one (15%) of 405 women were nonadherent. Of the 61 nonadherent women, 55 (90%) agreed to participate, 4 (7%) were unable to be contacted, and 2 (3%) declined participation. The average age of participants was 30 years. Beneficiary status of the 55 women was as follows: dependent, 27 (49%); active duty, 25 (45%); retired, 2 (4%); and veteran, 1 (2%). The most common reasons for default overall for 55 women were onset of menses (15 [27%]), unplanned family or personal event (9 [16%]), forgetting (8 [15%]), and work conflict (7 [13%]). Leading reasons for 25 active duty women included work conflict (7 [28%]) and menses (6 [24%]). Leading reasons for 27 dependent women included menses (9 [33%]), unplanned family or personal event (6 [22%]), and forgetting (5 [19%]). CONCLUSIONS: Despite unrestricted access to care in the military clinic, the default rate was similar to rates reported for civilian clinics. Previsit interventions likely to improve compliance include sending informational packets to patients, better attention to scheduling around the time of expected menses, and initiating an appointment reminder system. To decrease the high percentage of nonadherence attributable to work conflicts for active duty women, supervisors need to be better informed about both medical and deployment implications of an unevaluated abnormal Pap smear.

Primary appendiceal malignancy mimicking advanced stage ovarian carcinoma: a case series.

BACKGROUND: Primary appendiceal malignancy metastatic to the ovaries is a rare condition that may mimic late stage ovarian cancer. This condition is rarely diagnosed preoperatively. CASES: Three patients referred to our institution from 1994 to 1999 for presumed late stage ovarian cancer were found to have primary appendiceal adenocarcinoma, adenocarcinoid, and mucinous cystadenocarcinoma metastatic to the ovaries at laparotomy. We describe the clinical course of these patients and review the relevant literature. CONCLUSION: It is important for the gynecologic oncologist to be aware of the clinicopathological features and surgical management of these malignancies, as the incidence, prognosis, and recommended treatment vary with histological subtype.

Large cell neuroendocrine cervical carcinoma: a report of two cases and review of the literature.

BACKGROUND: Large cell neuroendocrine cervical carcinoma is a rare malignancy. These tumors appear to mimic the aggressive behavior of small cell neuroendocrine tumors. Metastasis and recurrent disease are common. Due to the low incidence of these tumors, optimal therapy has not been delineated. CASES: Two patients presented with large cell neuroendocrine cervical carcinoma, stage IB1 and IIA, at our institution from 1997 to 1999. We describe the clinical course for these two patients and review the relevant literature for the management of large cell cervical carcinoma. CONCLUSION: Unlike squamous cell carcinoma, early-stage large cell neuroendocrine tumors of the cervix are aggressive. Disease recurrences are frequent and distant metastasis is common. Multimodal therapy should be considered at the time of initial diagnosis.

Chemical analysis of adnexal cyst fluid.

OBJECTIVE: The purpose of the study was to determine if adnexal cyst fluid glucose, protein, and lactate dehydrogenase (LDH) levels can discriminate between cancerous and noncancerous adnexal masses. METHODS: Intracystic fluid was aspirated from adnexal masses immediately after operative excision. Patient age and menopausal status, mass size, and cyst fluid specific gravity were recorded. Cyst fluid and intraoperative serum glucose, protein, and LDH levels were measured. Masses were grouped by histopathologic diagnosis. Cyst fluid chemical levels and cyst fluid/serum ratios were compared among and between the groups. RESULTS: Fifty-eight adnexal masses were analyzed: 15 nonneoplastic (group 1), 23 benign neoplastic (group 2), and 20 malignant (group 3). There were no significant differences among the groups with regard to patient age, menopausal status, or cyst fluid specific gravity. Cyst size (cm2) was significantly different among the three groups (P < 0.01), with the largest mean size found in the cancer group. No significant differences in cyst chemistries or cyst fluid/serum ratios were found between groups 1 and 2. Comparing groups 1 and 3, all values were significantly different (P < 0.05), with the greatest level of significance attained by comparison of cyst fluid LDH levels (P < 0.001). Groups 2 and 3 statistically differed in cyst fluid levels and cyst fluid/serum ratios of both protein and LDH, with the highest levels of significance achieved by comparisons of cyst fluid levels and ratios of LDH (P = 0.001 and P < 0.001, respectively). The cyst fluid LDH level was found to be the best single chemistry for distinguishing noncancerous (groups 1 and 2) from cancerous (group 3) adnexal masses. A cyst fluid LDH level of >/=451 U/L imparted a 90% sensitivity and 71% specificity for detecting malignancy. CONCLUSIONS: Evaluation of adnexal cyst fluid LDH may help to distinguish benign from malignant adnexal masses. More cases are needed to adequately assess the predictive value and clinical utility of this approach.

Hyperspectral diagnostic imaging of the cervix: report on a new investigational device.

OBJECTIVE: To describe our experience with a noncontact in vivo fluorescence imaging device for the detection and localization of cervical intraepithelial neoplasia (CIN). MATERIALS AND METHODS: Sixty-two women with abnormal Papanicolaou (Pap) smears, and 4 women with normal Pap smears, were recruited to undergo fluorescence imaging of the cervix during colposcopy. After topically applying dilute acetic acid, the surface of the cervix was scanned with 365 nm ultraviolet light for about 12 sec. Colposcopy and biopsies of visualized lesions were then performed. The fluorescence emission curves generated by normal cervical tissue and various states of cervical pathology were inspected and assigned relative scores of 1-5 based on the height and slope of the curves at peak fluorescence emissions. A score of 1 indicated a curve with high magnitude and distinct peak, and a score of 5 described a curve of low magnitude and rounded/flattened peak. Scores of 2-4 represented curves with incremental changes of about 25% in the height of the curve between scores of 1 and 5. Biopsies were classified as high grade (HG, CIN 2/3), low grade (LG, HPV/CIN 1), or nondysplastic (ND). Among women with abnormal Pap smears, only those who had biopsies with concordant interpretations by two independent pathologists were included in the descriptive analysis. All of the patients with normal Pap smears were included. RESULTS: A total of 35 women were included in the analysis. Of 62 women with abnormal Pap smears who underwent fluorescence imaging and colposcopy, 31 met the inclusion criteria. Among these 31 women, Pap smears consisted of 6 atypical squamous cells of undetermined significance (ASCUS), 16 low-grade squamous intraepithelial lesions (LGSILs), and 9 high-grade squamous intraepithelial lesions (HGSILs). Of the 4 women with normal Pap smears, 1 had an abnormal colposcopy and a nondysplastic biopsy. Among all 35 women, 42 total biopsies were included, consisting of 11 HG, 25 LG, and 6 ND. Normal squamous tissue generated a score of 1, normal metaplastic tissue a score of 2 or 3, and normal columnar tissue of score of 5 in 35/35 (100%) women. Among the 11 HG lesions, 8 had a score of 4 and 2 had a score of 5. One case was uninterpretable due to a low signal-to-noise ratio. Among the 25 LG lesions, 15 had a score of 3, 6 had a score of 4 or 5, 2 had a score of 1, and 2 cases were uninterpretable. CONCLUSIONS: HG lesions generated spectra distinct from normal tissue in 8/10 (80%) evaluable cases, but LG lesions generated spectra indistinguishable from that of normal metaplastic tissue. Further modifications to this technique are needed before an objective, reproducible, and discriminatory scoring system can be developed. ▪.

Molecular characterization of adenocarcinoma of the cervix.

In an attempt to characterize the molecular alterations of cervical adenocarcinoma, we analyzed 32 paraffin-embedded specimens for the presence of K-ras mutations, p53 overexpression, p16 and Rb protein expression, and the presence of HPV 16 and 18 DNA. Overall 25/32 (78%) of the tumors displayed an abnormality in at least one of these analyses. K-ras mutations were detected by PCR amplification and RFLP analysis in 3 tumors, including 2 at codon 12 and 1 at codon 61. p53 overexpression determined by immunohistochemistry was demonstrated with > 80% of tumor nuclei staining in 4 cases, 10-15% of nuclei staining in 3 cases, and < 1% of nuclei staining in 5 cases. The pattern of staining was diffuse in 6 cases, focal in 1 case, and scattered in 5 cases. Analysis of p16 protein expression in 23 specimens revealed 1 tumor with abnormal staining, while Rb protein expression was determined to be normal in all 25 tumors tested. HPV DNA, detected by PCR with type-specific primers, was found in 16 tumors (50%), including 7 (22%) with HPV 16 and 9 (28%) with HPV 18. There was no correlation among these abnormalities except that the presence of HPV and strong p53 overexpression (> 80% tumor nuclei staining) were mutually exclusive events. Clinical correlation demonstrated that p53 overexpression involving the majority of tumor cell nuclei is characteristic of advanced stage disease, while HPV positivity and activated ras genes are associated with early stage disease.

Equal care ensures equal survival for African-American women with cervical carcinoma.

BACKGROUND: [corrected] It was the purpose of this study to investigate whether race is an independent prognostic factor in the survival of patients with cervical carcinoma in a health care system with minimal racial bias, and few barriers to access to care. METHODS: Records for patients with a diagnosis of invasive cervical carcinoma from 1988 to 1999 were obtained from the Automated Central Tumor Registry for the United States Military Health Care System. Clinical data including race, age at diagnosis, histology, grade, stage, socioeconomic status, treatment modality, and survival also were obtained. Survival analysis was performed with Kaplan-Meier survival curves. RESULTS: One thousand five hundred fifty-three patients were obtained for review. Sixty-five percent of patients were Caucasian, and 35% were minorities. Of the minorities, 29% were African Americans (AAs). Mean age of diagnosis was similar among AAs and Caucasians, 44 and 42 years, respectively. There was no statistically significant difference between the distribution of age, stage, grade, or histology between Caucasians and AAs. Forty-six percent of patients were treated with surgery and 56% with radiation therapy, with no difference in type of treatment between the Caucasian and AA groups. Five- and 10-year survival rates for Caucasians and AAs were 75%, and 76%, and 64% 65% (P = 0.59), respectively. CONCLUSIONS: In an equal access, unbiased, nonracial environment, race is not an independent predictor of survival for patients with cervical carcinoma. This study has shown, for the first time to the authors' knowledge, that when they receive equal treatment for cervical carcinoma, AA women's survival can approach that of their nonminority counterparts (75% at 10 years).