Comparative Study on Adaptive Bayesian Optimization for Batch Cooling Crystallization for Slow and Fast Kinetic Regimes.

Crystallization kinetic parameter estimation is important for the classification, design, and scale-up of pharmaceutical manufacturing processes. This study investigates the impact of supersaturation and temperature on the induction time, nucleation rate, and growth rate for the compounds lamivudine (slow kinetics) and aspirin (fast kinetics). Adaptive Bayesian optimization (AdBO) has been used to predict experimental conditions that achieve target crystallization kinetic values for each of these parameters of interest. The use of AdBO to guide the choice of the experimental conditions reduced material usage up to 5-fold when compared to a more traditional statistical design of experiments (DoE) approach. The reduction in material usage demonstrates the potential of AdBO to accelerate process development as well as contribute to Net-Zero and green chemistry strategies. Implementation of AdBO can lead to reduced experimental effort and increase efficiency in pharmaceutical crystallization process development. The integration of AdBO into the experimental development workflows for crystallization development and kinetic experiments offers a promising avenue for advancing the field of autonomous data collection exploiting digital technologies and the development of sustainable chemical processes.

Outcomes following iodine-125 brachytherapy in patients with Gleason 7, intermediate risk prostate cancer: a population-based cohort study.

BACKGROUND AND PURPOSE: To evaluate outcome in patients with Gleason 7 prostate cancer treated with iodine-125 brachytherapy at the British Columbia Cancer Agency. MATERIALS AND METHODS: Between 20th July 1998 and 7th February 2006, 1500 patients underwent I-125 prostate brachytherapy without supplemental external beam radiation therapy. Of these, 439 had Gleason 7 disease; 362 had Gleason 3+4 and 77 had 4+3 disease. Generally, patients received 6 months of androgen suppression. We compared biochemical no evidence of disease (bNED) between patients with Gleason ≤ 6 and Gleason 7 and between Gleason 3+4 and 4+3 using the Phoenix definition of biochemical recurrence. RESULTS: Median follow-up was 60 months. Estimated 5 year bNED was 97% for patients with Gleason score ≤ 6 and 94% for patients with Gleason 7 disease (p=0.037). Estimated bNED was 95% and 94% for 3+4 and 4+3, respectively (p=0.791). There was no difference in bNED between implants achieving D90 ≥ versus

Biochemical control with radiotherapy improves overall survival in intermediate and high-risk prostate cancer patients who have an estimated 10-year overall survival of >90%.

PURPOSE: To identify subgroups of patients with carcinoma of the prostate treated with radical radiotherapy that have improved overall survival when disease is biochemically controlled. METHODS AND MATERIALS: A cohort of 1,060 prostate cancer patients treated with radical radiotherapy was divided into nine subgroups based on National Comprehensive Cancer Network risk category and estimated 10-year overall survival (eOS 10y) derived from the age adjusted Charlson Comorbidity Index. Patients with and without biochemical control were compared with respect to overall survival. Actuarial estimates of overall survival were calculated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards models were used for analysis of overall survival. RESULTS: Median follow-up was 125 months (range, 51-176 months). Only the subgroups with high or intermediate risk disease and an eOS 10y of >90% had a statistically significantly improved overall survival when prostate cancer was biochemically controlled. In all other groups, biochemical control made no significant difference to overall survival. In the subgroup with high-risk disease and eOS 10y >90%, actuarial overall survival was 86.3% (95% confidence interval [CI] 78.5%-94.1%) and 62.1% (95% CI 52.9%-71.3%) for patients with biochemical control and biochemical relapse respectively (p = 0.002). In the intermediate risk group with eOS >90%, actuarial overall survival was 95.3% (95% CI 89.0%-100%) and 79.8% (95% CI 68.0%-91.6%) for biochemically controlled and biochemically relapsed patients (p = 0.033). On multivariate analysis, National Comprehensive Cancer Network risk group (p = 0.005), biochemical control (p = 0.033) and eOS 10y (p < 0.001) were statistically significant. CONCLUSION: Biochemical control translates into improved overall survival in patients with high or intermediate risk disease and an estimated 10-year overall survival of >90%.

Trends in prostate cancer incidence and mortality: an analysis of mortality change by screening intensity.

BACKGROUND: The rate of death from prostate cancer has recently declined in many areas of the world. Over the past 15 years prostate-specific antigen (PSA) screening has increased in popularity, which has resulted in increases in the incidence of prostate cancer. Over the same period there have been changes in the management of the disease and, in particular, the use of androgen ablation. We set out to examine the relation between changes in prostate cancer incidence (a surrogate for PSA screening) and subsequent changes in mortality in regions using common treatment recommendations. METHODS: We used data from prostate cancer cases and deaths reported to the British Columbia Cancer Registry during 1985-1999 to examine trends in incidence and mortality in 88 small health areas (SHAs) among men aged 50-74 years. We conducted 2 analyses. In the first we classified the SHAs by intensity of PSA screening (low, medium or high) according to their ranked age-standardized incidence rate of prostate cancer in 1990-1994 and examined subsequent trends in prostate cancer mortality. In the second analysis we examined the SHA-specific relative change in prostate cancer incidence between 1985-1989 and 1990-1994 and correlated it with the relative change in mortality for cases diagnosed after 1990. RESULTS: Between 1985-1989 and 1990-1994 the incidence of prostate cancer increased by 53.2% and 14.6% among men aged 50-74 and those 75 and over respectively. Between 1985-1989 and 1995-1999 prostate cancer mortality declined by 17.6% and 7.9% in the 2 age groups respectively. Among men aged 50-74 years SHAs with low, middle and high levels of screening had respective increases in prostate cancer incidence of 5.4%, 53.6% and 70.5% between 1985-1989 and 1990-1994. Corresponding decreases in mortality between 1985-1989 and 1995-1999 were 28.9%, 18.0% and 13.5%. Mortality declines were greatest in SHAs with low screening levels (p = 0.032). Before 1990 prostate cancer mortality was similar in the 3 screening groups (p = 0.72). Regions with the smallest increases in incidence had the largest declines in mortality. INTERPRETATION: We found no association between the intensity of PSA screening and subsequent decreases in prostate cancer mortality.