The Research Progress of PD-1/PD-L1 Inhibitors Enhancing Radiotherapy Efficacy

Approximately 60%–70% of patients with malignant tumours require radiotherapy. The clinical application of immune checkpoint inhibitors (ICIs), such as anti-PD-1/PD-L1, has revolutionized cancer treatment and greatly improved the outcome of a variety of cancers by boosting host immunity.However, radiotherapy is a double-edged sword for PD-1/PD-L immunotherapy. Research on how to improve radiotherapy efficacy using PD-1/PD-L1 inhibitor is gaining momentum. Various studies have reported the survival benefits of the combined application of radiotherapy and PD-1/PD-L1 inhibitor. To fully exerts the immune activation effect of radiotherapy, while avoiding the immunosuppressive effect of radiotherapy as much as possible, the dose selection, segmentation mode, treatment timing and the number of treatment sites of radiotherapy play a role. Therefore, we aim to review the effect of radiotherapy combined with anti-PD-1/PD-L1 on the immune system and its optimization.

Association between choriocapillaris flow deficit and choroidal neovascularization activity in eyes with myopic choroidal neovascularization

Although choriocapillaris flow deficit (CFD) around choroidal neovascularization (CNV) is less associated with CNV activity in myopic eyes, no reports are investigating its size as an indicator of CNV activity. We investigated the relationship between CFD and high myopia-related CNV. In this retrospective, observational study, patients underwent optical coherence tomography angiography (OCTA) with split-spectrum amplitude-decorrelation angiography for diagnosing pathological myopic CNV (mCNV); CFD features around CNV margins were evaluated. Of the 33 eyes (30 patients), 11 (33.3%) had active mCNV, and 22 (66.7%) had inactive CNV. Six eyes (18.2%) were treatment-naïve, while the remainder previously underwent anti-vascular endothelial growth factor therapy. On OCTA, blood flow signals were detected in CNV in the outer retinal layer in 28 (84.8%) eyes, including all active cases (11 cases) and 17 (77.3%) of 22 inactive cases. CNV flow signal size correlated significantly with activity (P < 0.001). CFD around CNV was observed in 24 eyes (72.7%), including all active cases (11 cases) and 13 (59.1%) of 22 inactive cases. CFD size correlated significantly with CNV activity (P < 0.001). The size of both the CFD area around CNV and CNV flow signal area are useful indicators of CNV activity in eyes with mCNV, which may help determine treatment timing.

Inadequate Sars-Cov-2 Vaccine Effectiveness in Patients with Multiple Myeloma: A Large Nationwide Veterans Affairs Study

Introduction Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, is particularly serious in patients with multiple myeloma (MM), with estimated mortality of over 30% in several studies. In the general population, SARS-CoV-2 vaccination has been demonstrated to be an effective approach to preventing infection. However, patients with MM were not included in vaccination trials. Recent studies suggest that patients with compromised immune systems exhibit reduced antibody response to SARS-CoV-2 vaccination, and MM patients are often immunocompromised both due to MM itself and due to MM treatment. Thus, the objective of this retrospective cohort study in the national Veterans Affairs (VA) healthcare system was to evaluate the real-world effectiveness of SARS-CoV-2 vaccination to prevent COVID-19 infection in MM patients during the 140-day period following initial vaccine availability. Methods This is a multicenter study of SARS-CoV-2 infection among vaccinated and unvaccinated patients at VA hospitals nationwide during the period from 12/15/2020 to 5/4/2021. We identified a cohort of MM patients who were alive and without prior SARS-CoV-2 infection on their date of vaccination or inclusion as a control. For added comparison with a less immunocompromised population, we also identified a cohort of cancer survivors, defined as patients with any solid or hematologic malignancy who had been treated with systemic cancer-directed therapy subsequent to 8/15/2010, but had not been treated with such therapy in the 6 months prior to vaccination or inclusion as a control, and were alive and without prior SARS-CoV-2 infection on that date. Vaccinated patients were exactly matched 1:1 to unvaccinated controls on race, VA facility, rurality of home address, cancer type, and treatment timing and modality with minimum distance matching on age. The primary exposure was receipt of a SARS-CoV-2 vaccine. The primary outcome was laboratory-confirmed SARS-CoV-2 infection. Vaccination effectiveness was defined as 1 minus the risk ratio of SARS-CoV-2 infection for vaccinated individuals compared to unvaccinated controls. Results 6,891 MM patients met eligibility criteria and 4,367 were vaccinated during the study period. Of those, 1,606 vaccinated MM patients were matched 1:1 to 1,606 unvaccinated or not yet vaccinated controls. In addition, for comparison, 2,476 vaccinated cancer survivors were matched 1:1 to 2,476 unvaccinated or not yet vaccinated controls. Median follow-up was 44 days among MM patients and 46 days among cancer survivors. Vaccine effectiveness in the matched cohort of MM patients was 22.2% (95% CI, -133 to 82.7%) starting 14 days after the second dose. In contrast, effectiveness was 82.3% (95% CI 16.4 to 100%) starting 14 days after the second dose in the matched cohort of cancer survivors. Among vaccinated MM patients in the matched cohort, 14 (8.7 per 1000 patients) were infected with SARS-CoV-2 subsequent to vaccination. Among vaccinated cancer survivors in the matched cohort, 10 (4.0 per 1000 patients) were infected subsequent to vaccination. Conclusion Vaccination is an effective strategy for preventing SARS-CoV-2. However, effectiveness may be reduced in patients with MM, likely due to a co-existing immunosuppression both due to the disease process as well as associated therapy. Future studies are needed to evaluate the relationship between MM disease states, types of therapy used and treatment timing that may impact vaccine effectiveness, and to also determine if MM patients would benefit from post-vaccination serologies or a booster vaccination. Disclosures Branch-Elliman: Gilead Pharmaceuticals: Research Funding. Brophy: Novartis: Research Funding. Munshi: Pfizer: Consultancy; Legend: Consultancy; Novartis: Consultancy; Adaptive Biotechnology: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Abbvie: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Bristol-Myers Squibb: Consultancy.

Spontaneous Retroperitoneal Hematoma: a Case Report, Review of Literature, and Proposal of Diagnostic and Management Algorithm

Background: Spontaneous retroperitoneal hematoma (SRH) is defined as bleeding in the retroperitoneal space without any triggers such as trauma, invasive procedures, and abdominal aortic aneurysm. Case presentation: A 48-year-old man who experienced sudden abdominal pain, severe hypotension, and decreased hemoglobin (Hb) was diagnosed with SRH. Contrast-enhanced computed tomography (CT) revealed massive left retroperitoneal hematoma; however, neither extravasation nor causative aneurysm was noted. Through conservative management with close monitoring, he was treated and discharged on the 10th hospital day without any morbidity. Conclusions: SRH treatment comprises conservative management, transcatheter arterial embolization, and surgical intervention. The mortality rate of SRH is so high that the optimal treatment timing needs to be carefully judged based on detailed evaluation and management algorithm with clear criteria.

The real-world outcomes of multiple myeloma patients treated with daratumumab

Most patients cannot be included in randomized clinical trials. We report real-world outcomes of all Danish patients with multiple myeloma (MM) treated with daratumumab-based regimens until 1 January 2019. Methods Information of 635 patients treated with daratumumab was collected retrospectively and included lines of therapy (LOT), hematologic responses according to the International Myeloma Working Group recommendations, time to next treatment (TNT) and the cause of discontinuation of treatment. Baseline characteristics were acquired from the validated Danish Multiple Myeloma Registry (DMMR). Results Daratumumab was administrated as monotherapy (Da-mono) in 27.7%, in combination with immunomodulatory drugs (Da-IMiD) in 57.3%, in combination with proteasome inhibitors (Da-PI) in 11.2% and in other combinations (Da-other) in 3.8% of patients. The median number of lines of therapy given before daratumumab was 5 for Da-mono, 3 for Da-IMiD, 4 for Da-PI, and 2 for Da-other. In Da-mono, overall response rate (ORR) was 44.9% and median time to next treatment (mTNT) was 4.9 months. In Da-IMiD, ORR was 80.5%, and mTNT was 16.1 months. In Da-PI, OOR was 60.6% and mTNT was 5.3 months. In patients treated with Da-other, OOR was 54,2% and mTNT was 5.6 months. The use of daratumumab in early LOT was associated with longer TNT (p<0.0001). Patients with amplification 1q had outcome comparable to standard risk patients, while patients with t(4;14), t(14;16) or del17p had worse outcome (p = 0.0001). Multivariate analysis indicated that timing of treatment (timing of daratumumab in the sequence of all LOT that the patients received throughout the course of their disease) was the most important factor for outcome (p<0.0001). Conclusion The real-world outcomes of multiple myeloma patients treated with daratumumab are worse than the results of clinical trials. Outcomes achieved with daratumumab were best when daratumumab was used in combination with IMIDs and in early LOT. Patients with high-risk CA had worse outcomes, but patients with amp1q had similar outcomes to standard-risk patients.

Quantitative Assessments of Crack Sealing Benefits by 3D Laser Technology

Crack sealing is one of the most commonly used methods to preserve asphalt pavements. However, quantification of crack sealing benefits (or the long-term delaying effects of crack sealing on crack propagation) remains unavailable because field crack lengths could not be measured accurately and efficiently. In this study, 3D laser technology is proposed to measure and compare the growth of crack lengths between sealed and non-sealed pavement sections and, for the first time, to accurately and efficiently quantify the crack sealing benefits. To validate the proposed method and find adequate treatment timing (or conditions), nine field sites in Georgia, U.S., with different pavement pre-treatment conditions and roadway environmental factors were monitored over 3 years from December 2016 to September 2019. The study results showed that crack sealing can retard crack growth by 40%–128%, and such delaying effects are more significant under better pavement pre-treatment conditions. The findings suggest that transportation agencies can prolong the service life of pavements by applying crack sealing before the pavement condition becomes poor. In addition, this work has been proved to be very valuable for transportation agencies to determine the best timing and treatment criteria for crack sealing.

Warning Signs in the Era of Unruptured Intracranial Aneurysms: Report on 2 Cases of Fatal Aneurysmal Hemorrhage

<b><i>Introduction:</i></b> The timing of treatment remains unresolved for patients with unruptured intracranial aneurysms (UIAs) and headaches, particularly when the pain is short term, localized, and related to the aneurysm site. We lack evidence to support the notion that when a headache accompanies an aneurysm, it elevates the risk of rupture. <b><i>Results:</i></b> We describe 2 cases of fatal subarachnoid hemorrhage in patients with a history of headache and known aneurysms. Both of these patients had good indications for treatment: a young age and an aneurysm &#x3e;7 mm, and both were qualified for elective surgery. However, both patients died of fatal aneurysm ruptures before the planned surgery. <b><i>Conclusion:</i></b> These cases suggested that treatment should be started as soon as possible, when a UIA is diagnosed based on a short-term period of severe headaches or when a UIA is observed and then severe headaches appear. There is no straightforward guideline for treatment timing in these patients. However, in this era of UIAs, the significance of sentinel headaches should be reevaluated. Given the incidence of headaches in the general population and the very low risk of aneurysm rupture, there may be a tendency to neglect the role of headache as a possible warning sign.

Goodness of Fit

Disorder (HD) is a complex mental health problem defined by an overabundance of clutter, difficulty with organization and discarding, and problems regulating acquisition. This chapter describes the features of HD, evidence-based intervention approaches and outcomes, and the elements of a manualized treatment approach with emphasis on flexible delivery to meet clients’ needs. Opportunities to flexibly implement cognitive and behavioral treatments (CBT) for HD include modification of assessment methods, the order of therapy components, treatment timing and focus, responsiveness to client comorbidity and context, consideration of treatment planning, and approaches to increasing motivation and building skills. Also covered are supports for cognitive and behavioral changes in acquisition/organizing/discarding, assessing the appropriateness of a home cleanout, and determining “flexibility within fidelity” (Kendall & Frank, 2018) for group HD treatments and online interventions.

Delays in Epidemic Outbreak Control Cost Disproportionately Large Treatment Footprints to Offset

Epidemic outbreak control often involves a spatially-explicit treatment area (quarantine, inoculation, ring cull) which covers the outbreak area and adjacent regions where hosts are thought to be latently infected. Emphasis on space however neglects the influence of treatment timing on outbreak control. We conducted field and in-silico experiments with wheat stripe rust (WSR), a long-distance dispersed plant disease, to understand interactions between treatment timing and area interact to suppress an outbreak. Full-factorial field experiments with three different ring culls (outbreak area only to a 25-fold increase in treatment area) at three different disease control timings (1.125, 1.25, and 1.5 latent periods after initial disease expression), indicated that earlier treatment timing had a conspicuously greater suppressive effect than the area treated. Disease spread computer simulations over a broad range of influential epidemic parameter values (R0, outbreak disease prevalence, epidemic duration) suggested that potentially unrealistically large increases in treatment area would be required to compensate for even small delays in treatment timing. Although disease surveillance programs are costly, our results suggest that treatments early in an epidemic disease outbreak require smaller areas to be effective, which may ultimately compensate for the upfront costs of proactive disease surveillance programs.