Understanding the Differential Response of Setaria viridis L. (green foxtail) and Setaria pumila Poir. (yellow foxtail) to Pyroxsulam.

Green foxtail [Setaria viridis (L) Beauv.] and yellow foxtail [Setaria pumila (Poir.) Roem. & Schult.] are among the most abundant and troublesome annual grass weeds in cereal crops in the Northern Plains of the United States and the Prairie Provinces of Canada. Greenhouse and laboratory experiments were conducted to examine the differential responses of both weed species to foliar applications of the new triazolopyrimidine sulfonamide acetolactate synthase-inhibiting herbicide, pyroxsulam, and to determine the mechanism(s) of differential weed control. Foliar applications of pyroxsulam resulted in >90% control of yellow foxtail at rates between 7.5 and 15 g ai ha-1, whereas the same rates resulted in a reduced efficacy on green foxtail (≤81%). The absorption and translocation of [14C]pyroxsulam in green and yellow foxtail were similar and could not explain the differential whole-plant efficacy. Studies with [14C]pyroxsulam revealed a higher percentage of absorbed pyroxsulam was metabolized into an inactive metabolite in the treated leaf of green foxtail than in the treated leaf of yellow foxtail. Metabolism studies demonstrated that, 48 h after application, 50 and 35% of pyroxsulam in the treated leaf was converted to 5-hydroxy-pyroxsulam in green and yellow foxtail, respectively. The acetolactate synthase (ALS) inhibition assay showed that ALS extracted from green foxtail was more tolerant to pyroxsulam than the enzyme extracted from yellow foxtail was. The in vitro ALS assay showed IC50 values of 8.39 and 0.26 µM pyroxsulam for green and yellow foxtail, respectively. The ALS genes from both green and yellow foxtail were sequenced and revealed amino acid differences; however, the changes are not associated with known resistance-inducing mutations. The differential control of green and yellow foxtail following foliar applications of pyroxsulam was attributed to differences in both metabolism and ALS sensitivity.

Pro-insecticidal approach towards increasing in planta activity.

BACKGROUND: The adrenergic mode of action was investigated for the development of potential new insecticides. Clonidine-related analogs were tested against Myzus persicae (Sulzer) and Bemisia tabaci (Gennadius). Clonidine analogs lack translation owing to a possible vacuole-trapping mechanism. Physical property modulation via a prodrug approach was attempted to overcome this mechanism. RESULTS: Clonidine showed insecticidal activity against M. persicae and B. tabaci. A prodrug of a known open-chain analog of clonidine was developed. While the prodrug had decreased pKa and increased lipophilicity and displayed good activity against M. persicae B. tabaci, the activity did not translate to cotton. Metabolic studies showed that the prodrug was quickly metabolized to the parent compound, and was further metabolized to a known vacuole-trapped oxazoline analog. CONCLUSIONS: Adrenergic active compounds, such as clonidine analogs, show potential as insecticides; however, a designed prodrug approach did not overcome the lack of translation in this case. Studies confirmed that the synthesized prodrug analog metabolized in planta to the proposed vacuole-trapped compound. One possible explanation for the failure of this approach is that the rate of metabolism and vacuole trapping is faster than translaminar flow, and therefore the released pesticide is not biologically available to the target organism. © 2016 Society of Chemical Industry.

Assessment of phloem mobility of xenobiotics in Triticum aestivum and Brachypodium distachyon.

Due to evolved resistance and environmental regulations, there is a particular need in the agricultural market for a new graminicide. An essential requirement of a novel, foliar applied graminicide is sufficient phloem mobility in the plant to reach meristematic tissues for the expression of activity leading to the desired control of unwanted vegetative growth. A robust and reliable phloem bioassay utilising a monocot species is highly desirable for early stage experimental compounds. Vascular tissues and translocation patterns of organic compounds in purple false brome (Brachypodium distachyon L. P. Beauv.), a model organism for temperate grasses, were studied and compared with those of wheat (Triticum aestivum L.). Microscopic studies with tracer dyes were used to determine if B. distachyon has a xylem discontinuity between the developing seed and the rachilla xylem, the same as found in T. aestivum. Based on 14C-radiolabelled and non-radiolabelled studies using known xylem and phloem mobile pesticidal compounds, there was a significant difference in the amount of the xylem mobile compounds in the chaff and stem as compared with the phloem mobile compounds found in the grain. The findings described in this report show a clear evidence of xylem discontinuity in B. distachyon, and provide a novel system for a rapid screening of phloem mobility of herbicides in monocot species.

Mevalocidin: a novel, phloem mobile phytotoxin from Fusarium DA056446 and Rosellinia DA092917.

A multiyear effort to identify new natural products was built on a hypothesis that both phytotoxins from plant pathogens and antimicrobial compounds might demonstrate herbicidal activity. The discovery of one such compound, mevalocidin, is described in the current report. Mevalocidin was discovered from static cultures of two unrelated fungal isolates designated Rosellinia DA092917 and Fusarium DA056446. The chemical structure was confirmed by independent synthesis. Mevalocidin demonstrated broad spectrum post-emergence activity on grasses and broadleaves and produced a unique set of visual symptoms on treated plants suggesting a novel mode of action. Mevalocidin was rapidly absorbed in a representative grass and broadleaf plant. Translocation occurred from the treated leaf to other plant parts including roots confirming phloem as well as xylem mobility. By 24 hr after application, over 20 % had been redistributed through-out the plant. Mevalocidin is a unique phytotoxin based on its chemistry, with the uncommon attribute of demonstrating both xylem and phloem mobility in grass and broadleaf plants.

The impact of uptake, translocation and metabolism on the differential selectivity between blackgrass and wheat for the herbicide pyroxsulam.

BACKGROUND: Wheat shows selectivity to pyroxsulam, a new broad-spectrum herbicide with high activity on blackgrass. Studies were performed to establish whether uptake, translocation or metabolism were responsible for the differential activity in wheat compared with blackgrass. In addition, the effect of the safener cloquintocet-mexyl on metabolism was evaluated in wheat and blackgrass shoots. RESULTS: Root uptake of pyroxsulam in blackgrass was significantly higher than in wheat, suggesting a possible activity enhancement in blackgrass owing to root uptake. Translocation to foliage from root uptake as well as translocation out of treated foliage following foliar applications was low in wheat compared with blackgrass, likely owing to the rapid metabolism of pyroxsulam in wheat. Wheat metabolized pyroxsulam significantly faster than blackgrass to the less active O-dealkylation product. Wheat shoots metabolized pyroxsulam faster when the safener cloquintocet-mexyl was present, but cloquintocet-mexyl did not increase the rate of metabolism in blackgrass. CONCLUSIONS: The selectivity of pyroxsulam to wheat relative to blackgrass was connected primarily with differences in the rate of metabolism and generation of an inactive metabolite. Metabolism in wheat restricted subsequent movement of radioactivity out of the treated leaf. The rapid metabolism in wheat was increased by the addition of cloquintocet-mexyl.

Discovery and characterization of sulfoxaflor, a novel insecticide targeting sap-feeding pests.

The discovery of sulfoxaflor [N-[methyloxido[1-[6-(trifluoromethyl)-3-pyridinyl]ethyl]-λ(4)-sulfanylidene] cyanamide] resulted from an investigation of the sulfoximine functional group as a novel bioactive scaffold for insecticidal activity and a subsequent extensive structure-activity relationship study. Sulfoxaflor, the first product from this new class (the sulfoximines) of insect control agents, exhibits broad-spectrum efficacy against many sap-feeding insect pests, including aphids, whiteflies, hoppers, and Lygus, with levels of activity that are comparable to those of other classes of insecticides targeting sap-feeding insects, including the neonicotinoids. However, no cross-resistance has been observed between sulfoxaflor and neonicotinoids such as imidacloprid, apparently the result of differences in susceptibility to oxidative metabolism. Available data are consistent with sulfoxaflor acting via the insect nicotinic receptor in a complex manner. These observations reflect the unique structure of the sulfoximines compared with neonicotinoids.

Phase I/II trial of metronomic chemotherapy with daily dalteparin and cyclophosphamide, twice-weekly methotrexate, and daily prednisone as therapy for metastatic breast cancer using vascular endothelial growth factor and soluble vascular endothelial growth factor receptor levels as markers of response.

PURPOSE Preclinical studies indicate that metronomic chemotherapy is antiangiogenic and synergistic with other antiangiogenic agents. We designed a phase I/II study to evaluate the safety and activity of adding dalteparin and prednisone to metronomic cyclophosphamide and methotrexate in women with measurable metastatic breast cancer (MBC). PATIENTS AND METHODS Patients received daily dalteparin and oral cyclophosphamide, twice-weekly methotrexate, and daily prednisone (dalCMP). The primary study end point was clinical benefit rate (CBR), a combination of complete response (CR), partial response (PR), and prolonged stable disease for > or = 24 weeks (pSD). Secondary end points included time to progression (TTP), duration of response, and overall survival (OS). Biomarker response to treatment was assessed by using plasma vascular endothelial growth factor (VEGF) and soluble VEGF receptors (sVEGFRs) -1 and -2. Results Forty-one eligible patients were accrued. Sixteen (39%) had no prior chemotherapy for MBC; 15 (37%) had two or more chemotherapy regimens for MBC. Toxicities were minimal except for transient grade 3 elevation of liver transaminases in 11 patients (27%) and grade 3 vomiting in one patient (2%). One patient (2%) had CR, six (15%) had PR, and three (7%) had pSD, for a CBR of 10 (24%) of 41 patients. Median TTP was 10 weeks (95% CI, 8 to 17 weeks), and median OS was 48 weeks (95% CI, 32 to 79 weeks). VEGF levels decreased but not significantly, whereas sVEGFR-1 and -2 levels increased significantly after 2 weeks of therapy. There was no correlation between response and VEGF, sVEGFR-1, or sVEGFR-2 levels. CONCLUSION Metronomic dalCMP is safe, well tolerated, and clinically active in MBC.

Systemic properties of myclobutanil in soybean plants, affecting control of Asian soybean rust (Phakopsora pachyrhizi).

BACKGROUND: The demethylation inhibitor (DMI) fungicide myclobutanil can be an effective component of spray programmes designed to control the highly destructive plant pathogen Phakopsora pachyrhizi Syd. & P. Syd., causal agent of Asian soybean rust. Myclobutanil is known from previous studies in grapevines to be xylem mobile. This study investigates the mobility profile of myclobutanil in soybean as an important component of its effective field performance. RESULTS: Over a 12 day period under greenhouse conditions, a constant uptake of myclobutanil from leaflet surfaces into the leaflet tissue was observed. Once in the leaflet, myclobutanil was seen to redistribute throughout the tissue, although no movement out of leaflets occurred owing to a lack of phloem mobility. The ability of myclobutanil to redistribute over distance within the soybean plant was revealed when visualizing movement of the compound to foliage above the point of application on the plant stem. An efficacy bioassay demonstrated that the systemic properties of myclobutanil allow control of disease at a point remote from the initial site of compound application. CONCLUSION: It is suggested that the high degree of xylem systemicity displayed by myclobutanil in soybean foliage is a contributory factor towards its commercial effectiveness for control of Asian soybean rust.

Prospective evaluation of quality of life in prostate cancer patients receiving combined treatment of postoperative radiotherapy plus androgen suppression for PT3 or positive resection margin after radical prostatectomy.

OBJECTIVES: To examine the effect of postoperative radiotherapy (RT) plus 2-yr androgen suppression (AS) on quality of life (QOL) in patients with pathologic T3 or positive resection margins after radical prostatectomy (RP). METHODS: Seventy-eight patients underwent postoperative RT followed by 2-yr AS, in a phase 2 study, between 1998 and 2002. Median age was 61 yr at the time of RP. QOL was prospectively assessed with the European Organization for Research and Treatment of Cancer (EORTC) QOL Questionnaire 30-item version 3.0 with the added prostate cancer-specific module at baseline and predefined follow-up visits. RESULTS: Patients experienced a significant increase in bowel dysfunction score (22%) by the end of RT, which would be considered a major change in QOL. This bowel dysfunction resolved after RT and showed no difference from baseline in the subsequent 2-yr AS period. A similar, but less pronounced, pattern of change occurred for the diarrhea domain. Urinary dysfunction score also increased at the end of RT by 6.6%, considered a clinically minor change in QOL. It then returned to baseline in the post-RT period. The cohort had poor erectile function at baseline; thus, it was difficult to assess any further decline in this domain brought on by RT or AS. In the remaining QOL domains, a change of minor or moderate clinical significance was observed at occasional time points for global health status, fatigue, pain, and insomnia. CONCLUSIONS: Postoperative RT plus 2-yr AS after RP did not result in any major, persistent, adverse effect on QOL.

Effect of combined treatment with salvage radiotherapy plus androgen suppression on quality of life in patients with recurrent prostate cancer after radical prostatectomy.

PURPOSE: To examine the effect of salvage radiotherapy (RT) plus 2-year androgen suppression (AS) on quality of life (QOL). METHODS AND MATERIALS: A total of 74 patients with biopsy-proven local recurrence or PSA relapse after radical prostatectomy were treated with salvage RT plus 2-year AS, as per a phase II study. Quality of life was prospectively assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30-Item Version 3.0 with the added prostate cancer-specific module at baseline and predefined follow-up visits. RESULTS: Patients experienced a significant increase in bowel dysfunction (23%) by the end of RT (p < 0.0001). This bowel dysfunction improved after RT but remained slightly elevated (5-10%) throughout the 2-year AS period. This extent of residual bowel dysfunction would be considered of minimal clinical importance. A similar, but less pronounced, pattern of change did occur for urinary dysfunction. Erectile function showed no change during RT, but had an abrupt decline (10%) with initiation of AS that was of moderate clinical significance (p < 0.01). None of the other QOL domains demonstrated a persistent, significant change from baseline that would be considered of major clinical significance. CONCLUSION: The combined treatment with salvage RT plus 2-year AS had relatively minor long-term effects on QOL.

Uptake, translocation and metabolism of the herbicide florasulam in wheat and broadleaf weeds.

Florasulam is a triazolopyrimidine sulfonanilide post-emergence broadleaf herbicide for use in wheat (Triticum aestivum L.). The selectivity of florasulam to wheat has been determined to be related primarily to a differential rate of metabolism between wheat with a half-life of 2.4 h and broadleaf weeds with half-lives ranging from 19 to >48 h. To a lesser extent, selectivity, at least for the broadleaf weed cleavers (Galium aparine L.), involves uptake differences. Rate of metabolism data were generated using greenhouse-grown plants injected with radiolabelled florasulam and subsequent extraction and processing by high-performance liquid chromatography (HPLC). Structures of metabolites were determined by isolation for nuclear magnetic resonance and liquid chromatography/mass spectrometry. Wheat plants metabolised florasulam by hydroxylation of the aniline ring para to the nitrogen, followed by conjugation to glucose. Metabolism by broadleaf weeds was so slow that isolation of metabolite was not possible, but comparison of HPLC data suggested hydroxylation as the major pathway.

Effect of androgen suppression on hemoglobin in prostate cancer patients undergoing salvage radiotherapy plus 2-year buserelin acetate for rising PSA after surgery.

PURPOSE: To examine the effect of 2-year androgen suppression (AS) on the pattern and extent of hemoglobin (Hb) change. METHODS AND MATERIALS: The basis of this report was a Phase II study evaluating a combined treatment of salvage radiotherapy plus 2-year AS for a rising prostate-specific antigen level after surgery. Patients had laboratory tests performed, including Hb and serum testosterone, and answered a quality-of-life questionnaire (European Organization for Research and Treatment of Cancer Quality-of-life Questionnaire 30 item) at regular intervals during the AS and post-AS period. The pattern and extent of the change in Hb was analyzed in relation to the testosterone level. The clinical significance of the Hb change was evaluated with a correlation analysis between Hb and the three specific domains of the questionnaire (Global Health Status, Physical Functioning, and Fatigue). RESULTS: Of a total of 74 accrued patients, 69 were identified as eligible for this report. The median patient age was 70 years. The median follow-up was 38.6 months. The mean Hb was 150.7 g/L at baseline and declined with radiotherapy by 5.9 g/L. The maximal Hb drop during AS was 16.0 g/L (p <0.0001), occurring at 16 months after the initiation of AS. Hb recovery in the post-AS period was slow. The decline and recovery of the mean Hb and hematocrit followed that of testosterone. The three quality-of-life domains did not show any significant correlation with the change in Hb. CONCLUSION: Two-year AS resulted in a statistically significant drop in the mean Hb, but had no clinically apparent adverse effect. The pattern of Hb change was similar to that of testosterone change.

Individualized planning target volumes for intrafraction motion during hypofractionated intensity-modulated radiotherapy boost for prostate cancer.

PURPOSE: The objective of the study was to access toxicities of delivering a hypofractionated intensity-modulated radiotherapy (IMRT) boost with individualized intrafraction planning target volume (PTV) margins and daily online correction for prostate position. METHODS AND MATERIALS: Phase I involved delivering 42 Gy in 21 fractions using three-dimensional conformal radiotherapy, followed by a Phase II IMRT boost of 30 Gy in 10 fractions. Digital fluoroscopy was used to measure respiratory-induced motion of implanted fiducial markers within the prostate. Electronic portal images were taken of fiducial marker positions before and after each fraction of radiotherapy during the first 9 days of treatment to calculate intrafraction motion. A uniform 10-mm PTV margin was used for the first phase of treatment. PTV margins for Phase II were patient-specific and were calculated from the respiratory and intrafraction motion data obtained from Phase I. The IMRT boost was delivered with daily online correction of fiducial marker position. Acute toxicity was measured using National Cancer Institute Common Toxicity Criteria, version 2.0. RESULTS: In 33 patients who had completed treatment, the average PTV margin used during the hypofractionated IMRT boost was 3 mm in the lateral direction, 3 mm in the superior-inferior direction, and 4 mm in the anteroposterior direction. No patients developed acute Grade 3 rectal toxicity. Three patients developed acute Grade 3 urinary frequency and urgency. CONCLUSIONS: PTV margins can be reduced significantly with daily online correction of prostate position. Delivering a hypofractionated boost with this high-precision IMRT technique resulted in acceptable acute toxicity.

Treatment of bone metastases with palliative radiotherapy: patients' treatment preferences.

PURPOSE: To determine the proportion of patients undergoing palliative radiotherapy (RT) for bone pain who would like to participate in the decision-making process, and to determine their choice of palliative RT regimen (2000 cGy in five fractions vs. 800 cGy in one fraction) for painful bone metastases. METHODS AND MATERIALS: Eligible patients were approached and all patients agreeing to participate provided written informed consent. Patients' decisional preferences were studied using a five-statement preference instrument. A decision board was used to help patients decide their preferred palliative RT regimen. Factors influencing patients' choices were studied using a visual analog scale. RESULTS: A total of 101 patients were enrolled in the study (55 women and 46 men). The preferences for decision-making were as follows: 30 active, 47 collaborative, and 24 passive. Most (55 [76%] of 72) patients favored one fraction of palliative RT (95% confidence interval, 65-86%). Patients were more likely to select the 800 cGy in one fraction because of the convenience of the treatment plan (odds ratio, 1.024; 95% confidence interval, 1.004-1044) but were less likely to choose it because of the chance of bone fracture (odds ratio, 0.973; 95% confidence interval, 0.947-1.000) compared with 2000 cGy in five fractions. CONCLUSION: Most participating patients preferred to decide either by themselves or with the radiation oncologists which treatment option they preferred. An 800-cGy-in-one-fraction regimen was favored, independent of the treated site. The convenience of the treatment plan and the likelihood of bone fracture were the most important factors influencing patients' choice.

How are hemoglobin levels affected by androgen deprivation in non-metastatic prostate cancer patients?

PURPOSE: To examine the change of hemoglobin in relation to testosterone level in non-metastatic prostate cancer patients receiving 2-year androgen suppression. METHODS AND MATERIALS: A cohort of 72 patients, as participants of a phase II study, were treated with adjuvant radiotherapy plus 2-year androgen suppression after surgery to reduce the risk of relapse. Patients had laboratory tests including hemoglobin (Hb) and testosterone, and a quality of life questionnaire at regular intervals during the androgen suppression and post-androgen suppression period. The pattern of the change in Hb was evaluated in relation to testosterone level. The clinical significance of Hb change was assessed with a correlation analysis between Hb and the three domains of the questionnaire (global health status, physical functioning, and fatigue). RESULTS: Median age was 64.2 years. Median follow-up was 37 months. Mean Hb at the baseline was 148.4 g/L. It declined slightly with radiotherapy by 2.2 g/L. Maximal Hb decline during androgen suppression was 10.5 g/L (p < 0.0001), occurring at 24 months after the initiation of androgen suppression. In most patients, Hb decline was < 20 g/L. In the post-androgen suppression period, the recovery of Hb was slow and followed that of testosterone. The three quality of life domains did not show any significant correlation with the change in Hb. CONCLUSION: The decline and recovery of Hb was closely related to that of testosterone. Two-year androgen suppression resulted in a statistically significant decline of Hb, which had, however, no clinically apparent adverse effect on the three quality of life domains.

Limited efficacy of salvage radiotherapy for biopsy confirmed or clinically palpable local recurrence of prostate carcinoma after surgery.

BACKGROUND AND PURPOSE: To assess the efficacy of salvage radiotherapy (RT) for biopsy confirmed or clinically palpable local recurrence of prostate adenocarcinoma after radical prostatectomy (RP). PATIENTS AND METHODS: We retrospectively analyzed 44 patients treated with salvage RT for biopsy confirmed or clinically palpable local recurrence between 1991 and 2000. Thirty-six had positive biopsy for local recurrence and the rest without histological confirmation had clinically palpable disease. All had rising PSA at the time of RT (median: 3.7). Median interval from RP to RT was 2.6 years. Thirty-six received salvage RT alone, while eight had a short course (<4 months) of androgen ablation prior to RT. RT doses were 60-66Gy in 30-33 fractions. Freedom from PSA failure was defined as the maintenance of PSA

Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination.

CONTEXT: Current recommendations for women who have a BRCA1 or BRCA2 mutation are to undergo breast surveillance from age 25 years onward with mammography annually and clinical breast examination (CBE) every 6 months; however, many tumors are detected at a relatively advanced stage. Magnetic resonance imaging (MRI) and ultrasound may improve the ability to detect breast cancer at an early stage. OBJECTIVE: To compare the sensitivity and specificity of 4 methods of breast cancer surveillance (mammography, ultrasound, MRI, and CBE) in women with hereditary susceptibility to breast cancer due to a BRCA1 or BRCA2 mutation. DESIGN, SETTING, AND PARTICIPANTS: A surveillance study of 236 Canadian women aged 25 to 65 years with BRCA1 or BRCA2 mutations who underwent 1 to 3 annual screening examinations, consisting of MRI, mammography, and ultrasound at a single tertiary care teaching hospital between November 3, 1997, and March 31, 2003. On the day of imaging and at 6-month intervals, CBE was performed. MAIN OUTCOME MEASURES: Sensitivity and specificity of each of the 4 surveillance modalities, and sensitivity of all 4 screening modalities vs mammography and CBE. RESULTS: Each imaging modality was read independently by a radiologist and scored on a 5-point Breast Imaging Reporting and Data System scale. All lesions with a score of 4 or 5 (suspicious or highly suspicious for malignancy) were biopsied. There were 22 cancers detected (16 invasive and 6 ductal carcinoma in situ). Of these, 17 (77%) were detected by MRI vs 8 (36%) by mammography, 7 (33%) by ultrasound, and 2 (9.1%) by CBE. The sensitivity and specificity (based on biopsy rates) were 77% and 95.4% for MRI, 36% and 99.8% for mammography, 33% and 96% for ultrasound, and 9.1% and 99.3% for CBE, respectively. There was 1 interval cancer. All 4 screening modalities combined had a sensitivity of 95% vs 45% for mammography and CBE combined. CONCLUSIONS: In BRCA1 and BRCA2 mutation carriers, MRI is more sensitive for detecting breast cancers than mammography, ultrasound, or CBE alone. Whether surveillance regimens that include MRI will reduce mortality from breast cancer in high-risk women requires further investigation.

Wide variation of prostate-specific antigen doubling time of untreated, clinically localized, low-to-intermediate grade, prostate carcinoma.

OBJECTIVE: To assess the prostate specific antigen (PSA) doubling time of untreated, clinically localized, low-to-intermediate grade prostate carcinoma. PATIENTS AND METHODS: A prospective single-arm cohort study has been in progress since November 1995 to assess the feasibility of a watchful-observation protocol with selective delayed intervention for clinically localized, low-to-intermediate grade prostate adenocarcinoma. The PSA doubling time was estimated from a linear regression of ln(PSA) against time, assuming a simple exponential growth model. RESULTS: As of March 2003, 231 patients had at least 6 months of follow-up (median 45) and at least three PSA measurements (median 8, range 3-21). The distribution of the doubling time was: < 2 years, 26 patients; 2-5 years, 65; 5-10 years, 42; 10-20 years, 26; 20-50 years, 16; >50 years, 56. The median doubling time was 7.0 years; 42% of men had a doubling time of >10 years. CONCLUSIONS: The doubling time of untreated clinically localized, low-to-intermediate grade prostate cancer varies widely.

Symptom control and palliative care content of abstracts presented at the Canadian Association of Radiation Oncologists annual meetings.

GOALS: Half of all patients referred for radiotherapy are treated with palliative intent. Recent emphasis has been placed on the importance of symptom control and palliative care (SCPC) in the radiation oncology community. The purpose of this study was to determine the number of abstracts relating to SCPC presented at the annual Canadian Association of Radiation Oncologists (CARO) meetings, and whether this number has increased over time. METHODS: SCPC abstracts presented at CARO from 1992 through 2002 were counted. Abstracts were included if they described a patient population with advanced or metastatic cancer treated with palliative intent. Abstracts were then categorized as reporting treatment outcomes, health services research, descriptive studies or literature reviews. Radiation treatment sites were recorded. MAIN RESULTS: An average of 6.7% (60/892; range 0-16.2%) of all abstracts presented at CARO from 1992 through 2002 pertained to SCPC. There was a significant increase in the proportion of SCPC abstracts accepted over time ( P=0.0012). Descriptive studies accounted for 46.7%, treatment outcomes 31.7%, health services research 13.3%, and literature reviews 8.3% of the SCPC abstracts. Bone metastases (48.3%), primary lung tumors (11.7%), and brain metastases (10.0%) were the most common treatment sites. Of all the SCPC abstracts, 45% came from dedicated palliative radiotherapy clinics. CONCLUSIONS: SCPC research is poorly represented at the annual CARO conferences. Research in this field should be promoted as the palliative patient population represents a large component of radiotherapy clinical practice. The recent emergence of dedicated palliative radiotherapy clinics should continue to increase palliative radiotherapy research.

Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma.

BACKGROUND & AIMS: Early detection of hepatocellular carcinoma (HCC) is critical for successful treatment. However, the differential diagnosis between HCC and benign hepatic lesions is sometimes difficult and new biochemical markers for HCC are required. It has been reported that glypican-3 (GPC3) messenger RNA (mRNA) is significantly increased in most HCCs compared with benign liver lesions or normal liver. The goal of this study is to determine whether GPC3 is also overexpressed at the protein level and whether GPC3 is detectable in the serum of patients with HCC. METHODS: GPC3 was assessed in liver tissue sections by immunohistochemistry and in serum by enzyme-linked immunosorbent assay. Serum alpha-fetoprotein (AFP) level was also measured in the same patients. RESULTS: Immunohistochemical studies showed that GPC3 is expressed in 72% of HCCs (21 of 29), whereas it is not detectable in hepatocytes from normal liver and benign liver diseases. Consistent with this, GPC3 was undetectable in the serum of healthy donors and patients with hepatitis, but its levels were significantly increased in 18 of 34 patients (53%) with HCC. In addition, only 1 of 20 patients with hepatitis plus liver cirrhosis displayed elevated levels of serum GPC3. Interestingly, in most cases, there was no correlation between GPC3 and AFP values. Thus, at least 1 of the 2 markers was elevated in 82% of the patients with HCC. CONCLUSIONS: GPC3 is specifically overexpressed in most HCCs and is elevated in the serum of a large proportion of patients with HCC. The simultaneous determination of GPC3 and AFP may significantly increase the sensitivity for diagnosis of HCC.