High precision optical cavity length and width measurements using double modulation.

We use doubly phase modulated light to measure both the length and the linewidth of an optical resonator with high precision. The first modulation is at RF frequencies and is set near a multiple of the free spectral range, whereas the second modulation is at audio frequencies to eliminate offset errors at DC. The light in transmission or in reflection of the optical resonator is demodulated while sweeping the RF frequency over the optical resonance. We derive expressions for the demodulated power in transmission, and show that the zero crossings of the demodulated signal in transmission serve as a precise measure of the cavity linewidth at half maximum intensity. We demonstrate the technique on two resonant cavities, with lengths 16 m and a 4 km, and achieve an absolute length accuracy as low as 70 ppb. The cavity width for the 16 m cavity was determined with an accuracy of approximately 6000 ppm. Through an analysis of the systematic errors we show that this result could be substantially improved with the reduction of technical sources of uncertainty.

Palladium-103 brachytherapy for prostate carcinoma.

PURPOSE: A report of biochemical outcomes for patients treated with palladium-103 (Pd-103) brachytherapy over a fixed time interval. METHODS AND MATERIALS: Two hundred thirty patients with clinical stage T1-T2 prostate cancer were treated with Pd-103 brachytherapy and followed with prostate-specific antigen (PSA) determinations. Kaplan-Meier estimates of biochemical failure on the basis of two consecutive elevations of PSA were utilized. Multivariate risk groups were constructed. Aggregate PSA response by time interval was assessed. RESULTS: The overall biochemical control rate achieved at 9 years was 83.5%. Failures were local 3.0%; distant 6.1%; PSA progression only 4.3%. Significant risk factors contributing to failure were serum PSA greater than 10 ng/ml and Gleason sum of 7 or greater. Five-year biochemical control for those exhibiting neither risk factor was 94%; one risk factor, 82%; both risk factors, 65%. When all 1354 PSA determinations obtained for this cohort were considered, the patients with a proportion of PSAs < or = 0.5 ng/ml continued to increase until at least 48 months post-therapy. These data conformed to a median PSA half-life of 96.2 days. CONCLUSIONS: Prostate brachytherapy with Pd-103 achieves a high rate of biochemical and clinical control in patients with clinically organ-confined disease. PSA response following brachytherapy with low-dose-rate isotopes is protracted.

Brachytherapy for clinically localized prostate cancer: results at 7- and 8-year follow-up.

In recent years, there has been a resurgence of interest in interstitial radiation as a cost-effective and efficient method of treating organ-confined prostate cancer. We describe our 7- and 8-year results with transperineal Iodine-125 and Palladium-103 implantation. A total of 551 consecutive patients were treated. Of these, 320/551 (58%) received implant alone (Group I), and 231/551 (42%)--considered higher risk patients--were also treated with a modest dose (45 Gy) of external beam irradiation (Group II). The median follow-up for Group I was 55 months, and for Group II, 60 months. At 7 years, the actuarial freedom from biochemical failure (prostate-specific antigen (PSA) < or = 1.0 ng/mL) was 80% in Group I patients, and, at 8 years, 65% in Group II patients. Morbidity was minimal if patients had not undergone prior transurethral prostate resections. The results indicate that interstitial radiation is a valid treatment for clinically localized prostate cancer.

Interstitial iodine-125 radiation without adjuvant therapy in the treatment of clinically localized prostate carcinoma.

BACKGROUND: This study was designed to evaluate the efficacy of iodine-125 interstitial radiation in the treatment of prostate carcinoma classified as T1 or T2. METHODS: One hundred twenty-six consecutive patients with adenocarcinoma of the prostate (T1, 23%; T2, 77%) were treated with iodine-125 radionuclides between January 1, 1988, and December 31, 1990. Four patients died of intercurrent illness within 1 year postimplant, leaving 122 men in the study. The prescribed minimum radiation dose was 160 gray. Median follow-up was 69.3 months. Prebiopsy prostate specific antigen (PSA) values (median, 5.0 ng/mL) were available for all patients. Posttherapy evaluation included clinical, biochemical (PSA), and pathologic (repeat needle biopsy) studies. No patient was surgically staged, and none received androgen deprivation therapy. Morbidity was graded according to the Radiation Therapy Oncology Group grading scale. Statistical appraisal was performed by the Kaplan-Meier method. PSA failure was defined in two ways: (1) PSA progression, i.e., 2 consecutive increases from a nadir value; and (2) failure to attain an arbitrary serum PSA value of 1.0 or 0.5 ng/mL at last follow-up. RESULTS: The overall 7-year survival was 77%; there were no deaths from prostate carcinoma in this cohort. The 7-year actuarial PSA progression free outcome was 89%, and the PSA < or = 1.0 ng/mL outcome was 87%. When PSA < or = 0.5 ng/mL was selected as an outcome end point, and PSA values in this series of radiation-treated patients were compared with PSA values proposed to indicate disease free survival after radical prostatectomy (PSA < or = 0.3-< or = 0.6 ng/mL), the 7-year actuarial disease free survival was 79%. Morbidity was minimal except in patients who had preimplant or postimplant transurethral prostate resection. CONCLUSIONS: Outpatient-based iodine-125 prostate brachytherapy for prostate carcinoma classified as T1 or T2 resulted in biochemical outcomes comparable to end points resulting from radical prostatectomy and external beam radiation.

Posttreatment biopsy results following interstitial brachytherapy in early-stage prostate cancer.

PURPOSE: To assess pathologic control rates for prostatic carcinoma as determined by postimplant prostate biopsy in a large series of consecutive patients who have received permanent interstitial brachytherapy using a contemporary transrectal ultrasound-directed, transperineal, computer generated, volume technique. METHODS AND MATERIALS: Four hundred and two patients received permanent 125I or 103Pd interstitial brachytherapy as primary treatment for early stage prostatic carcinoma at the Northwest Tumor Institute between January 1988 and January 1994. Of these, 201 have consented to biopsy 12 or more months postimplant with a median follow-up of 40 months (range: 12-83 months). None had received hormonal manipulation. A total of 361 biopsies was performed on 201 patients with a range of one to six annual biopsies per patient (91 received multiple, serial biopsies). Of the 161 patients more than 12 months postimplant who have not been biopsied, most have been unwilling or unable to submit to biopsy. Only six patients with biochemical progression have not been biopsied. There was no difference in the presenting characteristics or implant parameters between those patients biopsied and those that were not. One hundred and forty-three received 125I (71%) prescribed to a MPD of 160 Gy with a median activity of 35.5 mCi, and 58 (29%) received 103Pd prescribed to a MPD of 115 Gy with a median activity of 123 mCi. Multiple biopsies were performed under transrectal ultrasound guidance, and all specimens were classified as either negative, indeterminate, or positive. RESULTS: At the time of last biopsy, 161 (80%) have achieved negative pathology, 34 (17%) remain indeterminate, and 6 (3%) have been positive. Only 2 of the 186 patients with a PSA < 4.0 ng/ml at the time of biopsy were positive. Among those 33 indeterminate patients with a subsequent biopsy, 28 have converted to negative, 2 to positive, and 3 remain unchanged to date. CONCLUSIONS: These data demonstrate at least an 80% pathologically confirmed local control rate following permanent interstitial brachytherapy for early stage prostate cancer. A higher local control rate is expected with further follow-up as the majority of indeterminate biopsies convert to negative over time. The indeterminate category of postirradiation biopsy described here includes specimens that have probably been interpreted as positive in other series, but correlate clinically and biochemically with negative biopsies. These results support the use of modern interstitial brachytherapy techniques for selected patients with early stage adenocarcinoma of the prostate.

Prostate cancer: correlation of digital rectal examination, transrectal ultrasound and prostate specific antigen levels with tumor volumes in radical prostatectomy specimens.

Volume and distribution of prostatic carcinoma were measured in 30 radical prostatectomy specimens. Obtaining these data was facilitated by the use of whole tissue mounts. Similar measurements were obtained from preoperative transrectal ultrasound studies. With this information the ability of digital rectal examination and transrectal ultrasound to predict tumor burden was analyzed. It was concluded that both of these examinations are poor predictors of tumor volume, distribution and pathological stage. Preoperative prostate specific antigen levels were correlated with the pathological data. It appeared that prostate specific antigen levels of greater than 10 presage [corrected] tumor volumes of greater than 3 cc, and that levels of more than 50 are suggestive of stages C and D disease.

Microcalorimetric studies of the interaction of normal and thyrotoxic cardiac myosins with ATP and ADP.

The heat production of the interaction of normal and thyrotoxic cardiac myosins with ATP and ADP was studied in a microcalorimeter. As compared to the normal protein the thyrotoxic cardiac myosin gave a larger negative enthalpy, entropy, and heat capacity change. These results indicate that the enthalpy, entropy, and heat capacity differences between the two conformational states of myosin are larger in the thyrotoxic cardiac muscle than in the normal control. The ATP induced transition between the conformational states of the cardiac myosins appears to be connected to the powerstroke of the contractile cycle. Therefore the observed thermodynamic differences between the normal and thyrotoxic cardiac myosins may be related to the active site chemistries of these isomyosins and portend the functional abnormality of the thyrotoxic cardiac muscle.

An automated approach to characterize, in simple kinetic terms, the generation and inactivation of thrombin and the interaction of fibrinogen with thrombin.

Here, we used a fully automated, computer-directed centrifugal analyzer (which permitted simultaneous turbidimetry and calculation of results) and purified thrombin, fibrinogen, and various inhibitors to study clot formation. The Km and Vm for these reactions were useful in detecting and partly characterizing anticoagulants. We also explored the generation and inactivation of thrombin, using the two-stage prothrombin time and antithrombin activity tests. The amount of thrombin instantaneously generated and inactivated was monitored under artificially created pathological conditions. The pseudo-first-order rate constant for thrombin generation and inactivation and the instantaneous concentration of enzymatically active and inactive thrombin were used in the characterization of these conditions. We believe this approach is suitable for routine clinical use.

A fully automated immuno-turbidimetric determination of fibrin(ogen) degradation products.

A fully automated procedure for the determination of fibrin(ogen) degradation products was developed using the I. L. Multistat Centrifugal Analyzer (MCA). The assay is based on the turbidometric measurement of the interaction between antibodies to human fibrinogen and defibrinogenated specimens. The method allows, with high reproducibility, for the accurate quantitation of degradation products between 10 and 160 micrograms/ml. A comparative study of 100 normal and abnormal patient samples revealed an excellent correlation with the semi-quantitative manual procedure. The method can be adapted to existing automated coagulation procedures and can become part of coagulation panels.

Monoclonal antibodies specific for melanocytic tumors distinguish subpopulations of melanocytes.

The authors have generated monoclonal antibodies to an extract of melanoma. When tested on a variety of fixed, embedded sections of malignant tumors, one antibody (HMB-45) reacted with 60 of 62 melanomas and none of 168 nonmelanomas (carcinomas, lymphomas, and sarcomas). The antibody reacts with junctional nevus cells but not intradermal nevi, and recognizes fetal and neonatal melanocytes but not normal adult melanocytes. This antibody thus demonstrates absolute specificity for melanocytic tumors and thus has great utility for the surgical pathologist in distinguishing among poorly differentiated tumors of uncertain origin. It also identifies differences among populations of melanocytes which may be useful in understanding the biology of and interrelationships between these cells.

A fully automated method for clot based coagulation panels using an MCA Multistat Centrifugal Analyzer.

Small modifications of the commercially available software of the I.L. Multistat Centrifugal Analyzer (MCA) enabled us to evaluate clot based prothrombin times (PT), activated partial thromboplastin times (APTT) and thrombin times (TT) simultaneously within one run. This imparted a great deal of flexibility to this procedure in that batches and/or panels of clot based and other types of turbidimetric tests can be performed concurrently in any combination. The PT and TT by this turbidimetric procedure correlated very well with those of the Fibrometer in normal specimens as well as in a wide variety of coagulation defects. The turbidimetric APTT procedure, however, often produced clotting times longer than those achieved with the Fibrometer. The discrepancy between the Fibrometer and turbidimetric APTT procedures was shown to be the consequence of greater sensitivity of the latter to detect low concentrations of heparin, elevated fibrinogen split products and mild factor deficiencies. The available clot based procedures are suitable for use in detecting specific factor deficiencies and the presence of coagulation inhibitors.

Blockade of recruitment of ovarian follicles by suppression of the secondary surge of follicle-stimulating hormone with porcine follicular field.

The increased serum concentration of follicle-stimulating hormone (FSH; follitropin) between proestrus and estrus in the rat has been hypothesized to recruit the follicles destined to ovulate in the next cycle. Injection of porcine follicular fluid (PFF) late in proestrus suppresses the secondary FSH surge; injection early in proestrus suppresses the primary FSH surge without affecting the secondary FSH surge. Thus, it is possible to use PFF to test the FSH/follicular recruitment hypothesis and to distinguish between the contributions of the primary and secondary FSH surges to this recruitment. The normal recruitment of follicles occurs in the diameter range 350-499 microns between the day of proestrus and the day of estrus. When the secondary FSH surge was suppressed by injection of PFF late in proestrus, PFF, but not porcine serum (PS), blocked follicular recruitmenet into size groups of 350-499 microns on the morning of estrus. The number of ova ovulated did not differ between PFF- and PS-treated animals. When we suppressed only the primary FSH surge, by injecting PFF early in proestrus, there were no differences between PFF- and PS-treated animals in the number of ova ovulated, follicle size distribution, or hormones. In the last experiment, the secondary FSH surge was blocked with PFF but was replaced with exogenous ovine FSH which caused a dose-related increase in follicular recruitment, substantiating the interpretation that the follicular fluid suppressed recruitment by suppressing FSH secretion. Thus, in mammals with short reproductive cycles, the gonadotropin surges provide a "fail-safe" mechanism whereby luteinizing hormone triggers ovulation, thus ending one cycle, and the secondary increase in FSH levels recruits follicles for the next cycle.