DHEA inhibits acute microglia-mediated inflammation through activation of the TrkA-Akt1/2-CREB-Jmjd3 pathway.

Dehydroepiandrosterone (DHEA) is the most abundant circulating steroid hormone in humans, produced by the adrenals, the gonads and the brain. DHEA was previously shown to bind to the nerve growth factor receptor, tropomyosin-related kinase A (TrkA), and to thereby exert neuroprotective effects. Here we show that DHEA reduces microglia-mediated inflammation in an acute lipopolysaccharide-induced neuro-inflammation model in mice and in cultured microglia in vitro. DHEA regulates microglial inflammatory responses through phosphorylation of TrkA and subsequent activation of a pathway involving Akt1/Akt2 and cAMP response element-binding protein. The latter induces the expression of the histone 3 lysine 27 (H3K27) demethylase Jumonji d3 (Jmjd3), which thereby controls the expression of inflammation-related genes and microglial polarization. Together, our data indicate that DHEA-activated TrkA signaling is a potent regulator of microglia-mediated inflammation in a Jmjd3-dependent manner, thereby providing the platform for potential future therapeutic interventions in neuro-inflammatory pathologies.

Costs of treatment for elderly women with advanced ovarian cancer in a Medicare population.

OBJECTIVE: To analyze the cost of treating women with advanced stage epithelial ovarian cancer (EOC) undergoing primary debulking surgery (PDS) or neo-adjuvant chemotherapy (NACT). METHODS: The Surveillance, Epidemiology, and End Results (SEER) - Medicare database (1992 to 2009) was used to evaluate the 7-month cost of care following PDS and NACT for advanced EOC. Multivariate analyses were used to evaluate differences between women treated by PDS and NACT on cost and survival. RESULTS: Of the 4506 women eligible for analysis, 82.4% underwent PDS and 17.6% received NACT. Eighty-five percent with stage IIIC and 78.5% with stage IV EOC underwent PDS (p<0.0001). No significant difference in the median cost of care between PDS and NACT existed in women with stage IIIC EOC ($59,801 vs. $59,905). There was a 12% increase in adjusted cost of care for stage IV patients ($63,131 vs. $55,302) who received PDS (p<0.0001). Increasing Charlson score was associated with an increase in 7-month cost of care in both stages. NACT was associated with a decreased 5-year overall survival in women with stage IIIC EOC (HR=1.27, 95% CI: 1.10-1.47) and stage IV EOC (HR=1.19, 95% CI: 1.03-1.37) compared to PDS. CONCLUSION: NACT and PDS are comparable in cost for women with stage IIIC EOC, and PDS is minimally more expensive for women with stage IV EOC. PDS was associated with an increase 5-year overall survival. Future investigations should include cost-effectiveness analyses where additional measures such as quality adjusted life years and propensity scored survival are included.

VEGF directly suppresses activation of T cells from ascites secondary to ovarian cancer via VEGF receptor type 2.

BACKGROUND: Vascular endothelial growth factor action in tumour angiogenesis is well characterised; nevertheless, it functions as a key element in the promotion of the immune system's evasion by tumours. We sought to investigate the possible direct effect of VEGF on T-cell activation and through which type of VEGF receptor it exerts this effect on cells isolated from ovarian cancer patients' ascites. METHODS: T cells isolated from the ascites of ovarian cancer patients were cultured with anti-CD3 and IL-2, with or without VEGF for 14 days and the number of viable T cells was counted. Cytotoxic activity of cultured T cells and expression of VEGF receptor-2 (VEGFR-2), was assayed. RESULTS: The addition of VEGF in cultures significantly reduced the number and proliferation rate of T cells in a dose-dependent manner and CD3(+) T cells expressed VEGFR-2 on their surface upon activation. Experiments with specific anti-VEGFR-2 antibodies revealed that the direct suppressive effect of VEGF on T-cell proliferation is mediated by VEGFR-2. We also showed that VEGF significantly reduced the cytotoxic activity of T cells. CONCLUSION: Our study showed that ascites-derived T cells secrete VEGF and express VEGFR-2 upon activation. Vascular endothelial growth factor directly suppresses T-cell activation via VEGFR-2.

Torsion of the left fallopian tube without ovarian involvement in a 47-year-old woman: A case report.

Isolated torsion of the fallopian tube is an unusual finding in a female patient presenting with acute lower abdominal pain. Left tubal torsion is considered to be a particularly rare condition. The patient presented with lower abdominal pain due to torsion of the left hydrosalpinx with no ovarian involvement. The patient underwent laparotomy and a left salpingectomy. The follow-up was uneventful.

Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium.

The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.

Hypertension, diuretics and breast cancer risk.

It is unclear whether hypertension and antihypertensive medication use are associated with breast cancer. In order to examine these associations, we conducted a case-control study among women aged 50-75 years. Breast cancer cases were ascertained via a population-based cancer registry (n=523) and controls were ascertained via random-digit-dialing (n=131). Participants completed a self-administered questionnaire which queried history of hypertension, antihypertensive medication use and risk factors. Unconditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (CI), adjusted for age, body mass index (BMI), diabetes, smoking, alcohol use, menopausal status, family history of breast or ovarian cancer, age at first full-term pregnancy and education. History of treated hypertension was associated with significant increased risk of breast cancer (OR, 1.77; 95% CI, 1.04-3.03) and this association appeared only in women with BMI > or =25 kg/m(2) (OR, 2.30; 95% CI, 1.12-4.71). Diuretic use was also associated with elevated breast cancer risk (OR, 1.79; 95% CI, 1.07-3.01). The risk associated with diuretic use increased with duration of use (P for trend, <0.01). Use of other blood pressure medications was not found to be associated with breast cancer risk. These results support a positive association between treated hypertension, diuretic use and breast cancer risk among women aged 50-75 years.

Characterization of hereditary nonpolyposis colorectal cancer families from a population-based series of cases.

BACKGROUND: The incidence of hereditary nonpolyposis colon cancer (HNPCC) in the general population is not well defined because of the lack of large population-based studies. We characterized the incidence of HNPCC in a large, population-based cohort of colorectal cancer probands and analyzed the location of colorectal tumors. METHODS: Of the participating 1134 probands from three counties in Southern California, 907 had a negative family history of colorectal cancer and 227 had a positive family history of colorectal cancer. In addition, 11 referral case subjects with HNPCC were used to study mutation frequencies in two mismatch repair genes (MSH2 and MLH1) and microsatellite instability. All statistical tests were two-sided. RESULTS: Among the probands diagnosed in Orange County during 1994 (population-based sample, all ages), five were consistent with the Amsterdam criteria for HNPCC (0.9%; 95% confidence interval [CI] = 0. 3%-2.1%). Among probands diagnosed at less than 65 years of age-from the wider three-county area and a longer time span-16 (2.1%; 95% CI = 1.2%-3.4%) had a clinical history consistent with the Amsterdam criteria for HNPCC. Five (approximately 45%) of 11 of the referral HNPCC case subjects had a mutation in MSH2 or MLH1 and also showed microsatellite instability. The family members of case subjects with mutations tended to show an earlier age at diagnosis of HNPCC and more multiple primary cancers than those of case subjects without detectable mutations. Many of the known characteristics of HNPCC, including the presence of ureteral and endometrial cancers, were seen in both sets of families. The previously reported proximal location of colorectal tumors in HNPCC kindreds was not seen in the population-based dataset but was similar to the location reported in the referral cases. CONCLUSIONS: On the basis of our data, we believe that the prevalence of HNPCC in the general population is likely to be closer to 1% than to 5%. Furthermore, our study suggests that some previously reported characteristics of HNPCC, such as the proximal location of tumors in the syndrome, may not always hold true in a population-based sample.

Germ-line msh6 mutations in colorectal cancer families.

Hereditary nonpolyposis colorectal carcinoma (HNPCC) is due primarily to inherited mutations in two mismatch repair genes, MSH2 and MLH1, whereas germ-line mutations in other mismatch repair genes are rare. We examined the frequency of germ-line msh6 mutations in a population-based series of 140 colorectal cancer patients, including 45 sporadic cases, 91 familial non-HNPCC cases, and 4 HNPCC cases. Among the 91 population-based familial non-HNPCC cases, germ-line msh6 mutations were found in 6 patients (7.1% of probands analyzed; median age at diagnosis, 61 years). These mutations included a splice site mutation, a frameshift mutation, two missense mutations that were demonstrated to be loss of function mutations, and two missense mutations for which functional studies were not possible. In contrast, germ-line msh6 mutations were not found in any of the 45 sporadic cases and the 4 HNPCC cases in the population-based series or in the second series of 58 clinic-based, primarily HNPCC families. Our data suggest that germ-line msh6 mutations predispose individuals to primarily late-onset, familial colorectal carcinomas that do not fulfill classic criteria for HNPCC.

MEK1 mediates a positive feedback on Raf-1 activity independently of Ras and Src.

Growth factor stimulated receptor tyrosine kinases activate a protein kinase cascade via the serine/threonine protein kinase Raf-1. Direct upstream activators of Raf-1 are Ras and Src. This study shows that MEK1, the direct downstream effector of Raf-1, can also stimulate Raf-1 kinase activity by a positive feedback loop. Activated MEK1 mediates hyperphosphorylation of the amino terminal regulatory as well as of the carboxy terminal catalytic domain of Raf-1. The hyperphosphorylation of Raf-1 correlates with a change in the tryptic phosphopeptide pattern only at the carboxy terminus of Raf-1 and an increase in Raf-1 kinase activity. MEK1-mediated Raf-1 activation is inhibited by co-expression of the MAPK specific phosphatase MKP-1 indicating that the MEK1 effect is exerted through a MAPK dependent pathway. Stimulation of Raf-1 activity by MEK1 is independent of Ras, Src and tyrosine phosphorylation of Raf-1. MEK1 can however synergize with Ras and leads to further increase of the Raf-1 kinase activity. Thus, MEK1 can mediate activation of Raf-1 by a novel positive feedback mechanism which allows fast signal amplification and could prolong activation of Raf-1.

Low survival rate after cardiopulmonary resuscitation in a county hospital.

BACKGROUND: The standard of practice in hospitals in the United States is to perform cardiopulmonary resuscitation on all patients who suffer a cardiac arrest unless a specific order has been written to the contrary. In recent decades, however, data showing a low rate of survival to discharge under certain conditions have accumulated, leading some to question this policy. The objective of this study was to examine variables predictive of patient survival following cardiopulmonary resuscitation using standardized methods of measuring severity of illness. METHODS: All patients were identified who underwent cardiopulmonary resuscitation on the medicine service at Los Angeles County (California) Hospital from August 15, 1990, to February 15, 1991. Severity of illness was evaluated by examining diagnosis, Acute Physiology and Chronic Health Evaluation II score, and organ system failure. Cases were followed up prospectively until death or hospital discharge, and data concerning post-arrest mental status, utilization of resources, and disposition were gathered. RESULTS: Of the 131 patients identified, 22 patients (16.8%) survived for 24 hours but died before discharge; only four patients (3.1%) survived to discharge. CONCLUSIONS: This study suggests that in some settings (eg, institutions that are for sick patients under conditions where monitoring is limited because of scarcity of resources), survival after full cardiopulmonary arrest may be even lower than previously documented.

Cancer risk estimates for family members of a population-based family registry for breast and ovarian cancer.

Population-based breast and ovarian cancer family registries can facilitate studies to evaluate genetic and environmental factors in the etiology of these malignancies. The purpose of this study is to describe what is, as far as we know, the first population-based breast and ovarian cancer family registry and to estimate breast and ovarian cancer risk in relatives of breast and ovarian cancer probands. Population-based consecutive incident cases of breast and ovarian cancer were invited to participate in the University of California, Irvine breast and ovarian family registry. In this study, we report data on 1567 breast cancer and 328 ovarian cancer probands. The operational components of this family registry include enrollment of probands, family history interviewing, confidentiality, pathology, verification and review, biospecimen bank, statistical/genetic analysis, and special studies on positional cloning of known genes. All of the components are tracked through the University of California, Irvine Genetic Research Information System. In non-Hispanic-white breast cancer probands, relative risk (RR) of breast cancer in mothers and sisters is significantly elevated [RR = 1.7 and 95% confidence interval (CI) = 1.4-2.0 and RR = 2.8 and 95% CI = 2.3-3.3, respectively]. In families of ovarian cancer probands, mothers are at increased risk of ovarian cancer (RR = 4.6; 95% CI, 2.1-8.7). RR of breast cancer in mothers of Hispanic breast cancer probands is significantly elevated (RR = 4.9; 95% CI, 2.6-8.5). No elevation of breast or ovarian cancer risk was observed among relatives of Asian probands. In general, there is a decrease in RR among mothers and sisters with increase in age of onset of probands. In second-degree relatives and first cousins, the breast cancer hazards ratios increase with increase in the number of affected first-degree relatives and decrease with increase in age at onset of the proband.

Characteristics of BRCA1 mutations in a population-based case series of breast and ovarian cancer.

Breast and ovarian cancers account for approximately 210000 newly diagnosed cases per year. More than half a million American women are estimated to be carriers of a breast cancer susceptibility gene. The purpose of this study was to assess the association of characteristics such as, age at diagnosis, race/ethnicity and family history of cancer with inherited BRCA1 mutations in a population-based sample of breast and ovarian cancer cases. No selection was made by race, age at diagnosis or positive family history of breast or ovarian cancer. The population under study was all breast cancer cases diagnosed in Orange County, CA, during the 1-year period beginning 1 March 1994 and all ovarian cancer cases diagnosed in Orange County during the 2-year period beginning 1 March 1994. This report focuses on the first consecutively ascertained 802 participating probands enrolled in the study, of which 9 were male breast cancer probands, 673 were female breast cancer probands and 120 were ovarian cancer probands. We observed 11 BRCA1 mutations or 1.6% (95% CI: 0.8-2.9) among the 673 female breast cancer probands and 4 BRCA1 mutations or 3.3% (95% CI: 0.8-8. 3) among the 120 ovarian cancer probands. No BRCA1 mutations were identified among the 98 non-white breast and ovarian cancer probands. The prevalence of BRCA1 mutations in non-Hispanic-white breast cancer cases below the age of 50 years was 2%. Positive family history of breast or ovarian cancers was significantly associated with BRCA1 mutation status among breast cancer probands. Similarly, positive family history of breast or ovarian cancer was significantly associated with BRCA1 mutation status among the ovarian cancer probands. In summary, we present results on the prevalence of BRCA1 mutations in a significantly larger sample of population-based breast and ovarian cancer cases than previously reported. The results indicate that, using a conservative approach to targeted genotyping of BRCA1, the frequency of mutations was consistent with those reported using similar methods of population-based case ascertainment.

Intent-to-treat analysis of stage Ib and IIa cervical cancer in the United States: radiotherapy or surgery 1988-1995.

OBJECTIVE: To estimate the patterns of care and outcome of women with early cervical cancer in the United States based on surgical or radiation intent-to-treat principles. METHODS: The Surveillance, Epidemiology, and End Results 1995 public-use file was the data source. Subjects between the ages of 15 and 80 years at diagnosis who were treated for stage Ib or IIa cervical cancer were identified. The 1039 women who comprised the study group were stratified according to age at diagnosis (40 years or less, older than 40 years), primary treatment intent (surgery, radiotherapy), tumor size (4 cm or less, over 4 cm), registry site, and ethnicity. Survival analyses included 784 women who had at least 2 years of follow-up. RESULTS: There were 276 cancers (26.5%) over 4 cm, and 586 (56%) women were older than 40 years at diagnosis. There were 741 (71%) subjects in the surgical intent-to-treat group, and the remainder (298) were in the radiation intent-to-treat group. Kaplan-Meier analysis indicated a 5-year survival advantage for women with tumors 4 cm or less who were in the surgical intent-to-treat group compared with the radiation intent-to-treat group (86% and 71%, P <.001). Treatment group was not prognostic for cervical cancers over 4 cm (surgical intent-to-treat compared with radiation intent-to-treat; 72% and 68% survival, respectively). Multivariable analysis confirmed a survival advantage for women with surgical intent-to-treat and tumors of 4 cm or less. CONCLUSION: In the United States there is a survival advantage for surgical intent-to-treat compared with radiation intent-to-treat for women with tumors 4 cm or less, independent of ethnicity, adjuvant therapy, or age.

Repair of retinal detachment caused by cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome.

Twenty-two eyes of 19 patients with the acquired immunodeficiency syndrome who had pars plana vitrectomy and silicone-oil injection after retinal detachment caused by cytomegalovirus retinitis were studied. All patients but one were monitored until time of death. The postoperative survival time and the factors that predicted anatomic success (retinal attachment) and functional success (visual acuity) were analyzed. No intraoperative complications were encountered. The mean survival time after surgery was four months. Of all of the preoperative and intraoperative factors studied, only the duration of cytomegalovirus retinitis was predictive of survival (P less than .03). The anatomic success rate was 89.5% (17 of 19 patients). None of the factors showed a trend or statistical significance in relation to anatomic success. Fifteen of 19 patients (79%) had lost at least two lines of Snellen visual acuity at time of death. Vision declined in a bimodal pattern (within the first postoperative month and after four months postoperatively). The optic nerve was pink and well perfused preoperatively in 16 of 19 patients (81.8%), but optic-nerve atrophy was observed postoperatively in 18 of 19 patients (95.5%). There was a trend for functional success to be influenced by increased intraocular pressure and optic-nerve atrophy, although our sample size was too small for statistical significance.

Breast cancer survival and hormone replacement therapy: a cohort analysis.

Controversy exists regarding the safety of hormone replacement therapy (HRT) after a diagnosis of breast cancer. The objective of this study is to perform a matched cohort analysis to evaluate the impact of HRT on mortality in breast cancer survivors. Patients with breast cancer who received HRT after diagnosis of breast cancer were identified. Control subjects were identified from the regional cancer registry. Matching criteria included age at diagnosis, stage of breast cancer, and year of diagnosis. Controls were selected only if they were alive at the time of initiation of HRT of the matched case. Only subjects not included in a previously reported matched analysis were selected. One hundred twenty-five cases were matched with 362 controls. Ninety-eight percent (123/125) of the cases received systemic estrogen; 90/125 (72%) also received a progestational agent. The median interval between diagnosis of breast cancer and initiation of HRT was 46 months (range 0-401 months). The median duration of HRT was 22 months (range 1-357 months). The risk of death was lower among the HRT survivors; odds ratio 0.28 (95% confidence interval 0.11-0.71). This analysis does not suggest that HRT after the treatment of breast cancer is associated with an adverse outcome.

Evaluation of the effectiveness of the Minerva cervicothoracic orthosis.

STUDY DESIGN: This study evaluated a lightweight Minerva cervicothoracic orthosis with an occipital flare and forehead strap. OBJECTIVE: The orthosis was evaluated for its ability to immobilize the cervical spine in normal healthy volunteers. SUMMARY OF BACKGROUND DATA: Previous studies have been performed to evaluate cervical orthoses. Exception for the halo brace, none have controlled the upper cervical spine very well. The brace tested in the present report incorporates an occipital flare and forehead strap to better control the upper cervical spine. METHODS: Sixteen healthy male volunteers were evaluated in and out of the orthosis in three planes of motion. Maximal active cervical flexion, extension, and lateral bending were recorded and measured radiographically. Rotation was measured from overhead photographs. RESULTS: In a comparison of the present results with those of similar previous studies, improvement in control of flexion/extension of the upper cervical spine and in control of rotation was found. The occiput to C1 level, however, remained poorly controlled. CONCLUSION: This orthosis provides good control of the cervical spine below C1.

Urinary progesterone and pregnanediol. Use for monitoring progesterone treatment.

OBJECTIVE: To compare progesterone (P) and pregnanediol glucuronide (PDG) levels in urine with respect to their potential use for monitoring luteal activity and P treatment. STUDY DESIGN: Two different experiments were carried out. In the first experiment, each of seven normal, ovulatory women collected first morning urines daily throughout an entire menstrual cycle. The day of ovulation was determined by transvaginal ultrasound scanning. P, PDG, estrone glucuronide, luteinizing hormone and creatinine were measured in each urine specimen. In the second experiment, each of three normal, ovulatory women was given a single oral dose of 200 mg of micronized P and, 2 days later, a single intramuscular injection of 25 mg of P during days 2-5 of the cycle. Blood and urine were collected prior to each treatment and 1, 4, 8, 12 and 24 hours after treatment. P was measured in both serum and urine; PDG was quantified only in urine. RESULTS: The mean initial rises and peak days, as well as the patterns of urinary excretion of P and PDG during the menstrual cycles, were similar; however, the variability of PDG was much greater. Concentrations of PDG were 1,000-4,000 times greater than those of P. A significant correlation was observed between urinary P and PDG. Following either intramuscular or oral P treatment, serum P levels rose rapidly and reached peak levels (7.0-11.8 ng/mL) by one hour. In contrast, both urinary P and PDG peaked considerably later (4-12 hours). Twenty-four hours after intramuscular treatment, serum and urinary P and urinary PDG were still elevated. Following oral treatment the levels of these compounds decreased after peaking and were 10- to 20- fold lower at 24 hours. Also, after oral P treatment, urinary PDG levels were considerably higher and more variable as compared to urinary P levels. CONCLUSION: Urinary P appears to be as good a clinical marker of luteal activity and therapeutic P administration as PDG and may be measured in place of this metabolite. There appears to be greater variability in urinary PDG as compared to urinary P when P is administered.

Epidemiology of nasopharyngeal carcinoma in the United States: improved survival of Chinese patients within the keratinizing squamous cell carcinoma histology.

BACKGROUND: This study examined potential survival differences among nasopharyngeal carcinoma (NPC) patients from various ethnicities in the United States. PATIENTS AND METHODS: A total of 2436 newly diagnosed NPC patients from 1992 to 2002 were analyzed from the population-based Surveillance, Epidemiology, and End Results (SEER) program. Five-year survival rate estimates and Kaplan-Meier survival curves were calculated. Cox proportional hazard ratios (HRs) were used to identify independent prognostic factors for survival. RESULTS: By multivariate analyses, early age of diagnosis, localized stage at presentation (versus distant, HR=0.35; P<0.0001), radiation therapy (versus none; HR=0.48; P<0.0001), undifferentiated non-keratinizing carcinoma (versus keratinizing squamous cell carcinoma; HR=0.67; P<0.0001), and Chinese ethnicity (versus Caucasian; HR=0.78; P=0.0010) were associated with improved survival. Within keratinizing squamous cell carcinoma histology, the survival advantage of Chinese patients remained even after adjustment for other prognostic factors. CONCLUSIONS: The significant survival advantage of Chinese NPC patients within the keratinizing squamous cell carcinoma histology contributed largely to Chinese ethnicity being an independent and favorable prognostic factor for survival in NPC.

Long-term survival differences for bronchiolo-alveolar carcinoma patients with ipsilateral intrapulmonary metastasis at diagnosis.

BACKGROUND: It has been suggested that the current staging system does not accurately reflect survival outcomes for advanced bronchiolo-alveolar carcinoma (BAC) patients. METHODS: We conducted a case-only analysis of US Surveillance, Epidemiology, and End Results (SEER) data (1998-2002). Overall survival (OS) and lung cancer-specific survival (LCSS) univariate analyses were conducted using the Kaplan-Meier method. Multivariate survival analyses were performed using Cox proportional hazards ratios. RESULTS: 2345 incident cases of BAC were analyzed, including 707 patients with stage IIIB or IV BAC. Patients with stage IIIB BAC due to multiple lesions in the same lobe (n=93) had significantly improved median OS (46m) and LCSS (>58m) compared to other stage IIIB BAC patients (n=111; OS=9m, P<0.0001; LCSS=10m, P<0.0001). Among stage IV BAC patients, those with intrapulmonary metastasis (n=278) had significantly improved median OS (13m) and LCSS (15m) compared to those with distant metastasis (n=225; OS=7m, P<0.0001; LCSS=7m, P=0.0001). These survival differences persisted after adjustment for age, gender, ethnicity, and surgical treatment status. CONCLUSIONS: Among stage IIIB and IV BAC patients, those presenting with ipsilateral intrapulmonary metastasis have improved survival outcomes. Our results add further support for modification to the current staging system for BAC.

Non-natural phenolic amino acids Synthesis and application in peptide chemistry.

Several non-natural phenolic amino acids have been synthesized.t-Butylated tyrosine and thyroxine derivatives, on one-electron oxidation, give persistent radicals which can be used as positional and/or spin labels for amino acids. Two-electron oxidation ofN-protected tyrosines leads to spirolactones, useful active esters for peptide coupling.