Uncovering prostate cancer aggressiveness signal in T2-weighted MRI through a three-reference tissues normalization technique.

Quantitative T2-weighted MRI (T2W) interpretation is impeded by the variability of acquisition-related features, such as field strength, coil type, signal amplification, and pulse sequence parameters. The main purpose of this work is to develop an automated method for prostate T2W intensity normalization. The procedure includes the following: (i) a deep learning-based network utilizing MASK R-CNN for automatic segmentation of three reference tissues: gluteus maximus muscle, femur, and bladder; (ii) fitting a spline function between average intensities in these structures and reference values; and (iii) using the function to transform all T2W intensities. The T2W distributions in the prostate cancer regions of interest (ROIs) and normal appearing prostate tissue (NAT) were compared before and after normalization using Student's t-test. The ROIs' T2W associations with the Gleason Score (GS), Decipher genomic score, and a three-tier prostate cancer risk were evaluated with Spearman's correlation coefficient (rS ). T2W differences in indolent and aggressive prostate cancer lesions were also assessed. The MASK R-CNN was trained with manual contours from 32 patients. The normalization procedure was applied to an independent MRI dataset from 83 patients. T2W differences between ROIs and NAT significantly increased after normalization. T2W intensities in 231 biopsy ROIs were significantly negatively correlated with GS (rS = -0.21, p = 0.001), Decipher (rS = -0.193, p = 0.003), and three-tier risk (rS = -0.235, p < 0.001). The average T2W intensities in the aggressive ROIs were significantly lower than in the indolent ROIs after normalization. In conclusion, the automated triple-reference tissue normalization method significantly improved the discrimination between prostate cancer and normal prostate tissue. In addition, the normalized T2W intensities of cancer exhibited a significant association with tumor aggressiveness. By improving the quantitative utilization of the T2W in the assessment of prostate cancer on MRI, the new normalization method represents an important advance over clinical protocols that do not include sequences for the measurement of T2 relaxation times.

The addition of androgen deprivation therapy and pelvic lymph node treatment to prostate bed salvage radiotherapy (NRG Oncology/RTOG 0534 SPPORT): an international, multicentre, randomised phase 3 trial.

BACKGROUND: In men with a detectable prostate-specific antigen (PSA) level after prostatectomy for prostate cancer, salvage prostate bed radiotherapy (PBRT) results in about 70% of patients being free of progression at 5 years. A three-group randomised trial was designed to determine whether incremental gains in patient outcomes can be achieved by adding either 4-6 months of short-term androgen deprivation therapy (ADT) to PBRT, or both short-term ADT and pelvic lymph node radiotherapy (PLNRT) to PBRT. METHODS: The international, multicentre, randomised, controlled SPPORT trial was done at 283 radiation oncology cancer treatment centres in the USA, Canada, and Israel. Eligible patients (aged ≥18 years) were those who after prostatectomy for adenocarcinoma of the prostate had a persistently detectable or an initially undetectable and rising PSA of between 0·1 and 2·0 ng/mL. Patients with and without lymphadenectomy (N0/Nx) were eligible if there was no clinical or pathological evidence of lymph node involvement. Other eligibility criteria included pT2 or pT3 disease, prostatectomy Gleason score of 9 or less, and a Zubrod performance status of 0-1. Eligible patients were randomly assigned to receive PBRT alone at a dose of 64·8-70·2 Gy at 1·8 Gy per fraction daily (group 1), PBRT plus short-term ADT (group 2), or PLNRT (45 Gy at 1·8 Gy per fraction, and then a volume reduction made to the planning target volume for the remaining 19·8-25 ·2 Gy) plus PBRT plus short-term ADT (group 3). The primary endpoint was freedom from progression, in which progression was defined as biochemical failure according to the Phoenix definition (PSA ≥2 ng/mL over the nadir PSA), clinical failure (local, regional, or distant), or death from any cause. A planned interim analysis of 1191 patents with minimum potential follow-up time of 5 years applied a Haybittle-Peto boundary of p<0·001 (one sided) for comparison of 5-year freedom from progression rates between the treatment groups. This trial is registered with ClinicalTrials.gov, NCT00567580. The primary objectives of the trial have been completed, although long-term follow-up is continuing. FINDINGS: Between March 31, 2008, and March 30, 2015, 1792 eligible patients were enrolled and randomly assigned to the three treatment groups (592 to group 1 [PBRT alone], 602 to group 2 [PBRT plus short-term ADT], and 598 to group 3 [PLNRT plus PBRT plus short-term ADT]). 76 patients subsequently found to be ineligible were excluded from the analyses; thus, the evaluable patient population comprised 1716 patients. At the interim analysis (n=1191 patients; data cutoff May 23, 2018), the Haybittle-Peto boundary for 5-year freedom from progression was exceeded when group 1 was compared with group 3 (difference 17·9%, SE 2·9%; p<0·0001). The difference between groups 2 and 3 did not exceed the boundary (p=0·0063). With additional follow-up beyond the interim analysis (the final planned analysis; data cutoff May 26, 2021), at a median follow-up among survivors of 8·2 years (IQR 6·6-9·4), the 5-year freedom from progression rates in all 1716 eligible patients were 70·9% (95% CI 67·0-74·9) in group 1, 81·3% (78·0-84·6) in group 2, and 87·4% (84·7-90·2) in group 3. Per protocol criteria, freedom from progression in group 3 was superior to groups 1 and 2. Acute (≤3 months after radiotherapy) grade 2 or worse adverse events were significantly more common in group 3 (246 [44%] of 563 patients) than in group 2 (201 [36%] of 563; p=0·0034), which, in turn, were more common than in group 1 (98 [18%] of 547; p<0·0001). Similar findings were observed for grade 3 or worse adverse events. However, late toxicity (>3 months after radiotherapy) did not differ significantly between the groups, apart from more late grade 2 or worse blood or bone marrow events in group 3 versus group 2 (one-sided p=0·0060) attributable to the addition of PLNRT in this group. INTERPRETATION: The results of this randomised trial establish the benefit of adding short-term ADT to PBRT to prevent progression in prostate cancer. To our knowledge, these are the first such findings to show that extending salvage radiotherapy to treat the pelvic lymph nodes when combined with short-term ADT results in meaningful reductions in progression after prostatectomy in patients with prostate cancer. FUNDING: National Cancer Institute.

SMPDL3b modulates radiation-induced DNA damage response in renal podocytes.

The kidneys are radiosensitive and dose-limiting organs for radiotherapy (RT) targeting abdominal and paraspinal tumors. Excessive radiation doses to the kidneys ultimately lead to radiation nephropathy. Our prior work unmasked a novel role for the lipid-modifying enzyme, sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b), in regulating the response of renal podocytes to radiation injury. In this study, we investigated the role of SMPDL3b in DNA double-strand breaks (DSBs) repair in vitro and in vivo. We assessed the kinetics of DSBs recognition and repair along with the ATM pathway and nuclear sphingolipid metabolism in wild-type (WT) and SMPDL3b overexpressing (OE) human podocytes. We also assessed the extent of DNA damage repair in SMPDL3b knock-down (KD) human podocytes, and C57BL6 WT and podocyte-specific SMPDL3b-knock out (KO) mice after radiation injury. We found that SMPDL3b overexpression enhanced DSBs recognition and repair through modulating ATM nuclear shuttling. OE podocytes were protected against radiation-induced apoptosis by increasing the phosphorylation of p53 at serine 15 and attenuating subsequent caspase-3 cleavage. SMPDL3b overexpression prevented radiation-induced alterations in nuclear ceramide-1-phosphate (C1P) and ceramide levels. Interestingly, exogenous C1P pretreatment radiosensitized OE podocytes by delaying ATM nuclear foci formation and DSBs repair. On the other hand, SMPDL3b knock-down, in vitro and in vivo, induced a significant delay in DSBs repair. Additionally, increased activation of apoptosis was induced in podocytes of SMPDL3b-KO mice compared to WT mice at 24 h post-irradiation. Together, our results unravel a novel role for SMPDL3b in radiation-induced DNA damage response. The current work suggests that SMPDL3b modulates nuclear sphingolipid metabolism, ATM nuclear shuttling, and DSBs repair.

Percentage of Gleason pattern 4 and tumor volume predict adverse pathological stage and margin status at radical prostatectomy in grade Group 2 and grade Group 3 prostate cancers.

BACKGROUND: Increasing percentages of Gleason pattern 4 (GP4%) in radical prostatectomy (RP) correlate with an increased likelihood of nonorgan-confined disease and earlier biochemical recurrence (BCR). However, there are no detailed RP studies assessing the impact of GP4% and corresponding tumor volume (TV) on extraprostatic extension (EPE), seminal vesicle (SV) invasion (SV+), and positive surgical margin (SM) status (SM+). METHODS: In 1301 consecutive RPs, we analyzed each tumor nodule (TN) for TV, Grade Group (GG), presence of focal versus nonfocal EPE, SV+ , and SM+. Using GG1 (GP4% = 0) TNs as a reference, we recorded GP4% for all GG2 or GG3 TNs. We performed a multivariable analysis (MVA) using a mixed effects logistic regression that tested significant variables for risk of EPE, SV+, and SM+, as well as a multinomial logistic regression model that tested significant variables for risks of nonorgan-confined disease (pT2+, pT3a, and pT3b) versus organ-confined disease (pT2). RESULTS: We identified 3231 discrete TNs ranging from 1 to 7 (median: 2.5) per RP. These included GG1 (n = 2115), GG2 (n = 818), GG3 (n = 274), and GG4 (n = 24) TNs. Increasing GP4% weakly paralleled increasing TV (tau = 0.07, p < .001). In MVA, increasing GP4% and TV predicted a greater likelihood of EPE (odds ratio [OR]: 1.03 and 4.41), SV+ (OR: 1.03 and 3.83), and SM+ (1.01, p = .01 and 2.83), all p < .001. Our multinomial logistic regression model demonstrated an association between GP4% and the risk of EPE (i.e., pT3a and pT3b disease), as well as an association between TV and risk of upstaging (all p < .001). CONCLUSIONS: Both GP4% and TV are independent predictors of adverse pathological stage and margin status at RP. However, the risks for adverse outcomes associated with GP4% are marginal, while those for TV are strong. The prognostic significance of GP4% on BCR-free survival has not been studied controlling for TV and other adverse RP findings. Whether adverse pathological stage and margin status associated with larger TV could decrease BCR-free survival to a greater extent than increasing RP GP4% remains to be studied.

Heterogeneity in Genomic Risk Assessment from Tissue Based Prognostic Signatures Used in the Biopsy Setting and the Impact of Magnetic Resonance Imaging Targeted Biopsy.

PURPOSE: Genomic prognostic signatures are used on prostate biopsy tissue for cancer risk assessment, but tumor heterogeneity and multifocality may be an issue. We evaluated the variability in genomic risk assessment from different biopsy cores within the prostate using 3 prognostic signatures (Decipher, CCP, GPS). MATERIALS AND METHODS: Men in this study came from 2 prospective prostate cancer trials of patients undergoing multiparametric magnetic resonance imaging and magnetic resonance imaging targeted biopsy with genomic profiling of positive biopsy cores. We explored the relationship among tumor grade, magnetic resonance imaging risk and genomic risk for each signature. We evaluated the variability in genomic risk assessment between different biopsy cores and assessed how often magnetic resonance imaging targeted biopsy or the current standard of care (profiling the core with the highest grade) resulted in the highest genomic risk level. RESULTS: In all, 224 positive biopsy cores from 78 men with prostate cancer were profiled. For each signature, higher biopsy grade (p <0.001) and magnetic resonance imaging risk level (p <0.001) were associated with higher genomic scores. Genomic scores from different biopsy cores varied with risk categories changing by 21% to 62% depending on which core or signature was used. Magnetic resonance imaging targeted biopsy and profiling the core with the highest grade resulted in the highest genomic risk level in 72% to 84% and 75% to 87% of cases, respectively, depending on the signature used. CONCLUSIONS: There is variation in genomic risk assessment from different biopsy cores regardless of the signature used. Magnetic resonance imaging directed biopsy or profiling the highest grade core resulted in the highest genomic risk level in most cases.

A personalized decision aid for prostate cancer shared decision making.

BACKGROUND: A shared decision-making model is preferred for engaging prostate cancer patients in treatment decisions. However, the process of assessing an individual's preferences and values is challenging and not formalized. The purpose of this study is to develop an automated decision aid for patient-centric treatment decision-making using decision analysis, preference thresholds and value elicitations to maximize the compatibility between a patient's treatment expectations and outcome. METHODS: A template for patient-centric medical decision-making was constructed. The inputs included prostate cancer risk group, pre-treatment health state, treatment alternatives (primarily focused on radiation in this model), side effects (erectile dysfunction, urinary incontinence, nocturia and bowel incontinence), and treatment success (5-year freedom from biochemical failure). A linear additive value function was used to combine the values for each attribute (side effects, success and the alternatives) into a value for all prospects. The patient-reported toxicity probabilities were derived from phase II and III trials. The probabilities are conditioned on the starting state for each of the side effects. Toxicity matrices for erectile dysfunction, urinary incontinence, nocturia and bowel incontinence were created for the treatment alternatives. Toxicity probability thresholds were obtained by identifying the patient's maximum acceptable threshold for each of the side effects. Results are represented as a visual. R and Rstudio were used to perform analyses, and R Shiny for application creation. RESULTS: We developed a web-based decision aid. Based on preliminary use of the application, every treatment alternative could be the best choice for a decision maker with a particular set of preferences. This result implies that no treatment has determinist dominance over the remaining treatments and that a preference-based approach can help patients through their decision-making process, potentially affecting compliance with treatment, tolerance of side effects and satisfaction with the decision. CONCLUSIONS: We present a unique patient-centric prostate cancer treatment decision aid that systematically assesses and incorporates a patient's preferences and values to rank treatment options by likelihood of achieving the preferred outcome. This application enables the practice and study of personalized medicine. This model can be expanded to include additional inputs, such as genomics, as well as competing, concurrent or sequential therapies.

The role of radiomics in prostate cancer radiotherapy.

"Radiomics," as it refers to the extraction and analysis of a large number of advanced quantitative radiological features from medical images using high-throughput methods, is perfectly suited as an engine for effectively sifting through the multiple series of prostate images from before, during, and after radiotherapy (RT). Multiparametric (mp)MRI, planning CT, and cone beam CT (CBCT) routinely acquired throughout RT and the radiomics pipeline are developed for extraction of thousands of variables. Radiomics data are in a format that is appropriate for building descriptive and predictive models relating image features to diagnostic, prognostic, or predictive information. Prediction of Gleason score, the histopathologic cancer grade, has been the mainstay of the radiomic efforts in prostate cancer. While Gleason score (GS) is still the best predictor of treatment outcome, there are other novel applications of quantitative imaging that are tailored to RT. In this review, we summarize the radiomics efforts and discuss several promising concepts such as delta-radiomics and radiogenomics for utilizing image features for assessment of the aggressiveness of prostate cancer and its outcome. We also discuss opportunities for quantitative imaging with the advance of instrumentation in MRI-guided therapies.

Segmentation of prostate and prostate zones using deep learning : A multi-MRI vendor analysis.

PURPOSE: Develop a deep-learning-based segmentation algorithm for prostate and its peripheral zone (PZ) that is reliable across multiple MRI vendors. METHODS: This is a retrospective study. The dataset consisted of 550 MRIs (Siemens-330, General Electric[GE]-220). A multistream 3D convolutional neural network is used for automatic segmentation of the prostate and its PZ using T2-weighted (T2-w) MRI. Prostate and PZ were manually contoured on axial T2­w. The network uses axial, coronal, and sagittal T2­w series as input. The preprocessing of the input data includes bias correction, resampling, and image normalization. A dataset from two MRI vendors (Siemens and GE) is used to test the proposed network. Six different models were trained, three for the prostate and three for the PZ. Of the three, two were trained on data from each vendor separately, and a third (Combined) on the aggregate of the datasets. The Dice coefficient (DSC) is used to compare the manual and predicted segmentation. RESULTS: For prostate segmentation, the Combined model obtained DSCs of 0.893 ± 0.036 and 0.825 ± 0.112 (mean ± standard deviation) on Siemens and GE, respectively. For PZ, the best DSCs were from the Combined model: 0.811 ± 0.079 and 0.788 ± 0.093. While the Siemens model underperformed on the GE dataset and vice versa, the Combined model achieved robust performance on both datasets. CONCLUSION: The proposed network has a performance comparable to the interexpert variability for segmenting the prostate and its PZ. Combining images from different MRI vendors on the training of the network is of paramount importance for building a universal model for prostate and PZ segmentation.

Towards a universal MRI atlas of the prostate and prostate zones : Comparison of MRI vendor and image acquisition parameters.

BACKGROUND AND PURPOSE: The aim of this study was to evaluate an automatic multi-atlas-based segmentation method for generating prostate, peripheral (PZ), and transition zone (TZ) contours on MRIs with and without fat saturation (±FS), and compare MRIs from different vendor MRI systems. METHODS: T2-weighted (T2) and fat-saturated (T2FS) MRIs were acquired on 3T GE (GE, Waukesha, WI, USA) and Siemens (Erlangen, Germany) systems. Manual prostate and PZ contours were used to create atlas libraries. As a test MRI is entered, the procedure for atlas segmentation automatically identifies the atlas subjects that best match the test subject, followed by a normalized intensity-based free-form deformable registration. The contours are transformed to the test subject, and Dice similarity coefficients (DSC) and Hausdorff distances between atlas-generated and manual contours were used to assess performance. RESULTS: Three atlases were generated based on GE_T2 (n = 30), GE_T2FS (n = 30), and Siem_T2FS (n = 31). When test images matched the contrast and vendor of the atlas, DSCs of 0.81 and 0.83 for T2 ± FS were obtained (baseline performance). Atlases performed with higher accuracy when segmenting (i) T2FS vs. T2 images, likely due to a superior contrast between prostate vs. surrounding tissue; (ii) prostate vs. zonal anatomy; (iii) in the mid-gland vs. base and apex. Atlases performance declined when tested with images with differing contrast and MRI vendor. Conversely, combined atlases showed similar performance to baseline. CONCLUSION: The MRI atlas-based segmentation method achieved good results for prostate, PZ, and TZ compared to expert contoured volumes. Combined atlases performed similarly to matching atlas and scan type. The technique is fast, fully automatic, and implemented on commercially available clinical platform.

Assessment of specific versus combined purpose knowledge based models in prostate radiotherapy.

Knowledge-based planning (KBP) can be used to improve plan quality, planning speed, and reduce the inter-patient plan variability. KPB may also identify and reduce systematic variations in VMAT plans, something very important in multi-institutional clinical trials. Training of a KBP library is a complex and difficult process, and models must be validated prior to their clinical use. The purpose of this work is to assess the quality of the treatment plans generated using a specific versus combined purpose model KBP library for prostate cancer. Seven KBP model libraries were created from a set of patients treated on various Institutional Review Board (IRB) approved protocols. All KBP libraries were validated using an independent set of twenty patients (half treated Pr: Prostate alone half treated PLN: prostate plus pelvic lymph nodes). Two models were tested on the Pr patients only, four tested on PLN patients only, and one tested on all patients. All plans were normalized such that at least 95% of the prostate planning target volume received 100% of the planned dose. The plans based on different model libraries were compared to each other and the expert clinical plan. For Pr plans there were almost no statistically significant differences (P < 0.008) between the plans types except conformity index (CI) with library plans better than the expert. For PLN plans, all model libraries in generally showed femur doses and CI better than the expert plans (P < 0.003). This study demonstrated that no large differences were observed between specific versus combined KBP model libraries in dosimetry of prostate cancer patients. This would allow for a fewer specific plans to be needed to create a model library. Further studies are needed to evaluate benefits of combined purpose model libraries for planning of complex sites such as head and neck cancer.

Validation of a deformable MRI to CT registration algorithm employing same day planning MRI for surrogate analysis.

PURPOSE: Validating deformable multimodality image registrations is challenging due to intrinsic differences in signal characteristics and their spatial intensity distributions. Evaluating multimodality registrations using these spatial intensity distributions is also complicated by the fact that these metrics are often employed in the registration optimization process. This work evaluates rigid and deformable image registrations of the prostate in between diagnostic-MRI and radiation treatment planning-CT by utilizing a planning-MRI after fiducial marker placement as a surrogate. The surrogate allows for the direct quantitative analysis that can be difficult in the multimodality domain. METHODS: For thirteen prostate patients, T2 images were acquired at two different time points, the first several weeks prior to planning (diagnostic-MRI) and the second on the same day as the planning-CT (planning-MRI). The diagnostic-MRI was deformed to the planning-CT utilizing a commercially available algorithm which synthesizes a deformable image registration (DIR) algorithm from local rigid registrations. The planning-MRI provided an independent surrogate for the planning-CT for assessing registration accuracy using image similarity metrics, including Pearson correlation and normalized mutual information (NMI). A local analysis was performed by looking only within the prostate, proximal seminal vesicles, penile bulb, and combined areas. RESULTS: The planning-MRI provided an excellent surrogate for the planning-CT with residual error in fiducial alignment between the two datasets being submillimeter, 0.78 mm. DIR was superior to the rigid registration in 11 of 13 cases demonstrating a 27.37% improvement in NMI (P < 0.009) within a regional area surrounding the prostate and associated critical organs. Pearson correlations showed similar results, demonstrating a 13.02% improvement (P < 0.013). CONCLUSION: By utilizing the planning-MRI as a surrogate for the planning-CT, an independent evaluation of registration accuracy is possible. This population provides an ideal testing ground for MRI to CT DIR by obviating the need for multimodality comparisons which are inherently more challenging.

Dynamic contrast-enhanced MRI for automatic detection of foci of residual or recurrent disease after prostatectomy.

PURPOSE: This study aimed to develop an automated procedure for identifying suspicious foci of residual/recurrent disease in the prostate bed using dynamic contrast-enhanced-MRI (DCE-MRI) in prostate cancer patients after prostatectomy. MATERIALS AND METHODS: Data of 22 patients presenting for salvage radiotherapy (RT) with an identified gross tumor volume (GTV) in the prostate bed were analyzed retrospectively. An unsupervised pattern recognition method was used to analyze DCE-MRI curves from the prostate bed. Data were represented as a product of a number of signal-vs.-time patterns and their weights. The temporal pattern, characterized by fast wash-in and gradual wash-out, was considered the "tumor" pattern. The corresponding weights were thresholded based on the number (1, 1.5, 2, 2.5) of standard deviations away from the mean, denoted as DCE1.0, …, DCE2.5, and displayed on the T2-weighted MRI. The resultant four volumes were compared with the GTV and maximum pre-RT prostate-specific antigen (PSA) level. Pharmacokinetic modeling was also carried out. RESULTS: Principal component analysis determined 2-4 significant patterns in patients' DCE-MRI. Analysis and display of the identified suspicious foci was performed in commercial software (MIM Corporation, Cleveland, OH, USA). In general, DCE1.0/DCE1.5 highlighted larger areas than GTV. DCE2.0 and GTV were significantly correlated (r = 0.60, p < 0.05). DCE2.0/DCA2.5 were also significantly correlated with PSA (r = 0.52, 0.67, p < 0.05). Ktrans for DCE2.5 was statistically higher than the GTV's Ktrans (p < 0.05), indicating that the automatic volume better captures areas of malignancy. CONCLUSION: A software tool was developed for identification and visualization of the suspicious foci in DCE-MRI from post-prostatectomy patients and was integrated into the treatment planning system.

Quantification of the margin required for treating intraprostatic lesions.

Advances in magnetic resonance imaging (MRI) sequences allow physicians to define the dominant intraprostatic lesion (IPL) in prostate radiation therapy treat-ments allowing for dose escalation and potentially increased tumor control. This work quantifies the margin required around the MRI-defined IPL accounting for both prostate motion and deformation. Ten patients treated with a simultaneous integrated intraprostatic boost (SIIB) were retrospectively selected and replanned with incremental 1 mm margins from 0-5 mm around the IPL to determine if there were any significant differences in dosimetric parameters. Sensitivity analysis was then performed accounting for random and systematic uncertainties in both prostate motion and deformation to ensure adequate dose was delivered to the IPL. Prostate deformation was assessed using daily CBCT imaging and implanted fiducial markers. The average IPL volume without margin was 2.3% of the PTV volume and increased to 11.8% with a 5 mm margin. Despite these changes in vol-ume, the only statistically significant dosimetric difference was found for the PTV maximum dose, which increased with increasing margin. The sensitivity analysis demonstrated that a 3.0 mm margin ensures > 95% IPL coverage accounting for both motion and deformation. We found that a margin of 3.0 mm around the MRI defined IPL is sufficient to account for random and systematic errors in IPL posi-tion for the majority of cases.

Activation of Stimulator of Interferon Genes (STING): Promising Strategy to Overcome Immune Resistance in Prostate Cancer.

Prostate cancer (PCa) is the most frequent and second-lethal cancer among men. Despite considerable efforts to explore treatments like autologous cellular immunotherapy and immune checkpoint inhibitors, their success remains limited. The intricate tumor microenvironment (TME) and its interaction with the immune system pose significant challenges in PCa treatment. Consequently, researchers have directed their focus on augmenting the immune system's anti-tumor response by targeting the STimulator of the Interferon Genes (STING) pathway. The STING pathway is activated when foreign DNA is detected in the cytoplasm of innate immune cells, resulting in the activation of endoplasmic reticulum (ER) STING. This, in turn, triggers an augmentation of signaling, leading to the production of type I interferon (IFN) and other pro-inflammatory cytokines. Numerous studies have demonstrated that activation of the STING pathway induces immune system rejection and targeted elimination of PCa cells. Researchers have been exploring various methods to activate the STING pathway, including the use of bacterial vectors to deliver STING agonists and the combination of radiation therapy with STING agonists. Achieving effective radiation therapy with minimal side effects and optimal anti-tumor immune responses necessitates precise adjustments to radiation dosing and fractionation schedules. This comprehensive review discusses promising findings from studies focusing on activating the STING pathway to combat PCa. The STING pathway exhibits the potential to serve as an effective treatment modality for PCa, offering new hope for improving the lives of those affected by this devastating disease.

Radical prostatectomy cancer grade and percentage of Gleason pattern 4 estimated by global vs individual tumor grading correlate differently with the risk of biochemical recurrence in Grade Group 2 and 3 cancers.

OBJECTIVES: There are 2 grading approaches to radical prostatectomy (RP) in multifocal cancer: Grade Group (GG) and percentage of Gleason pattern 4 (GP4%). We investigated whether RP GG and GP4% generated by global vs individual tumor grading correlate differently with biochemical recurrence. METHODS: We reviewed 531 RP specimens with GG2 or GG3 cancer. Each tumor was scored separately with assessment of tumor volume and GP4%. Global grade and GP4% were assigned by combining Gleason pattern 3 and 4 volumes for all tumors. Correlation of GG and GP4% generated by 2 methods with biochemical recurrence was assessed by Cox proportional hazard regression and receiver operating characteristic curves, with optimism adjustment using a bootstrap analysis. RESULTS: Median age was 63 (range, 42-79) years. Median prostate-specific antigen was 6.3 (range, 0.3-62.9) ng/mL. In total, the highest-grade tumor in 371 (36.9%) men was GG2 and in 160 (30.1%) men was GG3. Global grading was downgraded from GG3 to GG2 in 37 of 121 (30.6%) specimens with multifocal disease, and 145 of 404 (35.9%) specimens had GP4% decreased by at least 10%. Ninety-eight men experienced biochemical recurrence within a median of 13 (range, 3-119) months. Men without biochemical recurrence were followed up for a median of 47 (range, 12-205) months. Grade Group, GP4%, and margin status correlated with the risk of biochemical recurrence using highest-grade tumor and global grading, but the degrees of these correlations varied and were statistically significantly different between the 2 grading approaches. CONCLUSIONS: Grade Group, GP4%, and margin status derived by global vs individual tumor grading predict postoperative biochemical recurrence statistically significantly differently. This difference has important implications if results derived from cohorts graded using different methods are compared.

Prognostic Significance of Immune Cell Infiltration in Muscle-invasive Bladder Cancer Treated with Definitive Chemoradiation: A Secondary Analysis of RTOG 0524 and RTOG 0712.

Chemoradiation therapy (CRT) is a treatment for muscle-invasive bladder cancer (MIBC). Using a novel transcriptomic profiling panel, we validated prognostic immune biomarkers to CRT using 70 pretreatment tumor samples from prospective trials of MIBC (NRG/RTOG 0524 and 0712). Disease-free survival (DFS) and overall survival (OS) were estimated via the Kaplan-Meier method and stratified by genes correlated with immune cell activation. Cox proportional-hazards models were used to assess group differences. Clustering of gene expression profiles revealed that the cluster with high immune cell content was associated with longer DFS (hazard ratio [HR] 0.53, 95% confidence interval [CI] 0.26-1.10; p = 0.071) and OS (HR 0.48, 95% CI 0.24-0.97; p = 0.040) than the cluster with low immune cell content. Higher expression of T-cell infiltration genes (CD8A and ICOS) was associated with longer DFS (HR 0.40, 95% CI 0.21-0.75; p = 0.005) and OS (HR 0.49, 95% CI 0.25-0.94; p = 0.033). Higher IDO1 expression (IFNγ signature) was also associated with longer DFS (HR 0.44, 95% CI 0.24-0.88; p = 0.021) and OS (HR 0.49, 95% CI 0.24-0.99; p = 0.048). These findings should be validated in prospective CRT trials that include biomarkers, particularly for trials incorporating immunotherapy for MIBC. PATIENT SUMMARY: We analyzed patient samples from two clinical trials (NRG/RTOG 0524 and 0712) of chemoradiation for muscle-invasive bladder cancer using a novel method to assess immune cells in the tumor microenvironment. Higher expression of genes associated with immune activation and high overall immune-cell content were associated with better disease-free survival and overall survival for patients treated with chemoradiation.

The impact of dose-escalated radiotherapy plus androgen deprivation for prostate cancer using 2 linked nomograms.

BACKGROUND: Randomized trials have demonstrated that escalated-dose external-beam radiotherapy (EDRT) is better than standard-dose radiotherapy (SDRT) for patients with prostate cancer and that adding androgen-deprivation therapy (ADT) to SDRT is better than SDRT alone; however, no trials have compared EDRT versus SDRT plus ADT or EDRT versus EDRT plus ADT. The authors designed a model to estimate the results of various doses of radiotherapy (RT) combined with various durations of ADT. METHODS: From 1989 to 2007, 3215 men consecutively received definitive EDRT with or without ADT. In total, 2012 patients had complete records available for creating the nomogram. The duration of ADT varied for patients who received no RT (n = 1562), ≤6 months of RT (n = 145), from >6 months to <24 months of RT (n = 140), and ≥24 months of RT (n = 165) with a median follow-up of 65.7 months, 66.2 months, 60.1 months, and 63 months, respectively. The model included the following covariates: palpation T-category, biopsy Gleason score, the percentage of tumor cells with a Gleason pattern of 4 or 5, the percentage of tumor tissue, initial pretreatment prostate-specific antigen (PSA) level, ADT duration, and RT dose. Two nomograms, for outcomes with and without ADT, were created from a single competing-risks model. Biochemical failure was defined as a rise in serum PSA of 2 ng/mL over the post-treatment PSA nadir. RESULTS: According to the results from analyzing representative intermediate-risk to high-risk patient parameters, the gains from increasing the RT dose from 70 Gray (Gy) to 80 Gy were far less than the gains from adding ≥3 months of ADT. CONCLUSIONS: The nomograms provided unique patient-specific estimates of the effects of various doses and durations of RT and ADT. The results indicated that adding ADT to treatment for intermediate-risk and high-risk prostate cancer is far more beneficial than a modest RT dose escalation.

Radiation nephropathy: Mechanisms of injury and recovery in a murine model.

BACKGROUND: Radiation nephropathy (RN) can be a severe late complication for patients treated with radiotherapy (RT) targeting abdominal and paraspinal tumors. Recent studies investigating the mechanisms of RT-mediated injury in the kidney have demonstrated that RT disrupts the cellular integrity of renal podocytes leading to cell death and loss of renal function. AIM: To determine if RT-induced renal dysfunction is associated with alterations in podocyte and glomerular function, and whether RT-induced podocyte alterations were associated with changes in the glomerular basement membrane (GBM). METHODS: C57BL/6 mice were treated with focal bilateral X-irradiation using a single dose (SD) of 4 Gy, 10 Gy, or 14 Gy or fractionated dosing (FD) of 5x6Gy or 24x2Gy. Then, 10-40 weeks after RT parameters of renal function were measured, along with glomerular filtration rate (GFR) and glomerular histology, as well as ultrastructural changes in GBM by transmission electron microscopy. RESULTS: RT treatment resulted in persistent changes in renal function beginning at 10 weeks with little recovery up to 40 weeks post RT. Dose dependent changes were seen with increasing SD but no functional sparing was evident after FD. RT-induced loss of renal function was associated with expansion of the GBM and significant increases in foot process width, and associated with significant reduction in GFR, podocyte loss, and renal fibrosis. CONCLUSION: For the first time, these data show that expansion of the GBM is one consequence of radiation injury, and disarrangement of the GBM might be associated with the death of podocytes. These data shed new light on the role podocyte injury and GBM in RT-induced renal dysfunction.