In vivo evaluation of [(123)I]-3-(4-iodobenzyl)-1,2,3,4-tetrahydro-8-hydroxychromeno[3,4-c]pyridin-5-one: a presumed dopamine D4 receptor ligand for SPECT studies

[(123)I]-3-(4-iodobenzyl)-1,2,3,4-tetrahydro-8-hydroxychromeno[3,4-c]pyridin-5-one ([(123)I]-ITCP), a presumed radioligand for visualization of the dopamine D4 receptor by single photon emission computed tomography, was evaluated in vivo in mice and rabbits. This new radioiodinated tracer exhibited high brain uptake (3.64% injected dose per gram of tissue at 10 min p.i.) in mice. No significant amounts (less than 5%) of labeled metabolites were present in the brain, as demonstrated by a metabolite study. Regional brain distribution in rabbits showed atypical CNS uptake with consistently low values in the cortex and high values in other brain parts including cerebellum. Saturable binding was confirmed by a competition experiment with unlabeled product. Selectivity was assessed by competition experiments with a known dopamine D4 ligand and later with a sigma receptor ligand. Both experiments showed no observable competition. In conclusion, our findings indicate that [(123)I]-ITCP is neither a dopamine D4 receptor ligand nor a sigma receptor ligand. The exact nature of [(123)I]-ITCP binding in the brain remains to be elucidated.     

Association of antiviral prophylaxis and rituximab use with posttransplant lymphoproliferative disorders (PTLDs): A nationwide cohort study

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplantation (SOT). Most PTLD cases are associated with Epstein–Barr virus (EBV) infection. The role of antiviral prophylaxis or rituximab therapy for prevention of PTLD in SOT recipients is controversial. In a nationwide cohort, we assessed the incidence, presentation, and outcome of histologically proven PTLD. We included 4765 patients with a follow-up duration of 23 807 person-years (py). Fifty-seven PTLD cases were identified; 39 (68%) were EBV positive (EBV+ PTLD). Incidence rates for EBV+ PTLD at 1, 2, and 3 years posttransplant were 3.51, 2.24, and 1.75/1000 py and 0.44, 0.25, and 0.29/1000 py for EBV− PTLD. We did not find an effect of antiviral prophylaxis on early and late EBV+ PTLD occurrence (early EBV+ PTLD: SHR 0.535 [95% CI 0.199–1.436], p = .264; late EBV+ PTLD: SHR 2.213, [95% CI 0.751–6.521], p = .150). However, none of the patients (0/191) who received a rituximab-containing induction treatment experienced PTLD, but 57 of 4574 patients without rituximab induction developed PTLD. In an adjusted restricted mean survival time model, PTLD-free survival was significantly longer (0.104 years [95% CI 0.077–0.131]) in patients receiving rituximab as induction treatment. This study provides novel data on the association of rituximab induction and reduced risk for PTLD.     

Microsatellite and RAS/RAF Mutational Status as Prognostic Factors in Colorectal Peritoneal Metastases Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC)

Background

Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) leads to prolonged survival for selected patients with colorectal (CRC) peritoneal metastases (PM). This study aimed to analyze the prognostic role of micro-satellite (MS) status and RAS/RAF mutations for patients treated with CRS.

Methods

Data were collected from 13 Italian centers with PM expertise within a collaborative group of the Italian Society of Surgical Oncology. Clinical and pathologic variables and KRAS/NRAS/BRAF mutational and MS status were correlated with overall survival (OS) and disease-free survival (DFS).

Results

The study enrolled 437 patients treated with CRS-HIPEC. The median OS was 42.3 months [95% confidence interval (CI), 33.4–51.2 months], and the median DFS was 13.6 months (95% CI, 12.3–14.9 months). The local (peritoneal) DFS was 20.5 months (95% CI, 16.4–24.6 months). In addition to the known clinical factors, KRAS mutations (p = 0.005), BRAF mutations (p = 0.01), and MS status (p = 0.04) were related to survival. The KRAS- and BRAF-mutated patients had a shorter survival than the wild-type (WT) patients (5-year OS, 29.4% and 26.8% vs 51.5%, respectively). The patients with micro-satellite instability (MSI) had a longer survival than the patients with micro-satellite stability (MSS) (5-year OS, 58.3% vs 36.7%). The MSI/WT patients had the best prognosis. The MSS/WT and MSI/mutated patients had similar survivals, whereas the MSS/mutated patients showed the worst prognosis (5-year OS, 70.6%, 48.1%, 23.4%; p = 0.0001). In the multivariable analysis, OS was related to the Peritoneal Cancer Index [hazard ratio (HR), 1.05 per point], completeness of cytoreduction (CC) score (HR, 2.8), N status (HR, 1.6), signet-ring (HR, 2.4), MSI/WT (HR, 0.5), and MSS/WT-MSI/mutation (HR, 0.4). Similar results were obtained for DFS.

Conclusion

For patients affected by CRC-PM who are eligible for CRS, clinical and pathologic criteria need to be integrated with molecular features (KRAS/BRAF mutation). Micro-satellite status should be strongly considered because MSI confers a survival advantage over MSS, even for mutated patients.

     

Acquired Idiopathic Stiffness After Contemporary Total Knee Arthroplasty: Incidence,Risk Factors,and Results Over 25 Years

BackgroundAcquired idiopathic stiffness (AIS) remains a common failure mode of contemporary total knee arthroplasties (TKAs). The present study investigated the incidence of AIS and manipulation under anesthesia (MUA) at a single institution over time, determined outcomes of MUAs, and identified risk factors associated with AIS and MUA.MethodsWe identified 9771 patients (12,735 knees) who underwent primary TKAs with cemented, modular metal-backed, posterior-stabilized implants from 2000 to 2016 using our institutional total joint registry. Mean age was 68 years, 57% were female, and mean body mass index was 33 kg/m². Demographic, surgical, and comorbidity data were investigated via univariate Cox proportional hazard models and fit to an adjusted multivariate model to access risk for AIS and MUA. Mean follow-up was 7 years.ResultsDuring the study period, 456 knees (3.6%) developed AIS and 336 knees (2.6%) underwent MUA. Range of motion (ROM) increased a mean of 34° after the MUA; however, ROM for patients treated with MUA was inferior to patients without AIS at final follow-up (102° vs 116°, P < .0001). Significant risk factors included younger age (HR 2.3, P < .001), increased tourniquet time (HR 1.01, P < .001), general anesthesia (HR 1.3, P = .007), and diabetes (HR 1.5, P = .001).ConclusionAcquired idiopathic stiffness has continued to have an important adverse impact on the outcomes of a subset of patients undergoing primary TKAs. When utilized, MUA improved mean ROM by 34°, but patients treated with MUA still had decreased ROM compared to patients without AIS. Importantly, we identified several significant risk factors associated with AIS and subsequent MUA.Level of EvidenceLevel III, retrospective comparative study.     

Changes of concave and convex rib�Cvertebral angle, angle difference and angle ratio in patients with right thoracic adolescent idiopathic scoliosis

The aim of this study is to describe the radiological changes in rib–vertebral angles (RVAs), rib–vertebral angle differences (RVADs), and rib–vertebral angle ratios (RVARas) in patients with untreated right thoracic adolescent idiopathic scoliosis and to compare with the normal subjects. The concave and convex RVA from T1 to T12, the RVADs and the RVARas were measured on AP digital radiographs of 44 female patients with right convex idiopathic scoliosis and 14 normal females. Patients were divided into three groups: normal subjects (group 1), scoliotic patients with Cobb’s angle equal or <30° (group 2) and scoliotic patients with Cobb’s angle over 30° (group 3). Overall values (mean ± SD) of the RVAs on the concave side were 90.5° ± 17° in group 1, 90.3° ± 15.8° in group 2 and 88.8° ± 15.4° in group 3. On the convex side, values were 90.0° ± 17.3° in group 1, 86.3° ± 13.7° in group 2 and 80.7° ± 14.4° in group 3. Overall values (mean ± SD) of the RVADs at all levels were 0.5° ± 0.7° in group 1, 4.0° ± 4.8° in group 2 and 8.0° ± 4.0° in group 3. The RVARa values (mean ± SD) at all levels was 1.008° ± 0.012° in group 1, 1.041° ± 0.061° in group 2 and 1.102° ± 0.151° in group 3. RVAD and RVARa values in the scoliotic segment were greater in patients with untreated scoliosis over 30° than in patients with an untreated deformity of <30° or normal subjects. A significant effect between groups was observed for the RVA, RVAD and RVARa variables. Measurement of RVA, RVAD and RVARa should not only be performed at and around the apex of a thoracic spinal deformity, but also extended to the whole thoracic spine.     

Randomized Clinical Trial of 2-Incision vs Mini-Posterior Total Hip Arthroplasty: Differences Persist at 10 Years

Background

A previous randomized clinical trial at our institution demonstrated slower recovery of 35 2-incision total hip arthroplasties (THAs) when compared with 36 mini-posterior THAs at 2 years. The primary aim of the present study was to report concise 10-year follow-up results.

Analgesia for total hip and knee arthroplasty: a multimodal pathway featuring peripheral nerve block

Patients undergoing total hip and knee arthroplasty experience substantial and sustained postoperative pain. Inadequate analgesia may impede physical therapy and rehabilitative efforts and delay hospital dismissal. Traditionally, postoperative analgesia after total joint replacement was provided by either intravenous patient-controlled analgesia or epidural analgesia. Each, however, had disadvantages as well as advantages. Peripheral nerve blockade of the lumbosacral plexus has emerged as an alternative analgesic approach. In several studies, unilateral peripheral block provided a quality of analgesia and functional outcomes similar to those of continuous epidural analgesia and superior to those of systemic analgesia, but with fewer side effects because of their opioid-sparing properties. Peripheral nerve block techniques may be the optimal analgesic method following total joint arthroplasty.