Setting Of Recurrent Disease Research Articles

Germline BRCA pathogenic variants in patients with ovarian cancer and post-poly (ADP-ribose) polymerase inhibitor myeloid neoplasms

Among patients with advanced high-grade ovarian carcinoma (aHGOC) treated with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis), the presence of a germline BRCA pathogenic variant (gBRCA-PV) may increase the risk of bone marrow mutagenesis resulting in postcytotoxic therapy myelodysplastic neoplasms (MDS-pCT) or acute myeloid leukemia (AML-pCT), as it is expressed in heterozygosity also by hematopoietic progenitors. We aimed to investigate the occurrence of post-PARPi MDSs/AMLs-pCTs according to gBRCA-PV status. We conducted a retrospective single-center study to evaluate MDS/AML-pCT in patients with aHGOC and a known gBRCA-PV status receiving at least 8 weeks of maintenance PARPi, in any line of therapy, from February 2017 to December 2022. The endpoint was the proportion of patients who experienced MDSs-pCT and AMLs-pCT during and after treatment with PARPi, in gBRCA-PV carriers and non-carriers. A total of 166 patients were included: 95 (57%) had a gBRCA-PV and 72% received PARPi for recurrent disease. The number of lines of chemotherapies before and after PARPi, median overall survival, and median follow-up were comparable between gBRCA-PV carriers and non-carriers. After a median follow-up of 40.0 (95% confidence interval: 35.7-44.3) months, 10 (6%) patients were diagnosed with an MDS-pCT and 4 (2%) with an AML-pCT. A higher proportion of MDSs/AMLs-pCT (10% versus 2%; P= 0.16) and, in particular, of MDSs-pCT (9% versus 1%; P= 0.04) was observed among gBRCA-PV carriers. The presence of a gBRCA-PV is associated with a higher risk of MDS-pCT and possibly of myeloid neoplasms after PARPi in patients with aHGOC who received PARPi, especially in the setting of recurrent disease.

Translating biological insights into improved management of endometrial cancer.

Endometrial cancer (EC) is the most common gynaecological cancer among women in high-income countries, with both incidence and mortality continuing to increase. The complexity of the management of patients with EC has evolved with greater comprehension of the underlying biology and heterogeneity of this disease. With a growing number of novel therapeutic agents available, emerging treatment regimens seem to have the potential to helpto address the concerning trends in EC-related mortality. In this Review, we describe the epidemiology, histopathology and molecular classification of EC as well as the role of the new (2023) International Federation of Gynecologists and Obstetricians (FIGO) staging model. Furthermore, we provide an overview of disease management in the first-line and recurrent disease settings. With increasing use of molecular profiling and updates in treatment paradigms, we also summarize new developments in this rapidly changing treatment landscape.

Imaging Recommendations for Diagnosis and Management of Primary Parathyroid Pathologies: A Comprehensive Review.

Parathyroid pathologies are suspected based on the biochemical alterations and clinical manifestations, and the predominant roles of imaging in primary hyperparathyroidism are localisation of tumour within parathyroid glands, surgical planning, and to look for any ectopic parathyroid tissue in the setting of recurrent disease. This article provides a comprehensive review of embryology and anatomical variations of parathyroid glands and their clinical relevance, surgical anatomy of parathyroid glands, differentiation between multiglandular parathyroid disease, solitary adenoma, atypical parathyroid tumour, and parathyroid carcinoma. The roles, advantages and limitations of ultrasound, four-dimensional computed tomography (4DCT), radiolabelled technetium-99 (99mTc) sestamibi or dual tracer 99mTc pertechnetate and 99mTc-sestamibi with or without single photon emission computed tomography (SPECT) or SPECT/CT, dynamic enhanced magnetic resonance imaging (4DMRI), and fluoro-choline positron emission tomography (18F-FCH PET) or [11C] Methionine (11C -MET) PET in the management of parathyroid lesions have been extensively discussed in this article. The role of fluorodeoxyglucose PET (FDG-PET) has also been elucidated in this article. Management guidelines for parathyroid carcinoma proposed by the American Society of Clinical Oncology (ASCO) have also been described. An algorithm for management of parathyroid lesions has been provided at the end to serve as a quick reference guide for radiologists, clinicians and surgeons.

Hyperthermic intraperitoneal chemotherapy (HIPEC) in the management of ovarian cancer

Key content Hyperthermic intraperitoneal chemotherapy (HIPEC) at the time of cytoreductive surgery is a proposed additional treatment in the management of advanced tubo‐ovarian cancer. Additional organisational approvals, costs, changes to theatre infrastructure and pre‐, intra‐, and post‐operative management considerations are required to implement HIPEC in a clinical setting. Current meta‐analysis data suggest that in the setting of interval cytoreductive surgery, HIPEC prolongs overall survival and progression‐free survival. There is currently no evidence of benefit in the setting of primary surgery or recurrent disease, but results of ongoing clinical trials are pending. Learning objectives To understand the mechanism of action, safety and efficacy of HIPEC as an adjuvant treatment in tubo‐ovarian cancer. Ethical issues Because of variation in treatment protocols and heterogeneity of reported outcomes, HIPEC has not yet been adopted into standard practice. Further studies assessing its benefit, mainly in the setting of primary cytoreduction, are ongoing.

Medical cannabis and its effect on oncological outcomes in patients with ovarian cancer treated with PARP inhibitors.

Poly (ADP-ribose) polymerase inhibitors (PARPi) play a pivotal role in ovarian cancer management. With medical cannabis emerging as a novel component of supportive care, this study investigated the impact of medical cannabis use on oncological outcomes in patients with ovarian cancer undergoing PARPi therapy. The study included patients from a single institution database treated for ovarian cancer between January 2014 and January 2020 who received PARPi maintenance therapy in a first-line or recurrent disease setting after a confirmed response to platinum-based treatment. The study categorized patients as cannabis users and cannabis-naïve. Univariate and multivariate Cox regression analysis and the Kaplan-Meier method were used to assess the effects of medical cannabis use on the duration of PARPi therapy, progression-free survival, and overall survival. Among the eligible patients (n=93), most were cannabis-naïve (69%, n=64) while the rest used medical cannabis (31%, n=29). Medical cannabis use rates were comparable for patients receiving PARPi therapy post-primary treatment or for recurrence (42%, n=9, vs 27%, n=20; p=0.1). Both groups exhibited similar median duration for PARPi therapy (12.1 vs 9.5 months; p=0.89) and progression-free survival (20 vs 21 months; p=0.83). Kaplan-Meier analysis detected no differences in progression-free survival associated with cannabis use. Although cannabis users had an extended overall survival compared with the cannabis-naïve group (129.3 vs 99 months; p=0.03), cannabis use was insignificant for overall survival on multivariate analysis (p=0.10). Multivariate analysis showed stage IV at diagnosis (p=0.02) to be the sole factor associated with progression-free survival (p=0.02). Medical cannabis usage in patients receiving PARPi treatment showed no association with duration of PARPi therapy, progression-free survival, or overall survival.

Concurrent Radiation and Deep Hyperthermia Therapy for the Treatment of Recurrent Prostate Cancer

Robustpreclinical and clinical data have established hyperthermia as an effective radiosensitizer which can be used in the setting of recurrent disease to enhance the therapeutic window. We present a single institution experience examining outcomes in recurrent prostate cancer (RPCA) patients treated with concurrent deep hyperthermia (DHT) and radiation (RT). We hypothesized that concurrent DHT and RT would be well tolerated and would provide durable local control without unexpected toxicity. Consecutive RPCA patients treated with concurrent DHT and pelvic RT were retrospectively analyzed. Patients received twice weekly DHT treatments in addition to daily or twice daily (BID) RT. DHT was delivered using a concentric ring radiofrequency phased array system to a target temperature of 40-43°C. Acute and late treatment associated toxicities, graded per Common Terminology Criteria for Adverse Events (CTCAE) v5.0, were evaluated. Survival and control outcomes were evaluated using the Kaplan-Meier method. Eighteen patients were included for analysis. Median patient age was 69 yrs (64-82 yrs). Fifteen (83%) patients had received prior RT and 12 (67%) patients had undergone radical prostatectomy. At time of treatment, two patients had RPCA which had dedifferentiated to a small cell phenotype. Eight (44%) patients had extra-pelvic disease at time of treatment. Seventeen (94%) patients received proton RT, while 1 (6%) received photon RT. Median RT dose was 49 Gy (range 30-73.8 Gy). Five (28%) patients received BID RT. Fifteen (83%) patients also received sequential or concurrent systemic therapy including androgen deprivation therapy or chemotherapy. A total of 142 DHT treatments were administered (median of 7.5 treatments). Fourteen (78%) patients completed ≥ 75% of planned DHT treatments. Reasons for inability to complete treatment included discomfort and abnormal vital signs during DHT. Only one patient reported Grade 2 pain and pruritus attributed to concurrent RT and DHT. One acute Grade 3 RT toxicity (diarrhea) was reported. No late Grade 3+ toxicities occurred. Of ten patients (56%) treated with curative intent, 8 (44%) had no reported failures at 2-year follow up while two had distant failure and biochemical failure respectively. Three (17%) patients were treated with palliative intent for disease related pain; two reported partial relief and one reported complete pain relief. With a median follow-up of 27 months (1-46 months), 2-year failure free survival was 41.4% (95% CI: 27.8-55%), local control was 76.5% (95% CI 66.2-86.8%) and overall survival was 70.9% (95% CI 58.4-83.3%). Our results suggest that concurrent RT and DHT is well tolerated and allows for safe escalation of local therapy for RPCA, providing patients with durable local control and palliation with an acceptable toxicity profile. Prospective validation is warranted.

LBA02-12 IS LEARNING CURVE IMPORTANT WHILE PERFORMING PSMA-PET? ANALYSIS OF DETECTION RATE ACCORDING TO GLEASON SCORE AND PSA LEVEL IN TWO TIMEFRAMES AT A BRAZILIAN HIGH-VOLUME CENTER

You have accessJournal of UrologyCME1 Apr 2023LBA02-12 IS LEARNING CURVE IMPORTANT WHILE PERFORMING PSMA-PET? ANALYSIS OF DETECTION RATE ACCORDING TO GLEASON SCORE AND PSA LEVEL IN TWO TIMEFRAMES AT A BRAZILIAN HIGH-VOLUME CENTER Paulo Lages, Michelle Barbosa, Paulo Bergerot, Luciana Lages, Luciano Prado, Leonardo Prado, Pamela Muniz, Mariane Fontes, Marcella Prado, and Daniel Almeida Paulo LagesPaulo Lages More articles by this author , Michelle BarbosaMichelle Barbosa More articles by this author , Paulo BergerotPaulo Bergerot More articles by this author , Luciana LagesLuciana Lages More articles by this author , Luciano PradoLuciano Prado More articles by this author , Leonardo PradoLeonardo Prado More articles by this author , Pamela MunizPamela Muniz More articles by this author , Mariane FontesMariane Fontes More articles by this author , Marcella PradoMarcella Prado More articles by this author , and Daniel AlmeidaDaniel Almeida More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003361.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: PSMA PET/CT scan (68Ga-PSMA PET/CT) has emerged as a highly accurate method for assessing disease staging in patients with newly diagnosed localized high-risk prostate cancer and for recurrent disease. This has resulted in treatment plan modification in up to two-thirds of patients. PSMA PET/CT is commercially available in Brazil for a decade and growing experience with this test has led to more precise results over the years. METHODS: We retrospectively reviewed the results of PSMA PET/CT scans performed on patients at all disease stages in a single institution in Brasilia from 2015-2018 and 2021-2022. The results were correlated with available clinicopathological information in patients with recurrent disease in two separated timeframes. RESULTS: From 2015-2019, 351 exams were performed, with 303 in the setting of recurrent disease. From 2021-2022, 297 tests were executed with 283 in the recurrent disease setting. Clinicopathological information was available for 648 patients, with 586 patients in the setting of recurrent disease after first line treatment. CONCLUSIONS: There was a clinically relevant increase in the detection rate for patients with PSA ≤ 0.5 ng/mL and Gleason score ≤3+4, possibly as a result of the learning curve for this challenging scenario. However, we found a similar detection rate among other clinicopathological characteristics. Our data supports the need for ongoing training for the analysis of PSMA PET/CT results. Source of Funding: The authors © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1191 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Paulo Lages More articles by this author Michelle Barbosa More articles by this author Paulo Bergerot More articles by this author Luciana Lages More articles by this author Luciano Prado More articles by this author Leonardo Prado More articles by this author Pamela Muniz More articles by this author Mariane Fontes More articles by this author Marcella Prado More articles by this author Daniel Almeida More articles by this author Expand All Advertisement PDF downloadLoading ...

PD-L1 and MHC Class I Expression in High-grade Ovarian Cancers, Including Platinum-resistant Recurrences Treated With Checkpoint Inhibitor Therapy.

Immune-modulating therapies targeting the programmed cell death-1/programmed cell death ligand-1 (PD-L1) immunosuppressive system have been used successfully in many solid tumor types. There is evidence that biomarkers such as PD-L1 and major histocompatibility complex (MHC) class I help identify candidates for anti-programmed cell death-1/PD-L1 checkpoint inhibition, though the evidence is limited in ovarian malignancies. PD-L1 and MHC Class I immunostaining was performed on pretreatment whole tissue sections in 30 cases of high-grade ovarian carcinoma. The PD-L1 combined positive score was calculated (a score of ≥1 is considered positive). MHC class I status was categorized as an intact or subclonal loss. In patients who received immunotherapy, drug response was assessed using RECIST criteria. PD-L1 was positive in 26 of 30 cases (87%; combined positive score: 1 to 100). Seven of 30 patients showed subclonal loss of MHC class I (23%), and this occurred in both PD-L1 negative (3/4; 75%) and PD-L1 positive (4/26; 15%) cases. Only 1 of 17 patients who received immunotherapy in the setting of a platinum-resistant recurrence responded to the addition of immunotherapy, and all 17 died of disease. In the setting of recurrent disease, patients did not respond to immunotherapy regardless of PD-L1/MHC class I status, suggesting that these immunostains may not be effective predictive biomarkers in this setting. Subclonal loss of expression of MHC class I occurs in ovarian carcinoma, including in PD-L1 positive cases, suggesting that the 2 pathways of immune evasion may not be mutually exclusive and that it may be important to interrogate MHC class I status in PD-L1 positive tumors to identify additional immune evasion mechanisms in these tumors.

Comparative analysis of contemporary and past PSMA PET/CT results for recurrent prostate cancer in a high-volume Brazilian center.

51 Background: PSMA PET/CT scan (68Ga-PSMA PET/CT) has emerged as a highly accurate tool when assessing disease staging both for newly diagnosed localized high-risk prostate cancer and for recurrent disease, with treatment plan modification in up to two-thirds of patients. PSMA PET/CT is commercially available in Brazil since last decade and growing experience with this test has led to a more accurate analysis of the results over the years. Methods: We retrospectively reviewed the PSMA PET/CT scans results of patients undergoing the exam in all disease stages in a single institution in Brasilia, Brazil, between October 2015 and July 2022 and analyzed the results correlated with clinicopathological information (when available) in two separated timeframes for those in the recurrent disease setting. Results: Overall, more than 2,500 PSMA PET-CT scans were performed since October 2015. Between 2015 and 2019, 351 exams were performed, of which 303 in the setting of recurrent disease, while 297 tests were executed between 2021 and 2022, with 283 of them being done in the recurrent disease setting. Any clinicopathological information was available for 648 patients, of whom 586 underwent the test in the setting of recurrent disease following treatment of primary disease. Conclusions: There was a similar positivity rate among the clinicopathological characteristics analyzed in an indirect comparison of the two timeframes. It is remarkable the increased positivity rate among patients with lower levels of PSA in the contemporary dataset, which may reflect the learning curve of this image method. Among patients selected by Gleason grade, no definitive information can be extracted given the distinct PSA levels between patients in the two selected timeframes. [Table: see text]

Updated experience on PSMA PET/CT for recurrent prostate cancer in a high-volume Brazilian center.

50 Background: PSMA PET/CT scan (68Ga-PSMA PET/CT) has emerged as a highly accurate tool when assessing disease staging both for newly diagnosed localized high-risk prostate cancer and for recurrent disease, with treatment plan modification in up to two-thirds of patients. Methods: We retrospectively reviewed the PSMA PET/CT scans results of patients undergoing the exam in all disease stages in a single institution in Brasilia, Brazil, between October 2015 and July 2022 and correlated clinicopathological information with test results for those in the recurrent disease setting. Results: Overall, more than 2,500 PSMA PET-CT scans were performed during the selected time interval. Any clinicopathological information was available for 648 patients, of whom 586 underwent the test in the setting of recurrent disease following treatment of primary disease. Positive results were found in 400 studies, with a median PSA level of 1.035 ng/mL (IQR 0.3–3.5) and most prevalent Gleason score of 7 (3+4). Metastatic disease was found in 26.2% of patients with a median PSA level of 4.61 ng/mL. Conclusions: A positive correlation between both PSA level and Gleason grade and the positivity rate of PSMA PET/CT was found in this large dataset, confirming the findings previously demonstrated in a prior presentation of our database. This result reinforces the importance of including more sensitive image methods when staging recurrent prostate cancer for the early detection of metastatic disease and adequate treatment planning. [Table: see text]

68Ga-PSMA-11 patients with newly diagnosed and recurrent prostate cancer (Firefly Study): Preliminary results.

54 Background: A primary challenge facing oncologists is the accurate identification of the source of the rising PSA in the recurrent disease setting and the failure of proper staging at the time of initial therapy. PSMA imaging allows for progress in this regard, however access remains an issue. As such, we designed the Firefly study to offer PSMA imaging to patients between May 2021 and May 2022, to better characterize their disease. Methods: This is a phase II expanded access intermediate sized clinical trial using 68Ga-PSMA-11 (Telix Pharma cold kit) under Tulane’s own Investigational New Drug (IND). Clinical trial information: NCT04854369. Two cohorts are utilized, recurrent disease with a PSA > 0.2 or > 2.0 post-radiation, and newly diagnosed high risk or oligo-metastatic patients as assessed by conventional imaging. Between May 2021 and May 2022, a total of 90 patients were enrolled. The study was designed for a maximum of 300 patients but was terminated when access to insurance approved PSMA scans was available. Patients received 1.8–2.2 MBq/kg body weight with 68Ga-PSMA-11 (per EANM guidelines). The lower and upper limits of the dose were set to 3 to 7 mCi respectively. Primary Objective(s): Utilize 68Ga-PSMA-11 PET to define uptake location for localization of prostate cancer metastatic sites in patients prior to initial therapy, and in both local recurrences and metastatic sites in patients with recurrent disease after initial therapy. Secondary Objectives: To assess the therapeutic consequences of 68Ga-PSMA-11 PET/CT imaging in prostate cancer patients with and without prior treatment. Results: Of the 90 patients enrolled 81 were in the recurrent disease cohort and nine had newly diagnosed disease. Of the 81 patients with recurrent disease; 30 were known metastatic and were scanned with the intention of application for expanded access to 177Lu-PSMA-617, 8 received radiation for their oligometastases, 12 received a combination of radiation and initiation of hormone therapy, 13 continued surveillance, 5 were sent for salvage therapy, 13 were treated with novel hormones. Of the 9 patients with newly diagnosed disease all of them were negative for metastasis on conventional imaging. However, when scanned with 68Ga-PSMA-11, 7/9 had a positive PSMA scan. A lesion in the prostate was identified in 2/7 patients, 2/7 were found to have de novo metastatic disease to the lymph nodes and 3/7 were found to have bone metastasis. All these patients were treatment naïve and 5/7 had changes to their planned definitive treatment plan based on these results, as high-risk patients found to have previously unidentified de novo metastatic disease. Conclusions: Further analysis of the data is planned to complete secondary objectives; however, this study demonstrates the potentially meaningful impact of PSMA imaging for patient treatment planning and individualized care. Clinical trial information: NCT04854369 .

Gestational trophoblastic disease: an update.

Gestational trophoblastic diseases (GTD) encompass a spectrum of rarepre-malignant and malignant entitiesoriginating from trophoblastic tissue. This updated review will highlight important radiological features, pathology and classification, and provide insight into the clinical management of these uncommon disorders. There is a wide geographic variation with the incidence of hydatidiform mole varying between 0.57 and 2 per 1000 pregnancies. The use of ultrasound (US)in the management of early pregnancy symptoms and complications has positively impacted the earlier detection of these diseases and resulted in diminished morbidity. Additional imaging modalities are reserved for problem solving or assessment of pulmonary manifestations of molar pregnancy. Having an awareness of their pleomorphic sonographic presentation and additional pathology that can mimic GTD is critical to avoiding pitfalls. Histologic and molecular analysis further aids in differential diagnosis. Gestational trophoblastic neoplasia (GTN) is inclusive of all malignant GTDs, and arises after 20% of molar pregnancies but can also be seen with non-molar gestations. Biochemical monitoring with human chorionic gonadotrophin is imperative for ongoing monitoring and surveillance and allows early detection of this entity. Doppler US is used for confirmation of diagnosis with magnetic resonance imaging (MRI) reserved for problem solving or assessment of myometrial invasion. This is of heightened relevance in patients undergoing surgical management. Cross sectional imaging is reserved for patients in the setting of GTN for the purposes of staging, prognostication and in the setting of recurrent disease. This may require a combination of computed tomography, MRI and positron emission tomography. Doppler US can provide insight into chemotherapeutic response/predict resistance in patients with GTN. As our understanding of these disorders evolves, there has been maturation in management options with a shift from traditional chemotherapy to innovative immunotherapy, particularly in the setting of resistant or high-risk disease.

The role of PARP inhibitor combination therapy in ovarian cancer.

The use of PARP inhibitors (PARPi) has transformed the care of advanced high-grade serous/endometrioid ovarian cancer. PARPi are now available to patients in both the first-line and recurrent platinum-sensitive disease settings; therefore, most patients will receive PARPi at some point in their treatment pathway. The majority of this expanding population of patients eventually acquire resistance to PARPi, in addition to those with primary PARPi resistance. We discuss the rationale behind developing combination therapies, to work synergistically with PARPi and overcome mechanisms of resistance to restore drug sensitivity, and clinical evidence of their efficacy to date.

Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) compared to computed tomography (CT) for advanced renal cell carcinoma (RCC).

4540 Background: There is emerging role of the use of PSMA PET in RCC. Herein, we report our experience in use of PSMA PET in recurrent or metastatic RCC in Brisbane, Australia. Methods: Patients (pts) who underwent PSMA PET and conventional diagnostic CT for metastatic or recurrent RCC between 2015 and 2020 at three institutions were identified. Retrospective chart reviews were conducted using standardized collection template. The outcomes included percentage of patients who had a change in management secondary to PSMA PET findings, comparison of metastasis detection for PSMA PET vs. CT, and biopsy histology of PSMA avid sites. Results: 42 PSMA PET were performed in 40 patients. 10 pts (25%) and 30 pts (75%) had PSMA PET in the metastatic disease and recurrent disease setting, respectively. Table 1 highlights demographics. Overall, 12 pts (30%, n=3 metastatic, n=9 recurrent) had a change in management following PSMA PET. In the metastatic disease group, 2 pts (20%) underwent initial systemic therapy (after histological confirmation) due to higher burden of disease shown with PSMA PET than CT, while systemic therapy was changed for 1 pt (10%). In the recurrent disease group, PSMA improved delineation of suspected recurrence (compared to CT) resulting in resection rather than surveillance (n=4; 13%) or change in surgical approach for resection (n=1; 3%). PSMA PET distribution showed more metastatic sites than CT leading to systemic therapy rather than resection of recurrence (n=2; 7%), while absent PSMA activity for suspected recurrence on CT led to surveillance rather than resection (n=2; 7%). PSMA PET detected more sites of metastases compared with conventional scan in 6 pts (60%) with metastatic disease and in 9 pts (30%) with recurrent disease. 26 pts had biopsy of PSMA avid sites. Majority of pts had confirmed recurrence of clear cell renal carcinoma (n= 22; 85%). Other histology included sarcomatoid renal cell carcinoma (n=2; 8%), carcinoid (n=1; 4%), and urothelial cancer (n=1; 4%). In 2 instances, biopsy/resection was performed of a suspected recurrence on CT that was not PSMA avid, and neither showed malignancy. Conclusions: PSMA PET detected more accurately metastatic and recurrent disease, with high pathological concordance, to result in change in management for 30% of patients. Prospective study is warranted to further investigate the utility of PSMA PET scan in advanced RCC.[Table: see text]

Targeting MUC1-C Suppresses Chronic Activation of Cytosolic Nucleotide Receptors and STING in Triple-Negative Breast Cancer.

Simple SummaryTriple-negative breast cancers (TNBCs) are recalcitrant tumors with limited therapeutic options. Cytotoxic agents, including platinum-based drugs, are a standard of care for advanced TNBCs. Olaparib is also used for the treatment of germline BRCA mutant TNBC tumors in the adjuvant and recurrent disease settings. Notably, however, the effectiveness of these genotoxic agents is often limited by intrinsic and adaptive DNA damage resistance. We demonstrate in TNBC cells that the oncogenic MUC1-C protein chronically activates the type I interferon (IFN) pathway, drives the cGAS/STING axis and induces expression of the DNA damage resistance gene signature (IRDS). Targeting MUC1-C inhibits activation of this pathway in the response to carboplatin and olaparib and sensitizes TNBC cells to these agents. These findings indicate that MUC1-C is a target, which is druggable, for overcoming the obstacle of DNA damage resistance in the treatment of TNBCs.The MUC1-C apical transmembrane protein is activated in the acute response of epithelial cells to inflammation. However, chronic MUC1-C activation promotes cancer progression, emphasizing the importance of MUC1-C as a target for treatment. We report here that MUC1-C is necessary for intrinsic expression of the RIG-I, MDA5 and cGAS cytosolic nucleotide pattern recognition receptors (PRRs) and the cGAS-stimulator of IFN genes (STING) in triple-negative breast cancer (TNBC) cells. Consistent with inducing the PRR/STING axis, MUC1-C drives chronic IFN-β production and activation of the type I interferon (IFN) pathway. MUC1-C thereby induces the IFN-related DNA damage resistance gene signature (IRDS), which includes ISG15, in linking chronic inflammation with DNA damage resistance. Targeting MUC1-C in TNBC cells treated with carboplatin or the PARP inhibitor olaparib further demonstrated that MUC1-C is necessary for expression of PRRs, STING and ISG15 and for intrinsic DNA damage resistance. Of translational relevance, MUC1 significantly associates with upregulation of STING and ISG15 in TNBC tumors and is a target for treatment with CAR T cells, antibody–drug conjugates (ADCs) and direct inhibitors that are under preclinical and clinical development.

Concise review of radiosurgery for contemporary management of pilocytic astrocytomas in children and adults.

Pilocytic astrocytoma (PA) may be seen in both adults and children as a distinct histologic and biologic subset of low-grade glioma. Surgery is the principal treatment for the management of PAs; however, selected patients may benefit from irradiation particularly in the setting of inoperability, incomplete resection, or recurrent disease. While conventionally fractionated radiation therapy has been traditionally utilized for radiotherapeutic management, stereotactic irradiation strategies have been introduced more recently to improve the toxicity profile of radiation delivery without compromising tumor control. PAs may be suitable for radiosurgical management due to their typical appearance as well circumscribed lesions. Focused and precise targeting of these well-defined lesions under stereotactic immobilization and image guidance may offer great potential for achieving an improved therapeutic ratio by virtue of radiosurgical techniques. Given the high conformality along with steep dose gradients around the target volume allowing for reduced normal tissue exposure, radiosurgery may be considered a viable modality of radiotherapeutic management. Another advantage of radiosurgery may be the completion of therapy in a usually shorter overall treatment time, which may be particularly well suited for children with requirement of anesthesia during irradiation. Several studies have addressed the utility of radiosurgery particularly as an adjuvant or salvage treatment modality for PA. Nevertheless, despite the growing body of evidence supporting the use of radiosurgery, there is need for a high level of evidence to dictate treatment decisions and establish its optimal role in the management of PA. Herein, we provide a concise review of radiosurgery for PA in light of the literature.

68ga-PSMA-11 patients with newly diagnosed and recurrent prostate cancer (Firefly).

TPS189 Background: A primary challenge facing oncologists is the accurate identification of the source of the rising PSA in the recurrent disease setting and the failure of proper staging at the time of initial therapy. Current imaging modalities perform poorly in this regard. PSMA imaging is FDA approved but reimbursement remains a considerable issue for most patients. Methods: This is a phase II expanded access intermediate sized clinical trial using 68Ga-PSMA-11 (Telix Pharma cold kit) under our own Investigational New Drug (IND) with the FDA. Two cohorts are utilized, recurrent disease with a PSA > 0.2 or > 2.0 post-radiation, and newly diagnosed high risk localized disease and/or oligo-metastatic patients as assessed by conventional imaging. 300 patients will be allowed to enroll and 63 are enrolled to date. Patients will be injected with 1.8–2.2 MBq/kg body weight with 68Ga-PSMA-11 (per EANM guidelines). The lower and upper limits of the dose are set to 3 to 7 mCi respectively. Primary Objective(s): Utilize 68Ga-PSMA-11 PET images to define uptake location for localization of prostate cancer metastatic sites in patients prior to initial therapy and to utilize 68Ga-PSMA-11 PET images to define uptake location for localization of prostate cancer including both local recurrences and metastatic sites in patients with recurrent disease after initial therapy. Secondary Objectives: To assess the therapeutic consequences of 68Ga-PSMA-11 PET/CT imaging in prostate cancer patients with and without prior treatment. As such the planned therapies after the PSMA scan will be annotated and recorded. In addition, we aim to determine the number of patients with metastatic disease prior to initial therapy that was not diagnosed with conventional imaging and we aim to determine the locations of recurrent disease for those patients who have demonstrated PSA recurrence after curative therapy. Percentage of positive scans will be assessed for PSA values 0.2-0.5 ng/mL, > 0.5-1.0 ng/mL, > 1.0- > 2.0 ng/mL, and > 2 ng/mL. Results will be summarized descriptively with 95% confidence intervals. Localization of all lesions will be performed with regard to lymph nodes (pelvic versus non-pelvis), bones (by location), and other (by site). Treatment planning will be captured and quantified by radiation, surgery, hormonal therapy (type and duration), and/or observation at the time of the initial clinical visit after the PSMA scan and 6 months later. This trial is open and recruiting patients. Data analysis has not been performed. Clinical trial information: NCT04854369.

Challenges with increased utilization of clinical tumor testing in ovarian cancer

Challenges with increased utilization of clinical tumor testing in ovarian cancer

Investigation and management of pulmonary embolism 1: a probability-based approach.

Pulmonary embolism remains a common and potentially deadly disease, despite advances in diagnostic imaging, treatment and prevention. Managing pulmonary embolism requires a multifactorial approach involving risk stratification, determining appropriate diagnostics and selecting individualised therapy. This article reviews the pathophysiology, risk factors, clinical presentation, diagnostic evaluation and therapeutic management and early outpatient management of pulmonary embolism. The second part summarises pulmonary embolism in the setting of pregnancy, COVID-19, recurrent disease and chronic thromboembolic pulmonary hypertension.

Investigation and management of pulmonary embolism 2: specific clinical conditions.

Pulmonary embolism remains a common and potentially deadly disease, despite advances in diagnostic imaging, treatment and prevention. Managing pulmonary embolism requires a multifactorial approach involving risk stratification, determining appropriate diagnostics and selecting individualised therapy. The first part of this article reviewed the pathophysiology, risk factors, clinical presentation, diagnostic evaluation and therapeutic management and early outpatient management of pulmonary embolism. This second part summarises pulmonary embolism in the setting of pregnancy, COVID-19, recurrent disease and chronic thromboembolic pulmonary hypertension.