Enhanced Overwintering Survival of Stevia by QoI Fungicides Used for Management of Sclerotium rolfsii.

Stevia (Stevia rebaudiana) is a herbaceous perennial under evaluation as a new crop in the southeastern United States. Stem rot caused by Sclerotium rolfsii is common in stevia plantings in North Carolina, with symptoms including wilting, root and stem necrosis, and plant death. Fungicide efficacy trials for management of S. rolfsii were conducted over 2 years. Fungicides evaluated included azoxystrobin, flutolanil, and tebuconazole applied at three timings. Azoxystrobin applied to transplants 1 week prior to planting had the lowest area under the disease progress curve values across all trials. Fungicide plots were also used to evaluate overwintering of stevia. End-of-season stand counts were compared with spring emergence counts to quantify overwintering survival. In spring 2015, plots treated with azoxystrobin in 2014 had greater overwintering survival (78%) than other fungicide treatments (38%) and the control (38%). Similar results were obtained at two locations in spring 2016 in plots treated with azoxystrobin or pyraclostrobin in 2015. Successful overwintering of stevia directly impacts the profitability of second- and third-year harvests and enhances the likelihood of long-term establishment of stevia as a viable crop. Future studies will be directed at elucidating the mechanism of the enhanced overwintering survival of plants treated with quinone outside inhibitor fungicides.

Electronic monitoring in medication adherence measurement. Implications for dermatology.

Poor adherence with prescribed therapy often results in decreased efficacy, annoying for patient both and physician. Negative health improvement adds extensive costs to the healthcare system. Thus, physicians need to carefully examine medication adherence before investigating possible pharmacologic reasons for drug failure or initiating alternative treatments and special diagnostic tests. Documenting medication adherence can also help with the development of new drugs and establishing optimized treatment regimens. Reliable distinction between non-adherence and nonresponse is a new issue for medicine, the pharmaceutical industry and its regulators. Investigation of adherence patterns has been established on evidence-based clinical and biostatistical research agendas. Originally, the term 'compliance' was used to describe how a patient adheres to a recommended therapy plan. Subsequently, 'compliance' has been changed to the more appropriate term 'adherence'. Several approaches to studying the relationship between medication adherence and medical outcome exist. This article provides an overview on medical adherence and methods of measuring adherence, especially electronic monitoring. Traditional methods of adherence assessment (patient interview, diaries, questionnaires, pill counts, prescription refill surveys) often do not deliver reliable data. Thus, researchers have tried to approach adherence by measuring serum drug concentrations or other biologic or chemical markers to gain more objective data. However, the state of the art for analyzing adherence is the use of electronic monitoring devices, electronic event monitors. Such devices not only provide more reliable data but also more detailed data about actual patient adherence, such as dose frequency, dose time, dose interval and dose timing--details that traditional methods do not show. Electronic monitoring shows that poor adherence, especially dosage omission or changing intervals, is more prevalent than previously recognized. The detailed adherence patterns provided by electronic monitoring show the need for a new kind of drugs. These drugs should provide good therapeutic coverage despite dosage omission and are therefore called 'forgiving pharmaceuticals'. Adherence and medical outcome have been extensively studied in patients with psychiatric disorders, hypertension and other cardiovascular disorders and most recently in patients receiving HIV/AIDS therapy. But non-adherence can be found in any medical field. Regarding the lack of equivalent studies on adherence and therapeutic efficacy in treating skin diseases, this topic should be looked at more closely in dermatology. Recalcitrant atopic dermatitis, psoriasis, tinea pedis and acne would be ideal study areas.

Skin hyporeactivity in relation to patch testing.

False-negative patch tests are clinically relevant. Skin hyporeactivity has been suggested as one possible cause. Evidence supports that failure to respond to a specific antigen might be due either to a faulty immune response, a defective inflammatory response or both. Thus, skin hyporeactivity may have clinical relevance in routine patch testing. Articles on this topic are infrequent and there is no index keyword for skin hyporeactivity as this phenomenon is poorly defined and investigated. This article summarizes several observations of skin hyporeactivity, reviews theories of possible mechanisms and discusses further consequences.

Design of a benchtop alpha particle irradiator.

The design, construction and calibration of a convenient irradiator is described that provides controlled exposure to a uniform external source of well-characterized alpha particles at a dose-rate of 0.99 cGy min-1. The use of a precis- ion photographic shutter allows the accurate delivery of doses as low as 0.01 mGy (1 mrad) to cultured cells. Special features also include a helium environment and reciprocal collimator that permits the use of collimators with different transmission factors to achieve differing dose-rates. A simple method is described to characterize the energy spectrum of alpha particles by use of particle range as measured by track etch.

Proton beam irradiation for treatment of experimental human retinoblastoma.

Proton beam irradiation was used to treat human retinoblastoma (Y-79 cell line) grown subcutaneously in the athymic "nude" mouse. Thirty-four tumors were included in the experimental groups, of which twenty-three were irradiated and eleven served as controls. Tumors were irradiated with protons produced at the 160 megavolts Harvard cyclotron. The dose delivered to the tumor ranged from 7.5 to 27.5 proton gray in a single treatment, and 25.0 proton gray delivered in two fractions separated by 24 hours. Reduction of tumor growth was significantly greater than controls (p less than 0.001) with treatment doses greater than or equal to 17.5 proton gray. Histologic examination revealed a marked decrease of mitotic activity in all specimens examined 48 hours after treatment at these higher doses. Total regression without evidence of remaining malignant cells was noted in three tumors treated at 17.5 proton gray or above. Our results indicate that human retinoblastoma in a murine host, with a tumor mass similar to that seen in a clinical setting, is sensitive to radiation by high energy protons.

Radiobiology of alpha particles. I. Exposure system and dosimetry.

A 238Pu alpha-particle exposure apparatus was designed and constructed for use in radiobiological studies with cultured cell systems. The system provides a wide dynamic range of absorbed doses and a uniform radiation field. Average dose rate in air was measured with a small-volume ionization chamber. Estimates of dose rate at the cell surface were obtained from measurements taken with a silicon surface barrier detector. Particle fluence uniformity and fluence rate were measured using track etch procedures. The design and dosimetric characterization of the apparatus are discussed.

Proton beam penumbra: effects of separation between patient and beam modifying devices.

The sharp lateral penumbra of a proton beam is often used to spare sensitive normal structures in treating clinical sites in which the target volume abuts, or even wraps around, these structures. Using Monte Carlo calculations and measurements, the factors which influence the penumbra of the proton beam at the Harvard Cyclotron Laboratory were investigated, with particular emphasis on the effects of separation between the patient and any beam modifying devices. Penumbra broadening, characterized by the distance over which the dose rises from 20% to 80% of the central dose, increases with greater amounts of scatterer introduced into the beam line. The broadening due to separation of the beam modifying devices and the patient is essentially linear with increasing air gap; the rate of increase depends on the details of these devices and on the depth of interest in the patient. For a particular portal, most of the parameters which affect the penumbra width are fixed by the patient's anatomy and the target volume. Only the thickness of the compensating bolus around the aperture edge and any air gap between the patient and the beam modifying devices can vary. Families of curves relating combinations of bolus thickness and air gap that maintain a constant penumbra width have been developed for guidelines during patient setup.

Proton beam irradiation and hyperthermia. Effects on experimental choroidal melanoma.

Ultrasonically induced hyperthermia (4.75 MHz) and proton irradiation (160 meV) were evaluated alone and combined to treat experimental choroidal melanoma in 58 rabbit eyes. Threshold tumoricidal doses were established for each modality. Therapy was performed combining subthreshold doses of heat and radiation. Focused ultrasonic energy via an external beam was found to deliver well-localized heat to an intraocular tumor. Ectopic temperature elevations due to soft-tissue-bone interfaces were alleviated by modifying beam alignment. The results indicate that hyperthermia (43 degrees C for one hour) potentiated the tumoricidal effects of radiation, while sparing normal ocular structures. Therefore, we believe that experimental hyperthermia is suitable as an adjuvant treatment modality. This shows that ultrasound hyperthermia has the potential to increase the efficacy of proton irradiation by lowering radiation doses and thus decreasing posttreatment ocular morbidity in human intraocular malignancies.

Proton therapy at Harvard.

Fractionated precision high-dose proton radiotherapy has been carried out at the Harvard Cyclotron Laboratory (HCL) since 1973, in a collaborative effort with the Radiation Medicine Department of Massachusetts General Hospital (MGH) and the Retina Service of the Massachusetts Eye and Ear Infirmary (MEEI). This paper will discuss proton treatment in general, treatment planning procedures, and results to date in major patient categories. 846 patients have been treated with fractionated proton therapy at the Harvard Cyclotron, with normal tissue and tumor responses consistent with an RBE of 1.1 for the proton beam. Proton beam therapy is the treatment of choice for patients with uveal melanomas, and chordomas and chondrosarcomas involving the skull base and cervical spine. Improved dose distribution possible with protons have allowed greater doses than are given conventionally to be delivered to patients with prostatic carcinoma, head and neck malignancies, ano-rectal cancers, and retroperitoneal tumors. Doses employed have been usually 10 to 20% greater than normally would be delivered in our department to such tumors. Generally, local control rates have been good.

Potential for low-LET charged-particle radiation therapy in cancer.

The current and likely future status of low-LET charged-particle therapy of cancer is reviewed with regard to both physical and clinical aspects. We conclude that such therapy has reached the stage at which clinical implementation is practical and that a broader program is needed if the clinical advantages of improved dose distributions are to be determined.

Progress in low-LET heavy particle therapy: intracranial and paracranial tumors and uveal melanomas.

The Harvard Cyclotron Laboratory in collaboration with the Department of Radiation Medicine of the Massachusetts General Hospital and the Retina Service of the Massachusetts Eye and Ear Infirmary provides low-LET heavy particle therapy with 160 MeV protons. The improved dose distribution of protons results from their physical characteristics. A total of 965 patients have been treated as of December 31, 1984. Dose is expressed in units of cobalt gray equivalent (CGE) which is the dose in Gy multiplied by the RBE (1.1) for modulated protons relative to 60Co radiation. Sixty-seven patients with chordomas or low-grade chondrosarcomas of the base of skull or cervical spine have received proton treatment. Forty-three of these patients have been followed for at least 8 months with a median follow-up of 27 months. The median dose is 69 CGE. The 3-year actuarial local control rate is 89%. Seven patients with gliomas, eight with craniopharyngiomas, and six with meningiomas have also received proton radiation treatments. A total of 615 patients with uveal melanomas have received a median dose of 70 CGE in five fractions. Tumor regression has been seen in 94% with 66% having vision of 20/100 or better.

Energy of proton accelerator necessary for treatment of choroidal melanomas.

We have reviewed 94 patients with choroidal melanoma treated by proton beam therapy at the Harvard Cyclotron Laboratory. A beam penetration of f27 mm would be required to treat 90% of the lesions. We conclude that a machine energy of at least 55 and, preferably, 60 MeV would be necessary for a clinically viable therapy unit for the treatment of choroidal melanomas. An extracted beam current of 10(-9) A would be more than sufficient.

Evaluation of the clinical applicability of proton beams in definitive fractionated radiation therapy.

We report on the treatment of 317 patients treated either wholly or in part with proton beams at the Harvard Cyclotron Laboratory. These include: 130 patients treated for definitive radiation therapy of choroidal melanoma; 17 patients treated for tumors of the base of skull, cervical spine and cranium, which abut structures of the central nervous system (CNS); 23 patients treated for sarcomas of soft tissue and bone; 65 patients treated for carcinoma of the prostate; 14 patients treated for carcinoma of the rectum and anus; and 23 patients treated for squamous carcinoma of the oral cavity and oro-pharynx. Data on causes of failure and morbidity of treatment are presented. Overall the results are judged to be extremely encouraging. In particular, the treatment of the choroidal melanomas and sarcomas abutting CNS structures have clear clinical value, and the treatment of prostatic tumors and tumors of the head and neck are thought to be promising.

Clinical experience with proton beam radiation therapy.

Our experience with modulated energy proton beams in the definitive treatment of cancer patients indicates that, for the patients accepted, treatment volumes have been smaller and total doses higher than would have obtained for photon techniques alone used in our institution. The reactions of normal tissue have, with very few exceptions, been readily acceptable. The higher radiation doses employed should yield higher tumor control frequencies. Clearly, we cannot assess the efficacy of this modality because of the small number of patients followed for short periods. However, the results are judged by use to warrant intensive evaluation of this modality.

Proton radiation as boost therapy for localized prostatic carcinoma.

A 160-MeV proton beam has been modified to irradiate patients with localized tumors by using convention treatment schedules. This proton beam has the physical advantage of megavoltage x-rays of reducing the radiation dose to normal tissues adjacent to the tumor volume. A perineal proton technique used as boost therapy (2,000 to 2,500 rads) was evaluated in the definitive irradiation of 17 patients with localized prostatic carcinoma. This technique allows repeated daily treatment of the carefully defined target volume with a precision of +/- 2 mm. Total dose to the prostatic tumor, but not to the posterior rectum, has been increased by 500 to 700 rads. After 12 to 27 months of observation, no noteworthy rectal reaction has developed in a patient, easily managed urethral strictures have developed in two patients, and all but one are locally controlled.

A heavy particle comparative study. Part I: depth-dose distributions.

The results of a comparative study of heavy particles of interest in radiotherapy, with peaks spread over a depth of 10 cm, are reported in four parts. The introduction to this study and the depth-dose distributions of the particles, (n, pi-, p, He, C, Ne, and Ar ions) are reported herein. The results indicate that protons give the best localization of dose. The degree of localization of dose with heavy ions is reduced with increasing charge on the ion. For ranges less than 15cm, heavier ions such as neon and argon still have favourable dose localization; however, for ranges in excess of 15 cm, heavy ions such as argon are unfavourable but superior to fast neutrons because penetration can be controlled by modulation of energy or range.