Nomograms to predict outcomes after 177Lu-PSMA therapy in men with metastatic castration-resistant prostate cancer: an international, multicentre, retrospective study.

BACKGROUND: Lutetium-177 (177Lu) prostate-specific membrane antigen (177Lu-PSMA) is a novel targeted treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). Predictors of outcomes after 177Lu-PSMA to enhance its clinical implementation are yet to be identified. We aimed to develop nomograms to predict outcomes after 177Lu-PSMA in patients with mCRPC. METHODS: In this multicentre, retrospective study, we screened patients with mCRPC who had received 177Lu-PSMA between Dec 10, 2014, and July 19, 2019, as part of the previous phase 2 trials (NCT03042312, ACTRN12615000912583) or compassionate access programmes at six hospitals and academic centres in Germany, the USA, and Australia. Eligible patients had received intravenous 6·0-8·5 GBq 177Lu-PSMA once every 6-8 weeks, for a maximum of four to six cycles, and had available baseline [68Ga]Ga-PSMA-11 PET/CT scan, clinical data, and survival outcomes. Putative predictors included 18 pretherapeutic clinicopathological and [68Ga]Ga-PSMA-11 PET/CT variables. Data were collected locally and centralised. Primary outcomes for the nomograms were overall survival and prostate-specific antigen (PSA)-progression-free survival. Nomograms for each outcome were computed from Cox regression models with LASSO penalty for variable selection. Model performance was measured by examining discrimination (Harrell's C-index), calibration (calibration plots), and utility (patient stratification into low-risk vs high-risk groups). Models were validated internally using bootstrapping and externally by calculating their performance on a validation cohort. FINDINGS: Between April 23, 2019, and Jan 13, 2020, 414 patients were screened; 270 (65%) of whom were eligible and were divided into development (n=196) and validation (n=74) cohorts. The median duration of follow-up was 21·5 months (IQR 13·3-30·7). Predictors included in the nomograms were time since initial diagnosis of prostate cancer, chemotherapy status, baseline haemoglobin concentration, and [68Ga]Ga-PSMA-11 PET/CT parameters (molecular imaging TNM classification and tumour burden). The C-index of the overall survival model was 0·71 (95% CI 0·69-0·73). Similar C-indices were achieved at internal validation (0·71 [0·69-0·73]) and external validation (0·72 [0·68-0·76]). The C-index of the PSA-progression-free survival model was 0·70 (95% CI 0·68-0·72). Similar C-indices were achieved at internal validation (0·70 [0·68-0·72]) and external validation (0·71 [0·68-0·74]). Both models were adequately calibrated and their predictions correlated with the observed outcome. Compared with high-risk patients, low-risk patients had significantly longer overall survival in the validation cohort (24·9 months [95% CI 16·8-27·3] vs 7·4 months [4·0-10·8]; p<0·0001) and PSA-progression-free survival (6·6 months [6·0-7·1] vs 2·5 months [1·2-3·8]; p=0·022). INTERPRETATION: These externally validated nomograms that are predictive of outcomes after 177Lu-PSMA in patients with mCRPC might help in clinical trial design and individual clinical decision making, particularly at institutions where 177Lu-PSMA is introduced as a novel therapeutic option. FUNDING: Prostate Cancer Foundation.

Peptide receptor radionuclide therapy for treatment of metastatic neuroendocrine tumors in children.

Neuroendocrine tumors (NETs) of the pancreas and midgut are extremely rare in children, and patients presenting with metastatic disease have poor survival. Given this rarity, treatments are extrapolated from guidelines for adults with NET. Recent clinical trials in adults with NETs have shown that the addition of peptide receptor radionuclide therapy (PRRT) with 177 Lu-DOTATATE resulted in a disease control rate of nearly 80%, with minimal side effects. We report our experience using 177 Lu-DOTATATE to treat two pediatric patients with metastatic NET.

NO FACE-DOWN POSITIONING SURGERY FOR THE REPAIR OF CHRONIC IDIOPATHIC MACULAR HOLES.

PURPOSE: To report visual and anatomical outcomes after the repair of chronic idiopathic macular holes (MHs) with no face-down positioning. METHODS: We conducted a retrospective review of chronic MH cases of greater than 1-year duration that were repaired through pars plana vitrectomy with broad internal limiting membrane peeling and no face-down positioning between March 2009 and December 2017. There were 18 eyes of 18 patients that met inclusion criteria. Patients with MH duration of less than 1 year and without at least 1 month of follow-up were excluded. Macular hole staging and measurements were performed with spectral domain optical coherence tomography. RESULTS: Mean MH duration was 5.0 ± 6.9 years. Two-thirds of MHs had a basal diameter of more than 1,000 µm. Mean preoperative Snellen visual acuity was 20/302 and improved to a mean postoperative visual acuity of 20/112 (P ≤ 0.0001). Visual acuity improved in all patients who achieved successful anatomical closure, 94.4% (17/18) of eyes. CONCLUSION AND RELEVANCE: Patients in this series with chronic MH who underwent no-face-down MH repair demonstrated a high single-surgery anatomical closure rate with a significant improvement in visual acuity.

Difficult Central Venous Cannulation under Laryngeal Mask Airway Anesthesia in Adolescent.

We report a case of difficult central venous cannulation under general anesthesia with laryngeal mask airway in a young female child. Our case demonstrated a difficulty in surgically finding the right internal jugular vein due to neck veins displacements by laryngeal mask airway, which caused morbidity such as prolonged surgical duration and excessive blood loss. Once the laryngeal mask airway was replaced with endotracheal tube, the internal jugular vein appeared on surface and procedure was successfully completed in a few minutes. Such difficulties warrant an alternate approach in airway management in order to prevent major adverse effects.

Breast Cancer and HIV: a South African perspective and a critical review of the literature.

BACKGROUND: The diagnosis of breast cancer and concurrent HIV in South Africa is common. The limited current evidence on this subject suggests that the patients thus afflicted appear to be younger, have a more advanced stage of breast cancer, have a higher treatment related complications and poorer outcomes. This paper reviews the literature related to HIV and breast cancer, with a view to improving the standard and quality of care of HIV positive breast cancer patients. METHOD: Pubmed, EBSCOhost, Google scholar and Science Direct electronic databases were searched from 2001 and 2015. using the terms ('HIV' OR 'human immunodeficiency virus' OR 'AIDS' OR 'Acquired Immunodeficiency Syndrome') and 'breast cancer' or 'breast carcinoma' to identify all publications related to HIV and breast cancer. Titles and abstracts were evaluated for eligibility and appropriate full text articles obtained. The data extraction variables included the type of study, year of publication, study setting, participants, sample size, outcome measures and main findings. RESULTS: Only five studies fulfilled the criteria, in respect of the aforementioned maladies, with twenty or more participants in each study. Evidence suggested that breast cancers develop at a much younger age in the HIV positive patient compared to the HIV negative patients, with more aggressive appearing tumour biology. Overall, it appears that HIV positive patients experienced a higher cancer-specific mortality than HIV negative patients, and this is independent of the stage of the cancer or the cancer therapy received, further the relationship between the HIV syndrome and breast cancer is currently marginal and inconclusive, and hence requires further investigation. CONCLUSION: The prescription and administration of chemotherapy is a challenge, with potential complications impacting on the morbidity and mortality in HIV positive patients. Currently there are no reliable predictors of those at risk to complications from chemotherapy; however, being on ART appears to provide an acceptable safety profile. HIV positive patients are best managed in the context of a multi-disciplinary team in order to achieve favourable outcomes in the treatment of cancer. Well-designed prospective trials to assess the response to multimodal therapy, and the long-term outcomes of HIV positive patients with breast cancer are needed.

HIV-associated salivary gland enlargement: a clinical review.

Salivary gland disease is well established as an important HIV associated oral lesion. It manifests as salivary gland swelling involving one or both parotid glands with or without xerostomia. In the context of HIV, the swelling may be due to a wide spectrum of pathological conditions that include reactive or inflammatory disorders, acute and chronic infections, and neoplasms. This paper reviews the epidemiology, pathogenesis, clinical presentation, aspects of diagnosis and management of HIV associated salivary gland enlargement, in particular parotid gland enlargement, due to benign lymphoepithelial cysts (BLEC). Parotid gland enlargement is typically an early manifestation in the HIV-positive patient and should alert healthcare professionals to the likelihood of HIV infection. FNAC of the parotid gland is required to confirm the diagnosis and instituting HAART forms an important part of the management. There is a shift away from surgery in the treatment of this essentially 'benign' condition.

The academic progress of female general surgery and orthopaedic surgery trainees in South Africa.

BACKGROUND: Globally, medical institutes have seen an increase in female graduates, however surgical disciplines remain male-dominated. An epidemiological shift towards non-communicable diseases and trauma may result in a shortage of surgical specialists. One strategy to improve the surgical workforce is the recruitment of female graduates. METHODS: A non-validated questionnaire was administered to females registered for the Master of Medicine (MMED) degree in General and Orthopaedic Surgery at the University of KwaZulu-Natal (UKZN) between 2000 and 2015. The study evaluated reasons for choice of surgery as a career, challenges faced on the domestic and work front, as well as factors that assisted with successful completion of training. RESULTS: Seventy-two female trainees in General Surgery and Orthopaedics were identified from the UKZN databases. The contact details for 62 of these trainees were available. The overall response rate was 71.0% (44/62). A total of 95.5% (42/44) of participants selected surgery due to a passion for the field. Major challenges identified were a poor home and work-life balance (72.1%, 31/43) and poor working conditions (62.8%, 27/43). Female trainees perceived that they were viewed as inferior by patients (65.9%, 29/44). Successful trainees had a good home support system (89.3%, 25/28) and mentorship during training (60.7%, 17/28), and 85.7% (24/28) did not regret their career choice. CONCLUSION: The recruitment and retention of females in surgery will contribute to maintaining an adequate surgical workforce. Training programmes need to improve work-life balance without compromising on producing competent surgeons. Improved visibility of female surgeons in leadership roles should be encouraged to promote mentorship and recruitment of trainees.

Efficacy of clear aligner therapy over conventional fixed appliances in controlling orthodontic movement: A systematic review.

OBJECTIVE: The purpose of the current systematic review was to answer the clinical research question "Is Clear Aligner Therapy (CAT) effective in controlling the orthodontic movement?" by bringing together the most up-to-date information about the available evidence for CAT. METHODOLOGY: On January 1, 2023, a search was conducted in PubMed, ERIC, Embase, and CINHAL for any research papers published in the previous 10 years that provided an overview of the PICO questions. Both the titles and abstracts of the selected studies were evaluated independently by two different authors, and if there was any disagreement between the two review authors, a third reviewer was brought in to settle it. RESULTS: Among included studies, three were retrospective non-randomized and two studies were prospective randomized clinical trials. Various authors reported better outcome for fixed orthodontic appliances than for clear aligner treatment (CAT) in relation to mandibular incisor proclination. The mean objective grading system score was better for braces (17) than for CAT (12) with no clinically significant difference, while staging had a significant impact on treatment efficacy. CONCLUSION: The results of this study suggest that clear aligners may be an effective alternative to traditional braces, but more research is needed to confirm these findings and determine the optimal size of future prospective studies evaluating this treatment.

Effectiveness and Safety of Retreatment with 177Lu-DOTATATE in Patients with Progressive Neuroendocrine Tumors: A Retrospective Real-World Study in the United States.

Advanced neuroendocrine tumors (NETs) are associated with a poor prognosis. A regimen of 4 cycles of 177Lu-DOTATATE has been shown to improve both progression-free survival (PFS) and overall survival (OS) in patients with advanced NETs. To the best of our knowledge, this is the first study in the United States to evaluate the effectiveness and safety of additional cycles of 177Lu-DOTATATE therapy in patients with progressive NETs. Methods: This was a retrospective chart review of adults with advanced NETs. The patients had undergone initial treatment with up to 4 cycles of 177Lu-DOTATATE and, after disease progression and a period of at least 6 mo since the end of the initial treatment, were retreated with at least 1 additional cycle at a single center (2010-2020). Patient characteristics, treatment patterns, and clinical outcomes were evaluated descriptively. Response was evaluated according to RECIST 1.1; toxicity was defined using criteria from Common Terminology Criteria for Adverse Events, version 5.0. Kaplan-Meier plots were used to evaluate PFS and OS. Results: Of the 31 patients who received 177Lu-DOTATATE retreatment, 61% were male and 94% were White. Overall, patients received a median of 6 cycles (4 initial cycles and 2 retreatment cycles), and the mean administered activity was 41.9 GBq. Two patients also went on to receive additional retreatment (1 and 2 cycles, individually) after a second period of at least 6 mo and progression after retreatment. Best responses of partial response and stable disease were observed in 35% and 65% of patients after the initial treatment and 23% and 45% of patients after retreatment, respectively. The median PFS after the initial treatment was 20.2 mo and after retreatment was 9.6 mo. The median OS after the initial treatment was 42.6 mo and after retreatment was 12.6 mo. Hematologic parameters decreased significantly during both the initial treatment and retreatment but recovered such that there was little difference between the values before the initial treatment and before the retreatment. Clinically significant hematotoxicity occurred in 1 and 3 patients after the initial treatment and retreatment, respectively. No grade 3 or 4 nephrotoxicity was observed. Conclusion: Retreatment with 177Lu-DOTATATE after progression appeared to be well tolerated and offered disease control in patients with progressive NETs after initial 177Lu-DOTATATE treatment.

Revealing the Effect of Impacted Canines on the Adjacent Teeth. A Three Dimensional Study Using CBCT.

Objective: The current cross-sectional study aimed to assess the relationship between impacted maxillary canines and their effect on root resorption of neighboring teeth using cone-beam computed tomography (CBCT). Materials and Methods: The study evaluated the effect of 24 impacted maxillary canines on the adjacent tooth roots. We used a CBCT to evaluate the position and size of the dental follicle of impacted maxillary canines and the severity of root resorption on adjacent teeth. We used a t-test to compare the significant differences between the width of the dental follicle and the severity of root resorption. The inter- and intra-rater agreements were assessed. Results: A number of 12 impacted canines had resorbed the roots of adjacent teeth. Lateral incisors were most affected (83.3%), followed by central incisors (16.7%). Mild root resorption was found in 10 cases, while severe resorption was found in two cases. We found no relation between the size of the dental follicle and the degree of root resorption. The inter- and intra-rater agreements were high. Conclusion: In cases with maxillary impacted canines, special consideration should be directed to the roots of the maxillary lateral incisors. Our findings could not confirm any relationship between the size of the dental follicle width of the maxillary impacted canines and the degree of root resorption of the adjacent incisors. More studies are needed to assess the proximity and path of eruption of impacted maxillary canines and their effect on the neighboring teeth.

Fundamentals and Applications of Isolated Perfused Lung (IPL) Model in the Development of Pulmonary Drug Delivery.

Estimating parameters such as pulmonary drug disposition and deposited dose, as well as determining the influence of pulmonary pharmacokinetics (PK) on drug efficacy and safety, are critical factors for the development of inhaled drug products and help to achieve a better understanding of the drugs' fate in the lungs. Pulmonary disposition and PK have remained poorly understood due to the difficulty to access pulmonary fluids, compared to other biological fluids, such as plasma, for direct or surrogate measurement of the concentration of the active compounds and their metabolites in the lung. The use of the isolated perfused lung model (IPL) has become more common, and it is considered a useful tool to increase understanding in this area since it offers the possibility of controlling the administration and easier sampling of perfusate and lavage fluid. The model also provides an opportunity to study the relationship between PK and pharmacodynamics. This review describes the fundamentals of the IPL model, such as preparation and setting up the method, species selection, drug administration, and lung viability investigation. Besides, different applications of the IPL model like pharmacodynamic studies, pharmacokinetic parameters studies such as absorption, distribution, and metabolism, and evaluation of inhaled formulation have also been reviewed.

Do women exhibit greater differences in established and novel risk factors between diabetes and non-diabetes than men? The British Regional Heart Study and British Women's Heart Health Study.

AIMS/HYPOTHESIS: Type 2 diabetes is associated with greater relative risk of CHD in women than in men, which is not fully explained by conventional cardiovascular risk factors. We assessed whether cardiovascular risk factors including more novel factors such as markers of insulin resistance, inflammation, activated coagulation and endothelial dysfunction differ more between diabetic and non-diabetic women than between diabetic and non-diabetic men, and the role of insulin resistance. METHODS: A cross-sectional study of non-diabetic and diabetic men and women (n = 7,529) aged 60-79 years with no previous myocardial infarction who underwent an examination was conducted. Measurements of anthropometry, blood pressure and fasting measurements of lipids, insulin, glucose and haemostatic and inflammatory markers were taken. RESULTS: Non-diabetic women tended to have more favourable risk factors and were less insulin resistant than non-diabetic men, but this was diminished in the diabetic state. Levels of waist circumference, BMI, von Willebrand factor (VWF), WBC count, insulin resistance (HOMA-IR), diastolic blood pressure, HDL-cholesterol, tissue plasminogen activator (t-PA) and factor VIII differed more between diabetic and non-diabetic women than between diabetic and non-diabetic men (test for diabetes × sex interaction p < 0.05). The more adverse effect of diabetes on these risk markers in women was associated with, and thereby largely attenuated by, insulin resistance. CONCLUSIONS/INTERPRETATION: The greater adverse influence of diabetes per se on adiposity and HOMA-IR and downstream blood pressure, lipids, endothelial dysfunction and systemic inflammation in women compared with men may contribute to their greater relative risk of coronary heart disease.

Association analysis of 31 common polymorphisms with type 2 diabetes and its related traits in Indian sib pairs.

AIMS/HYPOTHESIS: Evaluation of the association of 31 common single nucleotide polymorphisms (SNPs) with fasting glucose, fasting insulin, HOMA-beta cell function (HOMA-ß), HOMA-insulin resistance (HOMA-IR) and type 2 diabetes in the Indian population. METHODS: We genotyped 3,089 sib pairs recruited in the Indian Migration Study from four cities in India (Lucknow, Nagpur, Hyderabad and Bangalore) for 31 SNPs in 24 genes previously associated with type 2 diabetes in European populations. We conducted within-sib-pair analysis for type 2 diabetes and its related quantitative traits. RESULTS: The risk-allele frequencies of all the SNPs were comparable with those reported in western populations. We demonstrated significant associations of CXCR4 (rs932206), CDKAL1 (rs7756992) and TCF7L2 (rs7903146, rs12255372) with fasting glucose, with ß values of 0.007 (p = 0.05), 0.01 (p = 0.01), 0.007 (p = 0.05), 0.01 (p = 0.003) and 0.08 (p = 0.01), respectively. Variants in NOTCH2 (rs10923931), TCF-2 (also known as HNF1B) (rs757210), ADAM30 (rs2641348) and CDKN2A/B (rs10811661) significantly predicted fasting insulin, with ß values of -0.06 (p = 0.04), 0.05 (p = 0.05), -0.08 (p = 0.01) and -0.08 (p = 0.02), respectively. For HOMA-IR, we detected associations with TCF-2, ADAM30 and CDKN2A/B, with ß values of 0.05 (p = 0.04), -0.07 (p = 0.03) and -0.08 (p = 0.02), respectively. We also found significant associations of ADAM30 (ß = -0.05; p = 0.01) and CDKN2A/B (ß = -0.05; p = 0.03) with HOMA-ß. THADA variant (rs7578597) was associated with type 2 diabetes (OR 1.5; 95% CI 1.04, 2.22; p = 0.03). CONCLUSIONS/INTERPRETATION: We validated the association of seven established loci with intermediate traits related to type 2 diabetes in an Indian population using a design resistant to population stratification.

Mannheim carotid intima-media thickness and plaque consensus (2004-2006-2011). An update on behalf of the advisory board of the 3rd, 4th and 5th watching the risk symposia, at the 13th, 15th and 20th European Stroke Conferences, Mannheim, Germany, 2004, Brussels, Belgium, 2006, and Hamburg, Germany, 2011.

Intima-media thickness (IMT) provides a surrogate end point of cardiovascular outcomes in clinical trials evaluating the efficacy of cardiovascular risk factor modification. Carotid artery plaque further adds to the cardiovascular risk assessment. It is defined as a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value or demonstrates a thickness >1.5 mm as measured from the media-adventitia interface to the intima-lumen interface. The scientific basis for use of IMT in clinical trials and practice includes ultrasound physics, technical and disease-related principles as well as best practice on the performance, interpretation and documentation of study results. Comparison of IMT results obtained from epidemiological and interventional studies around the world relies on harmonization on approaches to carotid image acquisition and analysis. This updated consensus document delineates further criteria to distinguish early atherosclerotic plaque formation from thickening of IMT. Standardized methods will foster homogenous data collection and analysis, improve the power of randomized clinical trials incorporating IMT and plaque measurements and facilitate the merging of large databases for meta-analyses. IMT results are applied to individual patients as an integrated assessment of cardiovascular risk factors. However, this document recommends against serial monitoring in individual patients.

Differences in consumption of food items between obese and normal-weight people in India.

BACKGROUND: There is a rising prevalence of obesity in India, and diet may be a major determinant of this. We aimed to assess differences in types and quantities of food items consumed by obese and normal-weight people in India. METHODS: Cross-sectional data of 7067 factory workers and their families were used from the Indian Migration Study, conducted in four cities across northern, central and southern India. Food frequency questionnaire data were used to compare the quantities of consumption of 184 food items between 287 obese (body mass index>30 kg/m2) and 1871 normalweight (body mass index 18.50-22.99 kg/m2) individuals, using t tests and ANCOVAs. Individuals with diabetes,hypertension and cardio-vascular disease were excluded. SPSS 16.0 was used for analysis. RESULTS: After adjusting for age, sex, location and socioeconomic status, obese individuals were found to eat significantly larger quantities of 11 food items compared with normalweight individuals. These included phulkas, chapatis/parathas/naan, plain dosa, mutton/chicken pulao/biryani, chicken fried/grilled, rasam, mixed vegetable sagu, vegetable raitha, honey,beetroot and bottlegourd (p< 0.01). Consumption of plain milk was higher among normal-weight than among obese individuals (p< 0.05). Consumption of some of these food items was also found to increase by socioeconomic status, decrease by age, and be higher among men relative to women. CONCLUSION: Obese individuals were found to consume larger quantities of certain food items compared with normal weight individuals. Interventions should aim at limiting overall food consumption among obese individuals.

Consumption of iodized salt among households of Basra city, south Iraq.

Progress towards universal salt iodization in Iraq is uncertain. A cross-sectional study with cluster sampling was carried out to investigate the sources and packaging of salt in 900 households in Basra and assess the knowledge and practice of household members regarding iodized salt and iodine deficiency disorders. Adequately iodized salt was found in only 68.3% of households. Salt from local sources was significantly less likely to be iodized than salt from imported sources (15.3% versus 86.9% had > or = 15 ppm). Salt in plastic packages was mostly adequately iodized (95.0%) compared with loose packages (70.3%). Most respondents had heard about iodized salt (92.6%), yet only 27.1% knew about the health benefits. Significantly more household members with university education had iodized salt in the household than those who were illiterate or only could read/write (82.0% versus 57.7%). Better monitoring of local salt supplies and more education to improve the population's awareness of iodization are needed.

One-step electrodeposition of a polypyrrole/NiO nanocomposite as a supercapacitor electrode.

An electrochemical deposition technique was used to fabricate polypyrrole (Ppy)/NiO nanocomposite electrodes for supercapacitors. The nanocomposite electrodes were characterized and investigated by Fourier transform infrared spectroscopy (FTIR), X-ray Diffraction (XRD), scanning electron microscopy (SEM), cyclic voltammetry (CV), galvanostatic charge-discharge (GCD) and electrochemical impedance spectroscopy (EIS). The performance of supercapacitor electrodes of Ppy/NiO nanocomposite was enhanced compared with pristine Ppy electrode. It was found that the Ppy/NiO electrode electrodeposited at 4 A/cm-2 demonstrated the highest specific capacitance of 679 Fg-1 at 1 Ag-1 with an energy density of 94.4 Wh kg-1 and power density of 500.74 W kg-1. Capacitance retention of 83.9% of its initial capacitance after 1000 cycles at 1 Ag-1 was obtained. The high electrochemical performance of Ppy/NiO was due to the synergistic effect of NiO and Ppy, where a rich pores network-like structure made the electrolyte ions more easily accessible for Faradic reactions. This work provided a simple approach for preparing organic-inorganic composite materials as high-performance electrode materials for electrochemical supercapacitors.

A smartphone-based portable fundus camera for retinal photography in infants with suspected nonaccidental trauma.

We describe a novel, do-it-yourself smartphone-based fundus camera to help with documentation of retinal hemorrhages in infant patients with suspected nonaccidental trauma. This device can be easily assembled from commercially available and inexpensive materials. We discuss the advantages and limitations of our described fundus camera and provide representative images.

Targeted α-Emitter Therapy with 212Pb-DOTAMTATE for the Treatment of Metastatic SSTR-Expressing Neuroendocrine Tumors: First-in-Humans Dose-Escalation Clinical Trial.

Peptide receptor radiotherapy with somatostatin analogs has been successfully used for years as a treatment for somatostatin-overexpressing tumors. Treatment of neuroendocrine tumors (NETs) with the ß-particle emitter 177Lu-DOTATATE is currently considered the standard of care for subjects with gastroenteropancreatic NETs. Despite the success of 177Lu-DOTATATE, there remains significant room for improvement in terms of both safety and efficacy. Targeted α-emitter therapy with isotopes such as 212Pb has the potential to improve both. Here, we present the preliminary results of the phase 1 first-in-humans dose-escalation trial evaluating 212Pb-DOTAMTATE (a bifunctional metal chelator [DOTAM] and the SSTR-targeting peptide [TATE]) in patients with somatostatin receptor-positive NETs. Methods: Twenty subjects with histologically confirmed NETs, prior positive somatostatin analog scans, and no prior history of 177Lu/90Y/111In peptide receptor radiotherapy, with different primary sites of the disease, were enrolled. Treatment began with single ascending doses of 212Pb-DOTAMTATE, with subsequent cohorts receiving an incremental 30% dose increase, which was continued until a tumor response or a dose-limiting toxicity was observed. This was followed by a multiple ascending dose regimen. The recommended phase 2 dose regimen consisted of 4 cycles of 2.50 MBq/kg (67.6 µCi/kg) of 212Pb-DOTAMTATE administered at 8-wk intervals, intravenously. Results: Ten subjects received the highest dose, 2.50 MBq/kg/cycle (67.6 µCi/kg/cycle). Treatment was well tolerated, with the most common treatment-emergent adverse events being nausea, fatigue, and alopecia. No serious treatment-emergent adverse events were related to the study drug, and no subjects required treatment delay or a dose reduction. An objective radiologic response of 80% was observed for the first 10 subjects treated at the recommended phase 2 dose. Conclusion: Targeted α-therapy with 212Pb-DOTAMTATE has been shown to be well tolerated. Preliminary efficacy results are highly promising. If these results are confirmed in a larger, multicenter clinical trial, 212Pb-DOTAMTATE would provide a substantial benefit over currently Food and Drug Administration-approved therapies for patients with metastatic or inoperable SSTR-expressing NETs regardless of the grade and location of the primary tumor.