Compression of high-power laser pulses using only multiple ultrathin plane plates.

A proposal for additional temporal compression and peak power enhancement of intense (>TW/cm2) femtosecond laser pulses using two thin plane-parallel plates is presented. The first ultrathin plate (order of mm) induces spectral broadening due to self-phase modulation, and the second ultrathin plate (order of micron) corrects the spectral phase. The elimination of the negative dispersive multilayer coating from the scheme offers an improved laser-induced damage threshold for the post-compression process.

Small-scale patterns in snowmelt timing affect gene flow and the distribution of genetic diversity in the alpine dwarf shrub Salix herbacea.

Current threats to biodiversity, such as climate change, are thought to alter the within-species genetic diversity among microhabitats in highly heterogeneous alpine environments. Assessing the spatial organization and dynamics of genetic diversity within species can help to predict the responses of organisms to environmental change. In this study, we evaluated whether small-scale heterogeneity in snowmelt timing restricts gene flow between microhabitats in the common long-lived dwarf shrub Salix herbacea L. We surveyed 273 genets across 12 early- and late-snowmelt sites (that is, ridges and snowbeds) in the Swiss Alps for phenological variation over 2 years and for genetic variation using seven SSR markers. Phenological differentiation triggered by differences in snowmelt timing did not correlate with genetic differentiation between microhabitats. On the contrary, extensive gene flow appeared to occur between microhabitats and slightly less extensively among adjacent mountains. However, ridges exhibited significantly lower levels of genetic diversity than snowbeds, and patterns of effective population size (Ne) and migration (Nem) between microhabitats were strongly asymmetric, with ridges acting as sources and snowbeds as sinks. As no recent genetic bottlenecks were detected in the studied sites, this asymmetry is likely to reflect current meta-population dynamics of the species dominated by gene flow via seeds rather than ancient re-colonization after the last glacial period. Overall, our results suggest that seed dispersal prevents snowmelt-driven genetic isolation, and snowbeds act as sinks of genetic diversity. We discuss the consequences of such small-scale variation in gene flow and diversity levels for population responses to climate change.

Increased spring freezing vulnerability for alpine shrubs under early snowmelt.

Alpine dwarf shrub communities are phenologically linked with snowmelt timing, so early spring exposure may increase risk of freezing damage during early development, and consequently reduce seasonal growth. We examined whether environmental factors (duration of snow cover, elevation) influenced size and the vulnerability of shrubs to spring freezing along elevational gradients and snow microhabitats by modelling the past frequency of spring freezing events. We sampled biomass and measured the size of Salix herbacea, Vaccinium myrtillus, Vaccinium uliginosum and Loiseleuria procumbens in late spring. Leaves were exposed to freezing temperatures to determine the temperature at which 50% of specimens are killed for each species and sampling site. By linking site snowmelt and temperatures to long-term climate measurements, we extrapolated the frequency of spring freezing events at each elevation, snow microhabitat and per species over 37 years. Snowmelt timing was significantly driven by microhabitat effects, but was independent of elevation. Shrub growth was neither enhanced nor reduced by earlier snowmelt, but decreased with elevation. Freezing resistance was strongly species dependent, and did not differ along the elevation or snowmelt gradient. Microclimate extrapolation suggested that potentially lethal freezing events (in May and June) occurred for three of the four species examined. Freezing events never occurred on late snow beds, and increased in frequency with earlier snowmelt and higher elevation. Extrapolated freezing events showed a slight, non-significant increase over the 37-year record. We suggest that earlier snowmelt does not enhance growth in four dominant alpine shrubs, but increases the risk of lethal spring freezing exposure for less freezing-resistant species.

The beneficial effects of volunteering for older volunteers and the people they serve: a meta-analysis.

The current political-economic climate, which is generally supportive of both private and public sector down-sizing, increasingly demands that human service workers assess, engage, and creatively use consumer strengths and resources. This meta-analysis of thirty-seven independent studies provided the means of inferring not only that elder volunteers' sense of well-being seemed to be significantly bolstered through volunteering, but also that such relatively healthy older people represent a significant adjunct resource for meeting some of the service needs of more vulnerable elders, as well as those of other similarly vulnerable groups such as disabled children. Averaging across studies, 85 percent of the "clients" who received service from an older volunteer (e.g., peer-counseling of nursing home residents) scored better on dependent measures (e.g., diminished depression) than the average person in comparison conditions did (U3 = .847 [Cohen, 1988], combined p < .001). The policy implications of such beneficial effects among both older volunteers and the people they serve are discussed.

Tumor perfusion studies using fast magnetic resonance imaging technique in advanced cervical cancer: a new noninvasive predictive assay.

PURPOSE: This study investigated sequential changes in tumor blood supply using magnetic resonance (MR) perfusion imaging and assessed their significance in the prediction of outcome of patients with advanced cervical cancer. The purpose of this project was to devise a simple, noninvasive method to predict early signs of treatment failure in advanced cervical cancer treated with conventional radiation therapy. METHODS AND MATERIALS: Sixty-eight MR perfusion studies were performed prospectively in 17 patients with squamous carcinomas (14) and adenocarcinomas (3) of the cervix, Stages bulky IB (1), IIB (5), IIIA (1), IIIB (8), and IVA (1), and recurrent (1). Four sequential studies were obtained in each patient: immediately before radiation therapy (pretherapy), after a dose of 20-22 Gy/ approximately 2 weeks (early therapy), after a dose of 40-45 Gy/ approximately 4-5 weeks (midtherapy), and 4-6 weeks after completion of therapy (follow-up). Perfusion imaging of the tumor was obtained at 3-s intervals in the sagittal plane. A bolus of 0.1 mmol/kg of MR contrast material (gadoteridol) was injected intravenously 30 s after beginning image acquisition at a rate of 9 ml/s using a power injector. Time/signal-intensity curves to reflect the onset, slope, and relative signal intensity (rSI) of contrast enhancement in the tumor region were generated. Median follow-up was 8 months (range 3-18 months). RESULTS: Tumors with a higher tissue perfusion (rSI > or = 2.8) in the pretherapy and early therapy (20-22 Gy) studies had a lower incidence of local recurrence than those with a rSI of < 2.8, but this was not statistically significant (13% vs. 67%; p = 0.05). An increase in tumor perfusion early during therapy (20-22 Gy), particularly to an rSI of > or = 2.8, was the strongest predictor of local recurrence (0% vs. 78%; p = 0.002). However, pelvic examination during early therapy (20-22 Gy) commonly showed no appreciable tumor regression. The slope of the time/signal-intensity curve obtained before and during radiation therapy also correlated with local recurrence. Follow-up perfusion studies did not provide information to predict recurrence. CONCLUSION: These preliminary results suggest that two simple MR perfusion studies before and early in therapy can offer important information on treatment outcome within the first 2 weeks of radiation therapy before response is evident by clinical examination. High tumor perfusion before therapy and increasing or persistent high perfusion early during the course of therapy appear to be favorable signs. High perfusion suggests a high blood and oxygen supply to the tumor. The increase in tumor perfusion seen in some patients early during radiation therapy suggests improved oxygenation of previously hypoxic cells following early cell kill. Radiation therapy is more effective in eradicating these tumors, resulting in improved local control. Our technique may be helpful in identifying early-while more aggressive therapy can still be implemented-those patients who respond poorly to conventional radiation therapy.

Definitive radiotherapy for carcinoma of the vagina: outcome and prognostic factors.

PURPOSE: Primary carcinoma of the vagina is an uncommon tumor. Because of the long-standing interest in this disease at our institution a substantial number of patients with this disease has been accumulated, and this retrospective review was performed to define disease outcome, to delineate significant prognostic factors, and to provide treatment guidelines. METHODS AND MATERIALS: This was a retrospective review of 301 patients with vaginal carcinoma (271 with squamous cell and 30 with adenocarcinoma) who received definitive radiotherapy between 1953 and 1991. Prognostic factors for outcome (local control, pelvic control, metastatic relapse, survival, and complications) were evaluated using univariate and multivariate techniques. RESULTS: Patients disease was staged using the International Federation of Gynecology and Obstetrics (FIGO) system, and stages were distributed as follows: 0, 37 (12%); I, 65 (22%); II, 122 (40%); III, 60 (20%); and, IVA, 17 (6%). Treatment varied according to stage, with brachytherapy predominating for early disease but external beam playing a prominent role for more advanced disease. Patients with in situ disease received brachytherapy alone or transvaginal orthovoltage irradiation. For Stage I, brachytherapy alone was used in 25, external beam and brachytherapy in 38, and transvaginal alone in 2. For Stage II, brachytherapy alone was used in 20, external and brachytherapy in 66, and external irradiation alone in 36. For Stage III, external and brachytherapy was used in 15, and external alone in 45. Two patients with Stage IVA received brachytherapy alone, 10 received a combination of external and brachytherapy, and 6 received external irradiation alone. Total doses ranged from 10 to 154 Gy (mean 74.7 Gy, median 70.0 Gy), but only 18 (6%) received less than 55 Gy. At a median follow-up of 13 years, the 5-, 10-, 15-, 20-, and 25-year survival rates were 60%, 49%, 38%, 29%, and 23%, respectively. Beyond 5 years the survival rates relative to those for age-matched females in the general population were between 50 and 65%. Actuarial local recurrence rates were 23%, 26%, and 26% at 5, 10, and 15 years. Actuarial pelvic relapse rates were 26%, 30%, and 31% at 5, 10, and 15 years, and metastatic rates at those times were 15%, 18%, and 18%. Adenocarcinoma (nonclear cell) was a significantly worse disease than squamous cell carcinoma. The major determinants of local control for squamous carcinoma were tumor bulk (specified by size in centimeters, or by FIGO stage), tumor site (upper lesions faring better than others), and tumor circumferential location (lesions involving the posterior wall faring worse). Tumor bulk was an important determinant of metastatic relapse, but failure to achieve local control was also an independently significant determinant of metastases. Salvage after first relapse was uncommon and the survival rate at 5 years after relapse was only 12%. Serious complications occurred in 39 patients with an actuarial incidence of 19% at 20 years. CONCLUSION: Vaginal carcinoma poses a formidable therapeutic challenge. The disease is heterogeneous with respect to its prognostic factors. Nonclear cell adenocarcinoma has an extremely poor prognosis and should be distinguished from squamous carcinoma. Both external beam and brachytherapy play crucial roles in management and most patients with disease beyond in situ should receive a significant component of external irradiation prior to brachytherapy.

Usefulness of tumor volumetry by magnetic resonance imaging in assessing response to radiation therapy in carcinoma of the uterine cervix.

PURPOSE: Clinical evaluation of tumor size in cervical cancer is often difficult, and clinical signs of radiation therapy failure may not be present until well after completion of treatment. The purpose of this study is to investigate early indicators of treatment response using magnetic resonance (MR) imaging for quantitative assessment of tumor volume and tumor regression rate before, during, and after radiation therapy. METHODS AND MATERIALS: Thirty-four patients with cervical cancer Stages IB [5], IIB [8], IIIA [1], IIIB [14], IVA [3], IVB [1], and recurrent [2] were studied prospectively with four serial MR examinations obtained at the start of radiation therapy, at 2-2.5 weeks (20-24 Gy), at 4-5 weeks (40-50 Gy), and 1-2 months after treatment completion. Tumor volume was assessed by three-dimensional volumetric measurements using T2-weighted images of each MR examination. The volume regression rate was generated based on the four sequential MR studies. These findings were correlated with local control, metastasis rate, and disease-free survival. Median follow-up was 18 months (range: 9-43 months). RESULTS: The tumor regression rate after a dose of 40-50 Gy correlated significantly with treatment outcome. The actuarial 2-year disease-free survival was 88.4% in patients with tumors regressing to < 20% of the initial volume compared with 45.4% in those with > or = 20% residual (p = 0.007). The incidence of local recurrence was 9.5% (2 out of 21) and 76.9% (10 out of 13), respectively (p < 0.001). Analysis by initial tumor volume showed that this observation was valid in patients with initial volumes between 40 and 100 cm3. Analysis by FIGO stage confirmed this observation in all patients except those with Stage IB. CONCLUSION: Sequential tumor volumetry using MR imaging appears to be a sensitive measure of the responsiveness of cervical cancer to irradiation. Treatment response can be assessed as early as during the course of radiation therapy by measurement of initial tumor volume and regression rate at 40-50 Gy. In patients with large (> 40 cm3) and advanced (Stage > or = IIIA) tumors, this technique may be helpful in supplementing the clinical examination for response assessment. The identification of patients at high risk for treatment failure may ultimately lead to improved clinical outcome.

Brachytherapy and continuous infusion 5-fluorouracil for treatment of locally advanced, lymph node negative, prostate cancer: a phase I trial.

BACKGROUND: 5-fluorouracil (5-FU) is a known radiosensitizer that enhances efficacy, in vivo and in vitro, when administered during radiotherapy. The following study was performed to evaluate the toxicity of continuous infusion 5-FU administered concomitant with brachytherapy in patients with locally advanced prostate cancer. METHODS: Over a 26-month period, a total of 25 patients with newly diagnosed, locally advanced prostate cancer underwent radioactive gold (Au198) brachytherapy. Twenty-four of 25 patients were surgically staged and confirmed node negative. Au198 seed placement was performed transperineally under fluoroscopic and ultrasonographic guidance using an average of 195 mCi of Au198. Within 4 hours after seed placement, 25 patients received 5-FU administered as a continuous infusion over 4 days, at 1 of 8 dose levels ranging from 200-1100 mg/m2/day. Patients had clinical follow-up for a minimum of 1 year. Decreases in serum prostate specific antigen (PSA) and prostate volume (normalized to pretreatment values) were determined at 12 months. RESULTS: 5-FU associated toxicity was negligible, with Grade 1 nausea in four patients and no Grade 2 or higher toxicity. No unique locoregional toxicity was noted. At 12 months after treatment, PSA values decreased on average to 16.4% of pretreatment values. Twelve-month prostate volumes decreased to 55% of the pretreatment values. CONCLUSIONS: These findings suggest that continuous infusion 5-FU can be administered safely concomitant with brachytherapy at doses up to 1100 mg/m2 per day for 4 days.

ASTRO Research Fellowship: apoptosis as a predictor of tumor response to radiation in stage IB cervical carcinoma. American Society for Therapeutic Radiology and Oncology.

PURPOSE: Levels of apoptosis predict for tumor responsiveness to radiation in various animal systems. To investigate the potential role of apoptosis as a predictor of response in human tumors, a retrospective review was undertaken of patients with adenocarcinoma of the cervix whose primary lesion at presentation measured at least 4 cm and who underwent definitive radiation therapy. A previous report had indicated that roughly half this group of patients should have a long-term relapse free survival. METHODS AND MATERIALS: Pretreatment biopsy specimens of 44 patients with Stage IB adenocarcinoma of the cervix, whose primary lesion at presentation measured at least 4 cm in greatest dimension, were scored for apoptosis by two independent investigators without knowledge of the treatment outcome, and the results were averaged. Actuarial methods were used to assess overall survival, disease-free survival, determinate survival, and local control as a function of the baseline level of apoptosis. Patients ranged in age from 21 to 87 years and were treated with definitive radiotherapy between 1964 and 1989. Follow-up for the surviving patients ranged from 1 to 278 months, with a mean of 101 months. RESULTS: Patients whose tumors had a baseline level of apoptosis above the median value (2%) had a better overall survival than those with lower levels of apoptosis (p = 0.056). A similar trend for disease-free survival (p = 0.32) and determinate survival (p = 0.27) did not reach statistical significance, perhaps because of the small number of patients. Because only 6 of the 44 patients (13%) had a local tumor failure, it was not possible to establish a correlation between the pretreatment level of apoptosis and the local tumor control by radiation. CONCLUSION: The baseline level of apoptosis predicted for survival in patients with Stage IB cervical adenocarcinoma. Further investigation of the measurement of apoptosis as a potential predictive assay is warranted in other human tumor systems.

Dedifferentiation of locally recurrent prostate cancer after radiation therapy. Evidence for tumor progression.

BACKGROUND: Untreated or unsuccessfully treated prostatic adenocarcinoma may develop more malignant characteristics as time passes--the phenomenon of tumor progression. Whether this occurs after unsuccessful radiation therapy has not been answered. This study was designed to address that issue. METHODS: The histologic grades at initial diagnosis and at local recurrence were compared in 49 patients who experienced local recurrence after external beam radiation therapy. RESULTS: Tumor grades were assigned using the M. D. Anderson grading system. At the initial diagnosis, the grades were distributed as follows: Grade 1, 18 (37%), Grade 2, 22 (45%); Grade 3, 8 (16%); and Grade 4, 1 (2%). At recurrence, the grades were: Grade 1, 3 (6%); Grade 2, 14 (29%); Grade 3, 14 (29%); and Grade 4, 18 (37%). The shift to higher grades at recurrence was highly significant (P < 0.001). This dedifferentiation could not be accounted for by possible tissue sampling variability, and stepwise multiple variable logistic regression revealed that the only factor predicting for dedifferentiation was the time since treatment. The tumors that recurred later had a significantly higher likelihood to be dedifferentiated than those that recurred early. Patients whose tumors dedifferentiated had a poorer survival than those whose tumors retained their original grade. CONCLUSIONS: The possibilities were considered that the dedifferentiation could arise by tissue sampling error, by persistence and regrowth of high-grade components, by the development of new tumors, or by radiation-induced transformation. None of these mechanisms appeared to explain the data adequately, and it was concluded that the observed dedifferentiation was indeed a manifestation of time-dependent tumor progression. Eradication of the primary tumor is therefore important, not only to allay local symptoms, but also to prevent the emergence of more virulent and potentially lethal tumors.