Selective Sparing Research Articles

Delayed Surgical Reversal of Optic Nerve Compression Leads to Exponential Degeneration of Optic Nerve Fibers and Selective Sparing of the Small Fibers.

To evaluate the effectiveness of surgical reversal of experimental optic nerve compression in treating persistent compressive optic neuropathy and to explore the relationship between surgical outcomes and the timing of the procedure. Surgical reversal procedures (decompression surgery) were conducted at five time intervals: 1, 3, and 7 days and 2 and 3 weeks following optic nerve compression in a rabbit model. The groups were labeled as DC-1d, DC-3d, DC-7d, DC-2w, and DC-3w, respectively. The study investigated changes in ganglion cell complex (GCC) thickness using spectral-domain optical coherence tomography and the percentage of surviving retinal ganglion cells (RGCs) through immunofluorescence staining and optic nerve axons stained with p-phenylenediamine at 4 weeks after decompression. Additionally, the area distribution of surviving axons was analyzed. The decline in GCC thickness was halted following decompression. The remaining thickness of the GCC in group DC-1d was found to be statistically significantly higher at 2, 3, and 4 weeks postonset compared to the no-decompression group. Similarly, GCC thickness in group DC-3d was significantly higher at 3 and 4 weeks postonset. The percentage of surviving RGCs and axons at 4 weeks postonset exhibited an exponential correlation with the onset time of decompression, with R2 values of 0.72 and 0.78, respectively. The surviving axon area declined following delayed decompression. Persistent substantial compression on the optic nerve leads to exponential degeneration of the optic nerve, initially affecting larger optic nerve fibers. Early intervention aimed at relieving the compression on the optic nerve may offer potential benefits in mitigating the degenerative effects and conserving visual function.

An Algorithmic Approach to MR Imaging of Hypomyelinating Leukodystrophies.

Hypomyelinating leukodystrophies (HLDs) are a heterogeneous group of white matter diseases characterized by permanent deficiency of myelin deposition in brain. MRI is instrumental in the diagnosis and recommending genetic analysis, and is especially useful as many patients have a considerable clinical overlap, with the primary presenting complains being global developmental delay with psychomotor regression. Hypomyelination is defined as deficient myelination on two successive MR scans, taken at least 6 months apart, one of which should have been obtained after 1 year of age. Due to subtle differences in MRI features, the need for a systematic imaging approach to diagnose and classify hypomyelinating disorders is reiterated. The presented article provides an explicit review of imaging features of a myriad of primary and secondary HLDs, using state of the art genetically proven MR cases. A systematic pattern-based approach using MR features and specific clinical clues is illustrated for a quick yet optimal diagnosis of common as well as rare hypomyelinating disorders. The major MR features helping to narrow the differential diagnosis include extent of involvement like diffuse or patchy hypomyelination with selective involvement or sparing of certain white matter structures like optic radiations, median lemniscus, posterior limb of internal capsule and periventricular white matter; cerebellar atrophy; brainstem, corpus callosal or basal ganglia involvement; T2 hypointense signal of the thalami; and presence of calcifications. The authors also discuss the genetic and pathophysiologic basis of HLDs and recent methods to quantify myelin in vivo using advanced neuroradiology tools. The proposed algorithmic approach provides an improved understanding of these rare yet important disorders, enhancing diagnostic precision and improving patient outcomes. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 5.

Preclinical Evaluation of INCB160058 - a Novel and Potentially Disease-Modifying Therapy for JAK2V617F Mutant Myeloproliferative Neoplasms

The Janus kinase 2 ( JAK2) mutation, JAK2V617F, is the most common oncogenic driver in myeloproliferative neoplasms (MPNs), with nearly all cases of polycythemia vera (PV) and over half of primary myelofibrosis (MF) and essential thrombocythemia (ET) patients positive for the somatic mutation. Approved therapies for MPNs such as ruxolitinib, which act by directly inhibiting activity of the kinase domain (JH1) of JAK2, have demonstrated impressive clinical efficacy and safety in patients with MPNs; however, they do not address JAK2V617F allelic burden or achieve molecular remission of disease. A targeted JAK2V617F selective agent sparing wild-type (WT) JAK2 activity has potential to eliminate mutant cells, induce molecular remission, and theoretically lead to functional cure of MPNs. We report herein the preclinical development of pseudokinase (JH2)-targeting INCB160058, a first-in-class, orally bioavailable small molecule with the ability to selectively target JAK2V617F + cell populations derived from patients with JAK-mutant MPNs. Using structure- and function-guided molecular design, INCB160058 was designed to bind with picomolar affinity to the JH2 domain of JAK2V617F at the canonical ATP-binding site, with high specificity (>2500-fold) relative to binding at the active kinase domain (JH1) targeted by currently approved JAK inhibitors. Live cell single-molecule fluorescence microscopy showed that INCB160058 binding to JAK2V617F blocked ligand-independent thrombopoietin receptor dimerization induced by the mutation, and consequently led to loss of JH1 domain kinase activity. X-ray crystallography analysis indicates that the observed inhibition is likely driven by conformational disruption of the ⍺C helix motif at Phe 594 and Phe 595 in conjunction with a shift of the upstream region from Leu 583 to Asn 589 upon INCB160058 binding to the JH2 domain of JAK2V617F. We utilized both CD34 + human multipotent hematopoietic stem cells derived from patients with JAK2-mutant MF, engineered JAK2-mutant human hematopoietic cancer cell lines (eg, SET2 and UKE-1), and murine BA/F3 cell lines to explore the selective effects of INCB160058 on JAK2V617F compared with WT JAK2. INCB160058 treatment selectively reduced pathogenic phospho-STAT5 levels, decreased abnormal megakaryopoiesis, and suppressed colony formation only in JAK2V617F + CD34 + cells but not in CD34 + cells from healthy volunteers. Importantly, continuous exposure of mutant and WT JAK2 cells to INCB160058 in co-cultures at concentrations below IC 50 resulted in progressive elimination of JAK2V617F + cells without affecting WT cells. At the end of the testing period, the JAK2V617F-harboring population was no longer detectable in the co-culture assay. In NSG mice subcutaneously inoculated with JAK2V617F-expressing SET2 cells, INCB160058 was tolerated and exhibited significant antitumor activity. In addition, following INCB160058 treatment, a significant reduction in the engraftment of total human cells, particularly human erythroid progenitors (hCD45 − mCD45 − Ter119 − hCD71 + hCD235a +), was observed in NSGS mice xenotransplanted with JAK2V617F + CD34 + cells. Moreover, INCB160058 treatment also led to the normalization of various pathogenic cytokines, such as interleukin (IL)-6 and IL-8. Importantly, these observations were absent in NSGS mice engrafted with CD34 + cells from healthy volunteers following INCB160058 treatment, further demonstrating the selectivity of INCB160058 for JAK2V617F. In summary, our results indicate a novel mechanism of action of INCB160058, a high-affinity pseudokinase (JH2) binding inhibitor of JAK2V617F that blocks cytokine-independent activity of JAK2V617F while preserving cytokine-dependent signaling. Extended treatment with INCB160058 at low therapeutic doses results in the specific elimination of mutant JAK2V617F-harboring cells in mouse models and human cancer cells with minimal impact on WT counterparts. Clinical testing of INCB160058 may allow patients with MPNs to achieve molecular remission by eliminating cells with the main genetic aberration and afford an opportunity to overcome the disease.

2375P Neoadjuvant sintilimab combined with gemcitabine and cisplatin (GP) for muscle-invasive bladder cancer (MIBC) patients followed by selective bladder sparing surgery

2375P Neoadjuvant sintilimab combined with gemcitabine and cisplatin (GP) for muscle-invasive bladder cancer (MIBC) patients followed by selective bladder sparing surgery

Evaluation of Observer Variation as Natural Experiment to Detect Sensitive Heart Subregions

There is growing evidence associating dose to the base of the heart to reduced survival of lung cancer patients (McWilliam EJC 2017). However, randomized evidence on the benefits of sparing the base of the heart is missing. In this study we investigate variability in the shape between patients of heart contours used in planning as a natural experiment to evaluate selective heart sparing. The core assumption is that regions that are not included in the heart delineation will not be spared. Data was collected for 1705 lung cancer patients treated in one center between 2010 and 2016 with IMRT/VMAT (55-66Gy in 20-33#) or SABR (54-60Gy in 3-8#), planned using manual heart contours, called delineation 1. Consistent reference heart contours were obtained using a commercial autocontouring software, called delineation 2. Heart shapes were mapped to spherical coordinates (φ, Φ, r) and the difference in radius Δr = r1 - r2 for each set of angles φ, Φ was calculated for all patients. A large Δr means that the manual delineation use for planning is relatively large in the direction. Cox-regression was performed for each set of angles using Δr, r2 and its interaction using overall survival as endpoint. Permutation testing is used to avoid multiple testing issues. The aim is to locate a region of the heart where bigger delineations lead to better sparing and hence better survival. On average the heart base in our manual contours extends 34 mm more superior than automatic contours, because our protocol stipulates the inclusion of the full pericardial sac. Δr was not correlated with any clinical variables and is therefore a good candidate as instrumental variable in causal inference. Univariable Cox regression of Δr showed a uniform worsening of survival with larger manual delineations, likely due to reduced overall sparing given the use of volumetric dose constraints. After including the interaction with r2, no significant heart regions were found. However, analysis using the overall volume of the manual and auto-delineated heart did show a small but significant interaction effect where larger manual delineations improved outcome for smaller hearts. Our interpretation is that delineation variability relative to autocontouring (e.g., 1.9 mm SD at right atrium, up to 15 mm SD at apex) is not big enough to impact significantly on the heart dose and therewith survival because volumetric costs functions are used. In the future we will extend this analysis to include planned dose. Variability in contouring in our cohort is not large enough to be used as a natural experiment to test the impact of selective heart sparing. However, larger volume delineations of small hearts are associated with reduced mortality, suggesting the importance of sparing the base of the heart where most contouring variability occurs.

Clinical Characterization of a Novel Robotic IORT Unit

A novel mobile robotically-guided low-energy intra-operative radiation therapy device was characterized for clinical use. The compact system offers flexible positioning with treatment delivery up to 70 kV energy and 10 Gy/min dose rate with radially collimated emission, and underwent characterization for its dosimetric performance, positioning accuracy and overall clinical suitability. The Morpheus system (Empyrean Medical Systems) consists of a miniature electron esource and a partitioned partial-transmission tungsten target capable of producing 50, 60, and 70 kVp x-rays, mounted on a robotic arm and supported by a motorized mobile base. The radially collimated beam is partitioned in six segments with three radial positions per segment for selective emission, target irradiation and tissue sparing. The beam characteristics were assessed with ion chamber and film dosimetry, both in-air and in a water tank. Radiation levels were assessed for safety and shielding requirements. The absolute dose rate at the surface of a 2 cm radius sterilizable treatment balloon is 8 Gy/min for the 70 kV beam using the AAPM TG-61 formalism. The six treatments sectors emit radially in 60 degrees wedges to within +/- 15% of each other, which can be simply corrected for treatment delivery. The dose falls off to 50% of its initial value within 8 mm from the surface of a treatment balloon for a 70 kV beam. The robotic arm enables a free-hand positioning of the X-ray treatment head to within 1 mm. All interlocks and sterility requirements for operation within an operating room environment were found to be satisfactory. Radiation levels require mobile shielding or a shielded room to be within permissible public radiation levels. The clinical characterization shows the new unit provides a stable and flexible beam delivery platform suitable for IORT treatments. The simplified docking and collimated beam emission provides enhanced capabilities for patient treatment.

Selective sparing of bladder and rectum sub-regions in radiotherapy of prostate cancer combining knowledge-based automatic planning and multicriteria optimization

Background and PurposeThe association between dose to selected bladder and rectum symptom-related sub-regions (SRS) and late toxicity after prostate cancer radiotherapy has been evidenced by voxel-wise analyses. The aim of the current study was to explore the feasibility of combining knowledge-based (KB) and multi-criteria optimization (MCO) to spare SRSs without compromising planning target volume (PTV) dose delivery, including pelvic-node irradiation. Materials and MethodsForty-five previously treated patients (74.2 Gy/28fr) were selected and SRSs (in the bladder, associated with late dysuria/hematuria/retention; in the rectum, associated with bleeding) were generated using deformable registration. A KB model was used to obtain clinically suitable plans (KB-plan). KB-plans were further optimized using MCO, aiming to reduce dose to the SRSs while safeguarding target dose coverage, homogeneity and avoiding worsening dose volume histograms of the whole bladder, rectum and other organs at risk. The resulting MCO-generated plans were examined to identify the best-compromise plan (KB + MCO-plan). ResultsThe mean SRS dose decreased in almost all patients for each SRS. D1% also decreased in the large majority, less frequently for dysuria/bleeding SRS. Mean differences were statistically significant (p < 0.05) and ranged between 1.3 and 2.2 Gy with maximum reduction of mean dose up to 3–5 Gy for the four SRSs. The better sparing of SRSs was obtained without compromising PTVs coverage. ConclusionsSelectively sparing SRSs without compromising PTV coverage is feasible and has the potential to reduce toxicities in prostate cancer radiotherapy. Further investigation to better quantify the expected risk reduction of late toxicities is warranted.

Conventional versus oblique fiber-sparing endoscopic myotomy for achalasia cardia: a randomized controlled trial (with videos)

GERD is common after peroral endoscopic myotomy (POEM). Selective sparing of oblique fibers may reduce the incidence of reflux esophagitis after POEM. In this study, we compared the incidence of GERD between conventional myotomy (CM) versus oblique fiber-sparing (OFS) myotomy in patients with achalasia. Eligible patients with type I and II achalasia who underwent POEM from January 2020 to October 2020 were randomized into 2 groups (CM and OFS myotomy). Exclusion criteria were type III achalasia, sigmoid esophagus, and history of Heller's myotomy. The primary study outcome was incidence of reflux esophagitis (at least grade B) in the 2 groups. Secondary outcomes were reflux symptoms, esophageal acid exposure, clinical success, and adverse events. One hundred fifteen patients were randomized into CM (n= 58) and OFS myotomy (n= 57) groups. POEM was technically successful in all patients. Overall, reflux esophagitis was found in 56 patients (48.7%). The incidence of at least grade B esophagitis was similar in both groups (CM vs OFS myotomy: 25.9% vs 31.6%, P= .541). The mean number of reflux episodes (48.2 ± 36.6 vs 48.9 ± 40.3, P= .933), increased esophageal acid exposure >6% (45.5% vs 31.7%, P= .266), and high DeMeester scores (38.6% vs 41.5%, P= .827) were similar in both groups. There was no difference in the rate of symptomatic reflux (GERD questionnaire score >7) or use of proton pump inhibitors at 1 year. Sparing of sling fibers has no significant impact on the incidence of significant reflux esophagitis after POEM. Novel strategies need to be explored to prevent reflux after POEM. (Clinical trial registration number: NCT04229342.).

Emerging phase 1 data of BLU-451 in advanced NSCLC with EGFR exon 20 insertions.

9064 Background: In patients (pts) with NSCLC harboring EGFR exon 20 insertions (ex20ins), treatment options are limited, with platinum-based chemotherapy with/without programmed death-ligand 1 inhibitors being the standard of care in first line, and recent accelerated approvals of mobocertinib and amivantamab in the USA for second-line treatment. These second-line therapies have overall response rates of 28% and 40%, respectively, limited CNS activity, and are associated with AEs such as severe gastrointestinal AEs and edema. BLU-451 is an investigational, CNS-penetrant, potent, selective, and wild-type sparing EGFR tyrosine kinase inhibitor that is under investigation in the ongoing phase 1/2 CONCERTO trial (NCT05241873), including in pts with ex20ins. Methods: In phase 1 dose escalation using a 3+3 design, BLU-451 monotherapy was administered orally QD or BID and given in continuous 21-day cycles. The primary objectives include maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) determinations and safety. Key secondary objectives include antitumor activity, PK, and pharmacodynamics. Pts with EGFR ex20ins–positive NSCLC after prior platinum-based chemotherapy were enrolled. Prior ex20ins–targeted therapy and asymptomatic CNS disease were permitted. Tumor response was assessed per RECIST v1.1. Serial blood samples for analysis of BLU-451 PK and circulating tumor DNA (ctDNA) were collected. Results: As of Jan 20, 2023, 28 pts have been enrolled and dosed in 5 cohorts (100 mg–400 mg QD and 200 mg BID), including 19 (68%) pts with exon 20 insertions. The median number of prior systemic lines of therapy was 2.5 (range, 1–10), and 19/28 (68%) pts had prior ex20ins-targeted agents. The most common AEs were diarrhea (21%), cough (18%), fatigue (14%), pruritis (14%) and rash (14%); all were Grade 1 or 2. There were no dose-limiting toxicities. Partial responses, including a disappearance of a CNS target lesion, were seen, and early evidence of on-target activity with ctDNA reductions was observed. Conclusions: As of the data cutoff, BLU-451 monotherapy was generally well tolerated, with early evidence of clinical activity in heavily pretreated pts with EGFR ex20ins–positive NSCLC. Early data at initial dose levels consisted of tumor reduction including responses, CNS activity, and ctDNA responses. The dose escalation is ongoing to determine the MTD and/or RP2D. Clinical trial information: NCT05241873 .

A phase II study of weekly carboplatin and nab-paclitaxel with trastuzumab or bevacizumab as neoadjuvant therapy for patients with early-stage nonmetastatic breast cancer.

e12623 Background: Neo-Adjuvant chemotherapy (NAC) allows patients to undergo breast conserving surgery, treats micro metastatic disease and improves patient outcomes. Achieving a complete pathologic response to NACT has prognostic significance in HER2+ and triple negative breast cancer. Anthracyclines are commonly integrated to Neo-adjuvant regimens. Their use is limited by cardiac and hematologic toxicity. We proposed that weekly Carboplatin and Nab-Paclitaxel is a well-tolerated regimen and aim to demonstrate that this approach can be a selective anthracycline sparing regimen with comparable improvement in recurrence free survival (RFS) and pathologic complete response (pCR). Methods: We conducted a single institution, open label, prospective Phase II clinical trial for patients with non-metastatic breast cancer who were eligible to receive NACT. All Patients with stage I-III breast cancers were treated with weekly Nab-paclitaxel (90 mg/m2) and carboplatin (AUC 2) for 12 weeks. Patients with HER2+ breast cancer received trastuzumab (4 mg/kg induction, followed by 2 mg/kg/week) weekly for 12 weeks. Triple negative and HR + patients received bevacizumab (10 mg/kg) every other week for 5 doses. Results: We enrolled 125 patients from February 2008 to December 2015. 85 pts were HER2- and 42 pts were HER2+. The pCR rate was 17.6% (15 pts) in the HER2- cohort and 50% (21 pts) in the HER2+ cohort. In the subgroup analysis based on hormone receptor (HR) status, pts with HR- tumor had more favorable response with higher rate of pCR compared with pts with HR+ tumor. In the HER2- cohort, the total pCR rate was 34% in HR- tumors vs 8% in HR+ tumors, P = 0.0018. After a median follow up of 53 months, overall survival was 88.9% for pts who achieved pCR and 77.7% for those who did not. HR = 0.3664, CI = 0.06147 to 2.1843, P = 0.34.In the HER2+ cohort the pCR rate was 33% in pts with HR+ tumors vs 72% in pts with HR- tumor, P = 0.0137. After a median follow up of 53 months, overall survival was 100% for pts who achieved pCR vs 20% in those who did not. The relapse-free survival was 90% vs 25% respectively (HR = 0.0669, CI = 0.00454 to 0.9251 P = 0.0016). In the entire study population, 6 pts (4.7%) had treatment discontinuation and 12 pts (9.4%) had dose reduction due to side effects. The rate of treatment disruption was higher in the HER2- cohort. Nausea, vomiting, and neutropenia were the most common side effects in both cohorts (7.9%) followed by thrombocytopenia and anemia (4.7%). Hematologic toxicity was the most common toxicity grade 3 and 4. Conclusions: Combination of nab-paclitaxel and carboplatin plus targeted therapy as an anthracycline sparing neoadjuvant chemotherapy showed a good pCR rate in HER2+ subgroup and moderate activity in TNBC subset. High rate of pCR was associated with high survival outcomes in HER2+ cohort. The regimen was well tolerated among both cohorts. Clinical trial information: NCT00618657 .

Co-primary endpoint analysis of HCRN GU 16-257: Phase 2 trial of gemcitabine, cisplatin, plus nivolumab with selective bladder sparing in patients with muscle-invasive bladder cancer (MIBC).

447 Background: Transurethral resection of bladder tumor (TURBT) plus systemic therapy has been known for decades to achieve durable bladder-intact survival in a subset of patients with MIBC but efforts to advance this paradigm have been complicated by a lack of (a) prospective studies, (b) rigorous approaches to assess and define clinical complete response (cCR), and (c) integration of novel therapies. Methods: Eligible patients were cisplatin-eligible with cT2-T4aN0M0 urothelial bladder cancer. Patients received 4 cycles of gemcitabine, cisplatin, plus nivolumab followed by clinical restaging including urine cytology, MRI/CT of the bladder, cystoscopy and bladder biopsies. Patients achieving a cCR (normal cytology, imaging, and cT0/Ta) were eligible to proceed without cystectomy and receive nivolumab q2 weeks x 8 followed by surveillance. Patients not achieving cCR were recommended to undergo cystectomy. Coprimary endpoints included (1) cCR rate and (2) association between cCR and 2-year outcomes. The key secondary endpoint was the impact of pre-specified baseline genomic alterations on outcomes. Additional biomarkers to refine patient selection were also explored. Results: Between 8/2018-11/2020, 76 patients were enrolled at 7 sites (male 79%, median age 69; cT2 = 56%, cT3 = 32%, cT4 = 12%). Median follow-up is 27 months. 72/76 patients underwent clinical restaging and a cCR was achieved in 33/76 (43%; 95% CI: 32%, 55%). One cCR patient opted for immediate cystectomy (ypTaN0M0). Outcomes are summarized in the Table. Baseline ERCC2, ATM, FANCC, or RB1 alterations were not, but tumor mutational burden ≥ 10 mutations/mb was, significantly associated with the composite endpoint of ypT0 (immediate cystectomy) or 2-year bladder-intact metastasis-free survival (BIMFS). On landmark analysis, VI-RADS (Vesical Imaging–Reporting and Data System) score (3-5 versus 1-2) on restaging MRI (central blinded review) was associated with inferior BIMFS (HR 4.5; p = &lt;0.01) and MFS (HR 19.3; p &lt;0.01). Circulating tumor DNA data will be presented at the meeting. Conclusions: TURBT followed by gemcitabine, cisplatin, plus nivolumab achieves stringently defined cCR in a substantial subset of patients with MIBC. ≥2-year bladder-intact survival is achieved in the majority of patients with a cCR. Clinical trial information: NCT03558087 . [Table: see text]

Feasibility and Toxicity of Full-Body Volumetric Modulated Arc Therapy Technique for High-Dose Total Body Irradiation.

Introduction: High-dose total body irradiation (TBI) is often part of myeloablative conditioning in acute leukemia. Modern volumetric modulated arc therapy (VMAT)-based plans employ arcs to the inferior-most portion of the body that can be simulated in a head-first position and use 2D planning for the inferior body which can result in heterogeneous doses. Here, we describe our institution's unique protocol for delivering high-dose TBI entirely with VMAT and retrospectively compare dosimetric outcomes with helical tomotherapy (HT) plans. Additionally, we describe our method of oropharyngeal mucosal sparing that was implemented after fatal mucositis occurred in two patients. Methods: Thirty-one patients were simulated and treated in head-first (HFS) and feet-first (FFS) orientations. Patients were treated with VMAT (n = 26) or HT (n = 5). In VMAT plans, to synchronize doses between the orientations, images were deformably registered and the HFS dose was transferred to the FFS plan and used as a background dose when optimizing plans. Six to eight isocenters with two arcs per isocenter were generated. HT was delivered with an established technique. Patients were treated to 13.2 Gy over eight twice daily fractions. Dosimetric outcomes and toxicities were retrospectively compared. Results: Prescription dose and organ at risk (OAR) constraints were met for all patients. Lower lung doses were achieved with VMAT relative to HT plans (7.4 vs 7.7 Gy, P = .009). Statistically significant improvement in mucositis was not achieved after adopting a mucosal-sparing technique, however lower doses to the oropharyngeal mucosal were achieved (6.9 vs 14.1 Gy, P = .009), and no further mucositis-related deaths occurred. Conclusions: This full-body VMAT method of TBI achieves dose goals, eliminates risk of heterogenous doses within the femur, and demonstrates that selective OAR sparing with the purpose of reducing TBI-related morbidity and mortality is possible at any institution with a VMAT-capable linear accelerator.

Dissociations in white matter tracts and neuropsychological findings in a 17 years old patient with Subacute sclerosing panencephalitis

The present multimodal diffusion tensor imaging and neuropsychological study investigated the integrity of the white matter fascicles in a 17 years-old patient diagnosed with subacute sclerosing panencephalitis (SSPE).A brief neuropsychological testing showed that word and pseudoword repetition, naming, semantic and phonological fluency, long-term memory, working memory were impaired.A review of the literature on Diffusion weighted imaging (DWI) and Diffusion Tensor Imaging (DTI) evidenced that, studies investigating the integrity of white matter in this condition being a rare disease, are very few. Significant differences (p < 0.05) were found between the fractional anisotropy (FA) values of the controls and the patient in the Superior Longitudinal fasciculus, the Inferior Longitudinal Fasciculus, the Inferior Fronto-Occipital Fasciculus, the Uncinate Fasciculus, and the Arcuate Fasciculus with lower values in the patient. No differences were found for the corticospinal tract. The number of streamlines was significantly lower in the patient, compared to controls, for the left Superior Longitudinal fasciculus, and for the left Uncinate fasciculus while for all the other fascicles, the number did not significantly differ from controls. DTI results were consistent with the patient’s cognitive profile showing impairments at repetition, at tasks tapping lexical-semantics and long-term memory / retrieval. Diffusion tensor imaging results indicate that there were diffuse alterations of the degree of anisotropic diffusion along the white matter tracts distributed in posterior-anterior direction. Differently, a selective sparing of this measure was observed along the white matter tract distributed in inferior-superior direction (the corticospinal fascicle).

Moderne definitive Radiochemotherapie – State of the Art-Umsetzung und neue Konsolidierungsstrategien

BackgroundIn locally advanced non-small-cell lung cancer (NSCLC), the addition of chemotherapy to radiotherapy and consolidation with durvalumab leads to a significant increase in overall survival and represents the most profound innovation of the last decade.ObjectivesAnalysis of new possibilities for the state-of-the-art implementation of definitive radiochemotherapy concepts.Materials and methodsEvaluation of prospective and randomised studies regarding improvements in treatment outcomes.ResultsOverall survival benefit of consolidating checkpoint inhibitor therapy after combined radiochemotherapy with durvalumab is 43% (95% confidence interval 38–47%) versus 33% (27–40%) in the placebo group in an updated analysis of the PACIFIC trial for 5‑year survival; stratified hazard ratio for death is 0.72 (95% CI 0.59–0.89, p = 0.0025). In the dose escalation studies, increased pulmonary and oesophageal side effects were observed, so no immediate clinical benefit could be derived from the increase in local efficacy. Improved imaging before and during therapy and optimised possibilities of dose application, especially by using intensity-modulated radiotherapy (IMRT), allow selective sparing of healthy structures, which increases the ability to safely intensify radiotherapy also in connection with new immunomodulatory substance combinations.ConclusionThe integration of immunotherapy, the stringent use of fluorodeoxyglucose positron emission tomography (FDG-PET) in staging and radiation planning, the widespread use of highly conformal radiation techniques (IMRT; volumetric modulated arc therapy, VMAT) and the consistent application of image-guided radiotherapy have led to significant improvements in treatment outcomes.

Selective sparing of Purkinje fibres with pulsed-field myocardial ablation.

Selective sparing of Purkinje fibres with pulsed-field myocardial ablation.

Considerations in Treatment Planning and Dosimetric Specifications of Permanent 131Cs Brachytherapy Implantation in Treatment of Brain Tumor – An Institutional Experience

<h3>Purpose/Objective(s)</h3> Local recurrence after the operative management of several types of brain tumors remains common and is the rationale for the frequent use of adjuvant radiation. This report details the dosimetry and normal tissue exposure to organs at risk (OARs) for patients with brain tumors treated with a novel strategy of maximum safe resection (MSR) and permanent ¹³¹Cs brachytherapy implantation. <h3>Materials/Methods</h3> From 01/2019 to 02/2022, thirty-two patients with 35 brain tumors underwent MSR followed by permanent ¹³¹Cs source implantation using a collagen tile brachytherapy device. The pre-op GTV delineated on MRI within 30 days was used to estimate the number of tiles needed. The post-operative thin-slice (1 mm) CT and contrast-enhanced MRI were obtained within 24 hours of surgery. Dosimetry analysis was performed using a brachytherapy planning tool. A dose of 60 Gy was prescribed to the high-risk clinical target volume (HR-CTV), defined as the brain parenchyma within 5 mm isotropic expansion from the resection cavity, respecting unviolated anatomical borders. Implant quality was evaluated with the D₉₀, V₅₀, V₁₀₀, V₁₅₀, V₂₀₀ metrics for the HR-CTV; D_max and D_mean OAR metrics were recorded. When applicable, the residual gross tumor volume (GTV_r), defined as persistent, nodular contrast enhancement on post-operative T1-weighted MRI, was delineated, and the D₉₀ to GTV_r was recorded. <h3>Results</h3> The median volume was 17.8 cc (2.3-119.2 cc) for the pre-op GTV, 15.8 cc (4.6-78.3 cc) for the resection cavity, 21.2 cc (9.5-58.3 cc) for HR-CTV, and 1.2 cc (0.2-28.9 cc) for GTV_r. 36% (16/35) cavities were larger than pre-op GTV by an average of 9.1 cc (<0.1-31.3 cc). The median D₉₀ was 63.4 Gy to HR-CTV (n=35, 31.7- 148.3 Gy), and 68.7 Gy to GTV_r (n=24, 22.8-113.8 Gy). The median V₅₀, V₁₀₀, V₁₅₀, V₂₀₀ of HRCTV were 100% (91.1-100%), 93.2% (41.9-100%), 11.1 cc (3.7-51.9 cc), and 4.7 cc (1.2-43.7 cc). The dosimetric objective D₉₀ ≥ 54 Gy to the HR-CTV was met in 69% (24/35) of cavities; the objectives V₅₀ ≥ 99% and V₁₀₀ ≥ 90% were met in 83% (29/35) and 54% (19/35) of cavities. OAR metrics were summarized in Table 1. <h3>Conclusion</h3> Permanent ¹³¹Cs brachytherapy implantation can provide adequate dosimetric coverage of the HR-CTV and selective sparing of OARs after MSR.

Biochemical assessment of adrenal insufficiency after adrenalectomy for non-cortisol secreting tumors: clinical correlation and recommendations.

Data regarding changes in cortisol axis after adrenalectomy for non-cortisol secreting tumors and their correlation with adrenal insufficiency are limited. Our aim was to analyze these changes and their clinical correlations to guide management after adrenalectomy for non-Cushing's tumors. Following IRB approval, postoperative cortisol axis changes were analyzed in patients who underwent unilateral adrenalectomy for non-Cushing's tumors. A morning serum cortisol of ≥ 10μg/dl was accepted as a sufficient adrenal response. 223 adrenalectomies were analyzed. In 63% of patients, POD1 serum cortisol was ≥ 10μg/dl and in 37% &lt; 10μg/dl. No patient with a POD1 cortisol ≥ 10μg/dl developed AI symptoms, whereas symptoms of AI were observed in 4% of those with &lt; 10μg/dl. In patients with a POD1 cortisol of &lt; 10μg/dl, the rate of steroid replacement therapy initiation was 100%, 8%, and 25% when the decision was based on serum cortisol, clinical symptoms, and serum cortisol plus ACTH stimulation test results, respectively. In 90% of asymptomatic patients, hypocortisolemia resolved uneventfully within a week on repeat morning cortisol testing. 75% of patients with hypocortisolemia on POD1 demonstrated an adequate cortisol response to ACTH stimulation test. Although postoperative hypocortisolemia was observed in 37% of patients undergoing unilateral adrenalectomy for non-cortisol secreting tumors, majority did not develop symptoms of adrenal insufficiency. All three steroid initiation approaches appeared safe, with management based on clinical symptoms or selective ACTH stimulation testing sparing more patients from steroids compared to steroid initiation based on POD 1 cortisol levels alone.

Durvalumab with cetuximab and radiotherapy for locally advanced squamous cell carcinoma of the head and neck: A phase 1/2 trial

Background and purposeTo report on the anti-tumor activity of a novel combination in high-risk locally advanced head and neck squamous cell carcinoma. Materials and methodsAt a fixed dose of 1500 mg every 28 days, anti PD-L1 Durvalumab was given concomitantly to Radiotherapy and Cetuximab starting from the first week of combined treatment, followed by adjuvant Durvalumab to a maximum of 6 months after completion of radiation. The primary endpoint of the study was 2-year progression-free survival (PFS). A safety run-in was planned. Due to regulatory issues which prevented from opening multiple centers, COVID-19 pandemic and withdrawal of Durvalumab from supporting company, the study was prematurely terminated in April 2021. ResultsBetween July 2019 and August 2020, 9 patients were enrolled in the study. All tumors had a PD-L1 Combined Positive Score > 1. Optimal drug exposure was observed, with mean relative dose intensity of 85.5% and 87.5% for Cetuximab and Durvalumab, respectively. No radiation breaks were necessary. A grade 4 mucositis lasting for 14 days corresponded to the only dose limiting toxicity we reported. At a median follow-up of 11.5 months (IQR 7.7–16.7) all surviving patients (6 out of 9) are disease-free, with 1 and 2-year PFS rates of 77.7% and 58.3%, respectively. A selective sparing of node levels in the elective volume was performed in all cases, yielding a cumulative mean dose of 37.6 Gy (SD 8.4). ConclusionAlbeit limited by the small sample size, our preliminary observation of anti-tumor activity and tolerability of Durvalumab in addition to Cetuximab and radiation may warrant further investigations.

MR-guided radiotherapy for prostate cancer: state of the art and future perspectives.

Advances in radiotherapy technology have increased precision of treatment delivery and in some tumour types, improved cure rates and decreased side effects. A new generation of radiotherapy machines, hybrids of an MRI scanner and a linear accelerator, has the potential to further transform the practice of radiation therapy in some cancers. Facilitating superior image quality and the ability to change the dose distribution online on a daily basis (termed “daily adaptive replanning”), MRI-guided radiotherapy machines allow for new possibilities including increasing dose, for hard to treat cancers, and more selective sparing of healthy tissues, where toxicity reduction is the key priority.These machines have already been used to treat most types of cancer, although experience is still in its infancy. This review summarises the potential and current evidence for MRI-guided radiotherapy, with a predominant focus on prostate cancer. Current advantages and disadvantages are discussed including a realistic appraisal of the likely potential to improve patient outcomes. In addition, horizon scanning for near-term possibilities for research and development will hopefully delineate the potential role for this technology over the next decade.

In vitro assays for investigating the FLASH effect.

FLASH radiotherapy is a novel technique that has been shown in numerous preclinical in vivo studies to have the potential to be the next important improvement in cancer treatment. However, the biological mechanisms responsible for the selective FLASH sparing effect of normal tissues are not yet known. An optimal translation of FLASH radiotherapy into the clinic would require a good understanding of the specific beam parameters that induces a FLASH effect, environmental conditions affecting the response, and the radiobiological mechanisms involved. Even though the FLASH effect has generally been considered as an in vivo effect, studies finding these answers would be difficult and ethically challenging to carry out solely in animals. Hence, suitable in vitro studies aimed towards finding these answers are needed. In this review, we describe and summarise several in vitro assays that have been used or could be used to finally elucidate the mechanisms behind the FLASH effect.