Miniaturized electromagnetic tracking enables efficient ultrasound-navigated needle insertions.

Ultrasound (US) has gained popularity as a guidance modality for percutaneous needle insertions because it is widely available and non-ionizing. However, coordinating scanning and needle insertion still requires significant experience. Current assistance solutions utilize optical or electromagnetic tracking (EMT) technology directly integrated into the US device or probe. This results in specialized devices or introduces additional hardware, limiting the ergonomics of both the scanning and insertion process. We developed the first ultrasound (US) navigation solution designed to be used as a non-permanent accessory for existing US devices while maintaining the ergonomics during the scanning process. A miniaturized EMT source is reversibly attached to the US probe, temporarily creating a combined modality that provides real-time anatomical imaging and instrument tracking at the same time. Studies performed with 11 clinical operators show that the proposed navigation solution can guide needle insertions with a targeting accuracy of about 5 mm, which is comparable to existing approaches and unaffected by repeated attachment and detachment of the miniaturized tracking solution. The assistance proved particularly helpful for non-expert users and needle insertions performed outside of the US plane. The small size and reversible attachability of the proposed navigation solution promises streamlined integration into the clinical workflow and widespread access to US navigated punctures.

Impact of Sleeve Gastrectomy on Uric Acid Levels in Patients with Obesity: A Comparative Study.

PURPOSE: This study aimed to investigate the incidence of hyperuricemia in obese individuals with or without metabolic syndrome and assess the impact of sleeve gastrectomy surgery on the amelioration of hyperuricemia and metabolic syndrome. MATERIALS AND METHODS: A prospective study was conducted on patients with obesity who were candidates for laparoscopic sleeve gastrectomy. These patients were diligently followed for 1 year after the surgical procedure. The assessment of hyperuricemia and metabolic syndrome was carried out both before and one year after the surgery. RESULTS: A total of 198 patients (30 males and 168 females) underwent sleeve gastrectomy. After 1 year, there was a notable decline in the prevalence of hyperuricemia, decreasing from 77 to 36 cases (a reduction of 46.75%) among females and from 18 to 8 cases (a reduction of 44.44%) among males. Prior to the surgery, 60.6% of patients (120 out of 198) were diagnosed with metabolic syndrome, and 36.7% of these patients exhibited improvements in their metabolic syndrome status. Among individuals with metabolic syndrome, significant enhancements were observed in various anthropometric and laboratory measurements, including reductions in hypertriglyceridemia, hyperuricemia, and hypercholesteremia. A logistic regression analysis revealed that in females, changes in creatinine, glomerular filtration rate (GFR), weight loss, body mass index (BMI), and triglyceride reduction all had a notable impact on the likelihood of recovering from hyperuricemia. CONCLUSION: These findings underscore the clinical relevance of this surgical intervention in managing obesity-related conditions.

Safety and Efficacy of Selective Internal Radionuclide Therapy with 90Y Glass Microspheres in Patients with Progressive Hepatocellular Carcinoma after the Failure of Repeated Transarterial Chemoembolization.

Transarterial chemoembolization (TACE) is currently the standard of care in patients with unresectable hepatocellular carcinoma (HCC), and selective internal radionuclide therapy (SIRT) with 90Y microspheres is mainly used as an alternative modality in patients considered poor candidates for TACE. Treatment with sorafenib is the recommended option for patients with progressive disease after TACE. This study aims to evaluate the safety and efficacy of SIRT with glass microspheres in patients with progressive HCC after repeated TACE who are not eligible for treatment with sorafenib. Forty-seven patients with progressive HCC after a median of three TACE sessions (range 2-14) underwent SIRT (3.5 ± 1.5 GBq; liver target dose 110-120 Gy). Toxicity was recorded 4 and 12 weeks after treatment and reported according to the Common Terminology Criteria for Adverse Events Version 5.0. Treatment response was assessed three months after SIRT using multiphase computed tomography and modified criteria in solid tumors (mRECIST). Survival analyses were performed using Kaplan-Meier curves and a Cox proportional hazards model for uni- and multivariate analyses. Significant but reversible hepatotoxicity (≥grade 3) occurred in five patients (11%). No radioembolization-induced liver disease (REILD) was observed. The number of previous TACE sessions and cumulative administered activity did not predict the incidence of post-SIRT significant hepatotoxicity. Treatment responses consisted of partial responses in 26 (55%), stable disease in 12 (26%), and progressive disease in 9 (19%) patients. The median overall survival (OS) was 11 months (95% confidence interval (CI), 9-13), and objective responses to SIRT were associated with a longer OS (p = 0.008). Significant hepatotoxicity (≥grade 3) after SIRT was a contributor to impaired survival (median OS 6 months (95% CI, 4-8) vs. 12 months (95% CI, 10-14), p < 0.001). SIRT with glass microspheres is a safe and effective salvage treatment for patients with progressive HCC refractory to TACE who are considered poor candidates for sorafenib treatment.

The influence of thionamides on intra-thyroidal uptake of 131I during radioiodine-131 treatment of Graves' disease.

Graves' disease is one of the most common causes of hyperthyroidism. Guideline recommendations advocate the intake of thionamides for at least 1 year. If hyperthyroidism persists, subsequent radioiodine-131 treatment (RIT) is a therapeutic option. Thionamides are known to influence intra-thyroidal bio-kinetics of iodine and should therefore be discontinued at least 3 days prior to RIT if possible. However, the required therapeutic activity has to be calculated individually by pre-therapeutic measurement of the uptake prior to RIT [radioiodine-131 uptake test (RIUT)] in Germany according to national guidelines. Therefore, the aim of this study was to quantify the influence of thionamides on intra-therapeutic uptake. A cohort of 829 patients with Graves' disease undergoing RIUT and RIT was analysed. Patients were subdivided into three groups. Group A: patients with carbimazole medication (n = 312), group B: patients with methimazole medication (n = 252) and group C: patients without thionamides (n = 265). Group A and B were further subdivided depending on the reduction of dosage of thionamides. In order to analyse the influence of thionamides, the variance of the determined individual extrapolated maximum intra-thyroidal uptake (EMU) between RIUT and RIT within the single groups and within the subgroups was statistically evaluated. When administering an equal dose of thionamides or no thionamides in RIUT and RIT (groups A1, B1 and C) no significant differences were detected when comparing EMU in RIT to EMU in RIUT (p > 0.05). In the subgroups A2-A4 (reduced dosage of carbimazole prior to RIT) EMU was significantly increased in RIT compared to RIUT [21% for a reduction of 0 to < 10 mg/d (A2), 39% for a reduction of 10-15 mg/d (A3) and 80% for a reduction of > 15 mg/d (A4)]. In the subgroups B2-B4 (reduced dosage of methimazole prior to RIT) EMU was as well significantly increased in RIT compared to RIUT [26% for a reduction of 0 to < 10 mg/d (B2), 36% for a reduction of 10-15 mg/d (B3) and 59% for a reduction of > 15 mg/d (B4)]. A significant dose-dependent increase of EMU in RIT compared to EMU in RIUT in patients discontinuing or reducing thionamides was detected. Therefore, thionamides should be discontinued at least 2 days prior to RIUT in order to achieve the designated target dose more precisely and to minimize radiation exposure of organs at risk.

Heat sink effects in thyroid bipolar radiofrequency ablation: an ex vivo study.

The study aimed to investigate heat sink effects in radiofrequency ablation (RFA) under thyroid-specific conditions. In an ex vivo model, bovine thyroid lobes were ablated using bipolar RFA with 2.0 kJ energy input at a power level set to 10 W (n = 35) and 25 W (n = 35). Glass vessels (3.0 mm outer diameter) placed within the ablation zone were used to deliver tissue perfusion at various flow rates (0, 0.25, 0.5, 1, 5, 10, 20 ml/min). Temperature was measured in the proximity of the vessel (Tv) and in the non-perfused contralateral region of the ablation zone (Tc), at equal distances to the ablation electrode (d = 8 mm). Maximum temperature within the perfused zone was significantly lowered with Tv ranging from 54.1 ± 1.5 °C (20 ml/min) to 56.9 ± 1.5 °C (0.25 ml/min), compared to Tc from 63.2 ± 3.5 °C (20 ml/min) to 63.2 ± 2.6 °C (0.25 ml/min) (10 W group). The cross-sectional ablation zone area decreased with increasing flow rates from 184 ± 12 mm2 (0 ml/min) to 141 ± 20 mm2 (20 ml/min) at 10 W, and from 207 ± 22 mm2 (0 ml/min) to 158 ± 31 mm2 (20 ml/min) in the 25 W group. Significant heat sink effects were observed under thyroid-specific conditions even at flow rates ≤ 1 ml/min. In thyroid nodules with prominent vasculature, heat dissipation through perfusion may therefore result in clinically relevant limitations to ablation efficacy.

Intermittent Radioligand Therapy with 177Lu-PSMA-617 for Oligometastatic Castration-Resistant Prostate Cancer.

177Lu-PSMA-617 radioligand therapy (177Lu-PSMA-RLT) in patients with metastatic castration-resistant prostate cancer (mCRPC) currently consists of 4-6 cycles of 6.0-7.4 GBq of 177Lu-PSMA-617 each every 6-8 weeks. While safety and efficacy could be demonstrated in larger prospective trials irrespective of the tumor burden at 177Lu-PSMA RLT initiation, increased renal absorbed doses due to a reduced tumor sink effect in early responding, oligometastatic mCRPC patients pose difficulties. Response-adapted, dose distributing, intermittent treatment with up to six cycles has not been routinely performed, due to concerns about the potential loss of disease control. Treatment was discontinued in 19 early-responding patients with oligometastatic tumor burden after two (IQR 2-3) cycles of 177Lu-PSMA-RLT and 6.5 ± 0.7 GBq per cycle and resumed upon 68Ga-PSMA-11-PET/CT-based progression (according to the PCWG3 criteria). Subsequent treatment breaks were imposed if a PSMA-based imaging response could be achieved. A total of five (IQR 3-6) cycles reaching a cumulative activity of 32 ± 11 GBq were applied. A routine blood work-up including blood counts and liver and renal function was measured throughout the 177Lu-PSMA-RLT and follow-up to grade toxicity according to CTCAE v5.0 criteria. Survival outcome was calculated based on the Kaplan-Meier method. In total, treatment-free periods of 9 (IQR 6-17) cumulative months and the application of 177Lu-PSMA-RLT cycles over 16 (IQR 9-22) months could be achieved. Fifteen (84%) patients responded to subsequent cycles after the first treatment break and in 7/19 (37%) patients, intermittent 177Lu-PSMA-RLT consisted of ≥2 treatment breaks. The median PFS was 27 months (95% CI: 23-31) and overall survival was 45 months (95% CI: 28-62). No grade ≥3 hematological or renal toxicities could be observed during the 45 ± 21 months of follow-up. The cumulative mean renal absorbed dose was 16.7 ± 8.3 Gy and 0.53 ± 0.21 Gy/GBq. Intermittent radioligand therapy with 177Lu-PSMA-617 is feasible in early-responding patients with oligometastatic disease. A late onset of progression after subsequent cycles and the absence of significant toxicity warrants further investigation of the concept of intermittent treatment in selected patients.

Impact of [177Lu]Lu-PSMA-617 Radioligand Therapy on Reference Organ Uptake Assessed by [68Ga]Ga-PSMA-11-PET/CT.

This study aims to assess the change in uptake to reference organs, including the liver, parotid and salivary glands after radioligand therapy (RLT) with [177Lu]Lu-PSMA-617 in relation to pretreatment imaging metrics. Eighty-five patients with mCRPC underwent [68Ga]Ga-PSMA-11 PET/CT imaging prior to (pre RLT PET) and after (post RLT PET) a median of 3 (IQR 2-6) RLT cycles with [177Lu]Lu-PSMA-617. PSMA-positive tumor burden was stratified into 4 groups based on modified PROMISE criteria (oligofocal, multifocal, disseminated, diffuse). Uptake (SUVmean, SUVmax) in liver tissue, parotid and submandibular glands was measured. A control group was established with 54 patients who had received two separate PET acquisitions following the same protocol (PET1, PET2) within 12 months for localized or oligofocal prostate cancer without RLT in the interim. Baseline uptake values (SUVmean, SUVmax) in parotid (10.8 ± 3.2, 16.8 ± 5.4) and submandibular glands (11.3 ± 2.8, 18.1 ± 4.7) are 2-fold compared to liver uptake (4.9 ± 1.4, 7.7 ± 2.0), with no significant change between PET 1 and PET 2 in the control group. In the RLT group, increasing tumor burden class is significantly associated with decreasing uptake in the liver (p = 0.013), parotid (p < 0.001) and submandibular glands (p < 0.001); this tumor sink effect by respective tumor burden is widely maintained after RLT (p = 0.011, p < 0.001, p < 0.001). RLT has a significant impact on salivary gland uptake with decreasing values per patient in all groups of disease burden change (up to -30.4% in submandibular glands, p < 0.001), while liver tissue shows rising values in patients with declining tumor burden throughout RLT (+18.6%, p = 0.020). Uptake in liver tissue and salivary glands on [68Ga]Ga-PSMA-11 PET/CT imaging is inversely related to tumor burden prior to and following RLT with [177Lu]Lu-PSMA-617. Per patient, salivary gland uptake is further reduced throughout RLT independently from tumor burden, while changes in liver uptake remain burden-dependent. Liver and salivary gland uptake-derived metrics and segmentation thresholds may thus be of limited value when used as reference for response assessment to RLT.

Thyroid papillary cancer elements arising from struma ovarii with benign peritoneal strumosis: Utility of iodine-123 imaging in diagnostics and treatment planning.

Key Clinical Message: In this case of struma ovarii a right-sided ovarian mass contained features of papillary thyroid cancer. Diagnostic iodine-123 revealed multiple foci of extraovarian spread, likely as a manifestation of concomitant peritoneal strumosis. Unilateral oophorectomy, partial peritonectomy, and adjuvant iodine-131 treatment were performed for successful curative treatment. Abstract: Struma ovarii is a rare form of mature teratoma defined by a predominance of thyroid tissue. Approximately 5% of all ovarian strumae exhibit malignant transformation. Due to their extreme rarity, there has been a lack of consensus concerning uniform diagnostic criteria. Appropriate, risk-stratified treatment strategies also remain widely unelaborated, based only on a small number of cases reported in the literature. We describe the case of a 35-year-old female, who presented after undergoing unilateral oophorectomy for a right-sided ovarian mass. Histological workup revealed a struma ovarii containing papillary thyroid cancer (PTC). Postoperative I-123 scintigraphy with single photon emission computed tomography (SPECT) detected multifocal extra-ovarian spread to the peritoneum, containing likely benign strumosis upon pathological examination. The subsequent treatment strategy involved an ablative concept including total thyroidectomy and subsequent I-131 radioiodine therapy. Throughout a 3-year follow-up, the patient has remained without recurrence with thyroglobulin levels ranging below detection limits. Surgical resection with adjuvant radioiodine therapy is a curative therapeutic strategy in cases of struma ovarii with thyroid-type carcinoma and peritoneal strumosis. Its benefits lay in avoiding more extensive surgery, potentially maintaining fertility, facilitating follow-up, and minimizing the risk of recurrence. Reliable criteria for risk stratification are needed to identify patients who are most likely to benefit from this treatment approach.

Extended therapy with [177Lu]Lu-PSMA-617 in responding patients with high-volume metastatic castration-resistant prostate cancer.

PURPOSE: The currently used scheme for radioligand therapy (RLT) of patients with metastatic castration-resistant prostate cancer (mCRPC) consists of 4-6 cycles of 6.0-7.4 GBq [177Lu]Lu-PSMA-617 each. This standard treatment scheme has proved safe and effective resulting in objective response in most patients with no significant toxicity. Many patients, however, show high-volume residual tumor burden after the sixth cycle and may benefit from treatment continuation. Extended treatment with additional cycles has been withheld due to concerns on potential increased toxicity. METHODS: Twenty-six patients with high-volume residual tumor burden (according to CHAARTED) after standard RLT with [177Lu]Lu-PSMA-617 and no alternative treatment option received additional RLT cycles reaching a median of 10 (range 7-16) cycles with a mean activity of 7.4 ± 0.9 GBq per cycle. Response assessment with [68Ga]Ga-PSMA-11 PET/CT was done every 2-3 cycles or if disease progression was clinically suspected or based on change in PSA value (according to the PCWG3 criteria). Toxicity was measured using routine blood work up including blood counts, liver and renal function, and was graded according to CTCAE v5.0 criteria. Survival outcome was calculated based on the Kaplan-Meier method. RESULTS: Further PSA decline of 33 ± 28% during the extended treatment was observed in 21/26 (81%) patients, whereas 5/26 (19%) patients showed a PSA increase; correspondingly in 11/21 patients with an initial response (PR or SD) to extended cycles, treatment was discontinued due to progressive disease, whereas six (23%) patients achieved low-volume residual disease. Two (8%) patients died without showing progression, and two (8%) patients are still under therapy. The median progression-free survival was 19 (95% CI: 15-23) months, and the overall survival was 29 (95% CI: 18-40) months. Grade ≥ 3 hematological toxicities occurred in 4/26 (15%) patients during treatment extension, and nephrotoxicity (grade ≥ 3) was observed in 1/26 (4%) patient during the follow-up. CONCLUSION: Extended radioligand therapy is a feasible treatment option in patients with high-volume residual tumor after the completion of standard treatment with six cycles of [177Lu]Lu-PSMA-617. Improved survival and the acceptable safety profile warrant further investigation of the concept of additional cycles in selected patients.

Baseline [68Ga]Ga-PSMA-11 PET/CT before [177Lu]Lu-PSMA-617 Radioligand Therapy: Value of PSMA-Uptake Thresholds in Predicting Targetable Lesions.

Baseline uptake on prostate-specific membrane antigen (PSMA)-targeted imaging is a prerequisite for radioligand therapy (RLT) with [177Lu]Lu-PSMA-617. This study aims to quantify lesion-based response to RLT in relation to pretreatment standard molecular imaging metrics derived from [68Ga]Ga-PSMA-11 PET/CT. Sixty-one patients with mCRPC underwent [68Ga]Ga-PSMA-11 PET/CT imaging before and after a median of 4 (IQR 2−6) RLT cycles. Maximum and mean standardized uptake values (SUVmax, SUVmean), as well as tumor-to-liver ratio (TLR), were assessed. A median of 12 (IQR 7−17) lesions was analyzed per patient, resulting in a total of 718 lesions. Lesions with ≥30% SUVmax decline or falling below the blood pool uptake were considered responsive; ≥30% SUVmax increase marked lesion progression. Additionally, 4-point visual scoring was performed according to E-PSMA consensus. In total, 550/718 (76.6%) lesions responded to RLT, including 389/507 (76.7%) bone metastases and 143/181 (79.0%) lymph node metastases. Baseline SUVmax, SUVmean, and TLR values were associated with lesion response by a moderate but significant correlation (rs = 0.33, p < 0.001, rs = 0.32, p < 0.001, and rs = 0.31, p < 0.001, respectively). For the classification of lesion progression based on baseline PSMA uptake, receiver operating characteristics (ROC) found SUVmax, SUVmean, and TLR to have comparable discriminatory value (AUC 0.85, 0.87, and 0.83). Of 42 tumor sites with baseline uptake below the liver (V-score < 2), 19/42 (45.2%) were responsive, 9/42 (21.4%) were stable, and 14/42 (33.3%) showed progression, leaving liver uptake a threshold with low prognostic value for the identification of RLT-refractory lesions (PPV 33%). This was observed accordingly for various liver uptake-based thresholds, including TLR < 1.5, <2.0 with a PPV at 24%, 20%, respectively. Standard uptake parameters quantified by routine baseline [68Ga]Ga-PSMA-11 PET/CT are moderately associated with post-treatment lesion response to [177Lu]Lu-PSMA-617. Commonly applied liver-based uptake thresholds have limited value in predicting refractory lesions at individual tumor sites.

The influence of thyroid hormone medication on intra-therapeutic half-life of 131I during radioiodine therapy of solitary toxic thyroid nodules.

Despite a significantly improved dietary iodine supply, solitary toxic thyroid nodules (STN) are still a common clinical problem in former iodine deficient areas. Radioiodine treatment (RIT) is a well-established therapeutic option with few side effects and high success rates. As radioiodine biokinetics are individual for every patient, the necessary activity has to be calculated individually by a pre-therapeutic measurement of the intra-therapeutic effective half-life (EHL) in a radioiodine uptake test (RIUT). A suppressive medication with triiodothyronine (T3) or tetraiodothyronine (T4) is often needed to suppress uptake in normal thyroid tissue. Therefore, the aim of this study was to quantify the possible influence of this medication on intra-therapeutic radioiodine biokinetics. A cohort of 928 patients with STN undergoing RIUT and RIT was analysed. Patients were subdivided into 3 groups. Group T3: medication with T3 (n = 274), group T4: medication with T4 (n = 184) and group NM: no additional medication (n = 470). The T3 and T4 subgroups were further subdivided depending on the dose of thyroid hormone medication. In order to analyse the influence of thyroid hormone medication on individual intra-thyroidal biokinetics, the variance of the determined individual EHL between RIUT and RIT within the single groups and within the subgroups was investigated. EHL was significantly decreased between RIUT and RIT in the T3 and T4 subgroups (EHL: T3: 5.9 ± 1.1 d in RIUT and 3.3 ± 1.4 d in RIT (- 43%) (p < 0.05); T4: 5.9 ± 1.2 d in RIUT and 3.4 ± 1.5 d in RIT (- 42%) (p < 0.05). The decrease of EHL did not differ statistically between T3 or T4. However, both showed a highly significant difference compared to the NM group (p < < 0.05). A further subgroup analysis showed a significant dependence of the decrease in EHL related to the dose of thyroid hormone medication of 35-58% (T3) and 15-67% (T4) (p < 0.05). A significantly reduced EHL compared to RIUT in patients receiving thyroid hormone medication was detected. Moreover, a significant correlation between the dose of thyroid hormone medication (T3 or T4) and the decrease of EHL was found. Therefore, an adaption of the calculated activity should be considered in RIUT to obtain the required radiation dose in RIT of patients suffering from STN.

[Radiofrequency ablation of benign thyroid nodules]. / Radiofrequenzablation benigner Schilddrüsenknoten.

Radiofrequency ablation is an effective tool to treat benign thyroid nodules up to about 100 ml. It is well tolerated and is - together with echopulse therapy - currently the most frequently used technique in Germany for the local therapy of benign thyroid nodules. Overall, a volume reduction of about 50 % to 70 % can be expected. Cystic nodules and mixed-pattern lesions respond slightly better than solid nodules. Initial volume, structure and echogenicity are important parameters influencing the therapeutic efficacy. Bipolar as well as monopolar methods are used - the choice of the method depends mainly on the personal experience. For bigger nodules, the bipolar technique is preferred. Cooled systems should be favored, especially when using larger probes. Serious side effects are rare (< 1 %) and transient in most cases.

Retrospective Analysis of the Development of Human Thyroglobulin during Pregnancy in Patients with Treated Non-Recurrent Differentiated Thyroid Cancer.

Aim: Therapy success in patients with differentiated thyroid cancer (DTC) after thyroidectomy and radioiodine therapy (RIT) is proven by permanent decrease in human thyroglobulin (hTg) to <1 ng/mL. In this retrospective analysis hTg development before, during and after pregnancy were analyzed. Material and methods: A descriptive analysis of hTg courses in 47 women with 57 pregnancies under levothyroxine substitution was performed after treatment of DTC without evidence of residual or recurrent disease. We compared hTg levels before, during and after pregnancies. A median of four measurements were performed during pregnancy. Results: In five out of the 47 patients at least one hTg increase to ≥1.0 ng/mL occurred during pregnancy (P1: 1.1; P2: 1.75; P3: 1.0; P4: 1.1; P5: 1.07 ng/mL). In another three cases an increase to ≥0.5 ng/mL occurred. After delivery, all patients returned to undetectable hTg levels. Human Tg maxima during pregnancy were significantly elevated according to Friedman´s Chi2 and p Holm−Bonferroni. Conclusion: In women with ablative thyroid therapy after DTC, a temporary elevation in hTg levels during pregnancy may occur. The reason therefore remains unclear and requires further investigation.

[Anticipating Criteria for Discharge after Lu-177-PSMA Treatment - Discussion of Several Scenarios]. / Vorausschauende Entlassungskriterien nach Lu-177-PSMA-Therapie ­ Diskussion unterschiedlicher Szenarien.

AIM: The aim is to add a pragmatic contribution to the discussion of an algorithm to discharge patients treated with Lu-177-PSMA under the aspect of radiation protection. This also may be applied to therapies with other radioactive tracers in the future. MATERIAL AND METHODS: 478 cycles of Lu-177-PSMA-617 (140 patients) were analyzed. The remaining activity in the patient and the dose rate were correlated. From frequent intratherapeutic measurements (biexponential fit) scenarios for discharging patients are deduced. RESULTS: Thirty-four per cent of all patients treated with Lu-177-PSMA received 3 to 5 cycles per calendar year. The dose limit of 1 mSv per calendar year (German Law) at a distance of 2 m from the patient would be exceeded in 10 % and 15 % of the treated patients if discharged 72 hours after treatment given 3 and 4 cycles per calendar year, respectively. Mean specific dose rate was 0.00462µSv/(h MBq) at a distance of 1 m. A universal correlation between dose rate and the remaining activity in the patient could not be found. CONCLUSION: The multi cycle concept of the therapies with Lu-177 PSMA has to be taken into account prospectively when discharging the patients. Given the physical half-life of Lu-177 an anticipation of 4 treatment cycles per calendar year leads to a clearly arranged, conservative rule.

Safety and Efficacy of 177Lutetium-PSMA-617 Radioligand Therapy Shortly after Failing 223Radium-Dichloride.

Bone-seeking 223Radium-dichloride (223Ra) is an established treatment prolonging survival and reducing morbidity in selected patients with metastatic castration-resistant prostate cancer (mCRPC) with skeletal involvement. Radioligand therapy with 177Lutetium-PSMA-617 (177Lu-PSMA-617) has been increasingly implemented in patients with mCRPC failing conventional treatment options. In this study, the safety and efficacy of 177Lu-PSMA-617 in patients with progressive bone involvement under treatment with 223Ra was assessed. Twenty-eight men (median age 73 years, range 63-89 years) with progressive mCRPC, who started 177Lu-PSMA-617 within 8 weeks after the last 223Ra administration, received a median of 4 (IQR 3-6) and a total of 120 cycles of 223Ra and a median of 4 (IQR 2-7) cycles 177Lu-PSMA-617 with a mean treatment activity of 6.5 ± 1.2 GBq per cycle, reaching a mean cumulative activity of 30.7 ± 23.4 GBq. A PSA response (≥50% PSA decline 12 weeks after the first 177Lu-PSMA-617 cycle) was observed in 18/28 (64.3%) patients and imaging-based partial remission (PR) was observed in 11/28 (39.3%) patients. Median imaging-based progression-free survival (PFS) was 10 (95% CI, 6-14) months and median overall survival (OS) was 18 (95% CI, 14-22) months. Patients with low bone tumor burden (2-20 lesions) had a significantly longer OS (28 vs. 14 months, p < 0.045) compared to patients with a high tumor burden (>20 lesions). Grade ≥ 3 hematological toxicity was observed in six patients after their last treatment cycle with anemia, leukopenia and thrombocytopenia in 5/28 (17.9%), 4/28 (14.3%) and 6/28 (21.4%) patients, respectively. In progressive bone-metastatic mCRPC patients, prompt initiation of 177Lu-PSMA-617 after failing 223Ra is effective with an acceptable toxicity profile.

177 Lu-PSMA-617 radioligand therapy of metastatic castration-resistant prostate cancer: Initial 254-patient results from a prospective registry (REALITY Study).

PURPOSE: Preliminary data from retrospective analyses and recent data from large randomized controlled trials suggest safety and efficacy of radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) in men with metastatic castration-resistant prostate cancer (mCRPC). Limited data on this modality have been published regarding large samples treated in everyday practice. METHODS: We analyzed prospectively collected registry data regarding lutetium-177 (177Lu)-PSMA-617 RLT of 254 consecutive men with mCRPC seen in everyday academic practice. Since 177Lu-PSMA-617 was experimental salvage treatment following failure of individually appropriate conventional therapies, patients were generally elderly and heavily pretreated (median age 70 years; prior taxanes 74.0%, 188/254), with late-end-stage disease (visceral metastasis in 32.7%, 83/254). Primary endpoints were response to RLT, defined by changes from baseline serum prostate-specific antigen (PSA) concentration, PSA progression-free survival (PSA-PFS), and overall survival (OS), estimated with Kaplan-Meier statistics, and caregiver-reported and patient-reported safety. Unless noted, median (minimum-maximum) values are given. RESULTS: Patients received 3 (1-13) 177Lu-PSMA-617 activities (6.5 [2.5-11.6] GBq/cycle) every 5.7 (3.0-11.0) weeks. Best response was ≥ 50% PSA reduction in 52.0% of patients (132/254). PSA-PFS was 5.5 (95% confidence interval [95%CI] 4.4-6.6) months and OS, 14.5 (95%CI 11.5-17.5) months. In multivariable Cox proportional-hazards modeling, response to the initial ≤ 2 RLT administrations was the strongest significant prognosticator related to OS (hazard ratio 3.7 [95%CI 2.5-5.5], p < 0.001). No RLT-related deaths or treatment discontinuations occurred; the most frequent RLT-related Grade 3/4 adverse events were anemia (18/254 patients, 7.1%), thrombocytopenia (11/254, 4.3%), and lymphopenia (7/254, 2.8%). RLT-related xerostomia, all grade 1/2, was noted in 53/254 (20.9%). CONCLUSIONS: In a large, prospectively observed "real-world" cohort with late-stage/end-stage mCRPC and conventional treatment failure, 177Lu-PSMA-617 RLT was effective, safe, and well-tolerated. Early biochemical disease control by such therapy was associated with better OS. Prospective study earlier in the disease course may be warranted.

PSMA-RLT in Patients with Metastatic Hormone-Sensitive Prostate Cancer: A Retrospective Study.

BACKGROUND: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) is a novel treatment for patients with castration-resistant prostate cancer (CRPC). Given the mode of action, patients in an earlier disease stage, such as hormone-sensitive prostate cancer (HSPC), are also likely to benefit from [177Lu]Lu-PSMA- (177Lu-PSMA) or [225Ac]Ac-PSMA-radioligand treatment (225Ac-PSMA). In this retrospective study, we analyzed the safety and efficacy of PSMA-RLT in early-stage and hormone-sensitive metastatic prostate cancer patients. METHODS: A retrospective study was performed in patients who received 177Lu-PSMA and/or 225Ac-PSMA with early-stage metastatic prostate cancer. The primary outcome parameter evaluated in this study was the progression-free survival (PFS) after PSMA-RLT and toxicity according to the Common Terminology Criteria for Adverse Events. Secondary outcome parameters were prostate-specific antigen (PSA) response and the date of onset of CRPC state. RESULTS: In total, 20 patients were included of which 18 patients received 177Lu-PSMA radioligand and two patients received tandem treatment with both 177Lu-PSMA and 225Ac-PSMA radioligands. Patients received a median of 2 treatment cycles (range 1-6) and a median activity of 6.2 GBq 177Lu-PSMA per cycle (interquartile range (IQR) 5.2-7.4 GBq). PSMA-RLT was overall well-tolerated. The most common grade 1-2 side effects were xerostomia (n = 6) and fatigue (n = 8), which were only temporarily reported. One patient that received 225Ac-PSMA developed grade 3-4 bone marrow toxicity. The median PFS was 12 months (95% confidence interval (CI), 4.09-19.9 months). Seventeen (85%) patients had a ≥50% PSA response following PSMA-RLT. One patient developed CRPC 9 months following PSMA-RLT. CONCLUSIONS: In this small cohort study, PSMA-RLT appeared safe and showed encouraging efficacy for (metastasized) early-stage and hormone-sensitive prostate cancer patients. Prospective studies are awaited and should include long-term follow-up.

Prophylactic Peripheral Blood Stem Cell Collection in Patients with Extensive Bone-Marrow Infiltration of Neuroendocrine Tumours Prior to Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE.

Peptide receptor radionuclide therapy (PRRT) of metastatic neuroendocrine tumors (NET) can be successfully repeated but may eventually be dose-limited. Since 177Lu-DOTATATE dose limitation may come from hematological rather than renal function, hematological peripheral blood stem cell backup might be desirable. Here, we report our initial experience of peripheral blood stem-cell collection (PBSC) in patients with treatment-related cytopenia and therefore high risk of bone-marrow failure. Five patients with diffuse bone-marrow infiltration of NET and relevant myelosuppression (≥grade 2) received PBSC before one PRRT cycle with 177Lu-DOTATATE (7.6 ± 0.8 GBq/cycle). Standard stem-cell mobilization with Granulocyte-colony stimulating factor (G-CSF) was applied, and successful PBSC was defined as a collection of >2 × 106/kg CD34+ cells. In case of initial failure, Plerixafor was administered in addition to G-CSF prior to apheresis. PBSC was successfully performed in all patients with no adverse events. Median cumulative activity was 44.8 GBq (range, 21.3-62.4). Three patients had been previously treated with PRRT, two of which needed the addition of Plerixafor for stem-cell mobilization. Only one of five patients required autologous peripheral blood stem-cell transplantation during the median follow up time of 28 months. PBSC collection seems to be feasible in NET with bone-marrow involvement and might be worth considering as a backup strategy prior to PRRT, in order to overcome dose-limiting bone-marrow toxicity.

Response Assessment and Prediction of Progression-Free Survival by 68Ga-PSMA-11 PET/CT Based on Tumor-to-Liver Ratio (TLR) in Patients with mCRPC Undergoing 177Lu-PSMA-617 Radioligand Therapy.

At present, little is known about the molecular imaging-based response assessment of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy with 177Lutetium (177Lu-PSMA-617 RLT) in metastatic castration-resistant prostate cancer (mCRPC). Our study evaluated the response to RLT using both molecular imaging and biochemical response assessments, and their potential prediction of progression-free survival (PFS). Fifty-one consecutive patients given two cycles of RLT at 6-week intervals were analyzed retrospectively. 68Ga-PSMA-11 PET/CT was obtained about 2 weeks prior to the first and 4-6 weeks after the second cycle. Molecular imaging-based response using SUVpeak and tumor-to-liver ratio (TLR) was determined by modified PERCIST criteria. ∆TLR and ∆SUV were significantly correlated with ∆PSA (p < 0.001, each). After a median follow-up of 49 months, the median PFS (95% CI) was 8.0 (5.9-10.1) months. In univariate analysis, responders showing partial remission (PRPSA and PRTLR) had significantly (p < 0.001, each) longer PFS (median: 10.5 and 9.3 months) than non-responders showing either stable or progressive disease (median: 4.0 and 3.5 months). Response assessment using SUVpeak failed to predict survival. In multivariable analysis, response assessment using TLR was independently associated with PFS (p < 0.001), as was good performance status (p = 0.002). Molecular imaging-based response assessment with 68Ga-PSMA-11 PET/CT using normalization of the total lesion PSMA over healthy liver tissue uptake (TLR) could be an appropriate biomarker to monitor RLT in mCRPC patients and to predict progression-free survival (PFS) of this treatment modality.

Salvage Radioligand Therapy with Repeated Cycles of 177Lu-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer with Diffuse Bone Marrow Involvement.

Advanced stage metastatic prostate cancer with extensive bone marrow involvement is associated with a high risk of therapy-induced myelotoxicity and unfavorable outcomes. The role of salvage radioligand therapy (RLT) with 177Lu-PSMA-617 in this subset of patients remains to be further elucidated. Forty-five patients with progressive metastatic castration-resistant prostate cancer (mCRPC) and diffuse bone marrow involvement were treated with repeated cycles of RLT after having exhausted standard treatment options. A mean treatment activity of 7.4 ± 1.4 GBq 177Lu-PSMA-617 was administered in a median of four treatment cycles (IQR 2-6) and the mean cumulative activity was 32.6 ± 20.1 GBq. After two RLT cycles, ≥50% PSA decline was observed in 25/45 (56%) patients and imaging-based partial remission (PR) was observed in 18/45 (40%) patients. Median imaging-based progression-free survival (PFS) was 6.4 mo (95% CI, 3.0-9.8) and the median overall survival (OS) was 10.2 months (95% CI, 7.2-12.8). The biochemical response translated into a significantly prolonged PFS (12.9 vs. 2.8 mo, p < 0.001) and OS (13.5 vs. 6.7 mo, p < 0.001). Patients with PR on interim imaging after two cycles had a longer median OS compared to patients with stable or progressive disease (15.5 vs. 7.1 mo, p < 0.001). Previous taxane-based chemotherapy (HR 3.21, 95%CI 1.18-8.70, p = 0.02) and baseline LDH levels (HR 1.001, 95%CI 1.000-1.001, p = 0.04) were inversely associated with OS on a Cox-regression analysis. Grade ≥ 3 hematological decline was observed after 22/201 (11%) cycles with anemia, leukopenia and thrombocytopenia in 15/45 (33%), 6/45 (13%) and 8/45 (18%) patients, respectively. Cumulative treatment activity and absorbed whole-body dose were not correlated with new onset grade ≥ 3 hematotoxicity (p = 0.91, p = 0.69). No event of grade ≥ 3 chronic kidney disease was observed during RLT or the follow-up. Last line RLT with 177Lu-PSMA-617 in mCRPC patients with diffuse bone marrow involvement may thus contribute to prolonged disease control at an acceptable safety profile.