The novel toluidine sulphonamide EL102 shows pre-clinical in vitro and in vivo activity against prostate cancer and circumvents MDR1 resistance.

BACKGROUND: Taxanes are routinely used for the treatment of prostate cancer, however the majority of patients eventually develop resistance. We investigated the potential efficacy of EL102, a novel toluidine sulphonamide, in pre-clinical models of prostate cancer. METHODS: The effect of EL102 and/or docetaxel on PC-3, DU145, 22Rv1 and CWR22 prostate cancer cells was assessed using cell viability, cell cycle analysis and PARP cleavage assays. Tubulin polymerisation and immunofluorescence assays were used to assess tubulin dynamics. CWR22 xenograft murine model was used to assess effects on tumour proliferation. Multidrug-resistant lung cancer DLKPA was used to assess EL102 in a MDR1-mediated drug resistance background. RESULTS: EL102 has in vitro activity against prostate cancer, characterised by accumulation in G2/M, induction of apoptosis, inhibition of Hif1α, and inhibition of tubulin polymerisation and decreased microtubule stability. In vivo, a combination of EL102 and docetaxel exhibits superior tumour inhibition. The DLKP cell line and multidrug-resistant DLKPA variant (which exhibits 205 to 691-fold greater resistance to docetaxel, paclitaxel, vincristine and doxorubicin) are equally sensitive to EL102. CONCLUSION: EL102 shows potential as both a single agent and within combination regimens for the treatment of prostate cancer, particularly in the chemoresistance setting.

The impact of a fasting mimicking diet on the metabolic health of a prospective cohort of patients with prostate cancer: a pilot implementation study.

BACKGROUND: This pilot prospective study investigated the effect of a periodic fasting mimicking diet (FMD) on metabolic health factors in patients with Prostate Cancer (PC). There is a well-documented association between PC and metabolic health. Impaired metabolic health is a significant risk factor for the development of PC, and a metabolic syndrome can be induced by hormonal therapies commonly required for its management. (ClinicalTrials.gov Identifier: NCT04292041). METHODS: We introduced a periodic 4-day FMD -low in calories, sugars, and proteins but high in unsaturated fats -to a cohort of PC patients and features of metabolic syndrome. 29/35 patients completed 3-monthly cycles of the 4-consecutive day packaged FMD. We compared the subjects' baseline weight, abdominal circumference (AC), blood pressure (BP) and selected laboratory results to the same measurements 3-months after completing the FMD cycles. RESULTS: Several important metabolic factors showed improvements post-intervention. On average patients' weights dropped by 3.79 kg (95% CI: -5.61, -1.97, p = 0.0002). AC was reduced on average by 4.57 cm, (95% CI: -2.27, -6.87, p = 0.0003). There was also a decrease in systolic and diastolic BP by 9.52 mmHg (95% CI: -16.16, -2.88, p = 0.0066) and 4.48 mmHg (95% CI: -8.85, -0.43, p = 0.0316) respectively. A sub-analysis indicates that FMD had more relevant effects in 'at-risk' patients than those with normal values of risk factors for metabolic syndrome. For example, subjects with baseline levels of systolic BP > 130 mmHg experienced a greater reduction in BP(-16.04 mmHg, p = 0.0001) than those with baseline systolic BP < 130 mmHg (-0.78 mmHg, p = 0.89). CONCLUSIONS: The FMD cycles were safely introduced to this small cohort of PC patients with little or no observed toxicity, and a high overall compliance of 83%. Analysis of the metabolic variables showed an overall decrease in weight, AC, and BP. Larger clinical trials focused on metabolic risk factors, PC quality of life and progression free survival are needed to assess the effect of the FMD on prostate cancer patients.

Optical fibre based real-time measurements during an LDR prostate brachytherapy implant simulation: using a 3D printed anthropomorphic phantom.

An optical fibre sensor based on radioluminescence, using the scintillation material terbium doped gadolinium oxysulphide (Gd2O2S:Tb) is evaluated, using a 3D printed anthropomorphic phantom for applications in low dose-rate (LDR) prostate brachytherapy. The scintillation material is embedded in a 700 µm diameter cavity within a 1 mm plastic optical fibre that is fixed within a brachytherapy needle. The high spatial resolution dosimeter is used to measure the dose contribution from Iodine-125 (I-125) seeds. Initially, the effects of sterilisation on the sensors (1) repeatability, (2) response as a function of angle, and (3) response as a function of distance, are evaluated in a custom polymethyl methacrylate phantom. Results obtained in this study demonstrate that the output response of the sensor, pre- and post-sterilisation are within the acceptable measurement uncertainty ranging from a maximum standard deviation of 4.7% pre and 5.5% post respectively, indicating that the low temperature sterilisation process does not damage the sensor or reduce performance. Subsequently, an LDR brachytherapy plan reconstructed using the VariSeed treatment planning system, in an anthropomorphic 3D printed training phantom, was used to assess the suitability of the sensor for applications in LDR brachytherapy. This phantom was printed based on patient anatomy, with the volume and dimensions of the prostate designed to represent that of the patient. I-125 brachytherapy seeds, with an average activity of 0.410 mCi, were implanted into the prostate phantom under trans-rectal ultrasound guidance; following the same techniques as employed in clinical practice by an experienced radiation oncologist. This work has demonstrated that this sensor is capable of accurately identifying when radioactive I-125 sources are introduced into the prostate via a brachytherapy needle.

Optical fiber dosimeter for real-time in-vivo dose monitoring during LDR brachytherapy.

An optical fiber sensor for monitoring low dose radiation is presented. The sensor, based on radiation sensitive scintillation material, terbium doped gadolinium oxysulphide (Gd2O2S:Tb), is embedded in a cavity of 700µm diameter within a 1mm plastic optical fiber. The sensor is compared with the treatment planning system for repeatability, angular dependency, distance and accumulated radiation activity. The sensor demonstrates a high sensitivity of 152 photon counts/Gy with a temporal resolution of 0.1 seconds, with the largest repeatability error of 4.1%, to 0.361mCi of Iodine-125 the radioactive source most commonly used in LDR brachytherapy for treating prostate cancer.

Optical fibre sensors: their role in in vivo dosimetry for prostate cancer radiotherapy.

Review is made of dosimetric studies of current optical fibre technology in radiotherapy for therapeutic applications, focusing particularly on in vivo dosimetry for prostate radiotherapy. We present the various sensor designs along with the main advantages and disadvantages associated with this technology. Optical fibres are ideally placed for applications in radiotherapy dosimetry; due to their small size they are lightweight and immune to electromagnetic interferences. The small dimensions of optical fibres allows it to be easily guided within existing brachytherapy equipment; for example, within the seed implantation needle for direct tumour dose analysis, in the urinary catheter to monitor urethral dose, or within the biopsy needle holder of the transrectal ultrasound probe to monitor rectal wall dose. The article presents the range of optical fibre dosimeter designs along with the main dosimetric properties required for a modern in vivo dosimetry system to be utilised in a clinical environment.

Evaluation of tempol radioprotection in a murine tumor model.

Tempol, a stable nitroxide free radical compound, is an in vitro and in vivo radioprotector. Previous studies have shown that Tempol protects C3H mice against whole-body radiation-induced bone marrow failure. In this study, the radioprotection of tumor tissue was evaluated. RIF-1 tumor cells were implanted in female C3H mice 10 d prior to radiation. Groups of mice were injected intraperitoneally with Tempol (275 mg/kg) or PBS followed 10 min later by a single dose of radiation to the tumor bed. Tumor growth curves generated after 10 and 33.3 Gy doses of radiation showed no difference in growth between the Tempol- and PBS-treated animals. A full radiation dose-response experiment revealed a tumor control dose in 50% of the animals in 30 d (TCD(50/30)) value of 36.7 Gy for Tempol-treated mice and 41.8 Gy for saline-treated mice suggesting no protection of the RIF-1 tumor by Tempol. Tumor pharmacokinetics were done to determine why Tempol differentially protected bone marrow and not tumor cells. Differential reduction of Tempol in the RIF-1 tumor and bone marrow was evaluated with EPR spectroscopy 10, 20, and 30 min after injection. Bioreduction of Tempol to its corresponding hydroxylamine (which is not a radioprotector) occurred to a greater extent in RIF-1 tumor cells compared to bone marrow. We conclude that the differences in radioprotection may result from enhanced intratumor bioreduction of Tempol to its nonradioprotective hydroxylamine analogue. The nitroxides as a class of compounds may provide a means to exploit the redox differences between normal tissues and tumors.

Hemodynamic effect of the nitroxide superoxide dismutase mimics.

Reactive oxygen species play critical roles in a number of physiologic and pathologic processes. Nitroxides are stable free radical compounds that possess superoxide dismutase (SOD) mimetic activity and have been shown to protect against the toxicity of reactive oxygen species in vitro and in vivo. Tempol, a cell-permeable hydrophilic nitroxide, protects against oxidative stress and also is an in vitro and in vivo radioprotector. In the course of evaluating the pharmacology and toxicity of the nitroxides, Tempol and another nitroxide, 3-carbamoyl-PROXYL (3-CP), were administered intravenously in various concentrations to miniature swine. Tempol caused dose-related hypotension accompanied by reflex tachycardia and increased skin temperature. Invasive hemodynamic monitoring with Swan Ganz catheterization (SGC) confirmed the potent vasodilative effect of Tempol. However, 3-CP had no effect on porcine blood pressure. The hemodynamic effects of Tempol and 3-CP are discussed in the context of differential catalytic rate constants for superoxide disumation that may impact systemic nitric oxide (NO) levels and lead to vasodilation. These findings are consistent with a role for the superoxide ion in the modulation of blood pressure and have potential implications for the systemic use of nitroxides.

Nutritional aspects of high-altitude exposure in women.

The nutrient intake and urinary excretion characteristics of eight young university women were studied over a 4-day period at low altitude (140 m) and subsequently over a 7-day sojourn on Pikes Peak (4,300 m). High-altitude exposure was associated with a transient decrease in the consumption of protein, carbohydrate, fat, sodium, calcium, phosphorus, vitamin A, riboflavin, thiamin, and niacin and a more sustained decrease in the consumption of potassium and ascorbic acid. In most instances minimal values were observed during the first 3 days of exposure. The carbohydrate fraction of energy intake was increased at the expense of fat during this time period. Individual hypophagic responses appeared to be related to severity of acute mountain sickness. Altitude had no effect on water consumption but did lead to an average body weight loss of 1 kg. Urinary measurements revealed a marked oliguria during the entire sojourn. These measurements also showed the first 3 days to be associated with a net loss of body nitrogen and sodium. During this time period body potassium and phosphorus were conserved, and probably increased. The urea fraction of body potassium and phosphorus were conserved, and probably increased. The urea fraction of total urinary nitrogen was not affected by altitude exposure, nor was the daily excretion of uric acid and creatinine. Ammonia excretion, however, was reduced to 50% of the low-altitude value and remained at this level throughout the sojourn. With a few exceptions, the qualitative characteristics of altitude hypophagia in women were similar to those reported for men. Quantitatively, however, the responses were much more transient in women.

National Cancer Institute (phase II) study of high-grade glioma treated with accelerated hyperfractionated radiation and iododeoxyuridine: results in anaplastic astrocytoma.

PURPOSE: We report the outcome of a Phase II study of a cohort of patients with high-grade glioma treated with accelerated hyperfractionated radiation and the radiation sensitizer, iododeoxyuridine (IdUrd). METHODS AND MATERIALS: Between January 1988 and December 1990, 39 consecutive patients with high-grade glioma were enrolled and treated on a Phase II protocol including hyperfractionated radiation and IdUrd. Thirty-two patients were male and seven were female. Age range was 19 to 71 years with a median age of 38 years. IdUrd (1000 mg/m2 per day) was administered in two separate 14-day courses, the first during the initial radiation field and the second during the final cone-down field. All patients were treated consistently with partial brain technique and received 1.5 Gy/fraction twice daily to a mean total dose of 71.25 Gy (range 66-72 Gy excluding one patient who did not complete treatment). The initial field was treated to 45 Gy followed by a cone-down field covering the tumor volume plus a 1-cm margin to the final dose. Patients were assessed for acute and long-term morbidity and followed for outcome. Two patients had biopsies during the course of treatment. Flow cytometry and high performance liquid chromatography was used to evaluate the labeling index and the percent replacement of IdUrd in the biopsy specimen. RESULTS: Thirty-eight of 39 patients completed therapy. One patient died on treatment at 48 Gy and is included in the survival analysis. No patient was lost to follow-up. Twenty-one patients had Grade 3 (anaplastic astrocytoma) tumors and 18 patients had Grade 4 (glioblastoma multiforme). Median survival for the entire cohort was 23 months. For the glioblastoma multiforme patients, median survival was 15 months. The median survival of the anaplastic astrocytoma patients has not yet been reached. In the patients assessed, the range of IdUrd tumor cell incorporation was only 0-2.4%. CONCLUSION: Accelerated hyperfractionated radiation therapy with IdUrd was administered with acceptable acute toxicity. The major acute side effects of mucositis and thrombocytopenia were related to IdUrd infusion and were dose-dependent. There were no unacceptable acute toxicities referable to the radiation as delivered. With a median potential follow-up of 51 months, the actuarial median survival of the glioblastoma multiforme patients is comparable with the best previously published reports. The outcome of patients with anaplastic astrocytoma compares very favorably with even the most aggressive multi-modality approaches in the recent literature with a minimum of acute morbidity.

Biology of chronic radiation effect on tissues and wound healing.

Radiation therapy exerts both acute and chronic effects on normal tissue included within treatment fields. The physics of radiation therapy and treatment techniques to minimize deleterious effects of radiation are presented. Management of radiation-damaged skin is discussed. Radiation effect on tissue, wound healing, and tumorigenesis also are reviewed.

The initiation ritual as a model for oncology counseling.

This article examines the use of the initiation ritual of primitive people, described in the works of Mircea Eliade, as a model for counseling cancer patients, giving both meaning and structure to the interactions between patient and counselor. Within this model the patient's encounter with death, whether feared or actualized, can be used as impetus toward personal growth, whatever the stage of the person's disease process. Case examples are given to illustrate how the model can be used in practice. Comparison is also made between stages and components of the initiation ritual and other techniques used to alter a person's consciousness.

The precision of a special purpose analog computer in clinical cardiac output determination.

Three hundred dye-dilution curves taken during our first year of clinical experience with the Waters CO-4 cardiac output computer were analyzed to estimate the errors involved in its use. Provided that calibration is accurate and 5.0 mg of dye are injected for each curve, then the percentage standard deviation of measurement using this computer is about 8.7%. Included in this are the errors inherent in the computer, errors due to baseline drift, errors in the injection of dye and acutal variation of cardiac output over a series of successive determinations. The size of this error is comparable to that involved in manual calculation. The mean value of five successive curves will be within 10% of the real value in 99 cases out of 100. Advances in methodology and equipment are discussed which make calibration simpler and more accurate, and which should also improve the quality of computer determination. A list of suggestions is given to minimize the errors involved in the clinical use of this equipment.

Radiation biology of lung cancer.

The enormous problem that is lung cancer still defies satisfactory therapeutic strategy. This article summarizes some of the more important laboratory efforts directed at understanding the biology of this complex disease. The radiation sensitivities of established lung cancer cell lines are outlined. The effect of radiation dose rate and chemotherapy is explored. The emerging biology of oncogenetic alterations is explored as it relates to radiation sensitivity in general, and lung cancer in particular. Finally, novel therapeutic approaches including photodynamic therapy are introduced.

Circulating cerebriform lymphoid cells (Sezary-type cells) in a B-cell malignant lymphoma.

Circulating cerebriform lymphoid cells (Sezary cells) are considered to be highly predictive of cutaneous T-cell Lymphoma (CTCL). A leukemic peripheral blood (leukocyte count 24.5 x 10(9)/l) composed predominantly of cerebriform cells was found in a 75-year-old man presenting with weight loss and generalized lymphadenopathy but without skin lesions. Cell suspensions studies and immunohistochemistry of peripheral blood revealed that the cerebriform cells were B-cells (IgM+ Kappa+, HLA DR+, Leu 1+, CALLA-, B1+, and OKT 10+). A variety of T-cell markers (other than Leu1) was negative. Computer-assisted morphometry confirmed a nuclear profile typical of CTCL (mean nuclear contour index, 7.47). A lymph node that underwent subsequent biopsy revealed a follicular malignant lymphoma of small to intermediate cells with similar morphologic and immunologic characteristics to the circulating cerebriform cells. The findings of a leukemic presentation of a cerebriform B-cell lymphoma extends the recent observation of nodal B-cell lymphomas composed of cerebriform cells and indicates that circulating cerebriform cells should not be considered to be exclusively of T-cell origin.