Phase II open-label study investigating apalutamide in patients with biochemical progression after radical prostatectomy.

Apalutamide, a competent inhibitor of the androgen receptor, has shown promising clinical efficacy results for patients with advanced prostate cancer. Here, we describe the rationale and design for the SAVE trial, a multi-center, Phase II study, wherein 202 men with biochemical progression after radical prostatectomy are randomly assigned 1:1 to apalutamide plus salvage radiotherapy (SRT) or androgen-deprivation therapy with an luteinizing hormone-releasing hormone agonist or antagonist plus SRT. The primary objective is to compare sexual function between the two treatment arms based on the expanded prostate cancer index-26 sexual domain score at nine months after start of hormonal treatment. The key secondary objectives are to assess quality of life, to evaluate the safety profile and the short-term efficacy of apalutamide in combination with SRT. ClinicalTrials.gov identifier: NCT03899077.

Managing postoperative biochemical relapse in prostate cancer, from the perspective of the Francophone group of Urological radiotherapy (GFRU).

Up to 50% of patients treated with radical surgery for localized prostate cancer may experience biochemical recurrence that requires appropriate management. Definitions of biochemical relapse may vary, but, in all cases, consist of an increase in a PSA without clinical or radiological signs of disease. Molecular imaging through to positron emission tomography has taken a preponderant place in relapse diagnosis, progressively replacing bone scan and CT-scan. Prostate bed radiotherapy is currently a key treatment, the action of which should be potentiated by androgen deprivation therapy. Nowadays perspectives consist in determining the best combination therapies, particularly thanks to next-generation hormone therapies, but not exclusively. Several trials are ongoing and should address these issues. We present here a literature review aiming to discuss the current management of biochemical relapse in prostate cancer after radical surgery, in lights of recent findings, as well as future perspectives.

The State of the Art of Radiotherapy for Non-melanoma Skin Cancer: A Review of the Literature.

Due to the general aging population and the fashion trend of sun exposure, non-melanoma skin cancer (NMSC) is rising. The management of NMSC is difficult and necessitates a multidisciplinary team (i.e., pathologists, dermatologists, medical oncologists, surgeons, and radiation oncologists). When surgery is not an option or will cause unacceptably functional morbidity, radiation therapy (RT) may be a preferable tissue-preserving option. Whether used alone or in conjunction with other treatments, RT has been shown to be quite effective in terms of cosmetic results and local control. Contact hypofractionated RT, brachytherapy, and electronic brachytherapy are all promising new treatments. However, rigorous, randomized trials are missing, explaining the disparity in dose, fractionation, and technique recommendations. Therefore, it is essential that interdisciplinary teams better understand RT modalities, benefits, and drawbacks. Our review will provide the role and indications for RT in patients with NMSC.

Prostate Bed Delineation Guidelines for Postoperative Radiation Therapy: On Behalf Of The Francophone Group of Urological Radiation Therapy.

PURPOSE: Prostate bed (PB) irradiation is considered the standard postoperative treatment after radical prostatectomy (RP) for tumors with high-risk features or persistent prostate-specific antigen, or for salvage treatment in case of biological relapse. Four consensus guidelines have been published to standardize practices and reduce the interobserver variability in PB delineation but with discordant recommendations. To improve the reproducibility in the PB delineation, the Francophone Group of Urological Radiotherapy (Groupe Francophone de Radiothérapie Urologique [GFRU]) worked to propose a new and more reproducible consensus guideline for PB clinical target volume (CTV) definition. METHODS AND MATERIALS: A 4-step procedure was used. First, a group of 10 GFRU prostate experts evaluated the 4 existing delineation guidelines for postoperative radiation therapy (European Organization for Research and Treatment of Cancer; the Faculty of Radiation Oncology Genito-Urinary Group; the Radiation Therapy Oncology Group; and the Princess Margaret Hospital) to identify divergent issues. Second, data sets of 50 magnetic resonance imaging studies (25 after RP and 25 with an intact prostate gland) were analyzed to identify the relevant anatomic boundaries of the PB. Third, a literature review of surgical, anatomic, histologic, and imaging data was performed to identify the relevant PB boundaries. Fourth, a final consensus on PB CTV definition was reached among experts. RESULTS: Definitive limits of the PB CTV delineation were defined using easily visible landmarks on computed tomography scans (CT). The purpose was to ensure a better reproducibility of PB definition for any radiation oncologist even without experience in postoperative radiation therapy. CONCLUSIONS: New recommendations for PB delineation based on simple anatomic boundaries and available as a CT image atlas are proposed by the GFRU. Improvement in uniformity in PB CTV definition and treatment homogeneity in the context of clinical trials are expected.

Brachytherapy in Belgium in 2018. A national survey of the brachytherapy study group of the Belgian SocieTy for Radiotherapy and Oncology (BeSTRO).

PURPOSE: To explore the current practices patterns and evaluate the actual brachytherapy (BT) resources in Belgium. MATERIAL AND METHODS: In 2019, the Brachytherapy Study Group proposed to conduct a survey on behalf of the Belgian SocieTy of Radiation Oncology (BeSTRO) in order to identify current BT practice patterns. An electronic questionnaire was sent to all primary radiotherapy centers in Belgium. This questionnaire was based on the questionnaire that was used by the Italian Association of Radiation Oncology (AIRO) in 2016, asking for: (a) General information on the Radiation Oncology Centre; (b) BT equipment and human resources; (c) BT procedures; (d) BT assessment (number of patients treated annually, treated sites, and different modalities of treatments). RESULTS: All 24 radiation oncology centers (100% response rate) answered the questionnaire and gave also information on the performance of brachytherapy in their (eventual) satellite centers. Eighteen (18) BT afterloader units were installed and operational in 2018. Thirteen centers mentioned a prostate seed implant program, one center a prostate and eye plaque program and one center only an eye plaque program. Less than 50% of centers have the infrastructure to offer the full-range of BT in their own department. In 2018, 1486 patients received a BT-treatment, 28% of them were treated by prostate seed implant, 8% were treated by eye-(seed) BT and 64% by high dose rate (HDR)/pulsed dose rate (PDR) BT. Forty-five percent of HDR/PDR patients were treated by vaginal dome BT, 22% by intra-uterine BT, 11% by skin BT, 10% by breast BT (almost exclusively in one centre), 8% for benign pathology (keloid) and the remaining 4% were treated for prostate (as a boost or as salvage in one centre), anal, penile, lung or oesophageal cancer. CONCLUSIONS: Belgian radiotherapy departments often perform BT only in a (highly) selected group of pathologies, resulting in a limited number of patients treated by this technique despite the sufficient availability of BT equipment. Modern indications are often not covered, hence patients do not have regular access to recognized treatment options, possibly leading to inferior oncological outcome. BeSTRO will use the results of this survey to stimulate improvements in training, awareness, education, implementation, collaboration and cooperation in the field of brachytherapy.

Campylobacter jejuni in Foods: Its Occurrence, Isolation from Foods, and Injury.

The following aspects of Campylobacter jejuni has been reviewed: characteristics of C. jejuni , its occurrence in foods, methods to quantitatively recover the organism from food, and heat injury and freeze-thaw stress of C. jejuni . C. jejuni can be heat injured in 0.1 M potassium phosphate buffer at 46°C. Heat injury can be demonstrated as the differential count between brucella agar plus ferrous sulfate, sodium metabisulfite and sodium pyruvate (FBP) and brilliant green 2% bile broth agar plus FBP. Heat-injured C. jejuni will grow on brucella agar containing either of the three antibiotic mixtures typically used to isolate C. jejuni . Heat-injured C. jejuni will repair (regain dye and bile tolerance) in brucella broth plus FBP. C. jejuni can be freeze-thaw stressed. This stress is demonstrated as a sensitivity to the antibiotic polymyxin B or incubation at 42°C. Addition of succinate and cysteine increased recovery of freeze-thaw stressed C. jejuni . Although the presence of injured/stressed C. jejuni in foods has not yet been detected, methods are now available to begin this search. The injury/stress process may explain the often encountered difficulty in isolating C. jejuni , especially low numbers, from foods.

Is Refrigeration Enough to Restrain Foodborne Pathogens?

Holding foods at 5°C has traditionally been viewed as adequate to restrain the growth of foodborne pathogens. However, a group of "new" foodborne pathogens has emerged, some of which are capable of competitive growth at 5°C in foods. Bacteria fitting this criterion include Clostridium botulinum type E, Yersinia enterocolitica , enterotoxigenic Escherichia coli , Listeria monocytogenes and Aeromonas hydrophilia . A second area discussed is the effect of low temperature (5°C) on survival of foodborne pathogens. Both Campylobacter jejuni and Brucella survive for longer periods at 5°C compared to 25 or 37°C. A third area considered is the growth of certain pathogens ( Salmonella , Staphylococcus aureus , Vibrio parahaemolyticus , Bacillus cereus ) at temperatures slightly above 5°C up to 12°C. Hence, temperature abuse of a food could readily generate a hazard in a food. The use of refrigeration (5°C holding of a food) can no longer be deemed sufficient to keep foods safe from bacterial hazards either by growth of the "new" pathogens or increased survival. Further, even brief temperature abuse can create hazards from certain bacteria.

Repair of Heat-Injured Staphylococcus aureus 196 E on Food Substrates and Additives and at Different Temperatures.

Repair of heat-injured Staphylococcus aureus 196E was studied on a newly developed agar medium containing 25% ground beef. The cells were heat-injured at 50 C in 0.1 M potassium phosphate buffer (pH 7.2). After being heated, the cells were surface plated on: Tryptic soy agar (TSA); TSA + 7% NaCl (TSAS); ground beef agar (GBA) with and without various additions; and meat/food agar. Repair is defined as the number of organisms growing on GBA, GBA + addition, or meat/food agar that is greater than the number growing on TSAS by at least one log cycle. The following additives incorporated into GBA permitted repair of heat-injured S. aureus : nitrite (up to 400 ppm), ascorbate (up to 500 ppm), lactic acid (down to pH 5.5), liquid smoke preparations, and water activity-lowering substances including glycerol (10%), NaCl (2.5%), KCl (5%) and sucrose (30%). Cells regained salt tolerance on TSA when incubated at temperatures from 20 to 45 C, but not at 16 or 50 C. Repair was most rapid at 35 C. When ground beef was replaced in the plating medium, repair occurred on frankfurter and chili beef soup agars, but not on pepperoni and Lebanon bologna agars. Repair of heat-injured S. aureus can take place on meat-foods, in the presence of various meat additives, and at temperatures from 20 to 45C.

Use of Starter Cultures in Meats.

Use of starter cultures in meat products is reviewed, with emphasis on the types of microorganisms employed for production of various products, and the effect of starter cultures on food safety. Desirable starter culture characteristics are identified, and the effect of fermentation on the nutritive quality of meats is considered. Food safety aspects of starter culture use discussed include the effects on survival of viruses, trichinae, and pathogenic bacteria, and on the control of mycotoxin, nitrosamine, and pressor amine contamination.

Microorganisms as Food Additives.

Microorganisms, both bacteria and fungi, are used as additives in meats. milk, cereals, vegetables and fruits to produce fermented products. The fermented foods differ from the starting material in texture, flavor and keeping quality. Fermentation causes changes in the nutritional content of foods; vitamin and amino acid levels may increase, decrease or remain static, depending on the type of microorganism used and the product fermented. Microorganisms also impart desirable flavors, improve texture and enhance digestibility of foods. Fermentation destroys food spoilage organisms and permits preservation of food. Lactobacilli in cultured milks are used to supplement the normal intestinal flora in individuals suffering from digestive ailments or enteric diseases. Cultured milks are tolerated by lactose-intolerant individuals because of lactose utilization in the gastrointestinal tract by ingested lactobacilli. If sufficient acid is formed, foods which have undergone a lactic acid fermentation, such as fermented sausages or cheese. do not support growth of food poisoning microorganisms. Products which undergo controlled commercial fungal fermentations have been shown not to contain mycotoxins. Histamines and other biogenic amines are present in cheese and other fermented products. Fermentation offers a means of producing safe, nutritious foods with desirable organoleptic qualities and extended storage stability.

Effect of Temperature, Relative Humidity, and Suspending Menstrua on the Resistance of Listeria monocytogenes to Drying.

The ability of Listeria monocytogenes to survive dehydrated storage at different temperatures (5 vs. 25°C) and relative humidities (75, 59, 35, 14, and 1%) when suspended in different menstrua was studied. L. monocytogenes survived longer when held at 5°C compared to 25°C, and when suspended in beef extract, glycerol, Karo syrup, skim milk, and canned milk compared to distilled water. The contribution of relative humidity to survival was less clear, though survival tended to be longer at the lower relative humidities. At 5°C when suspended in beef extract and held at relative humidities of 59% and below, there was less than a 2 log10 decline in the viable population (starting count ca. 105/coverslip). L. monocytogenes was not injured during drying or storage at the various relative humidities. In addition, based on the Listeria selective media evaluated, these Listeria media permitted quantitative recovery of the organism dried on surfaces. These results suggested that once L. monocytogenes has contaminated a food processing plant, it can persist for long periods in the plant environment if the temperature is low and the organism is protected by various food components.

Survival and Growth Potential of Aeromonas hydrophila in Reconditioned Pork-Processing-Plant Water †.

The growth and survival of Aeromonas hydrophila K144 was studied in reconditioned pork-processing-plant water. Neutralization of residual chlorine by thiosulfate permitted growth and long-term survival of the bacterium at temperatures ranging from 5 to 28°C; growth was also observed at 37 and 42°C but survival times were shorter. The coliform growth response, a bioassay system to measure the amount of nutrients available for microbial growth, for the reconditioned water was 2.91 ± 0.61, which agreed with our observation that this water contained sufficient nutrients to support about 3 log units of growth of A. hydrophila . Our results indicate that residual chlorine levels are necessary to prevent the growth of any A. hydrophila which might contaminate reconditioned water.

Evaluation of Inosine Monophosphate and Hypoxanthine as Indicators of Bacterial Growth in Stored Red Meat.

Newly developed high performance liquid chromatography (HPLC) methods demonstrated that changes in inosine monophosphate (IMP) and hypoxanthine occurred during storage of beef held at 5°C. The inability of a spoilage organism ( Pseudomonas fluorescens ) to metabolize nucleotides in broth culture suggested that there was not a causal relationship between bacterial growth and these changes. Experiments designed to selectively inactivate (a) the bacteria flora of meat but not its enzymes (treatment with γ-irradiation or ethylene oxide), (b) meat enzymes (inoculating autoclaved meat with pure cultures of bacteria) or (c) both bacteria and meat enzymes (uninoculated autoclaved meat) demonstrated that changes in IMP and hypoxanthine levels were the result of activity of endogenous meat enzymes.

Population Changes and Verotoxin Production of Enterohemorrhagic Escherichia coli Strains Inoculated in Milk and Ground Beef Held at Low Temperatures.

This study investigated the influence of low temperature and background flora on growth and verotoxin production by strains of enterohemorrhagic Escherichia coli in milk and ground beef. In the presence of no or low background flora, there was growth of the strains at 8°C. High background flora in ground beef inhibited growth at this temperature. In the foods held at low temperatures, only small amounts of verotoxin were detected; however, even at the optimum 37°C, there was still relatively little verotoxin formed compared to that in broth cultures. Even under nongrowth conditions (high background flora or 5°C holding temperature), the strains remained viable. These data suggest any food contaminated by these bacteria and held at the recommended temperature of 5°C will remain hazardous, and under certain conditions, holding at temperatures :≥8°Cwould increase the hazard.

Minimum and Maximum Temperatures for Growth and Verotoxin Production by Hemorrhagic Strains of Escherichia coli.

The influence of temperature on growth and verotoxin production by Escherichia coli strains was studied in brain heart infusion (BHI) broth both in shake cultures at various temperatures and in a temperature-gradient incubator. All strains of E. coli surveyed grew from at least 10 to 45°C, with some strains growing at 8° C. Verotoxin production (determined using the Vero cell-assay system) was a function of both temperature and time, with the highest titers produced at temperatures supporting the fastest growth (based on days to visible turbidity) and highest viable cell counts. However, for strains producing verotoxin, toxin production was detected at any temperature supporting growth. Three strains (of 16 tested) increased 1000-fold in viable count in 4 to 6 days at 10°C. The data presented here indicate that most E. coli strains surveyed can easily grow at ca. 10°C and thus suggest the potential for growth in temperature-abused refrigerated foods.

Thermal Resistance of Salmonella spp. and Listeria monocytogenes in Liquid Egg Yolk and Egg Yolk Products †.

The effectiveness of various pasteurization procedures in destroying Listeria monocytogenes and Salmonella enteritidis in liquid egg products was evaluated. Survivor studies were perfonned on individual strains of L. monocytogenes and L. innocua in commercially broken raw egg yolk samples after heating at 61.1, 63.3, and 64.4°C using submerged vials, and on Salmonella spp. at 60.0, 61.1, and 62.2°C. Surviving bacteria were enumerated on TSA and results expressed as D-values. The influence of aw -lowering ingredients such as salt and sugar on thermal resistance in yolk was investigated using a five-strain mixture of L. monocytogenes or a mixture of Salmonella spp. (four strains of S. enteritidis , one stain each of S. senftenberg and S. typhimurium ) at 61.1°C to 66.7°C. At 61.1°C (present minimum temperature for pasteurization of plain egg yolk), a 7-log-unit reduction of Salmonella took 1.4 to 2.4 min, whereas a 7-log-unit reduction of L. monocytogenes took 4.9 to 16.1 min. The D-value for L. monocytogenes at 64.4°C increased from 0.44 min in plain yolk to 8.26 min after a 21.5-min lag (total time to achieve 1-log-unit reduction was 30.7 min) in yolk with 10% salt and 5% sugar, and 27.3 min after a 10.5-min lag (total time 37.8 min for 1-log-unit reduction) in yolk with 20% salt. The D-value for Salmonella in egg yolk at 64.4°C was < 0.2 min, but when 10% salt was added, the D-value was 6.4 min. Aw -lowering solutes in liquid egg yolk increased the thermal resistance of Salmonella and L. monocytogenes .

Model for the Aerobic Growth of Aeromonas hydrophila K144.

The combined effects of temperature (5 to 42°C), NaCl (0.5 to 4.5%), pH (5.3 to 7.3), and NaN02 (0 to 200 µg/ml) on the aerobic growth of Aeromonas hydrophila K144 were studied in brain heart infusion (BHI) broth using a modified central composite design. Variable combinations were tested in triplicate aerobic flasks; viable cell counts were made at intervals during incubation by surface plating on tryptic soy agar. Growth curves were generated using the Gompertz equation in conjunction with a nonlinear iterative regression analysis. Values for the four Gompertz parameters (A, C, B, and M) were obtained for the variable combinations tested. Using response surface techniques, quadratic and cubic equations containing the four variables of temperature, pH, NaCl, and NaN02 were developed to yield predictive values for the B and M Gompertz values. Goodness of fit evaluation of the models was by R2 values. Comparison of predicted and observed values of B and M and evaluation of predicted lag times and generation times indicated that the quadratic model gave a better fit. Overall, the variable combinations interacted to decrease the generation time and increase the lag time. The results indicate that pH, salt, and nitrite can decrease the growth of A. hydrophila when combined with low temperature incubation.

Determination of Irradiation D-Values for Aeromonas hydrophila.

This study examined the radiation resistance of Aeromonas hydrophila , a psychrotrophic pathogen of emerging importance. Five strains of Aeromonas hydrophila (three clinical and two food isolates) were irradiated in a Cesium-137 source at doses up to 150 Krads. The bacterium was irradiated in growth broth, phosphate buffer, ground bluefish or ground beef. Surviving bacteria were counted on nutrient agar or starch ampicillin agar. Radiation resistance was expressed as D-values (dose in Krads to yield a 10-fold decrease in viable number) and ranged from 14 to 22 Krads at 2 ± 1°C for most variables studied. Decreasing the temperature during irradiation increased the radiation resistance (raised the D-values). The results of this study indicate that a pasteurizing dose of ionizing radiation of 150 Krads is sufficient to kill the levels of Aeromonas hydrophila found in retail fresh foods.

Model for the Anaerobic Growth of Aeromonas hydrophila K144.

The combined effects of temperature (5 to 42°C), NaCl (0.5 to 4.5%), pH (5.3 to 7.3), and NaNO2 (0 to 200 µg/ml) on the anaerobic growth of Aeromonas hydrophila K144 were studied in brain heart infusion broth using a modified central composite design. Variable combinations were tested in triplicate anaerobic flasks (nitrogen atmosphere in sealed trypsinizing flasks); viable cell counts were made at intervals during incubation by surface plating on tryptic soy agar. Growth curves were generated using the Gompertz equation in conjunction with a nonlinear regression analysis program. Values for the four Gompertz parameters (A, C, B, and M) were obtained for the variable combinations tested. Using response surface techniques, regressions were performed on Ln (B), Ln (M), Sqrt (B), and Sqrt (1/M); quadratic and cubic equations containing the four variables of temperature, NaCl, pH, and NaNO2 were developed to yield predictive values for the B and M Gompertz values. Goodness of fit evaluation of the models was determined by R2 values. Comparison of predicted and observed values of B and M and evaluation of predicted lag and generation times indicated that the quadratic model gave the best fit. Overall, the variable combinations interacted to affect the generation and lag times. The results indicate that pH, salt level, and nitrite level can be manipulated to decrease the growth of A. hydrophila when combined with low temperature incubation and anaerobic conditions.

Interactive Effects of Temperature, Initial pH, Sodium Chloride, and Sodium Pyrophosphate on the Growth Kinetics of Clostridium perfringens †.

The interactive effects of temperature (12 to 42°C), initial pH (5.5 to 7), sodium chloride (0 to 3%) and sodium pyrophosphate concentrations (0 to 0.3%) on the growth in Trypticase-peptone-glucose-yeast extract broth of a three-strain mixture of Clostridium perfringens vegetative cells were determined. The number of viable C. perfringens cells was determined at appropriate intervals by plating on tryptose-sulfite-cycloserine agar. Growth data were analyzed by the Gompertz equation; the gompertz B and M parameters were then used to calculate lag-phase duration, exponential growth rate, generation time, and maximum population-density values. The data indicated that the growth kinetics of C. perfringens were dependent on the interaction of the four variables, particularly in regard to exponential growth rates and lag-phase durations. Cubic models based on the natural logarithm transformation of lag-phase duration and generation time were evaluated and appeared to adequately fit the data. The data suggest that sodium pyrophosphate can have significant bacteriostatic activity against C. perfringens and may provide processed meats with a degree of protection against this microorganism, particularly if employed in conjunction with a combination of acidic pH, high salt concentrations, and adequate refrigeration.