Alpha-1 Antitrypsin Augmentation Therapy in Chronic Pancreatitis Patients Undergoing Total Pancreatectomy and Islet Autotransplantation: A Randomized, Controlled Study.

Stress-induced islet graft loss during the peri-transplantation period reduces the efficacy of islet transplantation. In this prospective, randomized, double-blind clinical trial, we evaluated the safety and efficacy of 60 mg/kg human alpha-1 antitrypsin (AAT) or placebo infusion weekly for four doses beginning before surgery in chronic pancreatitis (CP) patients undergoing total pancreatectomy and islet autotransplantation (TP-IAT). Subjects were followed for 12 months post-TP-IAT. The dose of AAT was safe, as there was no difference in the types and severity of adverse events in participants from both groups. There were some biochemical signals of treatment effect with a higher oxygen consumption rate in AAT islets before transplantation and a lower serum C-peptide (an indicator of islet death) in the AAT group at 15 min after islet infusion. Findings per the statistical analysis plan using a modified intention to treat analysis showed no difference in the C-peptide area under the curve (AUC) following a mixed meal tolerance test at 12 months post-TP-IAT. There was no difference in the secondary and exploratory outcomes. Although AAT therapy did not show improvement in C-peptide AUC in this study, AAT therapy is safe in CP patients and there are experiences gained on optimal clinical trial design in this challenging disease.

Diagnostic Positron Emission Tomography Imaging with Zirconium-89 Desferrioxamine B Squaramide: From Bench to Bedside.

ConspectusMolecular imaging with antibodies radiolabeled with positron-emitting radionuclides combines the affinity and selectivity of antibodies with the sensitivity of Positron Emission Tomography (PET). PET imaging allows the visualization and quantification of the biodistribution of the injected radiolabeled antibody, which can be used to characterize specific biological interactions in individual patients. This characterization can provide information about the engagement of the antibody with a molecular target such as receptors present in elevated levels in tumors as well as providing insight into the distribution and clearance of the antibody. Potential applications of clinical PET with radiolabeled antibodies include identifying patients for targeted therapies, characterization of heterogeneous disease, and monitoring treatment response.Antibodies often take several days to clear from the blood pool and localize in tumors, so PET imaging with radiolabeled antibodies requires the use of a radionuclide with a similar radioactive half-life. Zirconium-89 is a positron-emitting radionuclide that has a radioactive half-life of 78 h and relatively low positron emission energy that is well suited to radiolabeling antibodies. It is essential that the zirconium-89 radionuclide be attached to the antibody through chemistry that provides an agent that is stable in vivo with respect to the dissociation of the radionuclide without compromising the biological activity of the antibody.This Account focuses on our research using a simple derivative of the bacterial siderophore desferrioxamine (DFO) with a squaramide ester functional group, DFO-squaramide (DFOSq), to link the chelator to antibodies. In our work, we produce conjugates with an average ∼4 chelators per antibody, and this does not compromise the binding of the antibody to the target. The resulting antibody conjugates of DFOSq are stable and can be easily radiolabeled with zirconium-89 in high radiochemical yields and purity. Automated methods for the radiolabeling of DFOSq-antibody conjugates have been developed to support multicenter clinical trials. Evaluation of several DFOSq conjugates with antibodies and low molecular weight targeting agents in tumor mouse models gave PET images with high tumor uptake and low background. The promising preclinical results supported the translation of this chemistry to human clinical trials using two different radiolabeled antibodies. The potential clinical impact of these ongoing clinical trials is discussed.The use of DFOSq to radiolabel relatively low molecular weight targeting molecules, peptides, and peptide mimetics is also presented. Low molecular weight molecules typically clear the blood pool and accumulate in target tissue more rapidly than antibodies, so they are usually radiolabeled with positron-emitting radionuclides with shorter radioactive half-lives such as fluorine-18 (t1/2 ∼ 110 min) or gallium-68 (t1/2 ∼ 68 min). Radiolabeling peptides and peptide mimetics with zirconium-89, with its longer radioactive half-life (t1/2 = 78 h), could facilitate the centralized manufacture and distribution of radiolabeled tracers. In addition, the ability to image patients at later time points with zirconium-89 based agents (e.g. 4-24 h after injection) may also allow the delineation of small or low-uptake disease sites as the delayed imaging results in increased clearance of the tracer from nontarget tissue and lower background signal.

An Interpretive Description of Drug Withdrawal Among Pregnant Women in Jail.

OBJECTIVE: To explore the experience of drug withdrawal among pregnant women in jail. DESIGN: A qualitative interpretive descriptive approach. SETTING/PROBLEM: The care of incarcerated pregnant women constitutes a complex and significant public health problem. Many have substance use disorder (SUD) and cycle in and out of jails in their community, resulting in repeated experiences of drug withdrawal. Most jails do not provide medication-assisted therapy for management of withdrawal, a situation that violates standards of care set by leading health organizations. The experience of drug withdrawal among pregnant women in jail has not been qualitatively explored in the literature. PARTICIPANTS: Five women completed interviews for the study. INTERVENTION: In-depth, qualitative interviews. RESULTS: Five themes with subthemes emerged from the interviews: Framing the Story Through Life History: I Need You to Know Where I Come From, Patterns of Thinking About Substance Use, The Manifestations of Withdrawal: Body and Mind, Perceived Punishment for Drug Use During Pregnancy, and Mixed Perceptions of Withdrawal Treatment. CONCLUSION: Participants told a story beyond that of the physical withdrawal symptoms, revealing new insights into their maternal distress and the need for compassionate, nonstigmatized care to address physical and mental symptoms, as well as advocacy for the provision of an evidence-based standard of care. Nurses who care for pregnant women with SUD in the jail setting could benefit from collaborative relationships with other health care professionals in the community to reduce disparate health outcomes for this vulnerable population.

Tumor targeted alpha particle therapy with an actinium-225 labelled antibody for carbonic anhydrase IX.

Selective antibody targeted delivery of α particle emitting actinium-225 to tumors has significant therapeutic potential. This work highlights the design and synthesis of a new bifunctional macrocyclic diazacrown ether chelator, H2MacropaSqOEt, that can be conjugated to antibodies and forms stable complexes with actinium-225. The macrocyclic diazacrown ether chelator incorporates a linker comprised of a short polyethylene glycol fragment and a squaramide ester that allows selective reaction with lysine residues on antibodies to form stable vinylogous amide linkages. This new H2MacropaSqOEt chelator was used to modify a monoclonal antibody, girentuximab (hG250), that binds to carbonic anhydrase IX, an enzyme that is overexpressed on the surface of cancers such as clear cell renal cell carcinoma. This new antibody conjugate (H2MacropaSq-hG250) had an average chelator to antibody ratio of 4 : 1 and retained high affinity for carbonic anhydrase IX. H2MacropaSq-hG250 was radiolabeled quantitatively with [225Ac]AcIII within one minute at room temperature with micromolar concentrations of antibody and the radioactive complex is stable in human serum for >7 days. Evaluation of [225Ac]Ac(MacropaSq-hG250) in a mouse xenograft model, that overexpresses carbonic anhydrase IX, demonstrated a highly significant therapeutic response. It is likely that H2MacropaSqOEt could be used to modify other antibodies providing a readily adaptable platform for other actinium-225 based therapeutics.

Real-World Incidence and Severity of Hypertension Caused by Abiraterone Acetate in Patients With Metastatic Prostate Cancer.

BACKGROUND: Abiraterone acetate (AA) is used in treatment of patients with metastatic prostate cancer. Despite the survival advantage, AA is associated with hypertension due to mineralocorticoid excess syndrome. OBJECTIVE: We conducted a single-center retrospective analysis to evaluate the real-world incidence and severity of AA-induced hypertension. METHODS: Electronic health records were used to collect baseline characteristics and prostate cancer history. Patient data, including blood pressure at each 4 (±2)-week interval, were collected for 24 weeks after the initiation of AA therapy. The primary endpoint was the incidence and severity of AA-induced hypertension. The secondary endpoints include effect of different prednisone dosing regimens and prostate cancer types on hypertensive incidence and the impact of clinical pharmacists' involvement in managing AA-induced hypertension. RESULTS: A total of 142 patients who met our inclusion criteria received AA for metastatic prostate cancer, 73 (51.4%) with metastatic castration-resistant prostate cancer (mCRPC), and 69 (48.6%) with metastatic castration-sensitive prostate cancer (mCSPC). Of all, 43.7% experienced all-grade hypertension, and 28.2% experienced grade 3-4 hypertension. There was no difference in incidence of hypertension between patients receiving 5 mg of prednisone daily and those receiving 5 mg of prednisone twice daily. All-grade hypertension occurred in 39.7% of mCRPC and 47.8% of mCSPC patients (P = 0.33). Thirty-two percent of patients were actively managed by a clinical pharmacist and had an overall trend of reduced hypertension severity after 12 weeks. CONCLUSION AND RELEVANCE: This single-center, retrospective cohort study found that real-world metastatic prostate cancer patients who received AA had substantially higher incidence and severity of hypertension compared with clinical trials regardless of prednisone dose. In patients with mCRPC and mCSPC, the role of prednisone dose in hypertension incidence and severity warrants further investigation. Overall, results indicate the need for closely monitoring hypertension and optimization of anti-hypertensive therapy by multidisciplinary teams in metastatic prostate cancer patients receiving AA.

Use of Digital Health Resources by Sexual and Gender Minority Caregivers of Older Adults: Findings From the 2020 Caregiving in the U.S. Survey.

We applied Andersen's Behavioral Model of Health Services Use to investigate the health needs and use of digital health resources among sexual and/or gender minority (SGM) caregivers. Data were from the Caregiving in the U.S. 2020 survey. Regression analyses were used to describe associations between predisposing, enabling, and need factors and usage of digital health resources. SGM caregivers provided more hours of care per week, reported higher levels of care intensity, and reported higher physical, emotional, and financial strain compared with non-SGM caregivers. Regression analyses indicated SGM status was a significant predictor of overall use of digital health resources. Younger caregivers, racial minority caregivers, those providing higher levels of care, and those reporting a poorer health status were more likely to use digital health resources. Digital health resources may be useful tools for SGM caregivers of older adults. More research is needed to investigate the reasons SGM caregivers use these resources.

Update on Total Pancreatectomy With Islet Autotransplantation.

Total pancreatectomy with islet autotransplantation is a therapeutic option to effectively achieve pain relief and improvements in quality of life for selected patients with debilitating pain from chronic pancreatitis. The understanding of the best application and clinical execution of this procedure is in evolution, with outcomes studies and clinical trials in progress.

Theranostic Nuclear Medicine with Gallium-68, Lutetium-177, Copper-64/67, Actinium-225, and Lead-212/203 Radionuclides.

Molecular changes in malignant tissue can lead to an increase in the expression levels of various proteins or receptors that can be used to target the disease. In oncology, diagnostic imaging and radiotherapy of tumors is possible by attaching an appropriate radionuclide to molecules that selectively bind to these target proteins. The term "theranostics" describes the use of a diagnostic tool to predict the efficacy of a therapeutic option. Molecules radiolabeled with γ-emitting or ß+-emitting radionuclides can be used for diagnostic imaging using single photon emission computed tomography or positron emission tomography. Radionuclide therapy of disease sites is possible with either α-, ß-, or Auger-emitting radionuclides that induce irreversible damage to DNA. This Focus Review centers on the chemistry of theranostic approaches using metal radionuclides for imaging and therapy. The use of tracers that contain ß+-emitting gallium-68 and ß-emitting lutetium-177 will be discussed in the context of agents in clinical use for the diagnostic imaging and therapy of neuroendocrine tumors and prostate cancer. A particular emphasis is then placed on the chemistry involved in the development of theranostic approaches that use copper-64 for imaging and copper-67 for therapy with functionalized sarcophagine cage amine ligands. Targeted therapy with radionuclides that emit α particles has potential to be of particular use in late-stage disease where there are limited options, and the role of actinium-225 and lead-212 in this area is also discussed. Finally, we highlight the challenges that impede further adoption of radiotheranostic concepts while highlighting exciting opportunities and prospects.

Nutritional Risks in Patients Undergoing Total Pancreatectomy Islet AutoTransplantation in the POST Consortium.

BACKGROUND AND AIMS: Total pancreatectomy with islet autotransplantation (TPIAT) can relieve pain for individuals with acute recurrent or chronic pancreatitis. However, TPIAT may increase the risk of poor nutritional status with complete exocrine pancreatic insufficiency, partial duodenectomy, and intestinal reconstruction. Our study's objective was to evaluate nutritional status, anthropometrics, and vitamin levels before and after TPIAT. METHODS: The multicenter Prospective Observational Study of TPIAT (POST) collects measures including vitamins A, D, and E levels, pancreatic enzyme dose, and multivitamin (MVI) administration before and 1-year after TPIAT. Using these data, we studied nutritional and vitamin status before and after TPIAT. RESULTS: 348 TPIAT recipients were included (68% adult, 37% male, 93% Caucasian). In paired analyses at 1-year follow-up, vitamin A was low in 23% (vs 9% pre-TPIAT, p < 0.001); vitamin E was low in 11% (vs 5% pre-TPIAT, p = 0.066), and 19% had vitamin D deficiency (vs 12% pre-TPIAT, p = 0.035). Taking a fat-soluble multivitamin (pancreatic MVI) was associated with lower risk for vitamin D deficiency (p = 0.002). Adults were less likely to be on a pancreatic MVI at follow-up (34% vs 66% respectively, p < 0.001). Enzyme dosing was adequate. More adults versus children were overweight or underweight pre- and post-TPIAT. Underweight status was associated with vitamin A (p = 0.014) and E (p = 0.02) deficiency at follow-up. CONCLUSIONS: Prevalence of fat-soluble vitamin deficiencies increased after TPIAT, especially if underweight. We strongly advocate that all TPIAT recipients have close post-operative nutritional monitoring, including vitamin levels. Pancreatic MVIs should be given to minimize risk of developing deficiencies.

Fiber-reinforced composite full-arch prosthetic reconstructions supported by three standard, short or extra-short implants: a two-center retrospective study.

OBJECTIVES: To evaluate the survival of implants and prostheses, and marginal bone level of fiber-reinforced composite implant supported fixed complete prostheses supported by 3 implants. MATERIALS AND METHODS: Patients with fiber-reinforced composite fixed prostheses supported by 3 standard-length, short or extra-short implants were included in this retrospective cohort study. Kaplan-Meier survival was computed for implants and prostheses. Univariate and multivariate Cox proportional hazard regressions, clustered by patient, were used to analyze bone level differences as a function of different study covariates. Linear regressions were used to investigate the relationship between distal extension lengths and bone levels. RESULTS: Forty-five patients with 138 implants were followed for up to 10 years after prosthesis insertion (mean 52.8; SD 20.5 months). Kaplan-Meier survival analysis showed overall survival rates of 96.5% for implants and of 97.8% for prostheses. The 10-year success rate for prostheses was 90.8%. Extra-short implants survived at similar rates to short and standard implants. Marginal bone levels surrounding implants remained stable over time, even showing slight bone gain on average (mean + 0.1 mm/year; SD ± 0.5 mm/year) Acrylic denture teeth, overdentures on the opposing arch, and implant placement in the posterior maxilla were correlated with bone gain. Screw retention, opposed to telescopic retention, was correlated with bone loss. Longer distal extensions were correlated with bone gain on the implants closest to the distal extensions. CONCLUSIONS: Fiber-reinforced composite fixed prostheses supported by only 3 implants, most of which were extra-short, presented high survival rates with stable bone levels. CLINICAL RELEVANCE: An encouraging prognosis can be expected for restoration of atrophic maxillary and mandibular arches, when restored with fixed fiber-reinforced composite frameworks with long distal extensions and supported on only 3 short implants.

Dose Intensity in Real-World Patients With Metastatic Renal Cell Carcinoma Taking Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) that target the vascular endothelial growth factor receptor (VEGFR) are oral therapies used to treat metastatic renal cell carcinoma (mRCC). VEGFR TKI treatment is often complicated by dose-limiting adverse events (AE). We sought to describe dose intensity and clinical outcomes in a real-world cohort of patients treated with VEGFR TKIs to better characterize dosing patterns and toxicity management compared with previously reported clinical trials. MATERIALS AND METHODS: We conducted a retrospective chart review of sequential patients with mRCC treated with VEGFR TKIs at 1 academic medical center from 2014 to 2021. RESULTS: 139 patients (75% male, 75% white, median age 63 years) were treated with 185 VEGFR TKIs in our real-world cohort. Per International Metastatic RCC Database Consortium criteria, 24% had good risk, 54% intermediate risk, and 22% poor risk mRCC. With their first VEGFR TKI, median relative dose intensity (RDI) was 79%. 52% of patients required a dose reduction, 11% discontinued treatment due to AEs, 15% visited the ED, and 13% were hospitalized for treatment-related adverse events. Cabozantinib had the highest rate of dose reductions (72%) but a low rate of discontinuation (7%). Real-world patients consistently had lower RDI than reported clinical trials with more frequent dose reductions, fewer drug discontinuations, shorter progression-free survival, and shorter overall survival. CONCLUSION: Real-world patients were less able to tolerate VEGFR TKIs compared to patients treated on clinical trials. Low real-world RDI, high dose reductions, and low overall discontinuation rates can inform patient counseling prior to treatment initiation and during therapy.

Pre-targeting amyloid-ß with antibodies for potential molecular imaging of Alzheimer's disease.

With the aim of developing the concept of pretargeted click chemistry for the diagnosis of Alzheimer's disease two antibodies specific for amyloid-ß were modified to incorporate trans-cyclooctene functional groups. Two bis(thiosemicarbazone) compounds with pendant 1,2,4,5-tetrazine functional groups were prepared and radiolabelled with positron emitting copper-64. The new copper-64 complexes rapidly react with the trans-cyclooctene functionalized antibodies in a bioorthogonal click reaction and cross the blood-brain barrier in mice.

How research into healthcare staff use and non-use of e-books led to planning a joint approach to e-book policy and practice across UK and Ireland healthcare libraries.

The research goals were to obtain an understanding of who the users of e-books in the NHS are, what they are using e-books for, and when and how they use them. This article presents the methodology used and the findings from the research. It also explores the outputs and next steps from the research, both for the individual countries and collectively. The Five Nations group, (library leads in England, Northern Ireland, Ireland, Scotland and Wales) commissioned research into healthcare staff use and non-use of e-books to understand the behaviours, needs and expectations of healthcare staff and to identify shared challenges around e-books to inform policy and practice.

Giant clams as open-source, scalable reef environmental biomonitors.

Valvometry, the electronic measurement of bivalve shell opening and closing, has been demonstrated to be a valuable biomonitoring technique in previous ecological and environmental studies. Valvometric data has been shown to relate significantly to pollution, predation, animal stress and feeding activity. However, there is a need for valvometric techniques applicable to coral reef environments, which may provide critical insights into reef resilience to ocean warming and acidification. Giant clams are endemic to coral reefs and hold great promise as valvometric recorders of light availability, productivity and other environmental variables. Despite this promise, prior valvometric work on giant clams has been limited by specialized hardware less accessible to developing countries where many coral reefs are found. Here we report on an open-source approach that uses off-the-shelf components to monitor smooth giant clam (Tridacna derasa) valve opening behavior, and tests this approach in the simulated reef environment of the Biosphere 2 Ocean. Valvometric data corroborates the influence of light availability on diurnal behavior of giant clams. The clams basked during daylight hours to expose their photosymbionts to light, and adopted a partially-closed defensive posture at night. The animals showed variations in the frequency of complete closures, with most occurring during night-time hours when the animals prioritize filter-feeding activity, clapping their valves to expel pseudofeces from their gills. Closure frequency showed a significant relation to pH and a significant lagged relationship to chlorophyll-a productivity, which are both a function of algal productivity in the Biosphere 2 Ocean tank. These results suggest that the animals fed on phytoplankton following periodic bloom events in the Biosphere 2 Ocean during the experiment. We propose that giant clams exhibit behavioral plasticity between individuals and populations, and advocate for the more widespread use of valvometry to enable comparative studies of reef environment and animal health.

Balance effects of tactile stimulation at the foot.

Balance relies on several types of sensory information, including somatosensory senses such as touch and position sense (proprioception). As these senses decline in older adults, there is a question of whether shoes limit somatosensory feedback from the floor. Textured insoles are designed to stimulate the soles of the feet to enhance tactile feedback. Textured insoles have shown balance benefits in some populations, but it is unclear if such tactile stimulation improves a person's balance even in cushioned athletic shoes, which dampen proprioceptive signals. Here we ask whether tactile vs. proprioceptive cues contribute differently to balance control in the healthy somatosensory system. We assessed balance in 20 healthy young adults under four footwear conditions: cushioned shoes with regular insoles, cushioned shoes with textured insoles, barefoot, and minimalist shoes. Each condition was evaluated using the Y-Balance Test (YBT) and the Balance Error Scoring System (BESS), validated tests of dynamic and static balance, respectively. YBT is a dynamic reaching test performed on one leg. The BESS includes various stance conditions with eyes closed. The results showed that footwear influenced dynamic balance only, with textured insoles leading to significantly better performance than barefoot and minimalist shoes did in the YBT. These results suggest that at least for dynamic balance, balance benefits of tactile stimulation from the textured insoles offset any dampening of proprioception caused by the athletic shoes' cushioning. Future research on how these conditions compare in older adults may lead to improved footwear recommendations to reduce fall risk and injuries for that population.

Stem Cell Therapy Improves Human Islet Graft Survival in Mice via Regulation of Macrophages.

Islet/ß-cell transplantation offers great hope for patients with type 1 diabetes. We assessed the mechanisms of how intrahepatic coinfusion of human α-1 antitrypsin (hAAT)-engineered mesenchymal stromal cells (hAAT-MSCs) improves survival of human islet grafts posttransplantation (PT). Longitudinal in vivo bioluminescence imaging studies identified significantly more islets in the livers bearing islets cotransplanted with hAAT-MSCs compared with islets transplanted alone. In vitro mechanistic studies revealed that hAAT-MSCs inhibit macrophage migration and suppress IFN-γ-induced M1-like macrophages while promoting IL-4-induced M2-like macrophages. In vivo this translated to significantly reduced CD11c+ and F4/80+ cells and increased CD206+ cells around islets cotransplanted with hAAT-MSCs as identified by multiplex immunofluorescence staining. Recipient-derived F4/80+and CD11b+ macrophages were mainly present in the periphery of an islet, while CD11c+ and CD206+ cells appeared inside an islet. hAAT-MSCs inhibited macrophage migration and skewed the M1-like phenotype toward an M2 phenotype both in vitro and in vivo, which may have favored islet survival. These data provide evidence that hAAT-MSCs cotransplanted with islets remain in the liver and shift macrophages to a protective state that favors islet survival. This novel strategy may be used to enhance ß-cell survival during islet/ß-cell transplantation for the treatment of type 1 diabetes or other diseases.

A randomized controlled trial of emotion regulation therapy for cancer caregivers: A mechanism-targeted approach to addressing caregiver distress.

BACKGROUND: Caregivers of patients with cancer play a crucial role in the health of the person they care for, and in the healthcare system at large. Family caregivers receive minimal support, despite being at greater risk for anxiety and depression than patients themselves. Cognitive behavioral therapy (CBT), an effective therapy for anxiety and depression, has shown mixed efficacy when delivered to cancer caregivers. Emotion Regulation Therapy (ERT), a contemporary CBT, may uniquely target processes underlying distress associated with caregiving. Therefore, we adapted both CBT and ERT to target the needs of caregivers (i.e., CBT-C and ERT-C) and are conducting a multi-site randomized trial to examine the comparative efficacy of these interventions. METHODS: Family cancer caregivers (n = 200) reporting distress related to caregiving are recruited from two academic cancer centers and randomly assigned to either ERT-C or CBT-C. Caregivers in both interventions engage in eight weekly one-hour sessions by videoconference with a trained interventionist. Caregiver participants complete study assessments at baseline, post-treatment, 3-and 6-months follow-up. Patients of each caregiver can also enroll in the study and complete assessments at baseline and 3-months follow-up. Outcome measures include psychosocial constructs such as anxiety, depression, quality of life, as well as proposed mechanistic constructs and salivary markers of stress and inflammation. CONCLUSIONS: The results of this study will advance the science of caregiving interventions in cancer by addressing a critical gap in our ability to mitigate anxiety and depression in caregivers, as well as further our understanding of how these changes may influence patients' outcomes.

Response to Selpercatinib in a Patient With Recurrent Glioblastoma and RET Amplification.

Glioblastoma (GBM) is a malignant central nervous system neoplasm that remains largely incurable. Limited treatment options currently exist after disease progression on standard-of-care first-line therapy. However, repurposing the use of approved therapies in patients with potentially targetable genomic alterations continues to be an emerging area of interest. This report presents the first description of a patient with isocitrate dehydrogenase wild-type GBM with an underlying RET amplification who demonstrated a near-complete response while receiving therapy with the RET inhibitor selpercatinib. The case highlights the excellent blood-brain barrier penetration of selpercatinib, as well as its potential role in the management of RET-amplified GBM. Larger biomarker-enriched studies are needed to confirm the results of this case report. Given the rare incidence of RET alterations in GBM, findings from this report can help guide and support optimal treatment strategies for patients with RET-altered GBM.

Antiresorptive therapy and dental implant survival: an up to 20-year retrospective cohort study in women.

OBJECTIVES: To investigate the effects of antiresorptive treatment on the survival of plateau-root form dental implants. MATERIALS AND METHODS: Patients undergoing antiresorptive therapy via oral or intravenous administration as well as patients not undergoing antiresorptive therapy and healthy control patients were included in this retrospective cohort study. In total, 1472 implants placed in 631 postmenopausal patients (M: 66.42 ± 9.10 years old), who were followed for a period of up to 20 years (8.78 ± 5.68 years). Kaplan-Meier survival analysis was performed, and univariate and multivariate Cox regression, clustered by each patient, was used to evaluate and study factors affecting the survival of their implants. RESULTS: Implants placed in patients undergoing oral antiresorptive treatment presented significantly higher survival rates, than implants placed in the osteoporosis/osteopenia control cohort (p value < 0.001), and similar survival rates, when compared to healthy controls (p value = 0.03). Additionally, clustered univariate and multivariate Cox regression analysis also revealed higher implant survival when oral antiresorptive drugs (p value = 0.01 and 0.007, respectively) were used, and lower implant survival in the presence of untreated osteoporosis/osteopenia (p value = 0.002 and 0.005, respectively). Overall, the 20-year implant survival in osteoporotic patients undergoing antiresorptive therapy was 94%. For the failed implants, newly replaced implants in patients under antiresorptive treatment presented a 10-year survival of 89%. CONCLUSIONS: Long-term plateau-root form implant survival in osteoporotic patients taking oral antiresorptives was similar to a healthy population and significantly higher than the untreated controls. CLINICAL RELEVANCE: These results suggest that plateau-root form implants provide a robust solution for treating tooth loss in patients, who are undergoing antiresorptive therapy.