Interplay Between Duration of Androgen Deprivation Therapy and External Beam Radiotherapy With or Without a Brachytherapy Boost for Optimal Treatment of High-risk Prostate Cancer: A Patient-Level Data Analysis of 3 Cohorts.

IMPORTANCE: Radiotherapy combined with androgen deprivation therapy (ADT) is a standard of care for high-risk prostate cancer. However, the interplay between radiotherapy dose and the required minimum duration of ADT is uncertain. OBJECTIVE: To determine the specific ADT duration threshold that provides a distant metastasis-free survival (DMFS) benefit in patients with high-risk prostate cancer receiving external beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT+BT). DESIGN, SETTINGS, AND PARTICIPANTS: This was a cohort study of 3 cohorts assembled from a multicenter retrospective study (2000-2013); a post hoc analysis of the Randomized Androgen Deprivation and Radiotherapy 03/04 (RADAR; 2003-2007) randomized clinical trial (RCT); and a cross-trial comparison of the RADAR vs the Deprivación Androgénica y Radio Terapía (Androgen Deprivation and Radiation Therapy; DART) 01/05 RCT (2005-2010). In all, the study analyzed 1827 patients treated with EBRT and 1108 patients treated with EBRT+BT from the retrospective cohort; 181 treated with EBRT and 203 with EBRT+BT from RADAR; and 91 patients treated with EBRT from DART. The study was conducted from October 15, 2020, to July 1, 2021, and the data analyses, from January 5 to June 15, 2021. EXPOSURES: High-dose EBRT or EBRT+BT for an ADT duration determined by patient-physician choice (retrospective) or by randomization (RCTs). MAIN OUTCOMES AND MEASURES: The primary outcome was DMFS; secondary outcome was overall survival (OS). Natural cubic spline analysis identified minimum thresholds (months). RESULTS: This cohort study of 3 studies totaling 3410 men (mean age [SD], 68 [62-74] years; race and ethnicity not collected) with high-risk prostate cancer found a significant interaction between the treatment type (EBRT vs EBRT+BT) and ADT duration (binned to <6, 6 to <18, and ≥18 months). Natural cubic spline analysis identified minimum duration thresholds of 26.3 months (95% CI, 25.4-36.0 months) for EBRT and 12 months (95% CI, 4.9-36.0 months) for EBRT+BT for optimal effect on DMFS. In RADAR, the prolongation of ADT for patients receiving only EBRT was not associated with significant improvements in DMFS (hazard ratio [HR], 1.01; 95% CI, 0.65-1.57); however, for patients receiving EBRT+BT, a longer duration was associated with improved DMFS (DMFS HR, 0.56; 95% CI, 0.36-0.87; P = .01). For patients receiving EBRT alone (DART), 28 months of ADT was associated with improved DMFS compared with 18 months (RADAR HR, 0.37; 95% CI, 0.17-0.80; P = .01). CONCLUSIONS AND RELEVANCE: These cohort study findings suggest that the optimal minimum ADT duration for treatment with high-dose EBRT alone is more than 18 months; and for EBRT+BT, it is 18 months or possibly less. Additional studies are needed to determine more precise minimum durations.

Radiation therapy dose and androgen deprivation therapy in localized prostate cancer: a meta-regression of 5-year outcomes in phase III randomized controlled trials.

BACKGROUND: While multiple randomized trials have evaluated the benefit of radiation therapy (RT) dose escalation and the use and prolongation of androgen deprivation therapy (ADT) in the treatment of prostate cancer, few studies have evaluated the relative benefit of either form of treatment intensification with each other. Many trials have included treatment strategies that incorporate either high or low dose RT, or short-term or long-term ADT (STADT or LTADT), in one or more trial arms. We sought to compare different forms of treatment intensification of RT in the context of localized prostate cancer. METHODS: Using preferred reporting items for systemic reviews and meta-analyses (PRISMA) guidelines, we collected over 40 phases III clinical trials comparing different forms of RT for localized prostate cancer. We performed a meta-regression of 40 individual trials with 21,429 total patients to allow a comparison of the rates and cumulative proportions of 5-year overall survival (OS), prostate cancer-specific mortality (PCSM), and distant metastasis (DM) for each treatment arm of every trial. RESULTS: Dose-escalation either in the absence or presence of STADT failed to significantly improve any 5-year outcome. In contrast, adding LTADT to low dose RT significantly improved 5-year PCSM (Odds ratio [OR] 0.34, 95% confidence interval [CI] 0.22-0.54, p < 0.001) and DM (OR 0.35, 95% CI 0.20-0.63. p < 0.001) over low dose RT alone. Adding STADT also significantly improved 5-year PCSM over low dose RT alone (OR 0.55, 95% CI 0.41-0.75, p < 0.001). CONCLUSION: While limited by between-study heterogeneity and a lack of individual patient data, this meta-analysis suggests that adding ADT, versus increasing RT dose alone, offers a more consistent improvement in clinical endpoints.

Identifying the Best Candidates for Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography as the Primary Staging Approach Among Men with High-risk Prostate Cancer and Negative Conventional Imaging.

Prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) is an emerging imaging modality with greater sensitivity and specificity over conventional imaging for prostate cancer (PCa) staging. Using data from two prospective trials (NCT03368547 and NCT04050215), we explored predictors of overall upstaging (nodal and metastatic) by PSMA PET/CT among patients with cN0M0 National Comprehensive Cancer Network high-risk PCa on conventional imaging (n = 213). Overall, 21.1%, 8.9%, and 23.9% of patients experienced nodal, metastatic, and overall upstaging, respectively, without histologic confirmation. On multivariable analysis, Gleason grade group (GG) and percent positive core (PPC) on systematic biopsy significantly predict overall upstaging (odds ratio [OR] 2.15, 95% confidence interval [CI] 1.33-3.45; p = 0.002; and OR 1.03, 95% CI 1.01-1.04; p < 0.001). Overall upstaging was significantly more frequent among men with GG 5 disease (33.0% vs. 17.6%; p = 0.0097) and PPC ≥50% (33.0% vs 15.0%; p = 0.0020). We constructed a nomogram that predicts overall upstaging using initial prostate-specific antigen, PPC, GG, and cT stage, with coefficients estimated from a standard logistic regression model (using maximum likelihood estimation). It is internally validated with a tenfold cross-validated area under the receiver operating characteristic curve estimated at 0.74 (95% CI 0.67-0.82). In our cohort, 90% of patients who had a nomogram-estimated risk below the cutoff of 22% for overall upstaging could have been spared PSMA PET/CT as our model correctly predicted no upstaging. In other words, the predictive model only missed 10% of patients who would otherwise have benefitted from PSMA PET/CT. PATIENT SUMMARY: We analyzed predictors of overall upstaging (lymph node or/and metastasis) by prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) from conventional imaging in men with high-risk prostate cancer undergoing initial staging deemed free of disease in the lymph nodes and distant metastasis by conventional imaging techniques. We found that the pathologic grade and disease burden in a prostate biopsy are associated with upstaging. We also developed a tool that predicts the probability of upstaging according to an individual patient's characteristics. Our study may help in defining patient groups who are most likely to benefit from the addition of a PSMA PET/CT scan.

Performance of a Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography-Derived Risk-Stratification Tool for High-risk and Very High-risk Prostate Cancer.

Importance: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) can detect low-volume, nonlocalized (ie, regional or metastatic) prostate cancer that was occult on conventional imaging. However, the long-term clinical implications of PSMA PET/CT upstaging remain unclear. Objectives: To evaluate the prognostic significance of a nomogram that models an individual's risk of nonlocalized upstaging on PSMA PET/CT and to compare its performance with existing risk-stratification tools. Design, Setting, and Participants: This cohort study included patients diagnosed with high-risk or very high-risk prostate cancer (ie, prostate-specific antigen [PSA] level >20 ng/mL, Gleason score 8-10, and/or clinical stage T3-T4, without evidence of nodal or metastatic disease by conventional workup) from April 1995 to August 2018. This multinational study was conducted at 15 centers. Data were analyzed from December 2020 to March 2021. Exposures: Curative-intent radical prostatectomy (RP), external beam radiotherapy (EBRT), or EBRT plus brachytherapy (BT), with or without androgen deprivation therapy. Main Outcomes and Measures: PSMA upstage probability was calculated from a nomogram using the biopsy Gleason score, percentage positive systematic biopsy cores, clinical T category, and PSA level. Biochemical recurrence (BCR), distant metastasis (DM), prostate cancer-specific mortality (PCSM), and overall survival (OS) were analyzed using Fine-Gray and Cox regressions. Model performance was quantified with the concordance (C) index. Results: Of 5275 patients, the median (IQR) age was 66 (60-72) years; 2883 (55%) were treated with RP, 1669 (32%) with EBRT, and 723 (14%) with EBRT plus BT; median (IQR) PSA level was 10.5 (5.9-23.2) ng/mL; 3987 (76%) had Gleason grade 8 to 10 disease; and 750 (14%) had stage T3 to T4 disease. Median (IQR) follow-up was 5.1 (3.1-7.9) years; 1221 (23%) were followed up for at least 8 years. Overall, 1895 (36%) had BCR, 851 (16%) developed DM, and 242 (5%) died of prostate cancer. PSMA upstage probability was significantly prognostic of all clinical end points, with 8-year C indices of 0.63 (95% CI, 0.61-0.65) for BCR, 0.69 (95% CI, 0.66-0.71) for DM, 0.71 (95% CI, 0.67-0.75) for PCSM, and 0.60 (95% CI, 0.57-0.62) for PCSM (P < .001). The PSMA nomogram outperformed existing risk-stratification tools, except for similar performance to Staging Collaboration for Cancer of the Prostate (STAR-CAP) for PCSM (eg, DM: PSMA, 0.69 [95% CI, 0.66-0.71] vs STAR-CAP, 0.65 [95% CI, 0.62-0.68]; P < .001; Memorial Sloan Kettering Cancer Center nomogram, 0.57 [95% CI, 0.54-0.60]; P < .001; Cancer of the Prostate Risk Assessment groups, 0.53 [95% CI, 0.51-0.56]; P < .001). Results were validated in secondary cohorts from the Surveillance, Epidemiology, and End Results database and the National Cancer Database. Conclusions and Relevance: These findings suggest that PSMA upstage probability is associated with long-term, clinically meaningful end points. Furthermore, PSMA upstaging had superior risk discrimination compared with existing tools. Formerly occult, PSMA PET/CT-detectable nonlocalized disease may be the main driver of outcomes in high-risk patients.

Comparison of Multimodal Therapies and Outcomes Among Patients With High-Risk Prostate Cancer With Adverse Clinicopathologic Features.

Importance: The optimal management strategy for high-risk prostate cancer and additional adverse clinicopathologic features remains unknown. Objective: To compare clinical outcomes among patients with high-risk prostate cancer after definitive treatment. Design, Setting, and Participants: This retrospective cohort study included patients with high-risk prostate cancer (as defined by the National Comprehensive Cancer Network [NCCN]) and at least 1 adverse clinicopathologic feature (defined as any primary Gleason pattern 5 on biopsy, clinical T3b-4 disease, ≥50% cores with biopsy results positive for prostate cancer, or NCCN ≥2 high-risk features) treated between 2000 and 2014 at 16 tertiary centers. Data were analyzed in November 2020. Exposures: Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy (ADT), or EBRT plus brachytherapy boost (BT) with ADT. Guideline-concordant multimodal treatment was defined as RP with appropriate use of multimodal therapy (optimal RP), EBRT with at least 2 years of ADT (optimal EBRT), or EBRT with BT with at least 1 year ADT (optimal EBRT with BT). Main Outcomes and Measures: The primary outcome was prostate cancer-specific mortality; distant metastasis was a secondary outcome. Differences were evaluated using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression models. Results: A total of 6004 men (median [interquartile range] age, 66.4 [60.9-71.8] years) with high-risk prostate cancer were analyzed, including 3175 patients (52.9%) who underwent RP, 1830 patients (30.5%) who underwent EBRT alone, and 999 patients (16.6%) who underwent EBRT with BT. Compared with RP, treatment with EBRT with BT (subdistribution hazard ratio [sHR] 0.78, [95% CI, 0.63-0.97]; P = .03) or with EBRT alone (sHR, 0.70 [95% CI, 0.53-0.92]; P = .01) was associated with significantly improved prostate cancer-specific mortality; there was no difference in prostate cancer-specific mortality between EBRT with BT and EBRT alone (sHR, 0.89 [95% CI, 0.67-1.18]; P = .43). No significant differences in prostate cancer-specific mortality were found across treatment cohorts among 2940 patients who received guideline-concordant multimodality treatment (eg, optimal EBRT alone vs optimal RP: sHR, 0.76 [95% CI, 0.52-1.09]; P = .14). However, treatment with EBRT alone or EBRT with BT was consistently associated with lower rates of distant metastasis compared with treatment with RP (eg, EBRT vs RP: sHR, 0.50 [95% CI, 0.44-0.58]; P < .001). Conclusions and Relevance: These findings suggest that among patients with high-risk prostate cancer and additional unfavorable clinicopathologic features receiving guideline-concordant multimodal therapy, prostate cancer-specific mortality outcomes were equivalent among those treated with RP, EBRT, and EBRT with BT, although distant metastasis outcomes were more favorable among patients treated with EBRT and EBRT with BT. Optimal multimodality treatment is critical for improving outcomes in patients with high-risk prostate cancer.

Patterns of Clinical Progression in Radiorecurrent High-risk Prostate Cancer.

The natural history of radiorecurrent high-risk prostate cancer (HRPCa) is not well-described. To better understand its clinical course, we evaluated rates of distant metastases (DM) and prostate cancer-specific mortality (PCSM) in a cohort of 978 men with radiorecurrent HRPCa who previously received either external beam radiation therapy (EBRT, n = 654, 67%) or EBRT + brachytherapy (EBRT + BT, n = 324, 33%) across 15 institutions from 1997 to 2015. In men who did not die, median follow-up after treatment was 8.9 yr and median follow-up after biochemical recurrence (BCR) was 3.7 yr. Local and systemic therapy salvage, respectively, were delivered to 21 and 390 men after EBRT, and eight and 103 men after EBRT + BT. Overall, 435 men developed DM, and 248 were detected within 1 yr of BCR. Measured from time of recurrence, 5-yr DM rates were 50% and 34% after EBRT and EBRT + BT, respectively. Measured from BCR, 5-yr PCSM rates were 27% and 29%, respectively. Interval to BCR was independently associated with DM (p < 0.001) and PCSM (p < 0.001). These data suggest that radiorecurrent HRPCa has an aggressive natural history and that DM is clinically evident early after BCR. These findings underscore the importance of further investigations into upfront risk assessment and prompt systemic evaluation upon recurrence in HRPCa. PATIENT SUMMARY: High-risk prostate cancer that recurs after radiation therapy is an aggressive disease entity and spreads to other parts of the body (metastases). Some 60% of metastases occur within 1 yr. Approximately 30% of these patients die from their prostate cancer.

Use and Impact of Positron Emission Tomography/Computed Tomography Prior to Salvage Radiation Therapy in Men with Biochemical Recurrence After Radical Prostatectomy: A Scoping Review.

CONTEXT: The use, common findings, and impact of modern molecular positron emission tomography (PET)/computed tomography (CT) imaging prior to salvage radiation therapy (RT) in men with biochemical recurrence after radical prostatectomy (RP) have not been evaluated comprehensively. OBJECTIVE: We performed a scoping systematic review of the literature assessing detection rates, detection patterns, changes in management, as well as changes in patient outcome resulting from molecular PET/CT imaging using three molecular tracers: 18F-fluciclovine, 8Ga prostate-specific membrane antigen (PSMA)-11, and 18F-DCFPyL. EVIDENCE ACQUISITION: A computerized bibliographic search of the Medline/PubMed database was carried out from inception to October 1, 2020. We included published reports and abstracts evaluating the utility of 1Fluciclovine, 68Ga-PSMA-11, and 18F-DCFPyL PET in the detection of recurrent disease in the post-RP, pre-salvage RT setting. Outcomes of interest were extracted and tabulated, and existing evidence was synthesized qualitatively. EVIDENCE SYNTHESIS: A total of 45 studies were included in our qualitative synthesis. Detection rates were high across most studies, and there was often a clear relationship between prostate-specific antigen (PSA) level and positive imaging findings. Though limited randomized data are available, there appears to be increased sensitivity with the use of PSMA ligands compared with fluciclovine at low PSA values. Most studies have shown that only one-third to one-half of patients with detected lesions have lesions in the prostatic fossa alone. Management changes occur in nearly 50% of patients undergoing molecular imaging, and biochemical response in patients who undergo molecular PET-based RT planning appears to be statistically superior to the response in patients who undergo conventional imaging -based RT planning alone. High biochemical responses from molecular PET-based salvage RT, ranging from 45% to 94%, did not appear to come at the expense of increased genitourinary or gastrointestinal toxicity. The presence or absence of avid lesions appears to be a strong prognostic factor. CONCLUSIONS: Molecular PET/CT imaging in the post-RP, pre-salvage RT setting often triggers management changes that result from detecting lesions in locations not typically included in consensus-driven postoperative RT fields. Ongoing trials will assess the benefit of PSMA PET in guiding salvage RT following RP and determine its impact on long-term outcomes. PATIENT SUMMARY: We reviewed and reported detection rates, detection patterns, and changes in management resulting from molecular positron emission tomography/computed tomography imaging in men with biochemically recurrent prostate cancer following radical prostatectomy. Prior to the receipt of salvage radiation therapy, molecular tracers targeting prostate-specific membrane antigen appear to be especially sensitive at identifying the place where prostate cancer has come back after surgery, which can help radiation oncologists better target the recurrent disease and potentially improve the rates of cure from prostate cancer in this setting. Future studies will determine whether these imaging tools will change cure rates and side effects, but early results are promising.

Dose-response with stereotactic body radiotherapy for prostate cancer: A multi-institutional analysis of prostate-specific antigen kinetics and biochemical control.

BACKGROUND AND PURPOSE: The optimal dose for prostate stereotactic body radiotherapy (SBRT) is still unknown. This study evaluated the dose-response relationships for prostate-specific antigen (PSA) decay and biochemical recurrence (BCR) among 4 SBRT dose regimens. MATERIALS AND METHODS: In 1908 men with low-risk (50.0%), favorable intermediate-risk (30.9%), and unfavorable intermediate-risk (19.1%) prostate cancer treated with prostate SBRT across 8 institutions from 2003 to 2018, we examined 4 regimens (35 Gy/5 fractions [35/5, n = 265, 13.4%], 36.25 Gy/5 fractions [36.25/5, n = 711, 37.3%], 40 Gy/5 fractions [40/5, n = 684, 35.8%], and 38 Gy/4 fractions [38/4, n = 257, 13.5%]). Between dose groups, we compared PSA decay slope, nadir PSA (nPSA), achievement of nPSA ≤0.2 and ≤0.5 ng/mL, and BCR-free survival (BCRFS). RESULTS: Median follow-up was 72.3 months. Median nPSA was 0.01 ng/mL for 38/4, and 0.17-0.20 ng/mL for 5-fraction regimens (p < 0.0001). The 38/4 cohort demonstrated the steepest PSA decay slope and greater odds of nPSA ≤0.2 ng/mL (both p < 0.0001 vs. all other regimens). BCR occurred in 6.25%, 6.75%, 3.95%, and 8.95% of men treated with 35/5, 36.25/5, 40/5, and 38/4, respectively (p = 0.12), with the highest BCRFS after 40/5 (vs. 35/5 hazard ratio [HR] 0.49, p = 0.026; vs. 36.25/5 HR 0.42, p = 0.0005; vs. 38/4 HR 0.55, p = 0.037) including the entirety of follow-up, but not for 5-year BCRFS (≥93% for all regimens, p ≥ 0.21). CONCLUSION: Dose-escalation was associated with greater prostate ablation and PSA decay. Dose-escalation to 40/5, but not beyond, was associated with improved BCRFS. Biochemical control remains excellent, and prospective studies will provide clarity on the benefit of dose-escalation.

C-MYC Amplification in Chronic Lymphocytic Leukemia: A Case Report and Review of the Literature.

OBJECTIVES: Chronic lymphocytic leukemia (CLL) is among the most common forms of leukemia diagnosed in the United States. It is associated with a variety of clinically significant genetic abnormalities, including cytogenetic abnormalities that are assessed routinely. Herein, we present a case of CLL for which molecular cytogenetic analysis revealed concomitant deletion of TP53 (17p13.1) in 87% of cells analyzed and amplification (3-20 signals) of C-MYC (8q24.1) in 47% of cells analyzed. Although rearrangements involving C-MYC are common in CLL, amplification is a rarer phenomenon that has not been investigated as thoroughly and may be overlooked during routine analysis. We review this case in the context of available literature on the plethora of genetic abnormalities involving C-MYC in CLL and their relevance to the pathogenesis of the disease. All in all, this case highlights the role of comprehensive, multidisciplinary genetic testing in the management of CLL.

Isochromosome 17q, a Rare Chromosomal Abnormality in a Female Patient with Pancytopenia.

OBJECTIVES: Myelodysplastic syndromes present with a range of cytogenetic abnormalities that are used to guide diagnosis and management of the disease. Herein, we present the case of a 72-year-old female patient who presented with pancytopenia. Peripheral blood showed Hb 9.0 g/dl, neutrophils less than 1800/mm3, and platelets less than 100,000/mm3. Bone marrow showed erythroid hyperplasia, megaloblastic changes, dyserythropoiesis, multinuclearity, nuclear bridges, nuclear budding, atypical mitoses, and ring sideroblasts. Also, CD34 and CD117 as well as myeloperoxidase positive populations were present. On this basis, a diagnosis of myelodysplastic syndrome was rendered. Chromosome studies showed an abnormal female karyotype with an isochromosome 17q as well as deletion 20q in 17 of the 20 metaphase cells examined. The remaining three cells were cytogenetically normal. Molecular cytogenetic studies using a TP53-specific probe showed only one TP53 signal in 87% of the nuclei examined. An i(17q) as a sole cytogenetic aberration is rare among both MDS and myeloid malignancies in general, but is functionally similar to aberrations of 17p that lead to loss of TP53. This case provides further insight into the spectrum of cytogenetic abnormalities present in MDS.

A Case of t(1;6)(p12;p11.1), Deletion 5q, and Ring 11 in a Patient with Myelodysplastic Syndrome with Excess Blasts Type 1.

OBJECTIVES: We present the case of a 56-year-old male with myelodysplastic syndrome (MDS) whose bone marrow immunophenotype showed lower positivity for CD45 and positivity for CD34; 8.66% of this population also expressed partial positives for MPO, CD16, CD117, CD36, CD33, and CD71, as well as positives for CD13, HLA-DR, and CD11b. No alterations in the pattern of maturation were seen in CD13 vs CD16 and CD13 vs CD11b. An analysis of a population of mature lymphocytes revealed CD45 high CD3+ in 87.5% of cells, CD45 high CD19+ in 7.6% of cells, and 4.9% NK cells. These results are consistent with a myelodysplastic syndrome with an excess of blasts type 1. Chromosome analysis of the bone marrow revealed an abnormal karyotype with a t(1;6)(p12;p11.1) as well as deletion 5q and a ring 11 in 12 of the 20 metaphase cells examined. The t(1;6)(p12;p11.1) has not been reported in association with any particular hematological malignancy and provides further insight into the range of cytogenetic abnormalities in MDS.

Prostate-specific antigen kinetics and biochemical control following stereotactic body radiation therapy, high dose rate brachytherapy, and low dose rate brachytherapy: A multi-institutional analysis of 3502 patients.

BACKGROUND AND PURPOSE: Stereotactic body radiation therapy (SBRT), low dose rate brachytherapy (LDR-BT) and high dose rate brachytherapy (HDR-BT) are ablative-intent radiotherapy options for prostate cancer (PCa). These vary considerably in dose delivery, which may impact post-treatment prostate-specific antigen (PSA) patterns and biochemical control. We compared PSA kinetics between SBRT, HDR-BT, and LDR-BT, and assessed their relationships to biochemical recurrence-free survival (BCRFS). METHODS AND MATERIALS: Retrospective PSA data were analyzed for 3502 men with low-risk (n = 2223; 63.5%), favorable intermediate-risk (n = 869; 24.8%), and unfavorable intermediate-risk (n = 410; 11.7%) PCa treated with SBRT (n = 1716; 49.0%), HDR-BT (n = 512; 14.6%), or LDR-BT (n = 1274; 36.4%) without upfront androgen deprivation therapy at 10 institutions from 1990 to 2017. We compared nadir PSA (nPSA), time to nPSA, achievement of nPSA <0.2 ng/mL and <0.5 ng/mL, rates of nPSA <0.4 ng/mL at 4 years, and BCRFS. RESULTS: Median follow-up was 72 months. Median nPSA and nPSA <0.2 ng/mL were stratified by risk group (interaction p ≤ 0.001). Median nPSA and time to nPSA were 0.2 ng/mL at 44 months after SBRT, 0.1-0.2 ng/mL at 37 months after HDR-BT, and 0.01-0.2 ng/mL at 51 months after LDR-BT (mean log nPSA p ≤ 0.009 for LDR-BT vs. SBRT or HDR-BT for low/favorable intermediate-risk). There were no differences in nPSA <0.4 ng/mL at 4 years (p ≥ 0.51). BCRFS was similar for all three modalities (p ≥ 0.27). Continued PSA decay beyond 4 years was predictive of durable biochemical control. CONCLUSION: LDR-BT led to lower nPSAs with longer continued decay compared to SBRT and HDR-BT, but no differences in BCRFS.

Gantry-Mounted Linear Accelerator-Based Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer.

PURPOSE: To establish the safety and efficacy of gantry-mounted linear accelerator-based stereotactic body radiation therapy (SBRT) for low- and intermediate-risk prostate cancer. METHODS: We pooled 921 patients enrolled on 7 single-institution prospective phase II trials of gantry-based SBRT from 2006 to 2017. The cumulative incidences of biochemical recurrence (defined by the Phoenix definition) and physician-scored genitourinary (GU) and gastrointestinal (GI) toxicities (defined per the original trials using Common Terminology Criteria for Adverse Events) were estimated using a competing risk framework. Multivariable logistic regression was used to evaluate the relationship between late toxicity and prespecified covariates: biologically effective dose, every other day versus weekly fractionation, intrafractional motion monitoring, and acute toxicity. RESULTS: Median follow-up was 3.1 years (range, 0.5-10.8 years). In addition, 505 (54.8%) patients had low-risk disease, 236 (25.6%) had favorable intermediate-risk disease, and 180 (19.5%) had unfavorable intermediate-risk disease. Intrafractional motion monitoring was performed in 78.0% of patients. The 3-year cumulative incidence of biochemical recurrence was 0.8% (95% confidence interval [CI], 0-1.7%), 2.2% (95% CI, 0-4.3%), and 5.1% (95% CI, 1.0-9.2%) for low-, favorable intermediate-, and unfavorable intermediate-risk disease. Acute grade ≥2 GU and GI toxicity occurred in 14.5% and 4.6% of patients, respectively. Three-year cumulative incidence estimates of late grade 2 GU and GI toxicity were 4.1% (95% CI, 2.6-5.5%) and 1.3% (95% CI, 0.5-2.1%), respectively, with late grade ≥3 GU and GI toxicity estimates of 0.7% (95% CI, 0.1-1.3%) and 0.4% (95% CI, 0-0.8%), respectively. The only identified significant predictors of late grade ≥2 toxicity were acute grade ≥2 toxicity (P < .001) and weekly fractionation (P < .01), although only 12.4% of patients were treated weekly. CONCLUSIONS: Gantry-based SBRT for prostate cancer is associated with a favorable safety and efficacy profile, despite variable intrafractional motion management techniques. These findings suggest that multiple treatment platforms can be used to safely deliver prostate SBRT.

Transient Myeloproliferative Disorder: A Cytogenomic Update.

OBJECTIVES: Transient myeloproliferative disorder (TMD), now more commonly known as transient abnormal myelopoiesis (TAM), is a condition closely associated with Down syndrome. Ninety-five percent of Down syndrome cases occur as a result of chromosomal nondisjunction and are rarely due to mosaicism or translocation. TMD is found exclusively in neonates and is most commonly characterized by trisomy 21, somatic GATA1 mutation, and the increased presence of megakaryoblasts. TMD often does not manifest clinically, but patients may show hepatomegaly, splenomegaly and other symptoms. While TMD is almost always present with trisomy 21, there are not many other cytogenetic abnormalities associated with TMD, with a few rare cases such as monosomy 7 and trisomy 8. Recent studies have suggested liver hematopoietic progenitor cells as the candidate for TMD origin. Furthermore, GATA1 mutations associated with TMD are found to encode for a stop codon in the N-terminal activation region of gene sequences. It has been shown that those mutations can cause overproliferation of megakaryocytes, which can cooperate with Down syndrome cells, which have trisomy 21, in the progression of TMD into acute megakaryoblastic leukemia (AMKL). Since GATA1 mutations are present in all cases of myeloid leukemia of Down Syndrome, monitoring GATA1 in patients with trisomy 21 may assist with earlier diagnosis of TMD. Another likely cause of TMD is the amplification of the RUNX1 transcription factor gene located on chromosome 21. It has been shown that RUNX1 is associated with leukemias of myeloid lineage. While most cases of TMD will spontaneously resolve, some will evolve into acute myeloid leukemia (AML). In this review, we will discuss the cytogenetic, molecular genetics and clinical aspects of TMD.

Prostate bed and organ-at-risk deformation: Prospective volumetric and dosimetric data from a phase II trial of stereotactic body radiotherapy after radical prostatectomy.

PURPOSE: Stereotactic body radiotherapy (SBRT) in the post-prostatectomy setting is investigational. A major concern is the deformable prostate bed clinical target volume (CTV) and the closely juxtaposed organs-at-risk (OARs). We report a volumetric and dosimetric analysis of kilovoltage cone-beam CT (CBCT) data from the first 18 patients enrolled on a phase II trial of post-prostatectomy SBRT. With instructions on bladder filling and rectal preparation, we hypothesized acceptable CTV coverage while minimal overdosing to OARs could be achieved. METHODS: All patients received 5 fractions of 6-6.8 Gy to the prostate bed. CBCT were taken prior to and halfway through each fraction. CTV and OARs were contoured for each CBCT. Changes in inter- and intra-fraction volume and dose were calculated. Relative changes in CTV V95%, bladder V32.5 Gy, and rectal V32.5 Gy and V27.5 Gy were evaluated. RESULTS: Interfraction CTV volume remained stable, with median change +5.69% (IQR -1.73% to +9.84%). CTV V95% exhibited median change -0.74% (IQR -9.15% to -0.07%). Volumetric and dosimetric changes were minor from interfraction rotation and intrafraction motion. CTV V95% was ≥93% in 13 of 18 (72%) patients; in the remaining five, median change was -14.09% (IQR -16.64% to -13.56%). Interfraction CTV volume change was significantly larger among patients with CTV V95% <93% (+25.04% vs. +2.85%, p = 0.002). CONCLUSIONS: With specific bladder and rectum filling protocols, CTV underdosing and overdosing to bladder and rectum are avoided in majority of patients. Changes in CTV shape may account for the underdosing that may be observed.

Prevalence and correlates of sexually transmitted infections in pregnancy in HIV-infected and- uninfected women in Cape Town, South Africa.

OBJECTIVES: Sexually transmitted infections (STIs) are associated with adverse outcomes in pregnancy, including mother-to-child HIV transmission. Yet there are limited data on the prevalence and correlates of STI in pregnant women by HIV status in low- and middle-income countries, where syndromic STI management is routine. METHODS: Between November 2017 and July 2018, we conducted a cross-sectional study of consecutive pregnant women making their first visit to a public sector antenatal clinic (ANC) in Cape Town. We interviewed women ≥18 years and tested them for Chlamydia trachomatis (CT), Neisseria gonorrhoea (NG) and Trichomonas vaginalis (TV) using Xpert assays (Cepheid, USA); results of syphilis serology came from routine testing records. We used multivariable logistic regression to identify correlates of STI in pregnancy. RESULTS: In 242 women (median age 29 years [IQR = 24-34], median gestation 19 weeks [IQR = 14-24]) 44% were HIV-infected. Almost all reported vaginal sex during pregnancy (93%). Prevalence of any STI was 32%: 39% in HIV-infected women vs. 28% in HIV-uninfected women (p = 0.036). The most common infection was CT (20%) followed by TV (15%), then NG (5.8%). Of the 78 women diagnosed with a STI, 7 (9%) were identified and treated syndromically in ANC. Adjusting for age and gestational age, HIV-infection (aOR = 1.89; 95% CI = 1.02-3.67), being unmarried or not cohabiting with the fetus' father (aOR = 2.19; 95% CI = 1.16-4.12), and having STI symptoms in the past three days (aOR = 6.60; 95% CI = 2.08-20.95) were associated with STI diagnosis. CONCLUSION: We found a high prevalence of treatable STIs in pregnancy among pregnant women, especially in HIV-infected women. Few women were identified and treated in pregnancy.

Multi-Institutional Analysis of Prostate-Specific Antigen Kinetics After Stereotactic Body Radiation Therapy.

PURPOSE: Understanding prostate-specific antigen (PSA) kinetics after radiation therapy plays a large role in the management of patients with prostate cancer (PCa). This is particularly true in establishing expectations regarding PSA nadir (nPSA) and PSA bounces, which can be disconcerting. As increasingly more patients are being treated with stereotactic body radiation therapy (SBRT) for low- and intermediate-risk PCa, it is imperative to understand the PSA response to SBRT. METHODS AND MATERIALS: PSA data from 5 institutions were retrospectively analyzed for patients with localized PCa treated definitively with SBRT alone from 2004 to 2016. Patients received 35 to 40 Gy in 5 fractions, per institutional standards. Patients who had less than 12 months of PSA data or received androgen deprivation therapy were excluded from this study. Linear and logistic multivariable analysis were performed to identify predictors of nPSA, bounce, and biochemical recurrence, and joint latent class models were developed to identify significant predictors of time to biochemical failure. RESULTS: A total of 1062 patients were included in this study. Median follow-up was 66 months (interquartile range [IQR], 36.4-89.9 months). Biochemical failure per the Phoenix criteria occurred in 4% of patients. Median nPSA was 0.2 ng/mL, median time to nPSA was 40 months, 84% of patients had an nPSA ≤0.5 ng/mL, and 54% of patients had an nPSA ≤0.2 ng/mL. On multivariable analysis, nPSA was a significant predictor of biochemical failure. Benign PSA bounce was noted in 26% of patients. The median magnitude of PSA bounce was 0.52 ng/mL (IQR, 0.3-1.0 ng/mL). Median time to PSA bounce was 18.1 months (IQR, 12.0-31.1 months). On multivariable analysis, age and radiation dose were significantly associated with a lower incidence of bounce. Joint latent class models modeling found that nPSA and radiation dose were significantly associated with longer time to biochemical failure. CONCLUSIONS: In this multi-institutional cohort of patients with long-term follow-up, we found that SBRT led to low nPSAs. In turn, lower nPSAs are associated with reduced incidence of, and longer time to, biochemical failure. Benign PSA bounces occurred in a quarter of patients, as late as several years after treatment. Further studies are needed to directly compare the PSA response of patients who receive SBRT versus other treatment modalities.

Elucidation of Novel Chromosomal Abnormalities in Pancreatic Cancer: Conventional and Molecular Cytogenetic Characterization of 16 Pancreatic Cell Lines.

Pancreatic carcinoma is a major cause of cancer-related death in the United States, with a five-year survival rate of approximately 5%. Cytogenetic analysis has identified clinically significant chromosomal abnormalities in numerous malignancies, but it is not utilized in the clinical management of pancreatic carcinoma. We performed conventional and molecular cytogenetic analysis of 16 pancreatic carcinoma cell lines using Giemsa banding and DNA-based fluorescence in situ hybridization (FISH). Conventional cytogenetic analysis revealed a diversity of recurrent and clonal numerical and structural abnormalities in all cell lines analyzed, many of which occurred at loci of genes implicated in pancreatic or related cancers. FISH analysis revealed significant decreases in copy number of numerous tumor-suppressor genes including TP53, CDKN2A, and SMAD4. In some cell lines, amplification of oncogenes HER2 and MYC was also observed. Finally, novel rearrangements involving ARID1A and TGFBR2 were identified in a small subset of cell lines by means of molecular cytogenetic analysis. All in all, these data provide additional insight into recurrent chromosomal abnormalities in pancreatic carcinoma that can potentially be utilized as biomarkers in the clinical management of the disease. Investigation of other aberrations as well as correlation of recurrent ones with clinicopathologic features is warranted in order to assess the utility of cytogenetic analysis of pancreatic carcinoma.

Novel Cytogenetic Findings in a Case of Mixed Phenotype Acute Leukemia within the Context of a Complex Karyotype.

BACKGROUND: Mixed phenotype acute leukemia (MPAL) is a rare hematological malignancy characterized by combinatorial aberrations involving cells of the myeloid, T-, and/or B- lineages, most often diagnosed by means of immunophenotyping in order to assess lineage-specific markers, which can still yield inconclusive diagnoses. MPAL with a complex karyotype (three or more chromosomal abnormalities) is a cytogenetic subtype of MPAL associated with a poor prognosis, but limited data is available about the cytogenetic abnormalities present in this context. FINDINGS: Herein, we present the case of a 67-year-old female whose bone marrow biopsy revealed an extensive blast population showing dual morphologic differentiation, including lymphoblasts and larger myeloblasts with monocytic differentiation. Multiparametric immunophenotyping by flow cytometry revealed a blast population that was positive for CD45, CD19, CD22, CD34, CD38, and HLA-DR. The blast populations were also immunereactive for both myeloperoxidase and TdT; thus, a diagnosis of mixed phenotype acute leukemia was rendered. Conventional cytogenetic analysis revealed a hyperdiploid composite karyotype with numerical abnormalities involving chromosomes 2, 6, 8, 10, 11, 14, 19, 20, 21, and 22, as well as structural abnormalities involving 1p, 1q, 9p, 16p, 17p, 19q, 20q, and a marker chromosome. Concurrent interphase and metaphase FISH studies were able to detect a deletion of CDKN2A/p16 at 9p21 and corroborated the presence of extra copies of chromosomes 8, 11, 20, and 22. CONCLUSIONS: This case provides further insight into the plethora of cytogenetic abnormalities not involving BCR-ABL1 and/or MLL present in MPAL with a complex karyotype and adds to the pool of cytogenetic information about this rare subset of hematological malignancies.

An Adult Male Presenting with Concurrent Plasma Cell Myeloma Involving a CCND1-IGH Translocation and Chronic Myelogenous Leukemia with a Variant (9;22) Translocation.

The t(11;14)(q13;q32) involving IGH and CCND1 a nd t(9;22) (q34;q11.2) involving BCR and ABL1 are common abnormalities in plasma cell myeloma (PCM) and chronic myelogenous leukemia (CML), respectively. However, the concurrence of the two malignancies is extremely rare. Herein, we present a case of an 87-year-old male who presented with anemia and monocytosis. FISH studies on a bone marrow sample enriched for plasma cells detected a t(11;14) positive for IGH and CCND1 fusion in 92% of nuclei. However, cytogenetic analysis of the bone marrow revealed a t(9;22)(q34;q11.2) in 40% of the metaphases. Interphase and metaphase FISH studies on the sample confirmed the presence of the BCR-ABL1 fusion in 88% of nuclei but did not show any signals corresponding to the derivative 9, suggesting a variant t(9;22) with a deletion or additional material of unknown origin at the 9q34 band of the derivative 9 and a derivative 22 bearing the BCR-ABL1 fusion gene. The concurrence of plasma cell myeloma and chronic myelogenous leukemia is extremely rare with less than 20 cases reported. The molecular pathway in which the multiple malignancies arise is still poorly understood, and this case provides insight into the concurrence of PCM and CML.