Citations

Abstract Lack of robust activation of Stimulator of Interferon Genes (STING) pathway and subsequent induction of type I IFN responses is considered a barrier to antitumor immunity in acute myeloid leukemia (AML). Using common human AML cell lines as in vitro tools to evaluate the efficacy of novel STING agonists, we found most AML lines to be poor producers of IFNs upon exposure to extremely potent agonists, suggesting cell-intrinsic suppression of STING signaling may occur. We observed unexpected patterns of response that did not correlate with levels of STING pathway components or of known enzymes associated with resistance. To identify a genetic basis for these observations, we cloned and sequenced STING from the cDNA of human AML cell lines and found both frequent mutations and deviations from normal RNA splicing. We identified two novel spliced isoforms of STING in these lines and validated their expression in primary human AML samples. When transduced into reporter cells, these novel STING isoforms exhibited complete insensitivity to agonist stimulation. These observations identify alternative splicing as a mechanism of STING pathway suppression and suggest that most AML silences the STING pathway through direct modification rather than through engagement of external inhibitory factors. Significance: We find that AML acquires resistance to innate immune activation via the STING pathway through aberrant splicing of the STING transcript including two novel forms described herein that act as dominant negatives. These data broaden understanding of how cancers evolve STING resistance, and suggest that the AML tumor microenvironment, not the cancer cell, should be the target of therapeutic interventions to activate STING.

Abstract Introduction Patients living in rural areas have worse cancer‐specific outcomes. This study examines the effect of family‐based social capital on genitourinary cancer survival. We hypothesized that rural patients with urban relatives have improved survival relative to rural patients without urban family. Methods We examined rural and urban based Utah individuals diagnosed with genitourinary cancers between 1968 and 2018. Familial networks were determined using the Utah Population Database. Patients and relatives were classified as rural or urban based on 2010 rural–urban commuting area codes. Overall survival was analyzed using Cox proportional hazards models. Results We identified 24,746 patients with genitourinary cancer with a median follow‐up of 8.72 years. Rural cancer patients without an urban relative had the worst outcomes with cancer‐specific survival hazard ratios (HRs) at 5 and 10 years of 1.33 (95% CI 1.10–1.62) and 1.46 (95% CI 1.24–1.73), respectively relative to urban patients. Rural patients with urban first‐degree relatives had improved survival with 5‐ and 10‐year survival HRs of 1.21 (95% CI 1.06–1.40) and 1.16 (95% CI 1.03–1.31), respectively. Conclusions Our findings suggest rural patients who have been diagnosed with a genitourinary cancer have improved survival when having relatives in urban centers relative to rural patients without urban relatives. Further research is needed to better understand the mechanisms through which having an urban family member contributes to improved cancer outcomes for rural patients. Better characterization of this affect may help inform policies to reduce urban–rural cancer disparities.

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of FLT3 ( FLT3-ITD) AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202 ) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit. METHODS Adults with FLT3-ITD AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS. RESULTS Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P = .0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = .575). CONCLUSION Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable FLT3-ITD MRD pre- or post-HCT who received gilteritinib treatment. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.

Objective To investigate the optimal number of induction chemotherapy cycles needed to achieve a pathological response in patients with clinically lymph node‐positive (cN+) bladder cancer (BCa) who received three or four cycles of induction chemotherapy followed by consolidative radical cystectomy (RC) with pelvic lymph node dissection. Patients and Methods We included 388 patients who received three or four cycles of cisplatin/gemcitabine or (dose‐dense) methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), followed by consolidative RC for cTanyN1–3M0 BCa. We compared pathological complete (pCR = ypT0N0) and objective response (pOR = yp ≤T1N0) between treatment groups. Predictors of pCR and/or pOR were assessed using uni‐ and multivariable logistic regression analysis. The secondary endpoints were overall (OS) and cancer‐specific survival (CSS). We evaluated the association between the number of induction chemotherapy cycles administered and survival outcomes on multivariable Cox regression. Results Overall, 101 and 287 patients received three or four cycles of induction chemotherapy, respectively. Of these, 72 (19%) and 128 (33%) achieved pCR and pOR response, respectively. The pCR (20%, 18%) and pOR (40%, 31%) rates did not differ significantly between patients receiving three or four cycles ( P > 0.05). The number of cycles was not associated with pCR or pOR on multivariable logistic regression analyses. The 2‐year OS estimates were 63% (95% confidence interval [CI] 0.53–0.74) and 63% (95% CI 0.58–0.7) for patients receiving three or four cycles, respectively. Receiving three vs four cycles was not associated with OS and CSS on uni‐ or multivariable Cox regression analyses. Conclusion Pathological response and survival outcomes did not differ between administering three or four induction chemotherapy cycles in patients with cN+ BCa. A fewer cycles (minimum three) may be oncologically sufficient in patients with cN+ BCa, while decreasing the wait for definitive local therapy in those patients who end up without a response to chemotherapy. This warrants further validation.

Abstract Patients treated with antineoplastic therapy often develop thrombocytopenia requiring platelet transfusion, which has potential to exacerbate pulmonary injury. This study tested the hypothesis that amotosalen-UVA pathogen–reduced platelet components (PRPCs) do not potentiate pulmonary dysfunction compared with conventional platelet components (CPCs). A prospective, multicenter, open-label, sequential cohort study evaluated the incidence of treatment-emergent assisted mechanical ventilation initiated for pulmonary dysfunction (TEAMV-PD). The first cohort received CPC. After the CPC cohort, each site enrolled a second cohort transfused with PRPC. Other outcomes included clinically significant pulmonary adverse events (CSPAE) and the incidence of treatment-emergent acute respiratory distress syndrome (TEARDS) diagnosed by blinded expert adjudication. The incidence of TEAMV-PD in all patients (1068 PRPC and 1223 CPC) was less for PRPC (1.7 %) than CPC (3.1%) with a treatment difference of –1.5% (95% confidence interval [CI], –2.7 to –0.2). In patients requiring ≥2 PCs, the incidence of TEAMV-PD was reduced for PRPC recipients compared with CPC recipients (treatment difference, –2.4%; 95% CI, –4.2 to –0.6). CSPAE increased with increasing PC exposure but were not significantly different between the cohorts. For patients receiving ≥2 platelet transfusions, TEARDS occurred in 1.3% PRPC and 2.6% CPC recipients (P = .086). Bayesian analysis demonstrated PRPC may be superior in reducing TEAMV-PD and TEARDS for platelet transfusion recipients compared with CPC recipients, with 99.2% and 88.8% probability, respectively. In this study, PRPC compared with CPC demonstrated high probability of reduced severe pulmonary injury requiring assisted mechanical ventilation in patients with hematology disorders dependent on platelet transfusion. This trial was registered at www.ClinicalTrials.gov as #NCT02549222.

Introduction and importance: Reports are limited on video-assisted thoracoscopic surgery for lung malignancy of patients with situs inversus totalis (SIT). Patients with SIT have significant anatomic differences with implications that are important for surgery, anesthesia, and nursing to understand in order to provide care for this patient population. Case presentation: A 64-year-old man with SIT and lung adenocarcinoma needed flexible bronchoscopy and wedge resection of a 9×8 mm adenocarcinoma in the right upper lobe and underwent video-assisted thoracoscopic surgery. Clinical discussion: Preoperative planning, including collaboration with the surgical team, allowed safe monitoring, induction of anesthesia, and airway isolation in this patient allowing them to have successful resection of their pulmonary malignancy. Postoperative care was enhanced by detailed communication and understanding of the patient’s anatomy and implications of this condition for post anesthesia care unit nursing care. Conclusion: Patients with rare clinical conditions and backgrounds may require surgical and anesthetic intervention. The authors describe important anesthetic considerations of preoperative evaluation, airway management, cardiac monitoring, and vascular access that should be noted and taken into account for patients with SIT. Proper preparation, planning, and communication allow for patients with SIT to safely undergo surgical procedures.

Background: Multisegmental pathologic autofusion occurs in patients with ankylosing spondylitis (AS) and diffuse idiopathic skeletal hyperostosis (DISH). It may lead to reduced vertebral bone density due to stress shielding. Methods: This study aimed to determine the effects of autofusion on bone density by measuring Hounsfield units (HU) in the mobile and immobile spinal segments of patients with AS and DISH treated at a tertiary care center. The mean HU was calculated for five distinct regions—cranial adjacent mobile segment, cranial fused segment, mid-construct fused segment, caudal fused segment, and caudal adjacent mobile segment. Means for each region were compared using paired-sample t-tests. Multivariable regression was used to determine independent predictors of mid-fused segment HUs. Results: One hundred patients were included (mean age 76 ± 11 years, 74% male). The mean HU for the mid-construct fused segment (100, 95% CI [86, 113]) was significantly lower than both cranial and caudal fused segments (174 and 108, respectively; both p < 0.001), and cranial and caudal adjacent mobile segments (195 and 115, respectively; both p < 0.001). Multivariable regression showed the mid-construct HUs were predicted by history of smoking (−30 HU, p = 0.009). Conclusions: HUs were significantly reduced in the middle of long-segment autofusion, which was consistent with stress shielding. Such shielding may contribute to the diminution of vertebral bone integrity in AS/DISH patients and potentially increased fracture risk.

Background Comparative evaluations of preventive migraine treatments can help inform clinical decision making for managing migraine in clinical practice. Methods An anchored matching-adjusted indirect comparison analysis was conducted using pooled participant-level data from two phase 3 atogepant trials (ADVANCE and PROGRESS) and one phase 2/3 rimegepant trial (BHV3000-305) to evaluate the relative efficacy and safety/tolerability of atogepant and rimegepant as preventive migraine treatments. Participants receiving atogepant 60 mg once daily, rimegepant orally disintegrating tablet 75 mg once every other day, and placebo were included. Only participants meeting the BHV3000-305 inclusion/exclusion criteria were analyzed: ≥6 monthly migraine days and ≤18 monthly headache days at baseline. The primary efficacy assessment of interest was change in monthly migraine days across weeks 1–12. Results There were 252 participants in the atogepant group and 348 in the rimegepant group. Across weeks 1–12, atogepant 60 mg demonstrated a significantly greater reduction in mean monthly migraine days compared with rimegepant 75 mg (mean difference [95% CI]: −1.65 [−2.49, −0.81]; p < 0.001). Both atogepant and rimegepant demonstrated similar safety/tolerability profiles. Conclusion In this matching-adjusted indirect comparison analysis, oral atogepant 60 mg once daily demonstrated a significantly greater reduction in monthly migraine days compared with rimegepant 75 mg orally disintegrating tablet once every other day.

Abstract Background: Mechanical thrombectomy (MT) has revolutionized the treatment of acute ischemic stroke (AIS) due to large vessel occlusion (LVO), but its efficacy and safety in medium vessel occlusion (MeVO) remain less explored. This multicenter, retrospective study aims to investigate the incidence and clinical outcomes of vessel perforations (confirmed by extravasation during an angiographic series) during MT for AIS caused by MeVO. Methods: Data were collected from 37 academic centers across North America, Asia, and Europe between September 2017 and July 2021. A total of 1373 AIS patients with MeVO underwent MT. Baseline characteristics, procedural details, and clinical outcomes were analyzed. Results: The incidence of vessel perforation was 4.8% (66/1373). Notably, our analysis indicates variations in perforation rates across different arterial segments: 8.9% in M3 segments, 4.3% in M2 segments, and 8.3% in A2 segments (p = 0.612). Patients with perforation had significantly worse outcomes, with lower rates of favorable angiographic outcomes (TICI 2c-3: 23% vs 58.9%, p &lt; 0.001; TICI 2b-3: 56.5% vs 88.3%, p &lt; 0.001). Functional outcomes were also worse in the perforation group (mRS 0–1 at 3 months: 22.7% vs 36.6%, p = 0.031; mRS 0–2 at 3 months: 28.8% vs 53.9%, p &lt; 0.001). Mortality was higher in the perforation group (30.3% vs 16.8%, p = 0.008). Conclusion: This study reveals that while the occurrence of vessel perforation in MT for AIS due to MeVO is relatively rare, it is associated with poor functional outcomes and higher mortality. The findings highlight the need for increased caution and specialized training in performing MT for MeVO. Further prospective research is required for risk mitigation strategies.

Right ventricular failure (RVF) is a significant cause of mortality in patients undergoing left ventricular assist device (LVAD) implantation. Although right ventricular assist devices (RVADs) can treat RVF in the perioperative LVAD period, liberal employment before RVF is not well established. We therefore compared the survival outcomes between proactive RVAD placement at the time of LVAD implantation with a bailout strategy in patients with RVF. Retrospectively, 75 adult patients who underwent durable LVAD implantation at our institution and had an RVAD placed proactively before LVAD implantation or as a bailout strategy postoperatively due to hemodynamically unstable RVF were evaluated. Patients treated with a proactive RVAD strategy had lower Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) and a higher proportion of these required temporary mechanical circulatory support (MCS) preoperatively. Preoperative hemodynamic profiling showed a low pulmonary artery pulsatility index (PAPi) score of 1.8 ± 1.4 and 1.6 ± 0.94 (p = 0.42) in the bailout RVAD and proactive RVAD groups, respectively. Survival at 3, 6, and 12 months post-LVAD implantation was statistically significantly higher in patients who received a proactive RVAD. Thus, proactive RVAD implantation is associated with short- and medium-term survival benefits compared to a bailout strategy in RVF patients undergoing LVAD placement.