To evaluatethe therapeutic response, progression free survival(PFS), overall survival (OS) and clinical toxicity of ¹⁷⁷Lu-PSMA-617 PRLT in the setting of heavily pre-treated mCPRC patients and also examine the association of prognostic variables with therapeutic outcome in such patient cohort.

We examined the medical records of mCRPC patients who had undergone ¹⁷⁷Lu-PSMA-617 PRLT from March 2017 to February 2019 in our institute. Patients receiving equal to or more than two cycles were included and analysed in this retro-prospective study.The ⁶⁸Ga-PSMA-11 PET-CT and ¹⁸FDG PET-CT scan findings, serum PSA change, health related quality of life (HRQoL) scales (ECOG/Karnofsky score) and Gleason scorewere assessed for their implications on the outcome of therapy. The treatment response was evaluated under three categories: (a) symptomatic (b) biochemical and (c) Imaging response.The PFS and OS following first PRLT were determined and the association of various variables with PSA doubling time (DT) and FDG uptake in the lesions were analysed. Toxicity assessment was undertaken objectively by NCI-CTCAE scale version 5.0 for haematological and nephrotoxicity, and salivary gland toxicity assessed by xerostomia inventory score.

A total of 40 mCRPC patients (age range: 46-84 years; median 63 years), who had undergone ¹⁷⁷Lu-PSMA-617 PRLT, of at least two cycles was identified and selected for the analysis. FDG uptake was noted in 87.5% of patients (n = 35). Out of 40 cases, 21 were responders (CR, PR and SD) and 19 were non-responders (PD) on symptomatic and biochemical scales while on molecular imaging response, 16 (43%) were responders and remaining 21 (57%) were non-responders. Lesion-wise, ⁶⁸Ga-PSMA-11 avid metastatic nodal disease responded well with ¹⁷⁷Lu PSMA-617 PRLT, as compared to hepatic and skeletal lesions. The median OS and PFS was 12 and 7 months respectively following first PRLT. Patients with negative serum PSA-DT demonstrated superior er 1 yearPFS as compared to those with positive serum PSA-DT (52.5 vs 47.5%) (p = 0.029). Patients receiving greater than two cycles PRLT demonstrated a higher negative PSA-DT as compared to those receiving two cycles (p value = 0.03). Grade one xerostomia was observed in two patients (5%) (mean xerostomia score of 23), hematotoxicity in seven patients [grade I (n = 2, 5%) and grade II (n = 5, 14%)].

¹⁷⁷Lu-PSMA-617PRLT was well-tolerated and able to produce disease control with good symptomatic and biochemical responses in the context of heavily pre-treated mCRPC with progressive disease, with low toxicity profile. Evident association of high FDG uptake was observed with aggressive disease biology coupled with increasing Gleason score and poorer 12 months PFS. Negative PSA-DT following therapy demonstrated longer PFS. The results demonstrate important future role of ¹⁷⁷Lu-PSMA-617 PRLT in the treatment of mCRPC.

The present work explored in a large teriary cancer care setting, the efficacy of ¹⁷⁷Lu-PSMA-617 PRLT, in an aggressive and unselected subset of mCRPC. The response and outcome was correlated with a number of prognostic variables, including molecular imaging findings (FDG uptake in the metastatic lesions), PSA doubling time and Gleason score.

Several recent studies have demonstrated that addicts behave less flexibly than healthy controls in the probabilistic reversal learning task (PRLT), in which participants must gradually learn to choose between a probably rewarded option and an improbably rewarded one, on the basis of corrective feedback, and in which preferences must adjust to abrupt reward contingency changes (reversals). In the present study, pathological gamblers (PG) and cocaine dependent individuals (CDI) showed different learning curves in the PRLT. PG also showed a reduced electroencephalographic response to feedback (Feedback-Related Negativity, FRN) when compared to controls. CDI's FRN was not significantly different either from PG or from healthy controls. Additionally, according to Standardized Low-Resolution Electromagnetic Tomography analysis, cortical activity in regions of interest (previously selected by virtue of their involvement in FRN generation in controls) strongly differed between CDI and PG. However, the nature of such anomalies varied within-groups across individuals. Cocaine use severity had a strong deleterious impact on the learning asymptote, whereas gambling intensity significantly increased reversal cost. These two effects have remained confounded in most previous studies, which can be hiding important associative learning differences between different populations of addicts.

Recent research has proposed that altered reward and punishment sensitivity, heightened impulsivity, and faulty dynamic decision-making are at the core of disordered gambling. However, each of these traits and cognitive aspects dimensionally vary in the normal population, such that the link between individual differences in these dimensions and gambling use can be ultimately informative to explain disordered gambling. The main aim of the present study was to investigate the contribution of such decision-making-related indices to gambling use parameters in a community sample of college students. Assessment included punishment and reward sensitivity (as measured by the shortened Sensitivity to Punishment and Sensitivity to Reward Questionnaire), impulsivity (as measured by the UPPS-P model and a motor inhibition Go/No-go task), and dynamic decision-making [as measured by the probabilistic reversal learning task (PRLT)]. A structured interview was conducted to explore quantitative aspects of the participants gambling habits (gambling presence, gambling frequency, and average amount of money spent in gambling per unit of time). Our results showed the existence of a decision-making profile of gambling, as it naturally occurs in college students, in which sensation seeking is directly and specifically related to gambling presence (gambling, or not gambling at all), punishment sensitivity is inversely related to gambling frequency, and inflexibility in the PRLT specifically predicts the losses accrued because of gambling. These results are compatible with the idea that sensation seeking and punishment insensitivity could increase exposure to gambling activities, whereas reversal learning inflexibility, in people who already gamble, could boost the risk to accumulate losses.

Bipolar disorder (BD) mania patients exhibit poor cognition and reward-seeking/hypermotivation, negatively impacting a patient's quality of life. Current treatments (e.g., lithium), do not treat such deficits. Treatment development has been limited due to a poor understanding of the neural mechanisms underlying these behaviors. Here, we investigated putative mechanisms underlying cognition and reward-seeking/motivational changes relevant to BD mania patients using two validated mouse models and neurochemical analyses.

The effects of reducing dopamine transporter (DAT) functioning via genetic (knockdown vs. wild-type littermates), or pharmacological (GBR12909- vs. vehicle-treated C57BL/6J mice) means were assessed in the probabilistic reversal learning task (PRLT), and progressive ratio breakpoint (PRB) test, during either water or chronic lithium treatment. These tasks quantify reward learning and effortful motivation, respectively. Neurochemistry was performed on brain samples of DAT mutants ± chronic lithium using high performance liquid chromatography.

Reduced DAT functioning increased reversals in the PRLT, an effect partially attenuated by chronic lithium. Chronic lithium alone slowed PRLT acquisition. Reduced DAT functioning increased motivation (PRB), an effect attenuated by lithium in GBR12909-treated mice. Neurochemical analyses revealed that DAT knockdown mice exhibited elevated homovanillic acid levels, but that lithium had no effect on these elevated levels.

Reducing DAT functioning recreates many aspects of BD mania including hypermotivation and improved reversal learning (switching), as well as elevated homovanillic acid levels. Chronic lithium only exerted main effects, impairing learning and elevating norepinephrine and serotonin levels of mice, not specifically treating the underlying mechanisms identified in these models.

Hearing loss and ovarian dysfunction are key features of Perrault syndrome (PRLTS) but the clinical and pathophysiological features of hearing impairment in PRLTS individuals have not been addressed. Mutations in one of five different genes HSD17B4, HARS2, LARS2, CLPP or TWNK (previous symbol C10orf2) cause the autosomal recessive disorder but they are found only in about half of the patients.

We report on two siblings with a clinical picture resembling a severe, neurological type of PRLTS. For an exhaustive characterisation of the phenotype neuroimaging with volumetric measurements and objective measures of cochlear hair cell and auditory nerve function (otoacustic emissions and auditory brainstem responses) were used. Whole exome sequencing was applied to identify the genetic cause of the disorder. Co-segregation of the detected mutations with the phenotype was confirmed by Sanger sequencing. In silico analysis including 3D protein structure modelling was used to predict the deleterious effects of the detected variants on protein function.

We found two rare biallelic mutations in TWNK, encoding Twinkle, an essential mitochondrial helicase. Mutation c.1196A>G (p.Asn399Ser) recurred for the first time in a patient with PRLTS and the second mutation c.1802G>A (p.Arg601Gln) was novel for the disorder. In both patients neuroimaging studies showed diminished cervical enlargement of the spinal cord and for the first time in PRLTS partial atrophy of the vestibulocochlear nerves and decreased grey and increased white matter volumes of the cerebellum. Morphological changes in the auditory nerves, their desynchronized activity and partial cochlear dysfunction underlay the complex mechanism of hearing impairment in the patients.

Our study unveils novel features on the phenotypic landscape of PRLTS and provides further evidence that the newly identified for PRLTS TWNK gene is involved in its pathogenesis.

The aim of the review was to evaluate patient and treatment characteristics for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with PSMA radioligand therapy (PRLT) associated with above-average outcome. The systematic review and meta-analysis followed recommendations by the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA). We searched for publications in PubMed, Embase, and ClinicalTrials.gov up to 31 September 2020. Thirty-six publications and four duplicates reported 2346 patients. Nearly two-thirds of the patients had bone metastases. Median overall survival (OS) was 16 months. Asymptomatic patients and patients with only lymph node metastases lived longer than symptomatic patients and patients with more extensive metastases. Patients treated with an intensified schedule of ¹⁷⁷Lu PRLT lived longer than those treated with a conventional schedule. Half of the patients obtained a PSA decline ≥ 50% and these patients lived longer than those with less PSA decline. Approximately 10% of the patients developed hematologic toxicity with anemia grade 3 as the most severe adverse effect. Characteristics for patients, cancer, restaging, and PRLT predict above average overall survival following treatment with PRLT.

Keywords: adverse effects; decline of prostate specific antigen; metastases; overall survival; predictive factors; prostate cancer; prostate-specific membrane antigen; theranostics.

Context: Castration-resistant prostate cancer (CRPC) treatment is an evolving challenge. Prostate-specific membrane antigen (PSMA)-targeted endoradiotherapy/radioligand therapy (PRLT) with small-molecule, urea-based agents labeled with the β-particle-emitting radionuclide lutetium-177 (¹⁷⁷Lu) is a promising new approach.

Objective: In this systematic review and meta-analysis, we evaluated the efficacy and toxicity of PRLT.

Evidence acquisition: A systematic search was performed in PubMed/Medline (last updated February 18, 2019). A total of 250 studies were reviewed, and 24 studies with 1192 patients were included in the analysis. Proportions of patients with ≥50% serum prostate-specific antigen (PSA) decrease, any PSA decrease, and any PSA increase were extracted. Proportions of patients showing any grade toxicity and those with grade 3/4 toxicities based on Common Terminology Criteria for Adverse Events (CTCAE) grading were extracted from manuscripts. Overall survival and progression-free survival were evaluated. A meta-analysis of single proportions was carried out. Furthermore, we compared the two most common PRLT agents, ¹⁷⁷Lu-PSMA with ¹⁷⁷Lu-PSMA-I&T, for effectiveness and toxicity.

Evidence synthesis: Among the 24 included studies, 20 included data on ¹⁷⁷Lu-PSMA-617, three included data on ¹⁷⁷Lu-PSMA-I&T, and one study had aggregated data for ¹⁷⁷Lu-PSMA-617 and ¹⁷⁷Lu-PSMA-I&T. The estimated proportion of ¹⁷⁷Lu-PSMA-617-treated patients who showed a serum PSA decrease of ≥50% with at least an 8-wk interval between therapy and PSA measurement was 0.44 (0.39; 0.50). Therapy with ¹⁷⁷Lu-PSMA-I&T demonstrated an estimated proportion of patients with ≥50% PSA reduction to be 0.36 (0.26; 0.47). The aggregate results for men treated with more than one cycle of any kind of PRLT showed an estimated proportion of 0.46 (0.41; 0.51) for PSA response ≥50%. Regarding aggregate data from all of the PRLT agents, we found that grade 3 and 4 toxicities were uncommon, with estimated proportions from 0.01 (0.00;0.04) for nausea, fatigue, diarrhea, and elevated aspartate transaminase up to 0.08 (0.05; 0.12) for anemia. There was considerable heterogeneity among the studies in the "any-grade toxicity" groups. Meta-regression showed that more than one cycle of PRLT is associated with a greater proportion of patients with ≥50% PSA reduction. Overall survival according to pooled hazard ratios (HRs) for any PSA decline was 0.29 (0.18; 0.46), and for >50% PSA reduction was 0.67 (0.43; 1.07). Progression-free survival according to a pooled HR of >50% PSA reduction was 0.53 (0.32; 0.86).

Conclusions: The relatively high number of PSA responders alongside the low rate of severe toxicity reflects the potentially promising role of PRLT in treating CRPC. The ultimate utility of this treatment modality will become clearer as multiple prospective studies continue to accrue. In the interim, this systematic review and meta-analysis can serve as a compendium of effectiveness and adverse events associated with PRLT for treating clinicians.

Patient summary: Prostate-specific membrane antigen-targeted endoradiotherapy/radioligand therapy (PRLT) is associated with ≥50% reduction in prostate-specific antigen level in a large number of patients and a low rate of toxicity, reflecting its potential in treating castration-resistant prostate cancer. This systematic review and meta-analysis presents as a compendium of the effectiveness and adverse events related to PRLT for treating clinicians.

Keywords: Endoradiotherapy; Prostate cancer; Prostate-specific membrane antigen–targeted endoradiotherapy/radioligand therapy.

OBJECTIVE

This study examined the profile of the choroidal thickness and photoreceptor layer thickness (PRLT) in healthy myopia subjects, with an attempt to find the connection between change of the choroidal thickness and retinal thickness changes.

METHODS

A total of 64 study participants (64 eyes) were divided into 3 groups in terms of their refractive status: normal sight group (+1.0 D~-1.0 D), mild or moderate myopia group (-1.0 D~-6.0 D), high myopia group >>-6.0 D). The fovea and parafoveal region (the region of 6 mm diameter of the fovea as center) of the images were selected by spectral domain optical coherence tomography. A circle of retinal pigment epithelium (RPE) layer simulated by applying the least square curve fitting technique was obtained. Along the vertical direction of the RPE layer, choroidal thickness (choroidal thickness involved the total thickness at the fovea and parafoveal), PRLT, retinal thickness (RT), ganglion layer thickness (GLT), and retinal nerve fiber layer thickness (RNFLT) in the fovea (PRLT-f, RT-f) or in the -parafoveal region (PRLT-pf, RT-pf, GLT and RNFLT) were calculated by Image J software manually.

RESULTS

As compared with group 1, PRLT-pf, RT-pf, and choroidal thickness were significantly reduced (p<0.05) in group while no significant difference was found in PRLT-f, RT-f, GLT, and RNFLT between the 2 groups. Both univariate and forward multivariate linear regression analysis showed that PRLT-pf and choroidal thickness intertwined obviously.

CONCLUSIONS

In high myopia subjects, not only choroidal thickness, but also photoreceptor layer thickness in the parafoveal region decreased significantly. On the basis of neuron vascular unit theory, the change in choroidal thickness is significantly related to the alternation in PRLT and vice versa.

Deficits in cognition and motivation are common and debilitating aspects of psychiatric disorders, yet still go largely untreated. The neuropeptide oxytocin (OT) is a potential novel therapeutic for deficits in social cognition and motivation in psychiatric patients. However, the effects of OT on clinically relevant domains of non-social cognition and motivation remain under studied. The present study investigated the effects of acute and chronic (21-day) administration of subcutaneous OT (0.04, 0.2, and 1 mg/kg) in cross-species translatable operant paradigms of reward learning and effortful motivation in male and female Brown Norway (BN) rats (n = 8-10/group). Reward learning was assessed using the probabilistic reversal learning task (PRLT) and effortful motivation was measured using the progressive ratio breakpoint task (PRBT). As predicted, BN rats exhibited baseline deficits in the detection of reversals of reward contingency in the PRLT relative to Long Evans (LE) rats. The two strains performed equally in the PRBT. Thirty minutes after a single OT injection (1 mg/kg), measures of both initial probabilistic learning (trials to first criterion) and subsequent reversal learning (contingency switches) were significantly improved to levels comparable with LE rats. The OT effect on switches persisted in male, but not female, BN rats 30 min, 24 h, and 6 days after long-term OT administration, suggesting the induction of neuroplastic changes. OT did not affect effortful motivation at any time-point. The beneficial effects of OT on reward learning in the absence of increased effortful motivation support the development of OT as a novel therapeutic to improve cognitive functioning.

OBJECTIVE

To prove the hypothesis that there may be different tumor suppressor genes (TSGs) involved in genesis of squamous cell carcinoma (SCC) and adenocarcinoma (ADC) in non-small cell lung cancer (NSCLC) in the Chinese.

METHODS

Twenty-two microsatellite markers flanking to or within 13 identified or candidate TSGs were used to detect loss of heterozygosity (LOH) in these regions in the specimens of 28 SCC patients and 13 ADC patients.

RESULTS

Our data demonstrated frequent allelic loss of FHIT, p53, IFNA, VHL and p16 both in SCC and ADC. Three genes, PRLTS, PTEN and p57, showed statistically significant differences in the LOH frequency between SCC and ADC.

CONCLUSIONS

The comparison of LOH frequencies between SCC and ADC indicates possible correlation between specific tumor suppressor genes and each type of lung cancer. The results also suggest that more attention should be paid to the PRLTS gene, which may play an important role in the development of ADC.

The aim of this study was to assess the safety, tolerability and effects on renal function as well as therapeutic efficacy of prostate-specific membrane antigen (PSMA) targeted radioligand therapy (PRLT) using lutetium-177 (¹⁷⁷Lu) labeled PSMA-617 in patients with metastatic castration-resistant prostate cancer (mCRPC) and a single functioning kidney before PRLT. Methods: Sixteen patients (age 53-78 y, mean age 64.7 ± 6.5 y) with a single functioning kidney received PRLT with ¹⁷⁷Lu-PSMA-617 between March 2015 and October 2018. All parameters of renal function (serum creatinine, blood urea nitrogen and electrolytes) were prospectively documented in a structured database and analyzed prior to each PRLT cycle and in follow-up. Renal function was further quantified by measuring TER using ^99mTc-MAG3 renal scintigraphy. Treatment-related adverse events (AEs) were graded according to the CTCAE v.5.0. Kaplan-Meier analysis was performed to obtain the progression-free survival and overall survival. Results: The median administered activity was 22.1 GBq (range 15.4-33.8 GBq). Calculated radiation-absorbed doses of kidney per cycle were 5.3 ± 2.1 Gy (0.81±0.32 Gy/GBq). Renal function was already impaired at baseline in 43.7% patients, including G1 renal impairment in 25.0% and G2 in 18.8%. G1 and G2 renal impairment, respectively, were present in 37.5% and 6.3% of the patients after the first PRLT cycle and in 31.3 % and 12.5% after the second cycle. No G3 or 4 nephrotoxicity was observed during or after treatment. There was no significant change in both tubular extraction rate (TER) and the ratio of to lower limit TER (TER/TERLoLi) after the last cycle of treatment (p>0.05). The median PFS was 8.1 months based on both EORTC and RECIST. The median overall survival has yet to be reached with a median follow-up time of 19.3 months (range 5.8-45.3 months). Conclusion: In patients with a single functioning kidney, ¹⁷⁷Lu-PSMA-617 radioligand therapy is feasible, seems to be effective and is very well tolerated without any signs of acute or subacute nephrotoxicity during a mean follow up of nearly 2 years (and up to 45.3 mo). Further long-term follow-up of this special patient group is warranted.

The successful use of theranostic twins in neuroendocrine tumors (NET) was the pioneering approach to radionuclide therapy in other tumor types. 64Cu/18F PSMA for molecular imaging with PET-CT and peptide radioligand therapy (PRLT) with 177Lu labeled PSMA inhibitors are the next theranostic twins in nuclear medicine. 68Ga/ 64Cu/18F PSMA PET-CT detects metastatic prostate cancer with high diagnostic sensitivity and specificity and can be used to select patients for PRLT and evaluate therapy response. Radionuclide therapy with 177Lu-PSMA inhibitors has been shown to be effective in the treatment of metastatic CRPC.

Keywords: 64CuCl2; CRPC; NET; PET-CT; Peptide radioligand therapy; Prostate cancer; glioblastoma; melanoma.

Objectives: Renal hypoperfusion is a common mechanism of cardiac surgery-related acute kidney injury (CS-AKI). However, the optimal amount of volume resuscitation to correct systemic hypoperfusion and prevent the postoperative development of CS-AKI has been a subject of debate. The goal of this study was to assess the association of volume responsiveness determined by stroke volume variation using the passive leg raise test (PLRT) at chest closure, with the development of CS-AKI according to the Kidney Disease Improving Global Outcomes criteria.

Design: Single-center, prospective observational study.

Setting: Tertiary hospital.

Interventions: None.

Measurements and main results: A total of 131 patients were studied from January 2015 until May 2017. All patients underwent cardiac surgery that required cardiopulmonary bypass. Volume responsiveness was assessed at chest closure using the PRLT. Stroke volume variation from the sitting to the recumbent positions was measured by transesophageal echocardiography. Fluid responsiveness was defined as an increase of >12% of stroke volume from sitting to recumbent positions. A total of 82 (68.3%) patients were fluid-responsive versus 38 (31.6%) who were fluid-unresponsive. CS-AKI occurred in 30% of patients. There was no difference in CS-AKI between fluid-responsive and fluid-nonresponsive groups. However, CS-AKI was associated independently with an increases in body mass index and preoperative diastolic blood pressure. CS-AKI also was associated with prolonged intensive care unit length of stay.

Conclusion: End-of-procedure volume responsiveness is not associated with a high risk for postoperative CS-AKI.

Keywords: acute kidney injury; cardiopulmonary bypass; passive leg raise test; volume responsiveness.

Aim: The objective of this study was to estimate the absorbed doses to the normal organs and tumor lesions in metastatic castration-resistant prostate cancer (mCRPC) patients treated with indigenously developed ¹⁷⁷Lu-PSMA-617 that could establish optimal treatment protocol with minimum risk to the dose-limiting organs. Furthermore, attempt was also made to compare radiation absorbed doses for normal organs and tumor lesions in subsequent cycles of ¹⁷⁷Lu-PSMA-617 peptide receptor radioligand therapy (PRLT) in the same group of patients during the course of treatment. Methods: A total of 30 patients of proven mCRPC were enrolled for this prospective study. These patients received up to 5 cycles of treatment with ¹⁷⁷Lu-PSMA-617 PRLT (1 cycle for 13 patients, 2 cycles for 9 patients, 3 cycles for 3 patients, and 5 cycles for 5 patients), at 11-12-week intervals between the two successive therapies. The patients underwent postadministration whole-body scintigraphy at five time points: 0.5 (prevoid), 2, 12, 24, and 72/96 h (postvoid). From time-activity curves generated by drawing regions of interests on the images, number of disintegrations was determined. Tumor masses were estimated from pretherapeutic ⁶⁸Ga-PSMA-11 positron emission tomography-computed tomography images. Absorbed doses for organs and tumors were calculated using OLINDA 2.0 software. Results: The average activity of ¹⁷⁷Lu-PSMA-617 (mean ± SD) administered per patient per cycle was 4.94 ± 0.45 GBq. The mean absorbed organ doses (mean ± SD) from first therapy cycle in Gy/GBq were as follows: kidneys 0.52 ± 0.16, spleen 0.17 ± 0.07, liver 0.08 ± 0.05, salivary glands 0.53 ± 0.30, lacrimal glands 1.45 ± 0.85, nasal mucosa membrane 0.46 ± 0.19, urinary bladder 0.23 ± 0.02, and bone marrow 0.04 ± 0.03. The mean effective dose for whole body from first therapy cycle was 0.05 ± 0.03 Sv/GBq. Among all the normal organs, lacrimal glands received the highest absorbed dose. The median dose for all lesions, bone lesions, lymph nodes, primary site, liver lesion, lung lesion, and soft tissue deposit from first therapy cycle was determined to be 4.17, 4.23, 3.96, 4.36, 10.27, 0.78, and 4.68 Gy/GBq respectively. Absorbed doses received by the normal organs in five consecutive cycles follow three different trends, (a) for kidneys, salivary glands, and nasal mucous membrane, absorbed doses increased from first therapy cycle to second therapy cycle and then slowly decreased in subsequently therapy cycles; (b) for spleen, liver, and lacrimal glands, absorbed doses decreased with the successive therapy cycles; and (c) in case of bone marrow, bladder, and whole body, mean absorbed dose almost remained constant in each therapy cycle. Absorbed doses to the lesions gradually decreased with increase of the number of therapy cycles. Conclusions: The organ and tumor absorbed doses of ¹⁷⁷Lu-PSMA-617 in mCRPC patients were found to be comparable to the data reported in the literature. The highest absorbed organ dose was observed in lacrimal glands and being a dose limiting organ, a cumulative activity up to 32.5 GBq (878 mCi) of ¹⁷⁷Lu-PSMA-617 in 4-5 therapy cycles appears safe and feasible to achieve full therapeutic window.

Success of transplantation is not limited to initial receipt of a donor organ. Many kidney transplant recipients experience graft loss following initial transplantation and the benefits of expedited placement on the waiting list and re-transplantation extend to this population. Factors associated with access to repeat transplantation may be unique given experience with the transplant process and prior viability as a candidate. We examined the incidence, risk factors, secular changes and center-level variation of preemptive re-listing or transplantation (PRLT) for kidney transplant recipients in the United States with graft failure (not due to death) using SRTR data from 2007-2018(n=39,557). Overall incidence of PRLT was 15% and rates of re-listing declined over time. Significantly lower PRLT was evident among patients that were African American and Hispanic, males, older, obese, publicly insured, lower educational attainment, diabetic, longer dialysis time prior to initial transplant, shorter graft survival, longer distance to transplant center and residing in distressed communities. There was significant variation in PRLT by center, median=13%, 10^th percentile=6%, 90^th percentile=24%. Cumulatively, results indicate that despite prior access to transplantation, incidence of PRLT is modest with pronounced clinical, social and center-level sources of variation suggesting opportunities to improve preemptive care among patients with failing grafts.

In this systematic review and network meta-analysis (NMA), we aimed to assess the benefits and harms of third-line (L3) treatments in randomized controlled trials (RCTs) of patients with metastatic castration-resistant prostate cancer (mCRPC). Two reviewers searched for publications from 1 January 2006 to 30 June 2021. The review analyzed seven RCTs that included 3958 patients and eight treatments. Treatment with prostate-specific membrane antigen (PSMA)-based radioligand therapy (PRLT) resulted in a 1.3-times-higher rate of median PSA decline ≥50% than treatment with abiraterone, enzalutamide, mitoxantrone, or cabazitaxel (p = 0.00001). The likelihood was 97.6% for PRLT to bring about the best PSA response, out of the examined treatments. PRLT resulted in a 1.1-times-higher six-month rate of median radiographic progression-free survival. Treatment with PRLT in the VISION trial resulted in 1.05-times-higher twelve-month median overall survival than L3 treatment with cabazitaxel in other RCTs. PRLT more often resulted in severe thrombocytopenia and less often in severe leukopenia than did cabazitaxel. In conclusion, for patients with mCRPC, L3 treatment with PRLT is highly effective and safe.

Keywords: advanced metastatic castration-resistant prostate cancer; benefits and harms of treatments; connected network; frequentist analysis; ranking of treatments.

The objective of this study was to determine the safety, kinetics and dosimetry of ¹⁷⁷Lu labeled prostate specific membrane antigen (PSMA) small molecules ¹⁷⁷Lu-PSMA-I&T and ¹⁷⁷Lu-PSMA-617 in a large cohort of patients with metastatic castration-resistant prostate cancer (mCRPC) undergoing PSMA radioligand therapy (PRLT). Methods: A total of 138 patients (mean age, 70±9 y; age range 46-90 y) with progressive mCRPC and PSMA expression verified by ⁶⁸Ga-PSMA-11 PET/CT underwent PRLT. 51 patients received 6.1±1.0 GBq (range, 3.4-7.6 GBq) ¹⁷⁷Lu-PSMA I&T and 87 patients received 6.5±1.1 GBq (range, 3.5-9.0 GBq) ¹⁷⁷Lu-PSMA-617. Dosimetry was performed in all patients on the identical protocol. The mean absorbed doses were estimated with OLINDA software (MIRD Scheme). Treatment-related adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Results: The whole-body half-lives were shorter for ¹⁷⁷Lu PSMA I&T (35 h) as compared to ¹⁷⁷Lu PSMA-617 (42 h). The mean whole-body dose of ¹⁷⁷Lu-PSMA-617 was higher as compared to ¹⁷⁷Lu-PSMA-I&T (0.04 Gy/GBq vs. 0.03 Gy/GBq, p<0.00001). Despite the longer half-life of ¹⁷⁷Lu-PSMA-617, the renal dose of ¹⁷⁷Lu-PSMA-617 was lower than for ¹⁷⁷Lu-PSMA-I&T (0.77 Gy/GBq vs 0.92 Gy/GBq, P = 0.0015). Both PSMA small molecules demonstrated a comparable dose to parotid glands (0.5 Gy/GBq, P = 0.27). Among all normal organs, lacrimal glands exhibited the highest mean absorbed dose of 5.1 Gy/GBq and 3.7 Gy/GBq for ¹⁷⁷Lu-PSMA-617 and ¹⁷⁷Lu-PSMA I&T, respectively. All tumor metastases exhibited a higher initial uptake when using ¹⁷⁷Lu-PSMA I&T, as well as shorter tumor half-life as compared to ¹⁷⁷Lu-PSMA-617 (p<0.00001). The mean absorbed tumor doses were comparable for both ¹⁷⁷Lu-PSMA I&T and ¹⁷⁷Lu-PSMA-617 (5.8 Gy/GBq vs. 5.9 Gy/GBq, P = 0.96). All patients tolerated the therapy without any acute adverse effects. There was a small, statistically significant reduction in hemoglobin, leukocyte counts and platelet counts after ¹⁷⁷Lu-PSMA-617 and ¹⁷⁷Lu-PSMA I&T which did not need any clinical intervention. No nephrotoxicity was observed after either ¹⁷⁷Lu-PSMA I&T or ¹⁷⁷Lu-PSMA-617 PRLT. Conclusion: Both ¹⁷⁷Lu-PSMA I&T and ¹⁷⁷Lu-PSMA-617 PRLT demonstrated favorable safety in mCRPC patients. Highest absorbed dose amongst healthy organs were observed for the lacrimal and parotid glands, however, not resulting in any significant clinical sequel. ¹⁷⁷Lu-PSMA-617 demonstrated higher whole-body and lacrimal glands absorbed dose, but lower renal doses as compared to ¹⁷⁷Lu-PSMA-I&T. The mean absorbed tumor doses were comparable for both ¹⁷⁷Lu-PSMA I&T and ¹⁷⁷Lu-PSMA-617. There was a large inter-patient variability of the dosimetry parameters. Therefore, individual patient-based dosimetry seems favorable for personalized PRLT.

Keywords: 177Lu-PSMA I&T; 177Lu-PSMA-617; Oncology: GU; PSMA radioligand therapy (PRLT); Radiobiology/Dosimetry; Radionuclide Therapy; dosimetry; prostate-specific membrane antigen (PSMA).

Objective: To explore the genetic etiology of two patients with Perrault syndrome (PRLTS) in a family.

Methods: Whole exome sequencing (WES) was carried out to screen potential variants within genomic DNA extracted from the proband. Suspected variants were validated by clinical data and results of Sanger sequencing.

Results: WES has identified two heterozygous variants of TWNK gene, namely c.1172G>A (p.Arg391His) and c.1844G>C (p.Gly615Ala). Sanger sequencing confirmed that the c.1172G>A (p.Arg391His), a known pathogenic variant, was derived from her father, while the c.1844G>C (p.Gly615Ala), a novel variant, was derived from her mother. Her brother, who was similarly affected, has carried the same compound heterozygous variants.

Conclusion: The compound heterozygous variants c.1172G>A (p.Arg391His) and c.1844G>C (p.Gly615Ala) of the TWNK gene probably underlie PRLTS in the sib pair. The above results have facilitated genetic counseling and prenatal diagnosis for the affected family.

Background and Aim: The employment of prostate-specific membrane antigen (PSMA)-based PET-CT imaging has grown rapidly over the recent years. The aim of the present study was to estimate the lesional uptake across the different levels of molecular imaging PSMA (miPSMA) expression score along with normal physiological concentration of ⁶⁸Ga-PSMA-11 in a cohort of mCRPC patients including their temporal variation on delayed imaging. Materials and Methods: Fifty patients of mCRPC who were being evaluated for ¹⁷⁷Lu-PSMA PRLT, and underwent ⁶⁸Ga-PSMA-11 PET-CT for evaluation of disease status, were retrospectively evaluated. The mean age of the patients undergoing the scan was 67.5 ± 8 years (52-84 years) with an average serum PSA level of 401 ± 1353 ng/ml (0.098-9235.13 ng/ml) at the time of scanning. All patients underwent standard ⁶⁸Ga-PSMA-11 PET-CT at 65 minutes post-injection on an average (60-90 mins). Tumoral analysis (n = 50) was undertaken to see their correlation with miPSMA expression score and their uptake values. The physiological tracer distribution was estimated by placing a spherical VOI of fixed diameter of 1 cm for smaller organs (in the regions of submandibular glands, parotid glands, lacrimal glands, tubarial glands, renal cortices, blood pool and bowel) and 3 cm for larger organs (liver and spleen). Standardised uptake value maximum (SUV_max) and mean (SUVmean) were estimated for each of the regions. Tumor-to-spleen (T/S), tumor-to-liver (T/L) and tumor-to-parotid (T/P) ratios were calculated for each lesion. A subgroup of 16 patients underwent a delayed scan at 135 mins post injection on average (120 - 150 mins), for whom an additional analysis was performed to evaluate the effect of delayed imaging on uptake values and ratios. Results: The maximum uptake was observed in renal cortices followed by salivary glands, bowel, spleen, liver, lacrimal glands and blood pool in the descending order. The average SUV_max with SD of the organs are as: 37.7 ±22.1 for renal cortices, 15.4 ±7.3 for submandibular glands, 14.4 ± 7.1 for parotid glands, 9.4± 4.9 for spleen, 6.2 ± 3.7 for lacrimal glands, 5.9± 2.3 for liver, 5.3 ± 1.41 for tubarial glands, 13.8 ±7.6 for bowel, and 2.4 ±1.9 for blood pool. The average SUV_max of miPSMA expression score 2 was 10.33 ± 3.27 (6.46 - 17) and 38.21 ± 25.9 (7.68 - 119.08) for score 3. The average tumor-to-spleen (T/S) and tumor-to-parotid (T/P) ratios for score 2 lesions were 1.21 ± 0.44 (0.48 - 2.04) and 0.6 ± 0.18 (0.39- 0.87) respectively. The average T/S and T/P ratios for score 3 lesions were 5.05 ± 4.46 (1.25 - 20.89) and 3.15 ± 2.09 (1.06 - 9.45) respectively. The average SUV_max of index score 3 lesions was 18.85 which increased to 26.24 on delayed imaging with statistically significant difference (P = 0.0001). However, the T/L, T/S and T/P ratios did not show any significant change. The temporal variation of normal organs showed that the SUV_max was significantly increased in delayed scan in salivary (submandibular and parotid) and lacrimal glands, and renal cortices, while the SUVmean significantly increased in spleen and liver, parotid, tubarial and lacrimal glands and not significant in other organs. Conclusion: Thus, the reference ranges of normal organs (physiological uptake) and tumor lesions for uptake and ratios for miPSMA score 2 and score 3 were documented and established in the present study, based upon which a consensus on standard reference range can be proposed for all quantitative assessment values on ⁶⁸Ga-PSMA-11 PET-CT. The temporal variation trends of the lesions and reference organs should be kept in mind for delayed acquisitions, the T/S, T/Lor T/P ratios could serve as better markers for such scenarios.

Keywords: 68Ga-PSMA-11 PET-CT; Metastatic Castrate Resistant Prostate carcinoma (mCRPC); Molecular Imaging; PET/CT; PSA; Peptide receptor radioligand therapy (PRLT); miPSMA score.

The present communication details on the imaging characteristics, peculiarities and response to PSMA targeted ¹⁷⁷Lu-PSMA-617 PRLT in accordance with Gleason score and use of dual tracer PET study (⁶⁸Ga-PSMA-11 and FDG) in patients with urinary bladder invasion/metastasis by prostate cancer, including the prognostic value of FDG-PET in predicting response to treatment. The CT attenuation units (HU) correlated with prostate primary in case of direct tumour extension from prostate, while in hematogenous metastatic seeding the HU was lower than the primary prostatic tumour. A particular point of note was that favorable outcome to ¹⁷⁷Lu-PSMA-617 PRLT was observed in patients with lesser or no baseline FDG uptake despite high Gleason score and high risk NCCN prognostic category, and did not correlate with the latter alone, while high SUV_max values on FDG PET-CT was found to be associated with adverse outcome. These findings suggested the promising role of FDG PET-CT in predicting therapeutic outcomes with more confidence, and hence the concept of dual tracer PET appeared to hold good in prostate adenocarcinoma theranostics.