177Lu-DOTATATE PRRT Safety and Organ-at-Risk Dosimetry in Patients With Gastroenteropancreatic Neuroendocrine Tumors: Data From the Prospective Phase 2 LUMEN Study.

PURPOSE: The aim of this study was to assess the association among toxicity, dosimetry of organs-at-risk, and disease progression in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) treated with 177Lu-DOTATATE. PATIENTS AND METHODS: Thirty-seven patients with GEP-NETs underwent 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in a single-arm, prospective, phase 2 study, where patients were followed up with blood tests, isotopic glomerular filtration rate (iGFR), and imaging examinations (CT/MRI and PET) every 6 months until disease progression. Adverse events (AEs) graded per CTCAEv4.03 and occurring during treatment were collected and followed up until resolution. Dosimetry, including biologically effective doses (BEDs) to kidneys, BED to bone marrow, and absorbed dose (AD) to spleen, was performed after each PRRT cycle. Statistical analyses explored associations among dosimetry, toxicity, and patient progression free-survival. RESULTS: The most common AEs were anemia and lymphopenia (65%), followed by thrombocytopenia and fatigue (each 51%), alopecia (46%), and nausea (41%). The most common grade ≥3 AE was lymphopenia (43%). There was no grade ≥3 nephrotoxicity. The median iGFR % decrease was 11% (P < 0.001), at a median follow-up of 23 months. iGFR %decrease and renal BED did not correlate (Spearman ρ = -0.09). Similarly, no significant association was found between bone marrow BED or spleen AD and the grades of hematological toxicities. We observed no association between progression free-survival and either the decline of renal function or the occurrence of hematological toxicities during PRRT. CONCLUSIONS: This study confirms the safety profile of 177Lu-DOTATATE PRRT in patients with GEP-NETs irrespective of the dosimetry of organs at risk. Kidney, bone marrow, and spleen dosimetry measures were not associated with renal or hematological toxicity.

Prediction of 177Lu-DOTATATE PRRT Outcome Using Multimodality Imaging in Patients with Gastroenteropancreatic Neuroendocrine Tumors: Results from a Prospective Phase II LUMEN Study.

Our objective was to predict the outcome of peptide receptor radionuclide therapy (PRRT) using multimodality imaging and tumor dosimetry on gastroenteropancreatic neuroendocrine tumor (GEP-NET) lesions and patients. Methods: This prospective study included patients with progressive GEP-NETs. Treatment consisted of 4 cycles of 7.4 GBq of 177Lu-DOTATATE. Imaging parameters were measured on 68Ga-DOTATATE PET/CT (SUVmax/mean, somatostatin receptor [SSTR] tumor volume [TV], total lesion SSTR expression, and tumor-to-blood and tumor-to-spleen ratios), 18F-FDG PET/CT (SUVmax/mean, metabolically active TV, and total lesion glycolysis), and diffusion-weighted MRI (apparent diffusion coefficient) in a maximum of 5 target lesions per patient at approximately 10 wk after each injection. Tumor dosimetry was performed using SPECT/CT at 3 time points for every cycle. Baseline imaging parameters, their relative changes after PRRT cycle 1 (C1), and the tumor-absorbed dose at C1 were correlated with lesion morphologic outcome. The average values of the imaging parameters and the minimal, maximal, and mean C1 tumor-absorbed dose in each patient were tested for association with progression-free survival (PFS) and best objective response (RECIST 1.1). Results: In the 37 patients, the median PFS was 28 mo. Eleven of the 37 (30%) achieved a partial response (RECIST 1.1). After a median follow-up of 57 mo, the median time to lesion progression had not been reached in 84 morphologically evaluable lesions, with only 12 (14%) progressing (size increase ≥ 20% from baseline). Patients receiving a minimal C1 dose of 35 Gy in all target lesions exhibited a significantly longer PFS (48.1 vs. 26.2 mo; hazard ratio, 0.37; 95% CI, 0.17-0.82; P = 0.02). Volumetric 68Ga-DOTATATE PET parameters correlated with lesion and patient outcome: patients with an SSTR TV decrease of more than 10% after C1 had a longer PFS (51.3 vs. 22.8 mo; hazard ratio, 0.35; 95% CI, 0.16-0.75; P = 0.003). There was no statistical evidence of an association between other dosimetric or imaging parameters and the lesion or patient outcome. Conclusion: Minimal tumor-absorbed dose at C1 is predictive of outcome in patients with GEP-NETs treated with PRRT, providing a basis for personalized dosimetry-guided treatment strategies. An SSTR TV decrease after C1 could be used for early therapy response assessment as a predictor of PRRT outcome.

Antiosteoporosis therapy after discontinuation of menopausal hormone therapy: a systematic review.

OBJECTIVE: Menopausal hormone therapy (MHT) has consistently shown a bone protective effect by reducing the risk of vertebral, non-vertebral, and hip fractures in postmenopausal women regardless of baseline fracture risk. However, the optimal sequential treatment after MHT discontinuation has not been determined. This systematic review aimed to obtain the best evidence regarding the effect of antiresorptive or osteoanabolic treatment on bone mineral density (BMD) and/or fracture risk following MHT. METHODS: A comprehensive search was conducted in the PubMed, Scopus, and Cochrane databases up to October 31, 2023. Randomized-controlled trials (RCTs) and observational studies conducted in postmenopausal women were included. RESULTS: After the exclusion of duplicates, 717 studies were identified. Two were eligible for qualitative analysis, one RCT and one retrospective cohort study. The RCT showed that alendronate 10 mg/day for 12 months further increased lumbar spine (LS) BMD by 2.3% following MHT and maintained femoral neck (FN) BMD in postmenopausal women (n = 144). It also decreased bone anabolic and resorption markers by 47 and 36%, respectively. In the retrospective study (n = 34), raloxifene 60 mg/day increased both LS and FN BMD at 12 months by 3 and 2.9%, respectively. No fractures were reported. CONCLUSIONS: Antiresorptive therapy with either a bisphosphonate (i.e., alendronate) or raloxifene could be considered a sequential antiosteoporosis therapy after MHT withdrawal since they have been shown in studies to further increase BMD. However, no safe conclusions can be drawn from the existing literature.

Prevalence of morphometric vertebral fractures in osteoporotic patients in Greece: the Vertebral Integrity Assessment (VERTINAS) study.

Our purpose was to assess the prevalence of morphometric vertebral fractures (VFs) in osteoporotic patients in our country. We found that 25.4% of patients had sustained a VF, and the majority of them (76.6%) were undiagnosed prior to inclusion in this study. INTRODUCTION: We assessed the prevalence of morphometric vertebral fractures (VFs) in osteoporotic patients in our country. METHODS: Patients were recruited via announcements by the national media, their attending physicians or the National patients' Society. Inclusion criteria were (1) age > 50 years, (2) postmenopausal status > 2 years (women), (3) > 1-year use of medication for osteoporosis and (4) lack of radiological vertebral assessment for > 1 year. Exclusion criteria were (1) bone metabolic diseases other than osteoporosis, (2) patients with secondary osteoporosis, (3) patients with inability to stand/walk, (4) previous high-energy VFs. All patients performed lateral X-rays of the thoracic and lumbar spine that were evaluated separately both by certified radiologists on site as well as 3 consultant orthopaedic surgeons remotely through a specifically designed web database system. The Genant semi-quantitative method was used for the classification and grading of VFs and statistical analysis of the results was performed. RESULTS: One thousand six hundred fifty-two patients (1516 female, 70.02 ± 8.28 years; 136 male, 74.78 ± 8.25 years) were included in the final analysis. The prevalence of VFs was 25.4%, 76.6% of fractured patients were previously undiagnosed, and of these 39.9% had > 1 VFs. The most common fracture was T12, most fractures were found to be mild (grade 1) across all age groups, and patients 70-79 years and > 80 years were found to have a statistically significantly higher number of fractures than younger patients (p < 0.001). CONCLUSIONS: Our results of the high prevalence of morphometric VFs emphasise the need for baseline assessment of vertebral fragility in patients receiving treatment for osteoporosis, as well as follow-up radiographs at specified time periods while on therapy.

Factors associated with SARS-CoV-2 infection and outcome in patients with solid tumors or hematological malignancies: a single-center study.

BACKGROUND: Immunocompromised cancer patients are presumed to be at high risk of developing COVID-19 infection. Predisposing factors to contracting COVID-19 and to severe outcomes have been described in registries but were not compared between solid tumors and hematological malignancies. METHOD: This retrospective single oncologic center study included adults with solid tumors or hematological malignancies referred to testing by naso-pharyngeal swab for a SARS-CoV-2 RT-PCR from March 10 to May 18, 2020. RESULTS: A total of 212 patients were included in the study. Forty-five (21%) were tested positive with SARS-CoV-2. The univariate analysis with positive SARS-CoV-2 PCR as a dependent variable reveals significant odds ratios (ORs) for age-with a mean of 62.5 years-(OR: 1.05, 95% CI: 1.02-1.08), performance status ≥2 (OR: 2.38, 95% CI: 1.22-4.70), inpatient status (OR: 2.36, 95%CI: 1.11-4.91), and hematological malignancies (OR: 2.48, 95% CI: 1.23-4.96). In contrast, OR for solid tumors reveals a negative association (OR: 0.40, 95% CI: 0.20-0.81). When integrating severe outcome (ICU admission or COVID-19-related death) as a dependent variable, the univariate logistic regression model shows significant ORs for pre-existing lymphopenia (OR: 4.0, 95% CI: 1.17-15.04), hematological malignancies (OR: 3.73, 95% CI: 1.09-13.80), and a negative association for solid tumors (OR: 0.27; 95% CI: 0.07-0.92). CONCLUSION: In patients referred for SARS-CoV-2 testing, hematological malignancies were associated with a higher risk of COVID-19 infection and severe outcomes. Other factors were age and inpatient status.

A reporting and analysis framework for structured evaluation of COVID-19 clinical and imaging data.

The COVID-19 pandemic has worldwide individual and socioeconomic consequences. Chest computed tomography has been found to support diagnostics and disease monitoring. A standardized approach to generate, collect, analyze, and share clinical and imaging information in the highest quality possible is urgently needed. We developed systematic, computer-assisted and context-guided electronic data capture on the FDA-approved mint LesionTM software platform to enable cloud-based data collection and real-time analysis. The acquisition and annotation include radiological findings and radiomics performed directly on primary imaging data together with information from the patient history and clinical data. As proof of concept, anonymized data of 283 patients with either suspected or confirmed SARS-CoV-2 infection from eight European medical centers were aggregated in data analysis dashboards. Aggregated data were compared to key findings of landmark research literature. This concept has been chosen for use in the national COVID-19 response of the radiological departments of all university hospitals in Germany.

The 2018 Guidelines for the diagnosis and treatment of osteoporosis in Greece.

We report the updated guidelines for the management of osteoporosis in Greece, which include guidance on fracture risk assessment, diagnosis-pharmacological treatment-follow-up of osteoporosis based on updated information, and national evidence from Greek clinical practice and the healthcare setting. PURPOSE: The purpose of this report was to update the Guidelines for the Management of Osteoporosis in Greece that was published in 2011. METHODS: In line with the GRADE system, the working group initially defined the main clinical questions that should be addressed when dealing with the diagnosis and management of osteoporosis in clinical practice in Greece. Following a literature review and discussion on the experience gained from the implementation of the 2011 Guidelines transmitted through the national electronic prescription network, the Hellenic Society for the Study of Bone Metabolism (HSSBM) uploaded an initial draft for an open dialogue with the relevant registered medical societies and associations on the electronic platform of the Greek Ministry of Health. After revisions, the Central Health Council approved the final document. RESULTS: The 2018 Guidelines provide comprehensive recommendations on the issues of the timing of fracture risk evaluation and dual-energy X-ray absorptiometry (DXA) measurement, interpretation of the DXA results, the diagnostic work-up for osteoporosis, the timing as well as the suggested medications for osteoporosis treatment, and the follow-up methodology employed during osteoporosis treatment. CONCLUSIONS: These updated guidelines were designed to offer valid guidance on fracture risk assessment, diagnosis-pharmacological treatment-follow-up of osteoporosis based on updated information and national evidence from clinical practice and the healthcare setting. Clinical judgment is essential in the management of every individual patient for the purpose of achieving the optimal outcome in the safest possible way.

Quantitative DCE-MRI for prediction of pathological complete response following neoadjuvant treatment for locally advanced breast cancer: the impact of breast cancer subtypes on the diagnostic accuracy.

OBJECTIVES: To assess whether DCE-MRI pharmacokinetic (PK) parameters obtained before and during chemotherapy can predict pathological complete response (pCR) differently for different breast cancer groups. METHODS: Eighty-four patients who received neoadjuvant chemotherapy for locally advanced breast cancer were retrospectively included. All patients underwent two DCE-MRI examinations, one before (EX1) and one during treatment (EX2). Tumours were classified into different breast cancer groups, namely triple negative (TNBC), HER2+ and ER+/HER2-, and compared with the whole population (WP). PK parameters Ktrans and Ve were extracted using a two-compartment Tofts model. RESULTS: At EX1, Ktrans predicted pCR for WP and TNBC. At EX2, maximum diameter (Dmax) predicted pCR for WP and ER+/HER2-. Both PK parameters predicted pCR in WP and TNBC and only Ktrans for the HER2+. pCR was predicted from relative difference (EX1 - EX2)/EX1 of Dmax and both PK parameters in the WP group and only for Ve in the TNBC group. No PK parameter could predict response for ER+/HER-. ROC comparison between WP and breast cancer groups showed higher but not statistically significant values for TNBC for the prediction of pCR CONCLUSIONS: Quantitative DCE-MRI can better predict pCR after neoadjuvant treatment for TNBC but not for the ER+/HER2- group. KEY POINTS: • DCE-MRI-derived pharmacokinetic parameters can predict response status of neoadjuvant chemotherapy treatment. • Ktrans can better predict pCR for the triple negative group. • No pharmacokinetic parameter could predict response for the ER+/HER2- group.

Impact on bone and muscle area after spinal cord injury.

Spinal cord injury (SCI) causes inactivation and consequent unloading of affected skeletal muscle and bone. This cross-sectional study investigated correlations of muscle and bone in spinal cord-injured subjects compared with able-bodied subjects. Thirty-one complete SCI paraplegics were divided according to the neurological level of injury (NLoI) into group A (n=16, above thoracic 7 NLoI, age: 33±16 years, duration of paralysis (DoP): 6±6 years) and group B (n=15, thoracic 8-12, age: 39±14 years, DoP: 5.6±6 years), compared with 33 controls (group C). All were examined with peripheral quantitative computed tomography at 66% of tibia length (bone and muscle area, bone/muscle area ratio). In able-bodied subjects, muscle area was correlated with bone area (P<0.001, r=0.88). Groups A and B differed significantly from the control group in terms of bone and muscle area (P<0.001). In paraplegics, less muscle per unit of bone area (bone/muscle area ratio) was found compared with controls (P<0.001). Bone area was negatively correlated with the DoP in the total paraplegic group (r=-0.66, P<0.001) and groups A and B (r=-0.77, P=0.001 vs r=-0.52, P=0.12, respectively). Muscle area and bone/muscle ratio area correlations in paraplegic groups with DoP were weak. Paraplegic subjects who performed standing and therapeutic walking had significantly higher bone area (P=0.02 and P=0.013, respectively). The relationship between bone and muscle was consistent in able-bodied subjects and it was predictably altered in those with SCI, a clinical disease affecting bone and muscle.

Strontium ranelate improves delayed healing of osteolytic lesions of the jaw in a man with chronic osteomyelitis. Case report.

We report the case of a man with osteolytic lesions of the right mandible due to chronic osteomyelitis, with delayed healing after six months of antibiotic therapy. The patient received off-label therapy with strontium ranelate, with significant radiological improvement of his condition after 3 months.

Postoperative spinal infection mimicking systemic vasculitis with titanium-spinal implants.

BACKGROUND: Secondary systemic vasculitis after posterior spinal fusion surgery is rare. It is usually related to over-reaction of immune-system, to genetic factors, toxicity, infection or metal allergies. CASE DESCRIPTION: A 14 year-old girl with a history of extended posterior spinal fusion due to idiopathic scoliosis presented to our department with diffuse erythema and nephritis (macroscopic hemuresis and proteinuria) 5 months post surgery. The surgical trauma had no signs of inflammation or infection. The blood markers ESR and CRP were increased. Skin tests were positive for nickel allergy, which is a content of titanium alloy. The patient received corticosteroids systematically (hydrocortisone 10 mg) for 6 months, leading to total recess of skin and systemic reaction. However, a palpable mass close to the surgical wound raised the suspicion of a late infection. The patient had a second surgery consisting of surgical debridement and one stage revision of posterior spinal instrumentation. Intraoperative cultures were positive to Staphylococcus aureus. Intravenous antibiotics were administered. The patient is now free of symptoms 24 months post revision surgery without any signs of recurrence of either vasculitis or infection. LITERATURE REVIEW: Systemic vasculitis after spinal surgery is exceptionally rare. Causative factors are broad and sometimes controversial. In general, it is associated with allergy to metal ions. This is usually addressed with metal on metal total hip bearings. In spinal surgery, titanium implants are considered to be inert and only few reports have presented cases with systemic vasculitides. Therefore, other etiologies of immune over-reaction should always be considered, such as drug toxicity, infection, or genetic predisposition. PURPOSES AND CLINICAL RELEVANCE: Our purpose was to highlight the difficulties during the diagnostic work-up for systemic vasculitis and management in cases of posterior spinal surgery.

Age-related differences of bone mass, geometry, and strength in treatment-naïve postmenopausal women. A tibia pQCT study.

Most studies addressing the effects of aging on bone strength have focused mainly on (areal) bone mineral densities and bone mineral content (BMC) and less on bone geometry. We assessed age-related differences of bone mass (grams of bone mineral), geometry, and derived strength in 219 treatment-naïve postmenopausal women using peripheral quantitative computed tomography of the load-bearing tibia. Subjects were separated in 3 age groups: A=48-59yr (N=80), B=60-69yr (N=84), C=70-80yr (N=55). Three slices were obtained for each individual, at the 4% (trabecular), 14% (subcortical and cortical), and 38% (cortical bone) of tibia length sites. Trabecular, subcortical, and cortical BMC (mg per 1-mm slice), volumetric bone mineral densities (mg/cm(3)), bone cross-sectional areas (mm(2)), periosteal (PERI_C, mm) and endosteal circumference (ENDO_C, mm), mean cortical thickness (CRT_THK, mm), and Stress Strain Indexes (SSIs, mm(3)) were studied. Trabecular and cortical BMC and volumetric densities were significantly lower in the elder subjects (group C) compared with younger subjects (groups A and B), p<0.0005. Cortical area and CRT_THK were significantly lower in group C (vs A and B, p<0.0005), whereas total cross-sectional area was higher in group C compared with A and B. ENDO_C was significantly higher in older subjects (group C vs A and B, p<0.0005), whereas PERI_C did not differ significantly between the age groups. SSIs were significantly lower in older subjects at the 14% site (group C vs A, p<0.0005 and C vs B, p<0.005), and at the 38% site (group C vs group A, p<0.01). Our results indicate that age-induced differences on bone strength entail significant alterations not only of bone mass, but also of bone geometry.

CT-guided fiducial placement for cyberknife stereotactic radiosurgery: an initial experience.

CyberKnife frameless image-guided radiosurgery has become a widely used system for parenchymal extracranial lesions. Gold fiducials are required for the planning and aiming of CyberKnife therapy. We report our initial experience and describe the technique of positioning tumor markers, under CT guidance. We conducted a retrospective review of 105 patients who were referred for CyberKnife stereotactic radiosurgery at Iatropolis CyberKnife Center in Athens. All patients underwent percutaneous fiducial placement via CT guidance. At the desired location, the 18-G needle was advanced into or near the tumor. Data collected included number and locations of fiducials placed and complications experienced to date. One hundred five patients underwent fiducial placement under CT guidance and a total number of 319 gold seeds were implanted. We experienced one episode of pneumothorax that required drainage, one mild pneumothorax, and three episodes of perifocal pulmonary hemorrhage. In conclusion, fiducial implantation under CT guidance appears to be a safe and efficient procedure, as long as it is performed by an experienced interventional radiologist.