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Abstract Background Diffusion-weighted magnetic resonance imaging (DWI) provides a measurement of tumor cellularity. We evaluated the potential of apparent diffusion coefficient (ADC) values obtained from post-external beam radiation therapy (EBRT) DWI and prior to brachytherapy (BT) to predict for complete metabolic response (CMR) in bulky cervical cancer. Methods Clinical and DWI (b value = 500 s/mm2) data were obtained from patients undergoing interstitial BT with high-risk clinical target volumes (HR-CTVs) > 30 cc. Volumes were contoured on co-registered T2 weighted images and 90th percentile ADC values were calculated. Patients were stratified by CMR (defined by PET-CT at three months post-BT). Relation of CMR with 90th percentile ADC values and other clinical factors (International Federation of Gynecology and Obstetrics (FIGO) stage, histology, tumor and HR-CTV size, pre-treatment hemoglobin, and age) was assessed both in univariate and multivariate logistic regression analyses. Youden’s J statistic was used to identify a threshold value. Results Among 45 patients, twenty-eight (62%) achieved a CMR. On univariate analysis for CMR, only 90th percentile ADC value was significant (p = 0.029) while other imaging and clinical factors were not. Borderline significant factors were HR-CTV size (p = 0.054) and number of chemotherapy cycles (p = 0.078). On multivariate analysis 90th percentile ADC (p

PurposeThe purpose of this study was to analyze the impact of prostate rectal spacers on sexual quality of life (QOL) following external beam radiation therapy (RT).Methods and materialsPatient- reported QOL was evaluated using the Expanded Prostate Cancer Index Composite (EPIC). Patients were pooled from two sources: a randomized controlled trial and a non-randomized cohort of patients from a single institution. Both cohorts used the same spacing product and QOL instrument. Analysis was limited to those with good baseline pre-treatment sexual QOL (EPIC >/= 60). Differences in QOL summary score and individual items were assessed compared with baseline and between treatment arms.ResultsA total of 128 men had good baseline sexual function and were evaluated (64% with spacer and 36% without) with QOL data available for median 33 months (range: 2.5–69.4 months). Men without spacer were more likely to have declines in sexual function (p < 0.0001), bother (p = 0.0002), and sexual summary score (p < 0.0001). A minimally important difference of 10 points (1xMID) and 20 point (2xMID) was more likely without rectal spacer [10 points: odds ratio 3.53, (95% confidence interval 1.11–11.2), p = 0.032; 20 points: odds ratio 3.29, (95% confidence interval 1.16–9.33), p = 0.025]. Seven of 13 QOL items were statistically superior with hydrogel (six of nine functional and one of four bother), while no items were statistically superior for control. At baseline, more men treated with hydrogel had erections sufficient for intercourse; however, when analyzed only by the men with best baseline erectile potential and excluding those with worse function, the benefit of rectal spacing was maintained with a higher likelihood of preservation of erections sufficient for intercourse in those treated with hydrogel.ConclusionIn this pooled analysis of QOL after prostate RT, the utilization of a hydrogel spacer was associated with better sexual QOL, less men with measurable declines in sexual QOL, and higher rates of adequate erectile function.

Objective/purpose: Previously patient reported quality of life (QOL) was reported in men with prostate cancer a mean 2 and 6 years post treatment with open radical prostatectomy (RP), 3D conformal radiation therapy (3D CRT), or 125I low dose rate (LDR) brachytherapy (BT). Herein we update the results 15 years post-treatment QOL. Materials/methods: The Expanded Prostate Cancer Index (EPIC) domains were scored with differences evaluated at a median 15.8 years follow up based upon mean EPIC summary domains by ANOVA with pairwise post-hoc comparisons adjusted for age. Patient differences of current survey from first cross-section are reported as median change in summary score for each treatment group at median of 2.2 and 6.0, and 15.8 years. Results: Among men still alive response rate was 52% in BT, 60% in 3D CRT, and 62% in RP resulting in 30, 41, and 330 QOL questionnaires to evaluate for each corresponding modality at median follow up of 15.8 years. Men were a mean 75.3, 83.6, and 79.3 years of age after RP, 3DCRT, and BT, respectively.At a median of 15.8 years, there were largely persistent differences in EPIC domains without substantial evolution in QoL from middle time points. Persistent worsening in urinary irritative and bowel domain with 3DRT or BT compared to RP. Trend towards worse urinary incontinence with RP were noted without statistical differences within radiotherapy options. Conclusion: As the EPIC patient reported outcomes with the longest follow-up, these data uniquely reveal temporal trends from 2 to 15 years post treatment. However, the treatment modalities of open RP, 3D CRT without image guidance or intensity modulation, and BT without peripheral loading or MRI guidance may not reflect modern techniques.

Introduction: Non-compliance to post-treatment cancer surveillance can lead to late detection of recurrence. This study aims to identify patients at high risk for loss of follow-up after radiotherapy for locally advanced cervical cancer. Methods: Consecutive patients with locally advanced cervical cancer treated with definitive chemoradiotherapy (2013–2020) at a community cancer center were retrospectively reviewed. The main outcome was overall follow-up compliance rate over time. Additionally, specialist-specific follow-up times, reasons for discontinuation and predictors of loss of follow-up events were evaluated. Results: The median age of the 154 patients included was 46.5 years (range: 26–84). The 6-month, 1-, 3-, and 5-year overall loss of follow-up rates were: 5.3%, 15.3%, 33.6%, and 48.2%, respectively. After a median overall follow-up time of 21.0 months, the median specialist-specific surveillance times were 17 months and 6 months with gynecologic and radiation oncologists, respectively (p

PURPOSE: Increased murine double minute 2 (MDM2) expression, independent of p53 status, is associated with increased cancer-specific mortality for men with prostate cancer treated with radiotherapy. We assessed MI-219, a small molecule inhibitor of MDM2 with improved pharmacokinetics over nutlin-3, for sensitization of prostate cancer cells to radiotherapy and androgen deprivation therapy, a standard treatment option for men with high-risk prostate cancer. EXPERIMENTAL DESIGN: The effect of MDM2 inhibition by MI-219 was assessed in vitro and in vivo with mouse xenograft models across multiple prostate cancer cell lines containing varying p53 functional status. RESULTS: MDM2 inhibition by MI-219 resulted in dose- and time-dependent p53 activation and decreased clonogenic cell survival after radiation in a p53-dependent manner. Mechanistically, radiosensitization following inhibition of MDM2 was largely the result of p53-dependent increases in apoptosis and DNA damage as evidenced by Annexin V flow cytometry and γ-H2AX foci immunofluorescence. Similarly, treatment with MI-219 enhanced response to antiandrogen therapy via a p53-dependent increase in apoptotic cell death. Lastly, triple therapy with radiation, androgen deprivation therapy, and MI-219 decreased xenograft tumor growth compared with any single- or double-agent treatment. CONCLUSION: MDM2 inhibition with MI-219 results in p53-dependent sensitization of prostate cancer cells to radiation, antiandrogen therapy, and the combination. These findings support MDM2 small molecule inhibitor therapy as a therapy intensification strategy to improve clinical outcomes in high-risk localized prostate cancer. TRANSLATIONAL RELEVANCE: The combination of radiotherapy and androgen deprivation therapy is a standard treatment option for men with high-risk prostate cancer. Despite improvements in outcomes when androgen deprivation therapy is added to radiation, men with high-risk prostate cancer have significant risk for disease recurrence, progression, and even death within the first 10 years following treatment. We demonstrate that treatment with MI-219 (an inhibitor of MDM2) results in prostate cancer cell sensitization to radiation and androgen deprivation therapy in vitro and in vivo. Triple therapy with MI-219, radiation, and androgen deprivation therapy dramatically decreased tumor growth compared with any single- or double-agent therapy. These findings provide evidence that inhibition of MDM2 is a viable means by which to enhance the efficacy of both radiation and androgen deprivation therapy and thereby improve outcomes in the treatment of prostate cancer. As such, further investigation is warranted to translate these findings to the clinical setting.

Purpose/Objective(s): We sought to assess the utility of docetaxel administered concurrently with salvage radiation therapy (SRT) following postprostatectomy biochemical failure (BF). Methods and materials: Men with postprostatectomy BF were accrued on a single-arm phase 2 clinical trial. SRT doses ranged from 64.8 to 70.2 Gy and were delivered in 1.8-Gy fractions to the prostate bed alone as the clinical target volume with a +1-cm uniform planning target volume expansion. The primary endpoint was progression-free survival at 4 years compared with the Stephenson nomogram estimate. Kaplan-Meier methods were used to assess late toxicity, BF, and distant metastases. An unplanned matched-pair analysis was performed with 19 patients treated with SRT alone. Results: Nineteen men were accrued and treated. Median follow-up was 4.8 years. Median pre-RT prostate-specific antigen level was 0.7 ng/mL (interquartile range, 0.4-1.3 ng/mL). All 8 cycles of docetaxel were completed in 17 (89%) patients. Acute grade 1-4 toxicities were observed in 79%, 50%, 58%, and 11%, respectively. A total of 68% of acute grade 1 toxicities were related to fatigue, urinary, or bowel symptoms. For grade 2 toxicities, 76% were related to neutropenia, fatigue, or urinary symptoms. Acute grade 3 and 4 toxicities were most commonly neutropenia (84% and 100%, respectively). All late toxicities were grade 1 to 2 with 89% related to bowel or urinary function. Predicted 4-year progression-free survival was 39% and observed was 42% (90% confidence interval [CI], 24-60). Matched-pair analysis demonstrated no significant improvement in BF (P = .96, hazard ratio, 0.98; 90% CI, 0.4-2.3) or distant metastases (P = .09; hazard ratio, 0.3; 90% CI, 0.07-1.2), and no difference between late bowel (P = .60) or urinary toxicity (P = .41). Conclusions: Docetaxel can safely be administered concurrently with SRT without significantly impacting posttreatment toxicity. Neutropenia was the most significant acute toxicity. Given the small sample size, no clear clinical benefit was observed. Larger studies are needed to determine the efficacy of concurrent docetaxel in this setting.

Objective: To better evaluate tertiary Gleason pattern reporting and to evaluate the impact of tertiary Gleason pattern 5 (TP5) on prostate cancer pathological features and biochemical recurrence at our large single institution. Methods: We retrospectively reviewed 1962 patients who underwent radical prostatectomy (RP) for prostate cancer; TP5 was reported in 159 cases (8.1%). Men with Gleason score (GS) 7 and GS 8 disease were divided into subgroups with and without TP5, and histopathological features were compared. Multivariate analyses were conducted to assess the impact on TP5 on biochemical-free survival (BFS). Results: Tumors possessing GS 3 + 4 with TP5 were more likely to exhibit extraprostatic extension (EPE) and had a larger tumor diameter (TD) than GS 3 + 4 alone. GS 3 + 4 with TP5 was also associated with positive surgical margins (SM), seminal vesicle involvement (SVI), and higher pre-operative prostate-specific antigen (PSA) values, but without statistical significance. GS 4 + 3 with TP5 more commonly presented with EPE, positive SM, SVI, and greater TD and pre-operative PSA level than GS 4 + 3 alone. In multivariate analysis, Gleason score, EPE, and TP5 were overall independent risk factors for PSA recurrence in this cohort. Additionally, GS 4 + 3 with TP5 was associated with shorter time to recurrence versus GS 4 + 3 alone. Conclusion: Our results emphasize the importance of TP5 and suggest that criteria for tertiary pattern reporting in prostate cancer should be standardized. Further studies are needed to evaluate the role of tertiary patterns in prognostic models.

The purpose of this work is to determine appropriate radiation therapy beam margins to account for intrafraction prostate translations for use with real-time electromagnetic position monitoring and correction strategies. Motion was measured continuously in 35 patients over 1157 fractions at 5 institutions. This data was studied using van Herk's formula of (αΣ+γσ') for situations ranging from no electromagnetic guidance to automated real-time corrections. Without electromagnetic guidance, margins of over 10 mm are necessary to ensure 95% dosimetric coverage while automated electromagnetic guidance allows the margins necessary for intrafraction translations to be reduced to submillimeter levels. Factors such as prostate deformation and rotation, which are not included in this analysis, will become the dominant concerns as margins are reduced. Continuous electromagnetic monitoring and automated correction have the potential to reduce prostate margins to 2-3 mm, while ensuring that a higher percentage of patients (99% versus 90%) receive a greater percentage (99% versus 95%) of the prescription dose.

Programmed cell death (apoptosis) is a ubiquitous means utilized by multicellular organisms for elimination of unwanted cells during development and homeostasis. Dysregulated apoptosis is implicated in an array of clinical disorders including cancer, autoimmune diseases, neurodegenerative disorders, and ischemia. During programmed cell death, a series of proteases, known as caspases, with different specificities play crucial roles in the apoptotic process. Caspase-3, a group II cysteine aspartate protease, recognizes and cleaves substrates harboring the amino acid sequence aspartic acid–glutamic acid–valine–aspartic acid (DEVD), and it plays an important role in the terminal phase of apoptosis. Here we report the development of a novel imaging platform for sensing the activation of cellular proteases. A recombinant chimeric protein was constructed, composed of a cell-surface-targeted single-chain antibody (sFv) fused to a Golgi retention signal. The DEVD tetrapeptide sequence was included between the single-chain antibody and the Golgi retention signal as a caspase-3 protease cleavage site. When expressed in cultured cells this fusion protein was localized to Golgi bodies and was not detected on the cell surface. Induction of apoptosis resulted in cleavage of the fusion protein releasing the single-chain antibody from the Golgi retention signal in a caspase-dependent manner. As a result, in cells undergoing apoptosis the single-chain antibody was visualized at the cell surface by immunofluorescence microscopy. The expression of sFv on the surface of cells in a protease-dependent manner provides a unique opportunity for real-time imaging through the use of targeted nanoparticles. This methodology may provide for a multimodal noninvasive real-time imaging of apoptosis and a new opportunity for high-throughput screening of cell-death-modulating therapeutic agents.