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Importance The choice of induction agent during rapid sequence intubation (RSI) of critically ill adults may affect clinical outcomes. Although ketamine and etomidate are frequently used for RSI, their comparative effectiveness remains controversial. Objective To compare the safety of etomidate vs ketamine for emergency RSI in critically ill adults. Design, Setting, and Participants This cohort study used a target trial emulation with observational data collected between March 1, 2022, and April 30, 2024, from 18 emergency departments across Brazil, with data from the Brazilian Airway Registry Cooperation. Adults who underwent RSI and received either etomidate or ketamine as a sole hypnotic agent were included; those with preintubation cardiac arrest or immediate postintubation transfer were excluded. Exposure Administration of etomidate or ketamine as the induction agent for RSI. Main Outcomes and Measures The primary outcome was 28-day in-hospital mortality. Secondary outcomes included 7-day in-hospital mortality, first-attempt intubation success, and major adverse events (new hemodynamic instability, severe hypoxemia, and cardiac arrest) within 30 minutes after intubation. Inverse probability of treatment weighting was used to adjust for confounding. Risk ratios (RRs) and risk differences (RDs) with 95% CIs were used to compare outcomes between groups. Results Among 1810 patients (median age, 64 years [IQR, 50-74 years]; 1048 men [57.9%]), 514 received ketamine and 1296 received etomidate. The median shock index was higher in the ketamine group than the etomidate group (0.81 [IQR, 0.65-1.01] vs 0.76 [IQR, 0.59-0.99]), and preintubation vasopressor use was more common in the ketamine group than the etomidate group (191 of 514 [37.2%] vs 391 of 1296 [30.2%]). Weighted 28-day mortality was higher with etomidate than ketamine (60.5% [95% CI, 57.2%-63.8%] vs 54.4% [95% CI, 45.0%-63.9%]; RR, 1.14 [95% CI, 1.03-1.27]; RD, 7.6% [95% CI, 2.0%-13.3%]). Seven-day mortality was also higher with etomidate than ketamine (35.2% [95% CI, 32.0%-38.3%] vs 30.1% [95% CI, 23.5%-36.7%]; RR, 1.19 [95% CI, 1.04-1.35]). New hemodynamic instability within 30 minutes after intubation was more frequent with ketamine (24.2% [95% CI, 20.4%-28.0%] vs 18.9% [95% CI, 16.7%-21.0%]; RR, 0.78 [0.64-0.95]). There were no statistically significant differences in the other secondary outcomes. Conclusions and Relevance In this cohort study of critically ill adults undergoing RSI, etomidate use was associated with higher in-hospital mortality at 7 and 28 days compared with ketamine. These findings highlight the need for definitive randomized clinical trials to compare both agents.

Background The past two decades have witnessed tremendous growth in the appreciation and treatment of sacroiliac joint (SIJ) complex pain, including anatomical dissections that shed light on innervation, an appreciation for the contribution of extra-articular components to SIJ complex pain, the advent of radiofrequency ablation (RFA) and a host of minimally-invasive surgical techniques. Yet, there is no standardization of diagnosis and treatment paradigms. Methods In February 2023, the Boards of Directors for the American Academy of Pain Medicine (AAPM) and American Society of Regional Anesthesia & Pain Medicine (ASRA-PM) approved the development of multispecialty guidelines on SIJ complex pain. Thirty partner organizations with clinical and scientific interests in SIJ complex pain were identified, and formal letters of request-for-participation were sent to each, along with a request for nominees to serve on the committee. Twenty five organizations agreed to participate in addition to the Departments of Defense and Veterans Affairs. A steering committee developed 21 questions, which spanned criteria for diagnosis, non-interventional and interventional treatments including surgery, technical parameters on how to optimize results, and what constitutes positive outcomes. Questions were methodically assigned to specialized modules comprising 4–5 members with complementary expertise, who collaborated with the Subcommittee Lead and one of three Committee Chairs to develop preliminary drafts. Following thorough revisions, these drafts were subsequently submitted to the full committee for comprehensive review. A modified Delphi method was used in which the answers to questions were sent to the committee en bloc and comments were returned in a non-blinded fashion to the Chairs, who incorporated the comments and sent out revised versions until consensus was achieved. During a committee meeting before commencement, it was agreed that recommendations would be noted when there was >50% agreement among committee members, but that a formal recommendation would require ≥75% consensus. Results Twenty-one organizations formally endorsed the guidelines. The American Society of Anesthesiologists, and American Academy of Physical Medicine & Rehabilitation, and the North American Spine Society affirmed the benefit of the guidelines but did not officially endorse them. The American Academy of Neurology declined to affirm the benefit of the guidelines citing ‘lack of relevance to their membership.’ Per policies, while the Departments of Defense and Veterans Affairs did not formally review the guidelines for endorsement, their representatives approved them. In addition to being endorsed or the benefit affirmed by all voting organizations, complete consensus from committee members was obtained on all 21 questions. On two recommendations, there were dissensions from three societies who thought that selecting patients for sacral lateral branch RFA and minimally-invasive fusion should be based on ≥75% relief from two blocks instead of at least 50% relief from a single block before RFA, and greater than 50% pain relief with documented functional improvement after a single block before fusion. One additional society (Latin American Society of Regional Anesthesia) abstained on the statement that the evidence is stronger for extra-articular than intra-articular injections. The committee found that a battery of physical exam tests has reasonable sensitivity, but lower specificity, for identifying intra-articular but not extra-articular pain, with negative tests having greater predictive value than positive ones. Intra-articular injections have diagnostic validity for SIJ intra-articular, but not extra-articular, pain. There is unclear or negative evidence for imaging. The prevalence rates of intra-articular and extra-articular pathology are comparable, with both intra- and extra-articular steroid injections providing at least 4 weeks of relief in well-selected patients. However, the evidence is slightly stronger for extra-articular corticosteroid injections to provide short-term relief. The evidence base for non-interventional therapies is indirect, extrapolated mostly from low back pain studies. There is weak evidence supporting dextrose-based prolotherapy and platelet-rich plasma to provide at least 3 months of pain relief. There is strong evidence for sacral lateral branch RFA to provide relief for at least 6 months in individuals with extra-articular pathology, with face validity and indirect evidence from randomized trials supporting sacral lateral branch blocks as a prognostic tool. There is stronger evidence for larger lesions or more aggressive lesioning strategies than for less stringent techniques. There is weak evidence to support non-steroidal anti-inflammatory drugs to prevent neuritis after RFA, and in most cases anticoagulation does not require cessation in the periprocedural period. With an aggressive lesioning strategy, sensory stimulation provides minimal therapeutic benefit, with weak, extrapolated evidence that motor stimulation can provide safety benefit. The cut-off to designate diagnostic or prognostic blocks as positive is most commonly set at 50%, with higher values not shown to improve outcomes for more definitive procedures; for therapeutic treatment outcomes, the evidence supports a lower threshold of ≥30% pain relief or meaningful benefit on non-pain outcomes (eg, opioid cessation) for designation of a positive response. For carefully selected patients with intra-articular SIJ complex pain based on controlled blocks who have failed conservative therapies, there is weak or very weak evidence that minimally invasive SIJ fusion can provide benefit for at least one year. Conclusions SIJ complex pain remains an underappreciated source of chronic low back pain, affecting between 15% and 30% of patients with axial pain predominantly below L5. Answers to many questions were limited by low-quality evidence, indicating the need for better research. SIJ complex pain is a multifarious condition (ie, pain can be from different portions of both the intra- and extra-articular components of the joint) for which an interdisciplinary, multimodal treatment plan can optimize treatment outcomes.

Abstract In this study, we investigated tumor intrinsic mechanisms of resistance to cevostamab, a bispecific T-cell engager targeting Fc receptor-like protein 5 (FCRL5) and CD3 that has shown promising clinical activity and durable responses in advanced MM. Longitudinal bone marrow aspirates from nine MM patients treated with cevostamab were analyzed. All patients had previously been treated with both immunomodulatory drugs (IMiDs) and proteasome inhibitors (PI) and eight patients had received daratumumab prior to cevostamab, which was, on average, the 6th line of treatment (mean treatment duration 220±273 days). Five of nine patients responded with ≥PR. Whole genome and transcriptome sequencing was performed on sorted CD138+ MM cells at baseline, and whole exome and transcriptome sequencing was performed on five and three samples, respectively, following cevostamab discontinuation. Baseline FCRL5 expression levels did not correlate with clinical response. However, in one non-responder patient, FCRL5 expression increased four-fold after 28 days of treatment. Given the location of the FCRL5 gene on chromosome 1q—commonly amplified in advanced MM—we evaluated the presence of Gain(1q) in our study cohort. All patients whose best response was ≤PR (n=6) harbored a Gain(1q), whereas it was absent in those who achieved VGPR and sCR (n=3). Crucially, one of the patients that achieved sCR was initially treated with 60 mg of cevostamab for one year and then escalated to a higher dose cohort (90 mg) in the second year. At progression, a clonal FCRL5E115A missense mutation (allelic frequency = 56%) and a subclonal FCRL5G455Efs*19(allelic frequency = 5%) frameshift deletion mutation were detected, both absent at baseline. The missense mutation was located on the extracellular domain of FCRL5 targeted by cevostamab. To validate the functional impact of FCRL5E115Aand FCRL5G455Efs*19 on the sensitivity to cevostamab in vitro, we generated a FCRL5 knockout (KO) model utilizing CRISPR-Cas9 technology in OPM2 MM cells. In vitro cevostamab cytotoxicity assay with PBMCs and pan T cells from healthy donors at various effector to target (E:T) ratios confirmed a complete loss of cevostamab sensitivity in our FCRL5KO models. cDNA encoding patient-derived FCRL5 alterations (FCRL5E115Aand FCRL5G455Efs*19) as well as FCRL5wtwere cloned into mammalian expression vector and reintroduced into FCRL5KO cells. Cevostamab sensitivity was reinstated by FCRL5wt expression in KO cells. In contrast, FCRL5E115A conferred complete resistance to cevostamab (p<0,001) and FCRL5G455Efs*19 depicted a significant decline in cevostamab sensitivity relative to FCRL5wt expressing models. Additional experiment utilizing direct stochastic optical reconstruction microscopy (dSTORM) are ongoing to monitor the membrane localization of FCRL5 mutants. By integrating genomic, transcriptomic and functional data with clinical outcomes, this work is the first to report on acquired FCRL5 mutations causing resistance to cevostamab. We hypothesize that the prolonged treatment duration may have contributed to the acquisition of the target mutations and note a subsequent durable sCR response to BCMA-targeted immunotherapy in the same patient, suggesting immune-related factors such as T cell exhaustion, were not drivers of cevostamab resistance. Due to the limited sample size, these findings require validation in larger cohorts. Nonetheless, our findings begin to elucidate tumor intrinsic mechanisms associated with cevostamab resistance.

Abstract Introduction: HMA monotherapy (HMAm) continues to be the standard of care for HR-MDS. While the addition of VEN to azacitidine (AZA) improved overall survival (OS) and complete remission (CR) rates among older pts with acute myeloid leukemia (AML) over AZA monotherapy, the recently completed phase III VERONA trial of AZA+/-VEN in HR-MDS failed to show an OS benefit for AZA/VEN over AZA monotherapy. Using the icMDS VALIDATE database, we compared outcomes of pts with HR-MDS treated with HMA or HMA/VEN as frontline therapy. Methods: The icMDS VALIDATE database includes over 4000 adult MDS pts who received HMA-based therapy from 32 international centers in 9 countries. For this analysis, we included pts with HR-MDS defined by International Prognostic Scoring System [IPSS] ≥1.5 or IPSS-revised [IPSS-R] ≥4 (at diagnosis or HMA initiation) and treated with HMAm or HMA/VEN as frontline therapy for HR-MDS. We assessed responses based on IWG 2023 criteria (Zeidan A et al, Blood 2023). Composite complete remission (cCR) was defined as CR+CRbi+CRuni+CRh+CRequivalent. We calculated OS from time of HMA initiation to date of death from any cause. Pts lost to follow-up were censored at the date they were last known to be alive. We used Kaplan-Meier methods to calculate OS and compared OS between different groups using the log-rank test. We used Cox and logistic regression models to adjust for baseline prognostic variables as appropriate. The study was funded by an independent grant from Abbvie. Results: A total of 1907 pts met eligibility and were included (1552 AZA, 221 decitabine, 134 HMA+VEN). 479 pts subsequently underwent allogeneic stem cell transplant (allo-SCT; 430 after HMAm [32.6%]; 49 after HMA/VEN [37.1%]). Our cohort was enriched for pts with adverse disease characteristics including complex karyotype (33.6%) and TP53 mutations (28.7%). Compared to pts treated with HMA/VEN, pts treated with HMAm were more likely to be male (p=0.012), have lower baseline platelet counts (p=0.037), peripheral blood (PB) blasts (p=0.004), or bone marrow blasts (p<0.001), and were less likely to have very high risk IPSS-M (p<0.001), TP53 mutations (p<0.001), or complex karyotype (p=0.020). In unadjusted analyses, the rate of cCR was significantly lower in HMAm treated pts compared to HMA/VEN treated pts (27.7% vs. 48.8%, p<0.001). However, CR rate was not significantly different (11.7% vs. 17.1% for HMAm and HMA/VEN, respectively, p=0.22). After adjusting for age, sex, and IPSS-M, pts treated with HMA/VEN were more likely to achieve cCR compared to HMAm with an odds ratio (OR) of 2.49 (95% CI: 1.56-3.96, p<0.001). When separated by TP53 mutation status, the OR for cCR for HMA/VEN vs HMAm was 4.17 (95%CI: 2.14-8.31; p<0.001) and 1.27 (95%CI: 0.54-2.86; p=0.57) for TP53 wild-type and TP53-mutant pts, respectively. In unadjusted analyses, median OS was 17.4 months for HMAm and 19.6 months for HMA+VEN, and OS did not differ significantly by treatment type (p=0.33). For HMAm treated pts, the OS rates at year 1, 2, 3 were 0.65 (95%CI: 0.63-0.67), 0.38 (95%CI: 0.36-0.40), and 0.27 (95%CI: 0.25-0.29), respectively. For HMA/VEN treated pts, the OS rates at year 1, 2, 3 were 0.64 (95%CI: 0.56-0.73), 0.45 (95%CI: 0.36-0.56), and 0.37 (95%CI: 0.27-0.51), respectively. In a multivariate analysis adjusting for age, sex, PB blast, IPSS-M and allo-SCT as a time-varying covariate, treatment with HMA/VEN vs HMAm did not significantly influence OS (hazard ratio (HR) of OS for HMA/VEN vs HMAm: 0.89, 95%CI: 0.69-1.13, p=0.33). When stratified by TP53 mutation status, HR of HMA/VEN vs. HMAm was favorable for TP53 wild-type (HR: 0.47; 95%CI: 0.29-0.74) but not TP53-mutant pts (HR=0.96; 95%CI: 0.66-1.41). Adjusting for other variables in the model, HR for pts who underwent vs. those who did not undergo allo-SCT were 0.65 (95% CI: 0.49-0.85) and 0.36 (95%CI: 0.24-0.53) in TP53 wild-type and mutant patients, respectively. Conclusion: In this large, international retrospective analysis from the icMDS VALIDATE database, HMA/VEN was associated with higher cCR rates—but not CR rates—compared to HMAm among pts with HR-MDS, though we observed no significant differences in OS. In our analysis, clinical benefit from the addition of VEN was most clear in TP53 wild-type pts, and allo-SCT was associated with improved OS regardless of baseline TP53 status. Our analysis was limited by the relatively small number of HMA/VEN-treated pts and heterogeneous real-world treatment patterns.

Abstract Introduction TP53MT are associated with poor outcomes in MDS, especially in the context of biallelic MT. We have previously reported on outcomes of pts with HR-MDS with TP53MT who received HMA in the VALIDATE dataset (Kewan T et al, ASH 2023). Here we provide expanded analyses focusing on outcomes post allo-HCT, and we explore the prognostic significance of different classification methods for biallelic TP53MT. Methods The VALIDATE database includes 4,732 pts with MDS who received HMA-based frontline therapy from 32 international centers in 9 countries. For this study, only pts with HR-MDS with molecular data at time of diagnosis were included. Biallelic TP53MT status was assessed using three classification schemes: WHO 2022, ICC 2022, and a VAF-based Cleveland Clinic Foundation (CCF) method.1TP53 copy neutral loss of heterozygosity (CN-LOH) was evaluable in 386 pts (118 had TP53MT). Treatment responses were evaluated using IWG 2023 criteria (Zeidan A et al, Blood 2023). Composite complete remission (cCR) was defined as CR+CRbi+CRuni+CRh+CRequivalent. We calculated OS from time of HMA initiation to date of death or last follow up. Unsupervised clustering (MOSAIC framework) was applied to identify molecular subgroups within the TP53MT cohort. The study was funded by an independent grant from Abbvie. Results A total of 1,485 pts were included. Median age was 69 years (IQR: 62–76), with 66% male pts. Median bone marrow blast was 7%, and 28% had a complex karyotype. Treatment regimens included azacitidine (68%), decitabine (15%), HMA/Venetoclax (8%), and other HMA combinations (9%); 34% underwent allo-HCT. Overall, 392 (26%) had TP53MT with 430 TP53 mutations (missense: 316; truncating: 89). Biallelic TP53MT % varied by classification: 72% (WHO), 84% (ICC), and 85% (CCF). Compared to TP53 wild-type (TP53WT) pts, pts with TP53MT had worse OS (median: 11.5 vs. 23.9 months [mo], p< 0.001), were younger (68 vs. 70 years, p=0.039), and had lower counts at diagnosis. Complex karyotype (81% vs. 14%) and chromosomal abnormalities were more frequent in TP53MT pts. Pts with TP53MT also had fewer co-mutations in other genes. Response to HMA was evaluable in 1,094 pts: cCR and CR were 32% and 13%, respectively. TP53MT pts had higher cCR (39% vs. 29%, p=0.001) than TP53WT, but similar CR rates (16% vs. 12%, p=0.093). According to WHO 2022, biallelic TP53MT had higher CR rates than monoallelic TP53MT (18% vs. 8%, p=0.03), but similar cCR. ICC and CCF classifications did not differentiate response rates. Median OS did not differ by TP53MT allelic status using WHO or ICC definitions. However, using the CCF method, pts with biallelic TP53MT had shorter OS than monoallelic TP53MT (10.4 vs. 17.2 mo, p=0.038). In multivariable models adjusted for age, gender, and allo-HCT, only the CCF-defined biallelic TP53MT group had significantly worse OS (HR: 1.6; 95% CI: 1.1–2.4). TP53MT pts undergoing allo-HCT had improved OS regardless of allelic status. Median OS for TP53MT pts with allo-HCT was 18.9 vs. 9.2 mo without all-HCT. This benefit was observed across WHO, ICC, and CCF classifications. However, a TP53MT VAF ≥19% predicted worse OS even post allo-HCT (14.6 vs. 47.1 mo, p<0.001). At 1 year, the survival rate was 78% (95%CI: 69-89%) in TP53MT pts who underwent allo-HCT and had cCR vs. 68% (95%CI: 55-84%) in pts who did not have cCR. However, 1 year survival rate was significantly higher for pts with TP53MT who did not have allo-HCT and achieved cCR (60%, 95%CI: 48-76%) vs. no cCR (26%, 95%CI: 20-35%). Unsupervised clustering of 335 TP53MT pts identified 9 molecular clusters (MCs). MC2, characterized by low TP53MT VAF (median 17%), fewer co-mutations, and frequent del17p, was associated with significantly improved OS (17.9 mo) and predicted favorable outcome (HR for death: 0.6; 95% CI: 0.4–0.8). Other clusters were enriched for adverse features (e.g., high VAF, multi-hit TP53MT).Conclusions The CCF method appears to best classify biallelic TP53MT pts with worse survival in the absence of accurate assessment of LOH status. Treatment response per IWG 2023 for TP53MT pts was associated with OS only in non-transplanted pts. Allo-HCT improved survival across TP53MT subsets, but TP53 VAF ≥19% at diagnosis remained a strong negative prognostic factor. Integrative clustering revealed a less aggresive molecular subset among TP53MT pts, suggesting refined risk stratification may guide therapy in this high-risk population. Ref: 1.Bahaj et al. J Hematol Oncol 2023.

Abstract Introduction: Marrow complete remission (mCR) in 2006 IWG criteria for MDS (Cheson B et al, Blood 2006) reflects achieving bone marrow (BM) blast percentage below 5% but is frequently not associated with meaningful count recovery. While mCR + hematologic improvement (HI) does reflect wide ranges of count improvement or transfusion reductions, HI is difficult to measure accurately in routine clinical practice. The 2023 International Working Group (IWG) response criteria (Zeidan A et al, Blood 2023) eliminated the mCR category without meaningful count recovery and reclassified mCR associated with meaningful count recovery into specific “less-than-CR” categories. Still, many clinical trials continue to use mCR as a secondary efficacy endpoint or as a part of overall response rate (ORR). Within the icMDS VALIDATE database, we assessed the association of mCR with OS in hypomethylating agent (HMA)-treated higher risk (HR)-MDS patients among both (1) transplanted and (2) non-transplanted patients. Methods We included patients with HR-MDS (defined as IPSS ≥1.5 and/or IPSS-R >3.5) who received HMA-based therapies from the international icMDS VALIDATE dataset. We evaluated the best response by IWG 2006 criteria into CR, mCR, or no CR/mCR. We then reclassified patients with mCR per IWG 2023 criteria into either (A) having achieved a composite CR (cCR) defined as CR + CR equivalent (CRequ) + CR with bilineage count recovery (CRbi) + CR with unilineage count recovery (CRuni) + CR with partial hematologic recovery (CRh) or (B) not having achieved cCR (no cCR). OS was calculated from time of HMA initiation to date of death or last follow-up by using 6-month landmark analyses. We used Kaplan-Meier methods to estimate OS, and the Log-rank test to compare OS. VALIDATE is supported by an independent grant from AbbVie. Results A total of1049 patients met eligibility.Median age of patients was 69 (range 21-95), 64% were men. While 61% received azacitidine, 17% received decitabine, and 22% received HMA-based combination therapy. In total, 37% underwent subsequent allogenic stem cell transplantation (allo-HCT). Based on IWG 2006 criteria, 17%, 33%, and 50% achieved CR, mCR, and no CR/mCR as their best response, respectively. Patients achieving CR had superior median OS (25 months, 95% CI: 21-34 months) compared to those with mCR (16 months, 95% CI: 13-18 months; p=0.038) and no CR/mCR (15 months, 95% CI: 12-17 months; p=0.001). In patients who received a subsequent allo-HCT, the median OS for patients with mCR (30 months, 95% CI: 21-54 months; 1 year OS: 71%, 2 year OS: 55%) did not significantly differ compared to patients with CR (59 months, 95% CI: 25 months-not reached, p=0.80; 1 year OS: 73%, 2 year OS 62%) and patients with no CR/mCR (32 months, 95% CI: 21-45 months, p=0.46; 1 year OS: 69%, 2 year OS 54%). In contrast, in patients treated with HMA therapy alone without subsequent allo-HCT, median OS for patients with mCR (11 months, 95% CI: 9-15 months; 1 year OS: 46%, 2 year OS: 23%) did not significantly differ compared to patients with no CR/mCR (11 months, 95% CI: 9-14 months, p=0.85; 1 year OS: 47%, 2 year OS: 22%) but was significantly shorter compared to patients with CR (20 months, 95% CI: 17-28 months, p<0.001; 1 year OS: 69%, 2 year OS: 46%). Patients with mCR by IWG 2006 (N=347) were reclassified per IWG 2023 into having either achieved a cCR (N=219, 63%) or no cCR (N=128, 37%). Specifically, patients with mCR were reclassified per IWG 2023 into CR (4.9%), CRequ (0.6%), CRbi (26.8%), CRuni (29.4%), CRh (1.4%), PR (0%), HI (10%), no response (21.9%) and PD (4.9%). Patients with mCR who were reclassified into cCR had an improved median OS (16 months, 95% CI: 15-26 months; 1 year OS: 62%; 2 year OS: 43%) compared to patients reclassified into no cCR per IWG 2023 (13 months, 95% CI: 11-17 months, p=0.023; 1 year OS: 52%; 2 year OS: 31%). Conclusions Using the large icMDS VALIDATE dataset, we found that achievement of mCR by 2006 IWG criteria was not associated with improved OS compared to patients who did not achieve CR/mCR. Reclassification of mCR using IWG 2023 highlights the heterogeneity within the mCR group and suggests that IWG 2023 criteria stratifies outcomes in patients previously labeled as mCR by IWG 2006. IWG 2023 should be the standard used for ORR assessment in all future clinical trials involving patients with HR-MDS.

PURPOSE Lung cancer remains a leading cause of cancer mortality in Brazil, with non–small cell lung cancer (NSCLC) accounting for 85% of cases, with 1.6% carrying epidermal growth factor receptor (EGFR) exon 20 mutations. In the phase I CHRYSALIS trial (ClinicalTrials.gov identifier: NCT02609776 ), amivantamab demonstrated a median overall survival (OS) of 22.8 months versus 8.3 months with docetaxel, the standard second-line Brazil's Unified Health System (SUS) therapy. Although the Brazilian Health Regulatory Agency approved amivantamab, the National Commission for the Incorporation of Technologies’ cost-effectiveness reviews result in an average 10-year delay before SUS incorporation. We aimed to estimate premature deaths and life-years lost attributable to this access gap. METHODS Using National Institute of Cancer (INCA) data, we estimated SUS-eligible patients, NSCLC prevalence, and EGFR exon 20 frequency. Stage distribution and 5-year recurrence rates identify candidates for amivantamab. A hazard ratio (HR) was derived from the inverse exponential method (ln(2)/OS ratio). Preventable deaths were calculated as: eligible patients × (1 – HR). Life-years gained per patient were estimated as OS difference. RESULTS Of the 26,548 new patients with lung cancer, 18,973 are SUS-eligible, 16,127 have NSCLC, and 258 have EGFR exon 20 mutations. Metastatic disease accounts for 114, whereas recurrences occur in 60 (stage III), eight (II), and four (I), totaling 186 candidates annually. With an HR of 0.364, the annual preventable death in the base-case scenario is equal to 186 × (1 – 0.364) × 95% = 112 patients. Over 10 years, 1,120 premature deaths and 1,353 life-years could be avoided. CONCLUSION Delayed SUS incorporation of amivantamab may result in over a 1,000 preventable deaths and life-years lost among Brazilian EGFR exon 20–mutated NSCLC. Urgent real-world studies and cost-effectiveness analyses are needed.

ABSTRACT Introduction Sinonasal sarcomas are exceedingly rare entities, constituting less than 7% of head and neck sarcomas. Their complex histology needs specialized treatment, which is often based on multimodal approaches including surgery, radiation therapy, and/or chemotherapy. This manuscript aims to gather expert opinions to establish common management principles for sinonasal sarcomas. Methods This international consensus followed a modified Delphi method in seven steps, including statements definition by the core group, expert panel recruitment, and a two‐round survey. Sixty‐two statements on sinonasal sarcoma management were developed. Experts from multiple continents participated, and results were anonymized and analyzed between March and May 2025. Results A total of 44 invited experts were recruited, 43.2% otorhinolaryngologists/head and neck surgeons, 31.8% medical oncologists, and 25% radiation oncologists. Participants varied in age and experience, representing Europe (70.5%), North America (18.2%), South America (6.8%), and Asia (4.5%). Among all histologies, biphenotypic sarcoma, chondrosarcoma, leiomyosarcoma, and myofibrosarcoma are principally treated with an upfront surgical management, differently from Ewing sarcoma and rhabdomyosarcoma in which chemotherapy, eventually associated with radiotherapy, is often chosen. In the remaining histologies (angiosarcoma, liposarcoma, malignant peripheral nerve sheath tumor [MPNST], osteosarcoma, and synovial sarcoma), a precise multimodal treatment is less standardized and needs to be discussed on a case‐by‐case basis. Conclusion Sinonasal sarcomas require a histology‐driven approach to determine upfront treatment, whether surgical, medical, or multimodal. Despite this structured strategy, prognosis remains highly variable across subtypes. Multidisciplinary evaluation and individualized management in referral centers are crucial to address the biological diversity and anatomical complexity of these rare malignancies.

Abstract Background The past two decades have witnessed tremendous growth in the appreciation and treatment of sacroiliac joint (SIJ) complex pain, including anatomical dissections that shed light on innervation, an appreciation for the contribution of extra-articular components to SIJ complex pain, the advent of radiofrequency ablation (RFA) and a host of minimally invasive surgical techniques. Yet, there is no standardization on diagnosis and treatment paradigms. Methods In February 2023, the Boards of Directors for the American Academy of Pain Medicine (AAPM) and American Society of Regional Anesthesia & Pain Medicine (ASRA-PM) approved the development of multispecialty guidelines on SIJ complex pain. Thirty partner organizations with clinical and scientific interests in SIJ complex pain were identified, and formal letters of request-for-participation were sent to each, along with a request for nominees to serve on the committee. Twenty five organizations agreed to participate in addition to the Departments of Defense and Veterans Affairs. A steering committee developed 21 questions, which spanned criteria for diagnosis, non-interventional and interventional treatments including surgery, technical parameters on how to optimize results, and what constitutes positive outcomes. Questions were methodically assigned to specialized modules comprising 4-5 members with complementary expertise, who collaborated with the Subcommittee Lead and one of three Committee Chairs to develop preliminary drafts. Following thorough revisions, these drafts were subsequently submitted to the full committee for comprehensive review. A modified Delphi method was used in which the answers to questions were sent to the committee en bloc and comments were returned in a non-blinded fashion to the Chairs, who incorporated the comments and sent out revised versions until consensus was achieved. During a committee meeting before commencement, it was agreed that recommendations would be noted when there was >50% agreement among committee members, but that a formal recommendation would require ≥75% consensus. Results Twenty-one organizations formally endorsed the guidelines. The American Society of Anesthesiologists, and American Academy of Physical Medicine & Rehabilitation, and the North American Spine Society affirmed the benefit of the guidelines but did not officially endorse them. The American Academy of Neurology declined to affirm the benefit of the guidelines citing “lack of relevance to their membership.” Per policies, while the Departments of Defense and Veterans Affairs did not formally review the guidelines for endorsement, their representatives approved them. In addition to being endorsed or the benefit affirmed by all voting organizations, complete consensus from committee members was obtained on all 21 questions. On 2 recommendations, there were dissensions from 3 societies who thought that selecting patients for sacral lateral branch RFA and minimally invasive fusion should be based on ≥75% relief from 2 blocks instead of at least 50% relief from a single block before RFA, and greater than 50% pain relief with documented functional improvement after a single block before fusion. One additional society (Latin American Society of Regional Anesthesia) abstained on the statement that the evidence is stronger for extra-articular than intra-articular injections. The committee found that a battery of physical exam tests has reasonable sensitivity, but lower specificity, for identifying intra-articular but not extra-articular pathology, with negative tests having greater predictive value than positive ones. Intra-articular injections have diagnostic validity for SIJ intra-articular, but not extra-articular pain. There is unclear or negative evidence for imaging. The prevalence rates of intra-articular and extra-articular pathology are comparable, with both intra- and extra-articular steroid injections providing at least 4 weeks of relief in well-selected patients. However, the evidence is slightly stronger for extra-articular corticosteroid injections to provide short-term relief. The evidence base for non-interventional therapies is indirect, extrapolated mostly from low back pain studies. There is weak evidence supporting dextrose-based prolotherapy and platelet-rich plasma to provide at least 3 months of pain relief. There is strong evidence for sacral lateral branch RFA to provide relief for at least 6 months in individuals with extra-articular pathology, with face validity and indirect evidence from randomized trials supporting sacral lateral branch blocks as a prognostic tool. There is stronger evidence for larger lesions or more aggressive lesioning strategies than for less stringent techniques. There is weak evidence to support non-steroidal anti-inflammatory drugs to prevent neuritis after RFA, and in most cases anticoagulation does not require cessation in the periprocedural perioid. With an aggressive lesioning strategy, sensory stimulation provides minimal therapeutic benefit, with weak, extrapolated evidence that motor stimulation can provide safety benefit. The cutoff to designate diagnostic or prognostic blocks as positive is most commonly set at 50%, with higher values not shown to improve outcomes for more definitive procedures; for therapeutic treatment outcomes, the evidence supports a lower threshold of ≥30% pain relief or meaningful benefit on non-pain outcomes (eg, opioid cessation) for designation of a positive response. For carefully selected patients with intra-articular SIJ complex pain based on controlled blocks who have failed conservative therapies, there is weak or very weak evidence that minimally invasive SIJ fusion can provide benefit for at least one year. Conclusions SIJ complex pain remains an underappreciated source of chronic low back pain, affecting between 15% and 30% of patients with axial pain predominantly below L5. Answers to many questions were limited by low-quality evidence, indicating the need for better research. SIJ complex pain is a multifarious condition (ie, pain can be from different portions of both the intra- and extra-articular components of the joint) for which an interdisciplinary, multimodal treatment plan can optimize treatment outcomes.