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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

Background and purposeThe 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 methodsIn 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 (35Gy/5 fractions [35/5, n=265, 13.4%], 36.25Gy/5 fractions [36.25/5, n=711, 37.3%], 40Gy/5 fractions [40/5, n=684, 35.8%], and 38Gy/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 ≤0.5ng/mL, and BCR-free survival (BCRFS).ResultsMedian follow-up was 72.3months. Median nPSA was 0.01ng/mL for 38/4, and 0.17-0.20ng/mL for 5-fraction regimens (p&nbsp

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% 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.

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 p p 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.

Key Points Question What is the optimal minimum duration of androgen deprivation therapy (ADT) when treating high-risk prostate cancer with high-dose radiotherapy? Findings This patient-level cohort study of 3 cohorts found a significant interaction between the type of high-dose radiotherapy (external beam radiotherapy with or without a brachytherapy boost) and optimal duration. Prolonging ADT for 18 to 28 months was associated with a 63% reduction in death or metastasis with external beam radiotherapy; when a brachytherapy boost was added, the nonlinear association between ADT and distant metastasis-free survival was broad and spanned 12 months. Meaning The findings of this cohort study suggest that patients receiving external beam radiotherapy alone may benefit from ADT durations of 18 months or more; if a brachytherapy boost is added, a duration of 18 months or possibly less may be optimal., 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, This cohort study explores associations between the duration of androgen deprivation therapy and distant metastasis-free survival in men undergoing external beam radiotherapy with and without a brachytherapy boost for treatment of high-risk prostate cancer.

INTRODUCTION AND OBJECTIVE:Dose escalation of radiation therapy (RT) and the addition or prolongation of androgen deprivation therapy (ADT) have been independently shown to improve long-term outcom...

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.

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.

Key Points Question Are external beam radiotherapy, with or without brachytherapy boost, or radical prostatectomy associated with differences in prostate cancer–specific mortality or distant metastasis outcomes in patients with high-risk prostate cancer after accounting for delivery of guideline-concordant multimodality therapy? Findings In this cohort study of 6004 men with high-risk prostate cancer and at least 1 additional adverse clinicopathologic feature, no differences in prostate cancer-specific mortality across treatment modalities were identified among patients who received guideline-concordant multimodality therapy, although differences in time to metastasis were observed. However, significant differences in prostate cancer–specific mortality were identified when guideline-concordant multimodality care was not delivered. Meaning These findings suggest that guideline-concordant multimodality care was associated with better prostate cancer–specific mortality outcomes for patients with high-risk prostate cancer., This cohort study assesses prostate cancer–specific mortality and distant metastasis outcomes among men with high-risk prostate cancer treated with radical prostatectomy or external beam radiotherapy with or without brachytherapy boost., 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

AIMS There is a lack of early predictive measures of outcome for patients with intermediate-risk prostate cancer (PCa) treated with stereotactic body radiotherapy (SBRT). The aim of the present study was to explore 4-year prostate-specific antigen response rate (4yPSARR) as an early predictive measure. MATERIALS AND METHODS Individual patient data from six institutions for patients with intermediate-risk PCa treated with SBRT between 2006 and 2016 with a 4-year (42-54 months) PSA available were analysed. Cumulative incidences of biochemical failure and metastasis were calculated using Nelson-Aalen estimates and overall survival was calculated using the Kaplan-Meier method. Biochemical failure-free survival was analysed according to 4yPSARR, with groups dichotomised based on PSA

PURPOSE/OBJECTIVE(S) There is a lack of early predictive measures of outcome for patients with intermediate-risk prostate cancer (PCa) treated with stereotactic body radiotherapy (SBRT). We aim to explore 4-year PSA response rate (4yPSARR) as an early predictive measure. MATERIALS/METHODS Individual patient data from 6 institutions for patients with intermediate-risk PCa treated with SBRT between 2006 and 2016 with a 4-year (42-54 months) PSA available were analyzed. Cumulative incidences of biochemical failure and metastasis were calculated using Nelson-Aalen estimates and overall survival was calculated using the Kaplan-Meier method. Biochemical failure-free survival was analyzed according to 4yPSARR with groups dichotomized based on PSA < 0.4 ng/mL or ≥ 0.4 ng/mL and compared using the log-rank test. Multivariable competing risk analysis was performed to predict for biochemical failure and development of metastasis. RESULTS Six-hundred thirty-seven patients were included, including 424 (67%) with favorable and 213 (33%) with unfavorable intermediate-risk disease. Median follow-up was 6.2 years (IQR 4.9-7.9). The cumulative incidence of biochemical failure and metastasis, and overall survival at 6 years was 7%, 0.6% and 97%, respectively. The cumulative incidence of biochemical failure at 6 years if 4yPSARR < 0.4ng/mL was 1.7%, compared to 27% if 4yPSARR ≥ 0.4 ng/mL (P < 0.0001). On multivariable competing risk analysis, 4yPSARR was a statistically significant predictor of biochemical failure-free survival (sHR 15.3, 95% CI 7.5-31.3, P < 0.001) and metastasis-free survival (sHR 31.2, 95% CI 3.1-311.6, P = 0.003). CONCLUSION 4yPSARR is an encouraging early predictor of outcome in patients with intermediate-risk PCa treated with SBRT. Validation in prospective trials is warranted.

PURPOSE/OBJECTIVE(S) Stereotactic body radiation therapy (SBRT) has emerged as a promising modality for the treatment of prostate cancer (PCa) and involves the delivery of ablative doses of radiation to the prostate. The patterns of failure at the time of biochemical recurrence (BCR) after SBRT remain unknown. The purpose of this study is to explore the development of distant metastasis (DM) following the diagnosis of BCR. MATERIALS/METHODS We queried a multi-institutional database of 2,430 patients who were prospectively treated with SBRT on single institution phase II trials or registries to identify patients who developed a BCR by the Phoenix criteria or by initiation of salvage therapy for PSA rise at a lower threshold. Patterns of distant failure were obtained for patients who had BCR, including presence and sites of DM. Multivariable analysis (MVA) using logistic regression was used to evaluate the association between multiple clinicopathologic and treatment variables and DM. RESULTS 150 patients with BCR were identified (6.2% of total). Of these, 19% presented with low-risk, 42% with intermediate-risk, and 39% with high-risk disease. The median PSA at BCR was 4.56, median time to BCR was 36 months, and median follow-up after BCR was 15.5 months. Sixty-seven patients (44.7%) had DM identified at or after the time of BCR. Among those with DM, 13 had M1a disease, 50 had M1b disease, 3 had M1c disease, and 1 had an unknown distribution of disease. Time to BCR was significantly shorter in patients with DM compared to those who did not have DM (28.1 vs. 41.4 months, P = 0.002) and initial PSA (iPSA) was significantly greater (11.0 vs. 8.0, P = 0.03). On MVA, Gleason Grade Group (GG) 4 (vs. GG 1, OR 3.76, P = 0.047) and higher SBRT dose (36.25 Gy vs. 35 Gy: OR 4.03, P = 0.02; 40 Gy vs. 35 Gy: OR 3.73, P = 0.03) were significantly associated with DM. CONCLUSION A substantial proportion of patients with BCR after SBRT for localized PCa ultimately develop DM, particularly those with higher iPSA and shorter time to BCR. The association with SBRT dose is likely reflective of the use of higher doses in more modern cohorts with higher-risk disease, while the association with GG likely reflects the more aggressive biology of these tumors at presentation. Further research into patterns of failure after SBRT is needed, especially in the context of more sensitive nuclear imaging. Early predictors of treatment failure are needed to facilitate timely treatment intensification.

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.

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.

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.

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.

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.

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).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 nPSA0.2 ng/mL and0.5 ng/mL, rates of nPSA0.4 ng/mL at 4 years, and BCRFS.Median follow-up was 72 months. Median nPSA and nPSA0.2 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 nPSA0.4 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.LDR-BT led to lower nPSAs with longer continued decay compared to SBRT and HDR-BT, but no differences in BCRFS.

Key Points Question Is previously occult, nonlocalized (regional or metastatic) disease detected on prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) associated with clinically significant outcomes in patients with high-risk and very high-risk prostate cancer? Findings In this cohort study of 5275 patients, a nomogram estimative of an individual’s risk of nonlocalized disease on PSMA PET/CT was significantly associated with long-term outcomes, including distant metastasis and prostate cancer–specific mortality. The nomogram performed favorably compared with other risk-stratification tools. Meaning These findings suggest that previously occult disease may be associated with outcomes in this patient population., This cohort study evaluates the prognostic significance of a nomogram that models an individual’s risk of nonlocalized upstaging on prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) and compares its performance with existing risk-stratification tools., 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

ObjectivesSexually 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.MethodsBetween 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.ResultsIn 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.ConclusionWe 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.

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.

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.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.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.

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.

Disorders of sex development (DSD) comprise a group of conditions in which genotypes do not correlate with the typical male and female phenotypes. Numerical and structural abnormalities involving both autosomes and sex chromosomes have been observed in DSD. Specifically, deletions, duplications, and translocations involving specific genes as well as point mutations and less common aberrations have been implicated in the pathogenesis of these conditions. Finally, recent advances in analytical tools, namely chromosomal microarrays and sequencing methods, have greatly enhanced the precision with which DSD are genetically characterized and phenotypically correlated. Herein, we review the genes and loci involved in the pathogenesis of disorders of sex development based on recent findings and illustrate the importance of cytogenetics and molecular genetics in the clinical management of these conditions.

Background B-cell acute lymphoblastic leukemia (B-ALL) is the most common malignancy in pediatric patients and the leading cause of cancer-related death in children and young adults. Translocations of 9p24 involving JAK2 (9p24) and gain-of-function mutations of JAK2 with subsequent activation of the JAK2 kinase have been described in several hematological malignancies including B-ALL. However, rearrangements involving JAK2 are rare in B-ALL as only few cases have been described in the literature. Findings Herein, we present a case of pediatric B-ALL whose conventional cytogenetics revealed an abnormal karyotype with a reciprocal translocation involving 9p24 (JAK2) and 12p11.2. Fluorescence in situ hybridization (FISH) studies using the RP11-927H16 Spectrum Green JAK2 probe on previously G-banded metaphases confirmed the involvement of JAK2 in this rearrangement. Further FISH studies on the same previously G-banded metaphases using the LSI MLL probe helped to characterize an insertion of MLL into 6q27 as an additional abnormality in this karyotype. FISH studies performed on interphase nuclei also revealed an abnormal clone with MLL rearrangements in 23.6% of the nuclei examined as well as an abnormal clonal population with a deletion of the 5'IGH@ region in 88.3% of the nuclei examined. Conclusions Rearrangements of 9p24 can result in constitutive activation of JAK2, and have been observed in B-ALL. Rearrangements of the MLL gene have also been described extensively in B-ALL. However, rearrangements of MLL with a partner at 6q27 and in conjunction with a translocation involving JAK2 have not been previously described. This case pinpoints the importance of FISH and conventional cytogenetics to characterize complex rearrangements in which JAK2 and MLL are involved. The therapeutic targeting of JAK2 and MLL in cases like this may be prognostically beneficial.

BackgroundAcute myeloid leukemia (AML) is commonly characterized by several chromosomal abnormalities resulting in the formation of chimeric genes that play various roles in leukemogenesis. Translocations resulting in the ETV6-ABL1 fusion gene are rare in AML and other hematologic malignancies with only thirty-two previously reported cases in the literature, five of which were AML.FindingsHerein, we report the case of a 73-year-old male with acute myeloid leukemia arising from MDS, negative for PDGFRA and PDGFRB, positive for bone marrow eosinophilia, rash, and marked fluid retention, which improved dramatically with imatinib therapy. Conventional cytogenetics revealed a t(3;9)(p25;q34), t(5;18)(q13;p11.2), and additional material of unknown origin at 12p11.2 in 2 out of 10 metaphases analyzed. Interphase FISH studies showed evidence of ETV6 (12p13) and ABL1 (9q34) rearrangements in 41.3% and 5.7% of the cells respectively. FISH studies on previously G-banded metaphases showed colocalization of ABL1 and ETV6 signals to the short arm of chromosome 3 at 3p25 suggesting a possible ETV6-ABL1 fusion. Subtelomeric metaphase FISH studies also showed the presence of a subtelomere 3p signal on the long arm of the derivative 9, and no subtelomere 3p signal on the derivative chromosome 12.ConclusionsThese findings suggest a complex rearrangement involving an insertion of ETV6 into 3p25 followed by a reciprocal translocation involving 3p25 and 9q34, resulting in a possible ETV6-ABL1 fusion. This case highlights the importance of FISH to characterize complex rearrangements in myeloid malignancies, particularly those resulting in clinically significant chimeric genes.

Background The t(1;19)(q23;p13), which can result in the TCF3-PBX1 chimeric gene, is one of the most frequent translocations in B-acute lymphoblastic leukemia (B-ALL) and is observed in both adult and pediatric populations at an overall frequency of 6%. It can occur in a balanced or unbalanced form and as a sole abnormality is associated with an intermediate prognosis. Additionally, this translocation is observed in the context of hyperdiploid B-ALL, in which case it is associated with a poor prognosis. However, due to different translocation partner genes at chromosomes 1 and 19, distinct subtypes of hyperdiploid B-ALL with t(1;19)/der(19)t(1;19) are recognized based on the presence or absence of the TCF3-PBX1 fusion gene, but the cytogenetic and etiologic differences between the two remain understudied. Findings We report a case of an adult with a history of relapsed precursor B-ALL whose conventional cytogenetics showed an abnormal female karyotype with both hyperdiploidy and a t(1;19)(q23;p13). Fluorescence in situ hybridization (FISH) on previously G-banded metaphases using the LSI TCF3/PBX1 Dual Color, Dual Fusion Translocation Probe confirmed the presence of the TCF3-PBX1 gene fusion. Conclusions This particular pattern with a TCF3-PBX1 fusion within the context of a hyperdiploid karyotype is seen in B-ALL and is usually associated with a poor outcome. This case is one of only a few cases with both hyperdiploidy and a confirmed TCF3-PBX1 fusion, demonstrating the importance of using FISH for proper molecular classification of these cases in order to distinguish them from those with hyperdiploidy but no TCF3-PBX1 fusion gene. Such molecular studies may provide insight into the precise differences between TCF3-PBX1 positive and negative hyperdiploid B-ALL bearing the t(1;19)(q23;p13).

Background Rearrangements involving ETV6 (12p13) are among the most common structural abnormalities in pediatric B-cell acute lymphoblastic leukemia (B-ALL) and involve numerous partner genes. Additionally, the t(8;14)(q11.2;q32), which can result in the placement of CEBPD (8q11.2) near the regulatory regions of IGH@ (14q32) and consequent overexpression of CEPBD, occurs at a higher frequency in individuals with Down syndrome-associated ALL (DS-ALL) compared to both the general and pediatric population. The coexistence of cytogenetically detectable ETV6 abnormalities and t(8;14)(q11.2;q32) is a rare occurrence in B-ALL and has only been reported in a single case in the literature. Findings Herein, we present a case of B-ALL in a 9-year old male with Down syndrome in which conventional cytogenetic analysis revealed two reciprocal translocations: a t(8;14)(q11.2;q32) and a t(2;12)(p12;p13). Interphase and metaphase fluorescence in situ hybridization (FISH) analysis using break apart probes confirmed the involvement of IGH@ and ETV6 in these translocations, respectively. Additionally, interphase FISH revealed a clonal subpopulation bearing biallelic IGH@ rearrangements not observed by conventional cytogenetic analysis. Conclusions To the best of our knowledge, this is the first reported case of B-ALL bearing an ETV6 translocation with a partner gene on the short arm of chromosome 2 confirmed by FISH. Additionally, it is the second reported case of t(8;14)(q11.2;q32)-ALL bearing a concomitant, cytogenetically detectable abnormality involving ETV6. This case provides insight into a novel translocation involving ETV6 as well as potentially unique and understudied mechanisms of clonal evolution in pediatric B-ALL.