Compact engineered human mechanosensitive transactivation modules enable potent and versatile synthetic transcriptional control.

Engineered transactivation domains (TADs) combined with programmable DNA binding platforms have revolutionized synthetic transcriptional control. Despite recent progress in programmable CRISPR-Cas-based transactivation (CRISPRa) technologies, the TADs used in these systems often contain poorly tolerated elements and/or are prohibitively large for many applications. Here, we defined and optimized minimal TADs built from human mechanosensitive transcription factors. We used these components to construct potent and compact multipartite transactivation modules (MSN, NMS and eN3x9) and to build the CRISPR-dCas9 recruited enhanced activation module (CRISPR-DREAM) platform. We found that CRISPR-DREAM was specific and robust across mammalian cell types, and efficiently stimulated transcription from diverse regulatory loci. We also showed that MSN and NMS were portable across Type I, II and V CRISPR systems, transcription activator-like effectors and zinc finger proteins. Further, as proofs of concept, we used dCas9-NMS to efficiently reprogram human fibroblasts into induced pluripotent stem cells and demonstrated that mechanosensitive transcription factor TADs are efficacious and well tolerated in therapeutically important primary human cell types. Finally, we leveraged the compact and potent features of these engineered TADs to build dual and all-in-one CRISPRa AAV systems. Altogether, these compact human TADs, fusion modules and delivery architectures should be valuable for synthetic transcriptional control in biomedical applications.

Assessment of an embedded primary care-derived electronic health record (EHR) frailty index (eFI) in older adults with acute myeloid leukemia.

INTRODUCTION: Assessing frailty is integral to treatment decision-making for older adults with acute myeloid leukemia (AML). Prior electronic frailty indices (eFI) derive from an accumulated-deficit model and are associated with mortality in older primary care populations. We evaluated use of an embedded eFI in AML by describing baseline eFI categories by treatment type and exploring associations between eFI categories, survival, and treatment received. MATERIALS AND METHODS: This was a retrospective study of subjects ≥60 years old with new AML treated at an academic medical center from 1/2018-10/2020. The eFI requires ≥2 ambulatory visits over two years and uses demographics, vitals, ICD-10 codes, outpatient labs, and available functional information from Medicare Annual Wellness Visits. Frailty was defined as fit (eFI ≤ 0.10), pre-frail (0.10 < eFI ≤ 0.21), and frail (eFI > 0.21). Chemotherapy was intensive (anthracycline-based) or less-intensive (hypomethylating agent, low dose cytarabine +/- venetoclax). Therapy type, pre-treatment characteristics, and chemotherapy cycles were compared by eFI category using chi-square and Fisher's exact tests and ANOVA. Median survival was compared by eFI category using log-rank tests stratified by therapy type. RESULTS: Among 166 older adults treated for AML (mean age 74 years, 61% male, 85% Caucasian), only 79 (48%) had a calculable eFI score before treatment. Of these, baseline eFI category was associated with treatment received (fit (n = 31): 68% intensive, 32% less intensive; pre-frail (n = 38): 37% intensive, 63% less intensive; frail (n = 10): 0% intensive, 100% less intensive; not calculable (n = 87): 48% intensive, 52% less-intensive; p < 0.01). The prevalence of congestive heart failure and secondary AML differed by frailty status (p < 0.01). Median survival did not differ between eFI categories for intensively (p = 0.48) or less-intensively (p = 0.09) treated patients. For those with less-intensive therapy who lived ≥6 months, eFI category was not associated with the number of chemotherapy cycles received (p = 0.97). The main reason for an incalculable eFI was a lack of outpatient visits in our health system prior to AML diagnosis. DISCUSSION: A primary care-derived eFI was incalculable for half of older adults with AML at an academic medical center. Frailty was associated with chemotherapy intensity but not survival or treatment duration. Next steps include testing adaptations of the eFI to the AML setting.

Real-world outcomes of adult patients with acute lymphoblastic leukemia treated with a modified CALGB 10102 regimen.

Acute lymphoblastic leukemia (ALL) is an aggressive bone marrow cancer with disparate outcomes. Data on patient outcomes in real world settings outside of clinical trials is limited. The current study reports on outcomes for 137 ALL patients who received an adult induction and consolidation regimen derived from the CALGB 10102 trial modified without alemtuzumab. Of the 137 patients, 32 were < 40 years old, 52 were between 40 and 59, and 53 were ≥ 60 years old. Overall, 109 (79.6%) patients achieved a complete remission (< 40: 96.1%, 40-59: 86.5%, and 62.3% ≥ 60 (p = 0.0002)). Progression free survival for the entire cohort was 13.5 months and by age was 19.8 months for less than 40, 23.4 months for 40 to 59 and 6.7 months for ≥ 60; p = 0.0002. Median survival was 22.1 months for the entire cohort (32.9 months for ages < 40, 26.6 months ages 40-59, 7.8 months ≥ 60, p < 0.001).

Prophylactic Pretransplant Ganciclovir to Reduce Cytomegalovirus Infection After Hematopoietic Stem Cell Transplantation.

OBJECTIVE/BACKGROUND: Cytomegalovirus (CMV) reactivation remains a serious complication after allogeneic hematopoietic cell transplantation (HCT) occurring in approximately 60-70% of CMV-seropositive HCT recipients. CMV reactivation leads to adverse outcomes including end-organ damage, graft-versus-host disease, and graft failure. METHODS: Ganciclovir was administered pretransplant at 5 mg/kg twice daily intravenously from the start of conditioning to Day T-2 to CMV-seropositive patients receiving their first allogeneic HCT. CMV DNA was monitored weekly until at least Day 100 posttransplant. RESULTS: A total of 109 consecutive patients were treated, median age 57 (range 20-73) years. Of these, 36 (33%) patients had a CMV reactivation within the first 105 days posttransplant with a median time of reactivation of 52.5 (range 36-104) days posttransplant. The cumulative incidence of CMV reactivation at Day 105 posttransplant was 33.1% (95% confidence interval: 24.4-42.0). One patient developed CMV disease. CONCLUSION: The use of pretransplant ganciclovir was associated with low incidence of CMV reactivation and disease. These data suggest that pretransplant ganciclovir with preemptive therapy for viral reactivation may be a useful strategy to reduce CMV reactivation. Future prospective trials are needed to compare strategies for CMV prophylaxis.

Diagnostic Discrepancies in Small-volume Biopsy for the Initial Diagnosis, Recurrence, and Transformation of Follicular Lymphoma: A Multi-Institutional Collaborative Study.

Small-volume biopsies (SVBs) including fine-needle aspiration (FNA), cell block, and needle core biopsies (NCB) are increasingly utilized to diagnose and guide the clinical management of lymphoma. We established a multi-institutional interdisciplinary collaboration of cytopathologists, hematopathologists, and oncologists focused on the role of SVB in the management of patients with follicular lymphoma (FL). To assess the performance characteristics of SVB in this setting, we evaluated all consecutive SVBs performed for clinical indications of initial diagnosis, recurrence, or transformation of FL over a 5-year period and focused on the 182 that had at least one subsequent biopsy within 3 months as part of the same clinical work-up. The most common outcome of a subsequent biopsy as part of the same clinical work-up was a more specific diagnosis usually assigning the pathologic grade (111/182, 61%), followed by a complete agreement with the SVB (24/182, 13%), and change from nondiagnostic on initial biopsy to diagnostic on subsequent biopsy (21/182, 12%). A minority resulted in a diagnostic change from benign to lymphoma (17/182, 9%), a change in FL grade (5/182, 3%), or change in the lymphoma diagnostic category (4/182, 2%). There were no cases where an initial diagnosis of lymphoma was overturned. The distribution of discrepancies was similar across initial SVB types (FNA, FNA + cell block, NCB with or without FNA). Tissue limitations were noted in a minority of cases (53/182, 29%) and were enriched among initially nondiagnostic biopsies (16/21, 76%). Flow cytometry immunophenotyping was performed in the majority of cases both at the first and last biopsy (147/182, 81%). SVB can be a powerful method to detect FL in various clinical indications, with discrepant cases mostly resulting from a refinement in the initial diagnosis.

Small volume biopsy diagnostic yield at initial diagnosis versus recurrence/transformation of follicular lymphoma: A retrospective Cyto-Heme Interinstitutional Collaborative study.

BACKGROUND: Few studies have evaluated diagnostic yield of small volume biopsies (SVB) for the diagnosis and management of follicular lymphoma (FL). METHODS: The authors performed a multi-institutional retrospective analysis of SVBs including fine-needle aspiration (FNA) and needle core biopsy (NCB) for initial FL diagnosis and suspected recurrence or transformation of FL. A total of 676 workups beginning with SVB were assessed for the mean number of biopsies per workup, the proportion of workups requiring multiple biopsies, and the proportion with a complete diagnosis including grade, on initial biopsy. RESULTS: Compared to workups performed for question transformation/recurrence, those done for initial FL diagnosis were significantly more likely to require multiple biopsies (p < .01), had a higher mean number of biopsies per workup (1.7 vs. 1.1, absolute standardized difference = 1.1), and a lower complete diagnosis rate at initial biopsy (39% vs. 56%). At initial FL diagnosis, NCB +/- FNA was associated with fewer biopsies per workup compared to FNA +/- CB (1.2 vs. 1.9), fewer workups requiring multiple biopsies (23% vs. 83%), and a higher complete diagnosis rate (71% vs. 18%). In contrast, during assessment for transformation/recurrence, NCB and FNA showed a similar mean number of biopsies per workup (1.2 vs. 1.2) and few workups required multiple biopsies (6% vs. 19%). CONCLUSIONS: SVB at initial FL diagnosis often required additional biopsies to establish a complete diagnosis. In contrast, when assessing for transformed/recurrent FL, additional biopsies were generally not obtained regardless of SVB type, suggesting that in these clinical settings SVB may be sufficient for clinical decision-making.

Targeting Apoptosis in ALL.

PURPOSE OF REVIEW: While the treatment of acute lymphoblastic leukemia (ALL) has improved significantly over the last 30 years, the majority of adult patients will have their disease relapse. The BCL-2 gene was initially discovered from follicular lymphoma research; however, the BH3 family of proteins has is emerging to be crucial in patients with ALL due to their reliance on the balance of these pro-apoptotic and anti-apoptotic proteins in the BH3 family. We discuss apoptosis in ALL, the reliance mechanisms, drug development in this space, and areas for future research. RECENT FINDINGS: The first drugs that were developed to inhibit the BCL-2 pathway include both venetoclax (BCL-2 specific inhibitor) and navitoclax (BCL-2, BCL-XL, and BCL-W). These drugs show promise and have obtained complete remissions, minimal residual disease negative status, and have been used as a bridge to allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia and chronic lymphocytic leukemia. There are multiple ongoing clinical trials looking to assess the use of BCL-2 inhibition with chemotherapy, targeted therapies, and bi-specific T-cell engager therapies not only in both frontline and relapsed refractory ALL but also in consolidation and maintenance phases. There is still a large need for improvement of ALL outcomes in adult patients. Research has shown that ALL depends on the BCL-2 family of proteins for cell survival and proliferation. Targeting this pathway with BCL-2 inhibition has led to encouraging results, and future research is aimed at incorporating this targeted therapy into current treatment paradigms.

Single-route CNS prophylaxis for aggressive non-Hodgkin lymphomas: real-world outcomes from 21 US academic institutions.

Prophylaxis is commonly used to prevent central nervous sy stem (CNS) relapse in diffuse large B-cell lymphoma (DLBCL), with no clear standard of care. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline therapy between 2013 and 2019. Prophylaxis was administered intrathecally(IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7%) had CNS relapse after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4% vs 6.8%, P = .4), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected vs observed CNS relapse rates were nearly identical (5.8% vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated, and reconsideration of prophylaxis strategies in DLBCL is of critical need.

Impact of initial biopsy type on the time to final diagnostic biopsy in patients with follicular lymphoma and suspected histologic transformation.

Diagnosis of histologic transformation (HT) of follicular lymphoma (FL) requires tissue biopsy. While surgical biopsy represents the gold standard, less invasive procedures such as fine-needle aspiration biopsy (FNAB) and core needle biopsy (CNB) are frequently performed. In this retrospective multi-institutional study including 269 patients with FL and suspected HT, the median time from initial clinical suspicion to final diagnostic biopsy was similar whether the workup began with FNAB, CNB, or surgical biopsy (4, 9, and 6 days, respectively; p=.27), despite more subsequent biopsies performed following initial FNAB. Periprocedural complications were uniformly minimal. Biopsy-proven HT was more common in the initial surgery group and in workups including positron emission tomography/computed tomography (PET/CT). Our findings, derived from US academic centers with specialized procedural and pathology expertise, suggest that FNAB, CNB, and surgical biopsy are all viable initial diagnostic procedures that can inform clinical decision-making in select FL patients with suspected HT.

Epidemiology of acute myeloid leukemia in Virginia: Excellent survival outcomes for patients in rural Appalachia.

BACKGROUND: Acute myeloid leukemia, the most common acute leukemia in adults, has a poor overall survival. Studies have suggested that certain socioeconomic factors such as living in a rural or farming area are associated with worse outcomes. Since 42% of acute myeloid leukemia patients seen in our academic center reside in a rural area, we have a unique opportunity to study outcomes of patients in rural versus urban settings. AIM: This analysis evaluates the effect of geography and socioeconomic factors on the biology, treatment, and overall survival of patients with acute myeloid leukemia, with the goal of understanding health care disparities. METHODS AND RESULTS: Patient characteristics, cytogenetic data, treatment history, and overall survival were collected and analyzed to identify differences between urban and rural residency. This cohort included 42% of patients who resided in a rural area at the time of acute myeloid leukemia diagnosis. There was no difference in overall survival between the cohorts. The 1 year overall survival for the entire cohort was 47.9%. There was no difference detected in rates of adverse cytogenetics between the rural and urban cohorts. Similar numbers of patients received induction chemotherapy or proceeded to allogeneic stem cell transplant between the cohorts. CONCLUSIONS: This study highlights that similar outcomes can be achieved in rural and urban patients, suggesting that intensive efforts at telehealth, education, and collaboration with local oncology practices may be beneficial.

Adapting isotonic dose-finding to a dynamic set of drug combinations with application to a phase I leukemia trial.

BACKGROUND/AIMS: This article describes the proposed design of a phase I study evaluating the safety of ceramide nanoliposome and vinblastine among an initial set of 19 possible dose combinations in patients with relapsed/refractory acute myeloid leukemia and patients with untreated acute myeloid leukemia who are not candidates for intensive induction chemotherapy. METHODS: Extensive collaboration between statisticians and clinical investigators revealed the need to incorporate several adaptive features into the design, including the flexibility of adding or eliminating certain dose combinations based on safety criteria applied to multiple dose pairs. During the design stage, additional dose levels of vinblastine were added, increasing the dimension of the drug combination space and thus the complexity of the problem. Increased complexity made application of existing drug combination dose-finding methods unsuitable in their current form. RESULTS: Our solution to these challenges was to adapt a method based on isotonic regression to meet the research objectives of the study. Application of this adapted method is described herein, and a simulation study of the design's operating characteristics is conducted. CONCLUSION: The aim of this article is to bring to light examples of novel design applications as a means of augmenting the implementation of innovative designs in the future and to demonstrate the flexibility of adaptive designs in satisfying changing design conditions.

Gilteritinib: An FMS-like tyrosine kinase 3/AXL tyrosine kinase inhibitor for the treatment of relapsed or refractory acute myeloid leukemia patients.

Acute myeloid leukemia has recently undergone a significant transition into identifying and successfully inhibiting driver mutations leading to disease. One of the most common mutations in acute myeloid leukemia involves the protein FMS-like tyrosine kinase 3 (FLT3), which leads to ligand-independent activation of intracellular signaling cascades leading to the survival and proliferation of the acute leukemia blast cell. Preclinical studies have demonstrated the presence of two dominant types of mutations of this protein: internal tandem duplication and tyrosine kinase domain mutations. Successful inhibition of this protein has proven to be challenging. While FLT3 has been shown to be successfully inhibited and shown to improve overall survival in the frontline therapy of acute myeloid leukemia in combination with cytarabine and anthracycline, relapsed and refractory (R/R) patients have not been shown to be a successful population until recently. A phase III trial (ADMIRAL trial) demonstrated significant overall survival benefit in patients receiving gilteritinib compared to patients receiving salvage chemotherapy. This review will provide an overview of the preclinical, clinical, and practical use of gilteritinib in the treatment of patients with relapsed and refractory acute myeloid leukemia with FLT3 mutation.

Enasidenib in acute myeloid leukemia: clinical development and perspectives on treatment.

Recently there has been a significant progression in the understanding of molecular mutations driving biochemical and cellular signaling changes leading to survival and proliferation of leukemia cells in patients with acute myeloid leukemia (AML). Preclinical studies have demonstrated a mutated enzyme in the citric acid cycle, isocitrate dehydrogenase (IDH), leads to the production of an oncogenic metabolite R-2-hydroxy-glutarate (R-2-HG). This causes the arrest in the differentiation of hematopoietic stem cells leading to the promotion of leukemia. Inhibitors of the IDH enzyme have been shown in preclinical studies to reduce the production of R-2-HG, resulting in terminal differentiation of leukemia blast cells. In recent phase I and II trials, the IDH2 inhibitor enasidenib has shown clinical activity in patients with relapsed and refractory (R/R) AML. This review will describe the preclinical and clinical developments of enasidenib and its Food and Drug Administration approval in R/R AML, treatment recommendations and management will be outlined.

A prospective study on urine alkalization with an oral regimen consisting of sodium bicarbonate and acetazolamide in patients receiving high-dose methotrexate.

PURPOSE: Intravenous (IV) sodium bicarbonate is typically used in alkalization regimens for the safe use of the chemotherapeutic agent high-dose methotrexate (HDMTX). Urine parameters including urine output and pH are important in order to minimize the risk of kidney injury, which increases adverse effects and hospital length of stay following HDMTX. IV sodium bicarbonate has been on shortage, and there are limited literature describing the safety of alternative regimens. PATIENTS AND METHODS: A single institution, prospective analysis of non-Hodgkin's lymphoma and acute lymphoblastic leukemia patients receiving HDMTX for central nervous system (CNS) prophylaxis or disease. Patients received an oral (PO) regimen of sodium bicarbonate and acetazolamide to achieve a urine pH >7. This cohort was compared to a subsequent IV sodium bicarbonate control cohort. Multiple co-primary safety outcomes assessed the incidences of acute kidney injury and delayed methotrexate clearance as well as change in liver function tests. Secondary outcomes included time to urine pH, time to urine output, and length of stay. RESULTS: A total of 126 encounters were studied for the primary safety outcome. There was no difference between AKI incidence in patients receiving the PO alkalization regimen compared to patients receiving IV sodium bicarbonate (14.5% vs 9.3%, respectively, P=0.41). There was no difference in methotrexate clearance between the PO and IV groups (26.5% vs 37.2%, respectively, P=0.21). The use of PO alkalization regimen is estimated to have saved 2002 vials of IV sodium bicarbonate and was approximately US$226 less expensive per encounter. CONCLUSION: This analysis supports the use of PO regimens to achieve urine alkalization necessary for safe administration of HDMTX during periods of IV sodium bicarbonate shortage. Further studies may determine optimal dosing strategies that decrease length of stay and ensure noninferiority of efficacy outcomes with PO regimens for urine alkalization with HDMTX.

Tadalafil for prevention of erectile dysfunction after radiotherapy for prostate cancer: the Radiation Therapy Oncology Group [0831] randomized clinical trial.

IMPORTANCE: Tadalafil is used to treat erectile dysfunction after prostate cancer treatment, but its role as a preventive agent is undefined. OBJECTIVES: To determine primarily whether tadalafil preserved erectile function in men treated with radiotherapy for prostate cancer, and secondarily to determine whether participant- or partner-reported overall sexual function and sexual and marital satisfaction were affected. DESIGN, SETTING, AND PARTICIPANTS: Stratified, placebo-controlled, double-blind, parallel-group study with 1:1 randomization at 76 community-based and tertiary medical sites in the United States and Canada. Two hundred forty-two participants with intact erectile function scheduled to receive radiotherapy for prostate cancer were recruited between November 2009 and February 2012 with follow-up through March 2013. INTERVENTIONS: One hundred twenty-one participants were assigned 5 mg of tadalafil daily and 121 were assigned placebo for 24 weeks starting with external radiotherapy (63%) or brachytherapy (37%). Participant-reported International Index of Erectile Function response before radiotherapy and at weeks 2 and 4, between weeks 20 and 24, between weeks 28 and 30, and 1 year thereafter. Participants and partners could respond also to the Sexual Adjustment Questionnaire and to the Locke Marital Adjustment Test before radiotherapy, between weeks 20 and 24 and weeks 28 and 30, and at 1 year. MAIN OUTCOMES AND MEASURES: Primary outcome was off-drug spontaneous erectile function 28 to 30 weeks after radiotherapy started. Secondary end points were spontaneous erection at 1 year; overall sexual function and satisfaction; marital adjustment; and partner-reported satisfaction and marital adjustment at 28 to 30 weeks and 1 year, predictors of tadalafil response; and adverse events. RESULTS: Among 221 evaluable participants, 80 (79%; 95% CI, 70%-88%) assigned to receive tadalafil retained erectile function between weeks 28 and 30 compared with 61 (74%; 95% CI, 63%-85%) assigned to receive placebo (P = .49); an absolute difference of 5% (95% CI, -9% to 19%). A significant difference was also not observed at 1 year (72%; 95% CI, 60%-84% vs 71%; 95% CI, 59%-84%; P = .93). Tadalafil was not associated with significantly improved overall sexual function or satisfaction; a significant difference was not observed in any domain subscale. Partners of men assigned tadalafil noted no significant effect on sexual satisfaction, and marital adjustment was not significantly improved in participants or partners. CONCLUSIONS AND RELEVANCE: Among men undergoing radiotherapy for prostate cancer, daily use of tadalafil compared with placebo did not result in improved erectile function. These findings do not support daily use of tadalafil to prevent erectile dysfunction in these patients. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00931528.

A prospective randomized comparison of stranded vs. loose 125I seeds for prostate brachytherapy.

PURPOSE: To compare seed loss and dosimetric parameters between stranded and loose 125I seeds (LS) for prostate brachytherapy. METHODS AND MATERIALS: Sixty-four patients with 1997 American Joint Commission on Cancer (AJCC) clinical stage T1c or T2a prostate carcinoma were prospectively randomized to brachytherapy (144Gy) with RAPID Strand 125I seeds (RS) vs. LS (Oncura, Plymouth Meeting, PA) The treatment plan for each patient was devised before randomization, and was not modified based on the randomization. Each patient underwent magnetic resonance, computed tomography, and plain film radiographs on the day of the implant (Day 0) and 30 days later (Day 30). RESULTS: Overall, 21 of 62 patients (30%) experienced seed loss. Seed loss occurred in 15 of 32 of LS patients (47%) vs. 6 of 30 RS patients (23%; p=0.053). Mean seed loss was 1.09 in the LS patient vs. 0.43 in RS patients (p=0.062). Eight LS patients (25%) lost multiple seeds, compared to 3 stranded patients (10%). Despite the lesser degree of seed loss in patients who received stranded seeds, they had a paradoxical trend toward lower V100 and D90 values. CONCLUSION: This prospective randomized trial showed a strong trend toward a decrease in postimplant seed loss with stranded seeds. Improved seed retention may be more advantageous in a setting of less generous periprostatic coverage. The lowered risk seed migration seen with stranded seeds would presumably also decrease the likelihood of lung or cardiac seed embolization.

Effect of post-implant edema on prostate brachytherapy treatment margins.

PURPOSE: To determine if postimplant prostate brachytherapy treatment margins calculated on Day 0 differ substantially from those calculated on Day 30. METHODS: Thirty patients with 1997 American Joint Commission on Cancer clinical stage T1-T2 prostatic carcinoma underwent prostate brachytherapy with I-125 prescribed to 144 Gy. Treatment planning methods included using loose seeds in a modified peripheral loading pattern and treatment margins (TMs) of 5-8 mm. Postimplant plain radiographs, computed tomography scans, and magnetic resonance scans were obtained 1-4 hours after implantation (Day 0). A second set of imaging studies was obtained at 30 days after implantation (Day 30) and similarly analyzed. Treatment margins were measured as the radial distance in millimeters from the prostate edge to the 100% isodose line. The TMs were measured and tabulated at 90 degrees intervals around the prostate periphery at 0.6-cm intervals. Each direction was averaged to obtain the mean anterior, posterior, left, and right margins. RESULTS: The mean overall TM increased from 2.6 mm (+/-2.3) on Day 0 to 3.5 mm (+/-2.4) on Day 30. The mean anterior margin increased from 1.2 mm on Day 0 to 1.8 mm on Day 30. The posterior margin increased from 1.2 mm on Day 0 to 2.8 mm on Day 30. The lateral treatment margins increased most over time, with mean right treatment margin increasing from 3.9 mm on Day 0 to 4.7 mm on Day 30. CONCLUSION: Treatment margins appear to be durable in the postimplant period, with a clinically insignificant increase from Day 0 to Day 30.

Intraoperative fluoroscopic dose assessment in prostate brachytherapy patients.

PURPOSE: To evaluate a fluoroscopy-based intraoperative dosimetry system to guide placement of additional sources to underdosed areas, and perform computed tomography (CT) verification. METHODS AND MATERIALS: Twenty-six patients with prostate carcinoma treated with either I-125 or Pd-103 brachytherapy at the Puget Sound VA using intraoperative postimplant dosimetry were analyzed. Implants were performed by standard techniques. After completion of the initial planned brachytherapy procedure, the initial fluoroscopic intraoperative dose reconstruction analysis (I-FL) was performed with three fluoroscopic images acquired at 0 (AP), +15, and -15 degrees. Automatic seed identification was performed and the three-dimensional (3D) seed coordinates were computed and imported into VariSeed for dose visualization. Based on a 3D assessment of the isodose patterns additional seeds were implanted, and the final fluoroscopic intraoperative dose reconstruction was performed (FL). A postimplant computed tomography (CT) scan was obtained after the procedure and dosimetric parameters and isodose patterns were analyzed and compared. RESULTS: An average of 4.7 additional seeds were implanted after intraoperative analysis of the dose coverage (I-FL), and a median of 5 seeds. After implantation of additional seeds the mean V100 increased from 89% (I-FL) to 92% (FL) (p < 0.001). In I-125 patients an improvement from 91% to 94% (p = 0.01), and 87% to 93% (p = 0.001) was seen for Pd-103. The D90 increased from 105% (I-FL) to 122% (FL) (p < 0.001) for I-125, and 92% (I-FL) to 102% (FL) (p = 0.008) for Pd-103. A minimal change occurred in the R100 from a mean of 0.32 mL (I-FL) to 0.6 mL (FL) (p = 0.19). No statistical difference was noted in the R100 (rectal volume receiving 100% of the prescribed dose) between the two techniques. The rate of adverse isodose patterns decreased between I-FL and FL from 42% to 8%, respectively. The I-125 patients demonstrated a complete resolution of adverse isodose patterns after the initial isodose reconstruction (I-FL). The Pd-103 patients demonstrated a final rate of 8% gaps, 0% islands, and 0% holes on corrected isodose reconstruction. CONCLUSION: The use of intraoperative fluoroscopy-based dose assessment can accurately guide in the implantation of additional sources to supplement inadequately dosed areas within the prostate gland. Additionally, guided implantation of additional source, can significantly improve V100s and D90s, without significantly increasing rectal doses.