Distribution of Ca2+-activated K+ channel isoforms along the tonotopic gradient of the chicken's cochlea.

In some cochleae, the number and kinetic properties of Ca2+-activated K+ (KCa) channels partly determine the characteristic frequency of each hair cell and thus help establish a tonotopic map. In the chicken's basilar papilla, we found numerous isoforms of KCa channels generated by alternative mRNA splicing at seven sites in a single gene, cSlo. In situ polymerase chain reactions demonstrated cSlo expression in hair cells and revealed differential distributions of KCa channel isoforms along the basilar papilla. Analysis of single hair cells by the reverse transcription polymerase chain reaction confirmed the differential expression of channel variants. Heterologously expressed cSlo variants differed in their sensitivities to Ca2+ and voltage, suggesting that the distinct spatial distributions of cSlo variants help determine the tonotopic map.

Breast cancer in men: aspects of familial aggregation.

Familial aggregation of breast cancer in males was investigated in a population-based case-control study. Cases were ascertained from 10 Surveillance, Epidemiology, and End Results Program registries in the United States between 1983 and 1986. Controls were identified by random-digit dialing and from lists of Medicare recipients. The relative odds of developing breast cancer were similar in men with affected paternal and maternal relatives and in men with affected mothers and sisters. The risk increased with the number of affected relatives. The relative odds of developing breast cancer were greater in men with first-degree relatives who developed their mammary neoplasm before the age of 45 than in men with older first-degree affected relatives; the enhancement of risk in men with an affected sister was greater in those under age 60 than in older men. These results are similar to those observed by others in studies of breast cancer in women.

Investigations on the thermal behavior of omeprazole and other sulfoxides.

Thermoanalytical and chromatographic investigations were performed to elucidate the reason for the uncommon thermal behavior of omeprazole prepared according to a newly developed route of synthesis. Differential scanning calorimetry revealed that the position of the melting endotherm of omeprazole strongly depended on the heating rate. High heating rates (20-30 degrees C/min) led to endothermic peaks at high temperatures (comparable to literature data), while lower rates induced a shift of the signal to lower temperatures. In thermogravimetric experiments weight loss was observed which started about 20 degrees C lower at the heating rate of 1 degrees C/min in comparison with the rate of 20 degrees C/min. Thermomicroscopic investigations indicated a decomposition prior to melting at low (1 degrees C/min) but not at high heating rates (20 degrees C/min). Investigation of the violet melt by HPLC and TLC showed that omeprazole was decomposed quantitatively. Decomposition started at 135 degrees C and depended on the rate of heating. The results indicate that eutectic behavior with decomposition products leads to a melting point depression of omeprazole upon slow heating. Similar behavior was observed for the related sulfoxides lansoprazole and pantoprazole which showed the same onset temperature for decomposition as omeprazole in chromatographic investigations. The heating rate dependent melting behavior was, however, much less pronounced for pantoprazole which has a melting range only slightly above the onset temperature for decomposition. In contrast, a constant value for the melting temperature could not be achieved for lansoprazole, the substance with the highest melting range under investigation, even at high heating rates up to 30 degrees C/min. In conclusion, a very dynamic method and exactly standardized measurement conditions, particularly with regards to heating rate, (e.g., in DSC) have to be employed to enable reliable determination of a melting point of these decomposable substances.

Adrenal ganglioneuroma in a patient presenting with severe hypertension and diarrhea.

Ganglioneuromas (GNs) are neural crest cell-derived tumors and rarely occur in the adrenal gland. There are presently no markers that can reliably distinguish benign and malignant neuroendocrine tumors. Here we describe a 63-year-old woman who developed sudden chest pain and hypertension combined with increased stool frequency. An incidental adrenal mass 5 cm in size with a bright signal on T2-weighted magnetic resonance imaging was discovered. Biochemical evaluation and (131)I-metaiodobenzylguanidine (MIBG) scintigraphy were negative. Histopathological examination revealed a mature adrenal GN. Neuroblastoma, the immature form of a GN, is known for deletions on chromosomal locus 1p36, and adrenal tumors frequently show allele loss on 17p. To further elucidate the histo- and pathogenesis of adrenal GN, we performed loss of heterozygosity studies on chromosomal loci 1p34-36 and 17p13 (the p53 gene locus) after careful microdissection of tumor and normal tissue. We did not detect allelic losses at these loci with the informative polymorphic markers used, suggesting that these loci are not involved in tumorigenesis. In addition, immunohistochemical investigation of the GN was positive for vasoactive intestinal peptide, a hormone commonly expressed in ganglion cells. We suggest that in our patient with an adrenal GN, the combination of biochemical, scintigraphic, molecular, immunohistochemical, and histopathological findings are all consistent with the benign morphology of this tumor.

Reduced risk of ovarian cancer in women with a tubal ligation or hysterectomy. The World Health Organization Collaborative Study of Neoplasia and Steroid Contraceptives.

Possible relationships between tubal ligation and hysterectomy and epithelial ovarian cancer were assessed in data that were collected for a multinational hospital-based case-control study conducted between 1979 and 1988. Histologically confirmed incident cases (n = 393) were compared with controls (n = 2563) matched on age, hospital, and year of interview. A nonsignificant reduction in risk was observed for tubal ligation [odds ratio (OR), 0.72; 95% confidence interval (CI), 0.48-1.08] and hysterectomy (OR, 0.58; 95% CI, 0.26-1.27). There was no trend in risk with time since tubal ligation. The possible protective effect of tubal ligation was greatest in women of parity less than four. The apparent protective effect of tubal ligation was seen only for clear cell (OR, 0.32; 95% CI, 0.006-2.50) and endometrioid (OR, 0.20; 95% CI, 0.046-1.46) tumors, suggesting a hormonal mechanism for the observed associations.

High-dose and low-dose combined oral contraceptives: protection against epithelial ovarian cancer and the length of the protective effect. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives.

The relations between use of high-dose and low-dose combined oral contraceptives and epithelial ovarian cancer were compared in an international hospital-based case-control study. 393 cases from seven countries were compared with 2561 matched controls. The odds ratio (OR) was somewhat lower for women who used high-dose oestrogen oral contraceptives (OR = 0.68) than for women who used low-dose preparations (OR = 0.81) although the difference could have occurred by chance. After controlling for time since last use, risk was slightly lower for long-term users of high-dose preparations than for long-term users of low-dose pills. Both high-dose and low-dose oral contraceptives protect against ovarian cancer, but the degree of protection may be slightly weaker for the newer, low-dose products.

Contraceptive methods and induced abortions and their association with the risk of colon cancer in Shanghai, China.

267400 female textile workers in Shanghai, who were administered a questionnaire at enrollment into a randomised trial of breast self-examination between October 1989 and October 1991, were followed up until the middle of 2000. Based on the 655 women who developed colon cancer, rate ratios (RRs) were estimated and trends in risk assessed using Cox Proportional Hazards Models. Risk was increased in women who used oral contraceptives for over 3 years (RR=1.56, 95% Confidence Interval (CI) 1.01-2.40). A possible increase in risk was also observed in women who received progestational injections during pregnancy (RR=1.24, 95% CI 0.95-1.62), but not in relation to the use of injectable contraceptives. A possible reduction in risk was associated with tubal ligation (RR=0.86, 95% CI 0.71-1.03) and ever having had an induced abortion (RR=0.84, 95% CI 0.71-1.00). No trends in risk were observed in relation to the duration of hormonal contraceptive use or the number of induced abortions. Additional studies of the possible roles contraceptives may play in the aetiology of colon cancer in women at low risk of this disease are warranted.

Prolonged lactation and endometrial cancer. WHO Collaborative Study of Neoplasia and Steroid Contraceptives.

BACKGROUND: The risk of endometrial cancer is related to oestrogen levels, showing an increased risk with increasing endogenous or exogenous oestrogen stimulation and a reduced risk when oestrogen is opposed by progesterone. During breastfeeding, the reduction of endogenous oestrogen exposure is larger than that of progesterone, suggesting that breastfeeding may possibly reduce the risk of endometrial cancer. METHODS: The relationship between lactation and endometrial cancer was assessed in data from six countries, including four developing countries, that were collected for a multinational hospital-based case-control study conducted between 1979 and 1988. In all, 136 cases were compared with 933 controls matched on age, hospital, and year of interview. Standardized questionnaires, administered in the local language, ascertained information on the length of time breastfed, age started and stopped breastfeeding, reproductive and contraceptive practices, and other risk factors for endometrial cancer. Conditional logistic regression was used to control for the confounding effects of gravidity and age at menarche. RESULTS: Significant decreasing trends in risk were observed with increasing duration of lactation, and with months of breastfeeding per pregnancy. Risk was lowest in women who had most recently lactated, and the apparent protective effect declined with time since cessation of breastfeeding, so that there was no evidence for a protective effect after age 55 even in women who had breastfed for over 5 years. CONCLUSIONS: The long-term lactation that takes place in developing countries probably reduces the risk of endometrial cancer, but this effect may not persist into the ages at which this disease is most common.

Lactation and the risk of epithelial ovarian cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives.

The relationship between lactation and the development of epithelial ovarian cancer was assessed in data from seven countries that were collected for a multinational hospital-based case-control study conducted between 1979 and 1988. Three hundred and ninety-three cases of ovarian cancer were compared to 2565 controls matched on age, hospital, and year of interview. A non-significant reduction in risk with short-term lactation was observed but no further reduction in risk was seen with long-term lactation. The reduction in risk associated with months of lactation was not as great as the reduction with months of pregnancy, which may be a result of lactation being a less effective form of ovulation suppression than pregnancy. The short-term lactation that takes place in developed countries, may provide as great a reduction in risk as the long-term lactation practised in the developing countries included in this study.

Characteristics of women who use perineal powders.

OBJECTIVE: To examine demographic and behavioral factors related to perineal application of powders. METHODS: Controls from three case-control studies (N = 1206) were asked identical questions about the use of genital powders by direct perineal application. The relationship of perineal powder application with demographic factors, reproductive factors, body mass index (BMI), douching, and alcohol and tobacco use was assessed. Data were analyzed by multiple logistic regression. RESULTS: Women who douched (prevalence odds ratio [prevalence OR] 2.0, 95% confidence interval [CI] 1.0, 3.9), drank alcohol (prevalence OR 1.8, 95% CI 1.2, 2.8), smoked cigarettes (prevalence OR 1.3, 95% CI 1.0, 1.8), or were in the highest BMI quartile were more likely to engage in perineal use of powder (prevalence OR 1.6, 95% CI 1.1, 2.6). There appeared to be a close response relationship between the number of perineal applications of powder and BMI (P < .002). CONCLUSION: Body mass index might confound the relationship between perineal powder application and the development of ovarian cancer. Other factors, such as alcohol and tobacco use and douching, are related to perineal use of powder and may represent similar behavioral characteristics.

Intrauterine devices and endometrial cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives.

The relationship between intrauterine device (IUD) use and the development of endometrial cancer was assessed in data from seven countries that were collected between 1979 and 1988 for a multinational hospital-based case-control study. Two hundred twenty-six cases of endometrial cancer were compared with 1,529 controls matched for age, hospital, and year of interview. No significant association between use of an IUD and risk of endometrial cancer was observed (OR = 0.74, 95% CI = 0.4-1.33). There were no trends in risk with respect to duration of use, time since first use, or ages at first or last use. No cases had used a copper IUD (OR = 0, 95% CI = 0-1.71). Although women over age 55 who had used an IUD were at significantly increased risk, this unexpected finding is based on small numbers of users and requires independent confirmation. These results, along with those from other studies, provide reassurance that risk of endometrial cancer is unlikely to be increased by use of an IUD.

Vimentin is a novel AKT1 target mediating motility and invasion.

The PI3K/AKT signaling pathway is aberrant in a wide variety of cancers. Downstream effectors of AKT are involved in survival, growth and metabolic-related pathways. In contrast, contradictory data relating to AKT effects on cell motility and invasion, crucial prometastatic processes, have been reported pointing to a potential cell type and isoform type-specific AKT-driven function. By implication, study of AKT signaling should optimally be conducted in an appropriate intracellular environment. Prognosis in soft-tissue sarcoma (STS), the aggressive malignancies of mesenchymal origin, is poor, reflecting our modest ability to control metastasis, an effort hampered by lack of insight into molecular mechanisms driving STS progression and dissemination. We examined the impact of the cancer progression-relevant AKT pathway on the mesenchymal tumor cell internal milieu. We demonstrate that AKT1 activation induces STS cell motility and invasiveness at least partially through a novel interaction with the intermediate filament vimentin (Vim). The binding of AKT (tail region) to Vim (head region) results in Vim Ser39 phosphorylation enhancing the ability of Vim to induce motility and invasion while protecting Vim from caspase-induced proteolysis. Moreover, vimentin phosphorylation was shown to enhance tumor and metastasis growth in vivo. Insights into this mesenchymal-related molecular mechanism may facilitate the development of critically lacking therapeutic options for these devastating malignancies.

Mycosis fungoides associated with B-cell malignancies.

BACKGROUND: The coexistence of mycosis fungoides, a peripheral T-cell lymphoma, and B-cell malignancies or Hodgkin's lymphoma in the same patient is unusual. Most descriptions are isolated case reports and case series are strikingly sparse. OBJECTIVES: To detect cases of mycosis fungoides associated with B-cell malignancies or Hodgkin's lymphoma and to analyse the characteristics of and the interplay between the lymphoproliferative neoplasms. METHODS: Patients with mycosis fungoides who had B-cell malignancies or Hodgkin's lymphoma were selected from among 398 patients either treated or followed up in two tertiary medical centres during a 7-year period. RESULTS: Eleven patients with mycosis fungoides and B-cell malignancy were detected (seven of non-Hodgkin's lymphoma, three of chronic lymphocytic leukaemia, one of multiple myeloma). No case of Hodgkin's lymphoma was found. In seven patients the mycosis fungoides preceded the B-cell malignancy whereas in four it was the B-cell malignancy which occurred first. The time elapsed between onset of the two malignancies ranged from 4 to 22 years (average: 12 years). Patients who had mycosis fungoides as the first neoplasm presented with earlier stages of mycosis fungoides (four of seven: IA, three of seven: IB) than those who had mycosis fungoides as their second neoplasm (of four, one: IB, one: folliculotropic, two: IIB). Among the four patients in whom the appearance of mycosis fungoides followed the B-cell malignancy, three had been treated with multiagent chemotherapy. Two patients who presented with early-stage mycosis fungoides (IA) as the first lymphoma developed mycosis fungoides tumours after becoming immunosuppressed. In two patients infiltrates composed of both malignant T- and B-cell populations were found in a single biopsy. One showed two distinct populations of the malignant cells in the skin tumour, thus constituting a classical composite lymphoma of mycosis fungoides and chronic lymphocytic leukaemia, while in the other patient the two malignant populations of marginal B-cell lymphoma and mycosis fungoides (as evidenced by both phenotypic and genotypic findings) were intermingled. CONCLUSIONS: This case series indicates that while the coexistence of Hodgkin's lymphoma and mycosis fungoides is extremely rare, the association of mycosis fungoides and B-cell malignancies is not as rare as reflected in the literature, with non-Hodgkin's lymphoma constituting the most common associated B-cell malignancy. In this series as well as in the cases reported in the literature mycosis fungoides usually preceded the development of B-cell malignancies, which may be in accordance with previous reports of an increased risk of developing a second haematological neoplasm. The importance of a competent immune system for patients with mycosis fungoides is well demonstrated in these cases. It is suggested that for greater precision the criteria for diagnosis of composite lymphoma of the skin should include both phenotypic and genotypic features.

Hormonal content of combined oral contraceptives in relation to the reduced risk of endometrial carcinoma. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives.

The relationship between the strength of the estrogenic and progestational components of combined oral contraceptives and risk of endometrial carcinoma was examined in a multinational hospital-based case-control study comparing 220 cases from 7 countries with 1,537 age- and hospital-matched controls. Oral contraceptives were classified according to their relative content of estrogen and progestin. The risk was not altered in women who used preparations containing high-dose estrogen/low-dose progestin compounds [odds ratio (OR) = 1.10, 95% CI = 0.13-9.96]. In contrast, the risk among users of low-dose estrogen/high-dose progestin oral contraceptives was greatly decreased (OR = 0, 95% CI = 0-1.08). Risks observed for users of high-dose estrogen/high-dose progestin (OR = 0.15, 95% CI = 0.045-0.50) and low-dose estrogen/low-dose progesterone (OR = 0.59, 95% CI = 0.26-1.30) preparations were intermediate between those for users of the 2 other types of preparation. A significantly lower risk was observed for high-dose progestin users than for low-dose users [ratio of odds ratios (ROR) = 0.21, 95% CI = 0.05-0.84]. Although the numbers are small, findings from this study suggest that combined oral contraceptives with varying strengths of estrogen and progestin have different effects on the risk of endometrial carcinoma.

Liver cancer in Asian migrants to the United States and their descendants.

The incidence of primary liver cancer in Chinese, Japanese, and Filipino migrants to the United States and their descendants is compared with that of United States-born Whites. Incident liver cancer cases were ascertained between 1973 and 1986 from population-based cancer registries serving the San Francisco/Oakland (CA) metropolitan area, 13 counties of western Washington, and Hawaii. The population of these three areas, with regard to age, race, and country of birth, was estimated from a special tabulation of the 1980 US census. Rates of primary liver cancer were higher for men born in Asia than Asian men born in the US, who, in turn, had higher rates than did US Whites (respective annual rates per 100,000: Chinese, 26.5 and 9.8; Japanese, 16.5 and 6.6; Filipinos, 11.4 and 6.5; US Whites, 3.4). Among Asian American women, the trends were not as consistent (respective annual rates per 100,000: Chinese, 2.2 and 3.7; Japanese, 1.9 and 1.4; Filipino, 2.6 and 0; US Whites, 1.1). In general, liver cancer incidence among Asian Americans was lower than among residents of Asia. These findings are compatible with substantial variation among Asians in the prevalence of one or more etiologic factors for liver cancer, such as hepatitis-B infection and aflatoxin consumption, in relation to residence and place of birth.

Sexual factors and the risk of prostate cancer.

A population-based case-control study of prostate cancer was performed in King County, Washington, in White men and Black men aged 40-64 years, between 1993 and 1996. Incident prostate cancer cases (n = 753) were identified from the Seattle-Puget Sound Surveillance, Epidemiology, and End Results (SEER) cancer registry. Controls (n = 703) were identified through random digit dialing and were frequency matched to cases on age. Sexual behavior, medical history, and other potential prostate cancer risk factors were ascertained through an in-person interview. There was no relation between sexual orientation and prostate cancer, although the number of men who had sex with men was small. Risk estimates increased directly with the lifetime number of female sexual partners (trend p < 0.001) but not with male partners (trend p = 0.62). Risk also increased with decreasing age at first intercourse, but this effect disappeared after adjusting for the number of female partners. Prior infection with gonorrhea was positively associated with risk (odds ratio = 1.50; 95% confidence interval: 1.0, 2.2), but no effect was seen among men with other sexually transmitted diseases. No relation between lifetime frequency of sexual intercourse and risk of prostate cancer was apparent. These findings are consistent with previous studies that support an infectious etiology for prostate cancer.

Incidence of malignant fallopian tube tumors.

Incidence rates were examined for epithelial malignant fallopian tube neoplasms diagnosed between 1973 and 1984 and reported to nine population-based cancer registries in the United States. The average annual incidence was 3.6 per million women per year and there was no evidence of a change in the rate during the study period. Age-specific incidence followed a pattern similar to that observed for ovarian and endometrial neoplasms, rising rapidly during the reproductive years and flattening out thereafter. The incidence rate varied only slightly by race, with whites having a higher rate than blacks. Considerable variation in incidence was observed among the registries. While this could have been due to true regional differences in incidence, we cannot rule out the possibility that misclassification of fallopian tube tumors as ovarian tumors was responsible. Further investigations into the etiology of fallopian tube neoplasms should focus on the role of reproductive factors that have previously been reported as risk factors for ovarian and endometrial neoplasms.

Primary lymphoma of bone--a retrospective study. Experience at the Northern Israel Oncology Center (1979-2000).

OBJECTIVE: This retrospective study describes our experience with the diagnosis, treatment, results and long-term follow-up of primary bone lymphoma (PBL). PATIENTS AND METHODS: Nineteen patients diagnosed with PBL were reviewed. Seven patients presented with stage I(E) disease, four with stage II(E) (regional lymphadenopathy), and eight with stage IV disease (disseminated bone involvement). Only one stage IV patient exhibited 'B' symptoms. The majority (72%) demonstrated diffuse, large cell, B-type lymphoma. All patients were treated with adriamycin-based chemotherapy and consolidation radiotherapy to the primary site (8 patients: early PBL) or the most bulky area (3 patients: stage IV PBL). RESULTS: Ten stage I(E)/II(E) patients are alive with no evidence of disease (NED) and only one died due to metastatic secondary lung cancer while with NED from his PBL. Eight stage IV patients are alive with NED. Median follow-up for all living patients: 77 months. Side effects were mild and did not necessitate delay in treatment. CONCLUSIONS: Our departmental policy of treating PBL patients with an anthracycline-based regimen and involved field radiotherapy proved to be successful in achieving excellent long-term, disease-free survival. Phase III randomized, controlled, clinical trials will determine the true role of consolidation radiotherapy in PBL, when considering severe late side effects, including radiation-induced bone tumors.

Antigenic stimulation and the occurrence of chronic lymphocytic leukemia.

Data from a population-based case-control study of chronic lymphocytic leukemia were analyzed to assess the possible etiologic role of chronic antigenic stimulation. The study, conducted in four geographic areas of the United States (the metropolitan areas surrounding Seattle, Washington, Salt Lake City, Utah, Detroit, Michigan, and Atlanta, Georgia) sought to identify all incident cases (n = 430) among residents diagnosed between July 1, 1977 and December 31, 1981. The responses of these cases to questions about possible sources of antigenic stimulation were compared with the responses of controls selected from the populations of these areas. Little difference between cases and controls was present for a history of most forms of viral and bacterial infection and for a history of allergies or allergy treatment. However, a relation was observed with antecedent syphilis infection (odds ratio (OR) = 5.0, 95% confidence interval (Cl) 2.0-12.9). Associations of smaller magnitude were observed with a history of tuberculosis (OR = 1.9, 95% Cl 1.0-3.7) and of urinary tract infection (OR = 1.4, 95% Cl 1.1-1.9). Overall, however, the authors found little evidence of a relation between chronic antigenic stimulation and the occurrence of chronic lymphocytic leukemia. Nonetheless, because the measure of prior antigenic stimulation was restricted to that obtained through interviews and undoubtedly was an insensitive one, these negative results should not be interpreted as ruling out antigenic stimulation as a possible cause of some cases of chronic lymphocytic leukemia.