Patient Selection Strategies Research Articles

Current Trends in Neurosurgical Management of Adult Diffuse Low-Grade Gliomas in Canada.

There is considerable variability in the management of diffuse low-grade gliomas (LGGs). To characterize treatment paradigms, a survey of Canadian neurosurgeons was performed with forty neurosurgeons responding. Their responses show that the management of patients with LGGs has evolved in the past decade and findings from the RTOG9802 trial have been integrated into the practice of Canadian neurosurgeons. Most respondents stated that the patient selection and treatment strategy advocated by the RTOG9802 trial needs further evaluation. Overall, there is a trend toward more aggressive surgical resections, and future investigations will have to more accurately stratify patient risk profiles.

Selected Articles from This Issue

Despite the proven benefits of antibody-based therapies for HER2-amplified cancers, there remains an urgent need for novel therapeutic approaches to combat acquired and innate drug resistance. Here, O'Brien and colleagues demonstrate that tucatinib, a small molecule inhibitor of HER2, has selective activity in HER2-driven cancers. Tucatinib showed single agent and combined efficacy with trastuzumab and inhibitors of CDK4/6 in cell line xenograft models. The selective nature of tucatinib make it an ideal combination partner for HER2-based therapies. Data presented here provide insight into the optimal patient selection and combination strategies for the expanded clinical development of tucatinib.Head and neck squamous cell carcinoma (HNSCC) is a common cancer with limited treatment options. Recent clinical trials in patients with HRAS-mutant HNSCC have shown the efficacy of tipifarnib, a farnesyl transferase inhibitor (FTI) that blocks a required posttranslational modification of HRAS and other proteins. Here, Javaid and colleagues have validated HRAS as a key therapeutic target of tipifarnib and identified multiple signaling pathways that could cause treatment resistance. Combining FTI with an ERK inhibitor blocked compensatory signaling changes, enhancing the efficacy of FTI and showing that this combination could be a promising treatment strategy for patients with HRAS-mutant HNSCC.Pancreatic ductal adenocarcinoma (PDAC) is the most RAS-addicted of all cancers and development of anti-RAS therapies is a major priority. RRSP-DTB is an engineered biologic with specific RAS proteolytic activity. Vidimar and colleagues conducted a study to assess in vitro RAS degradation and in vivo activity of RRSP-DTB in RAS-driven PDAC models. As a single agent, RRSP-DTB effectively degraded RAS in cells and engaged RAS in mice leading to nearly complete regression of PDAC patient-derived xenografts without development of resistance. These results support further study of RRSP-DTB as an unprecedented RAS biodegrader for RAS-addicted tumors.Clinical outcomes in FLT3-mutant acute myeloid leukemia (AML) remain exceedingly poor due to FLT3 tyrosine kinase inhibitor (TKI) resistance. FF-10101 is the first covalent FLT3 inhibitor and recently completed phase I clinical evaluation. Here, Ferng and colleagues profile FF-10101 against a panel of FLT3 TKI resistance-mutations and off-target resistance mechanisms. FF-10101 suppresses all clinically described on-target mutations but not those that compromise covalent binding to FLT3. FF-10101 also exhibits activity in an in vitro model of cytokine-driven TKI resistance. Thus, FF-10101 shows the potential to benefit AML patients already treated with existing FLT3 TKIs or patients harboring certain FLT3 mutations.

Valve-Preserving Root Reimplantation Combined with Arch Procedure: Optimizing Patient Selection.

Objective: Patients with thoracic aortic disease commonly present with concomitant multisegment pathology. We describe the patient population, analyze outcomes, and define the patient selection strategy for valve-preserving aortic root reimplantation (VPARR) combined with the arch procedure. Methods: From 2008 to 2018, 98 patients underwent VPARR combined with the aortic arch procedure (hemi-arch, 50% [n = 49, limited repair]; total arch, 50% [n = 49, complete repair] including 39 with elephant trunk). Indications for surgery were aneurysmal disease (61%) and aortic dissection (39%). The median follow-up was 17 months (IQR, 8 to 60 months). Results: There were no operative deaths or paraplegia, and 5 patients underwent re-exploration for bleeding. During follow-up, 2 patients required aortic valve replacement for severe aortic insufficiency at 1 and 5 years, and 4 patients died. In the limited repair group, 1 patient underwent reintervention for aortic arch replacement, whereas 4 patients underwent planned intervention (1 endovascular and 3 open thoracoabdominal aortic repair). In the complete repair group, 23 patients underwent planned intervention (15 endovascular and 8 open thoracoabdominal repair). Conclusions: Single-stage, complete, proximal aortic repair including VPARR combined with total aortic arch replacement is as safe and feasible to perform as limited arch repair and facilitates further intervention in carefully selected patients with diffuse aortic pathology at centers of expertise.

Impella to Treat Acute Myocardial Infarct-Related Cardiogenic Shock.

Acute myocardial infarction complicated by cardiogenic shock (AMICS), is characterized by critically low cardiac output and decreased myocardial contractility. In this situation, a treatment that unloads the myocardium and restores CO without increasing the myocardial oxygen demand is theoretically appealing. Axial flow pumps offer hemodynamic support without increasing myocardial oxygen consumption. Consequently, the use of axial flow pumps, especially the Impella devices, is increasing. It is likely that the SCAI C patient with predominantly left ventricular failure and without prolonged cardiac arrest is the best candidate for these devices. Registry data suggest that pre-PCI Impella may be advantageous to post-PCI placement. However, several gaps in knowledge exist regarding optimal patient selection, futility criteria, timing, weaning and escalation strategy, and until data from adequately sized randomized trials are available, immediate individual evaluation for mechanical circulatory support by a shock team is warranted when a patient is diagnosed with AMICS.

Mohs micrographic surgery revisited: A multidisciplinary, collaborative approach for the treatment of aggressive and recurrent basal cell carcinoma on the head and neck

Mohs micrographic surgery is the preferred surgical option for high-risk basal cell carcinomas. In our institution, the method is exclusively used for the treatment of aggressive and recurrent facial tumours selected via multidisciplinary team meetings and consistently managed using a multidisciplinary approach. The aim of this retrospective patient-record study was to examine the outcomes for basal cell carcinomas managed with Mohs micrographic surgery and to present our experience from multidisciplinary team meetings and interdisciplinary collaborations. All patients treated between September 2009 and March 2019 at Karolinska University hospital were included. In a total of 143 facial basal cell carcinomas in 138 patients, 86 primary and 57 recurrent, the recurrence rate was 4.9% after a median follow-up of 24 months. In regions, where highly specialised Mohs surgeons performing all the steps of the procedure are limited, interdisciplinary collaboration can be an effective strategy for appropriate patient selection and for performing all steps of Mohs surgery with dermatosurgeons eradicating the tumour, pathologists evaluating the histopathology, followed by reconstructive surgery by plastic surgeons. The approach we present here provides a robust and functioning Mohs surgical service during the build-up of the organisation, while providing the opportunity to train new surgeons. Once the clinic has been set up, the multidisciplinary approach should always be considered and applied when dealing with complex cases.

Patient selection strategies in an intensive primary care program

BackgroundIntensive primary care programs have had variable impacts on clinical outcomes, possibly due to a lack of consensus on appropriate patient-selection. The US Veterans Health Administration (VHA) piloted an intensive primary care program, known as Patient Aligned Care Team Intensive Management (PIM), in five medical centers. We sought to describe the PIM patient selection process used by PIM teams and to explore perspectives of PIM team members regarding how patient selection processes functioned in context. MethodsThis study employs an exploratory sequential mixed-methods design. We analyzed qualitative interviews with 21 PIM team and facility leaders and electronic health record (EHR) data from 2,061 patients screened between July 2014 and September 2017 for PIM enrollment. Qualitative data were analyzed using a hybrid inductive/deductive approach. Quantitative data were analyzed using descriptive statistics. ResultsOf 1,887 patients identified for PIM services using standardized criteria, over half were deemed inappropriate for PIM services, either because of not having an ambulatory care sensitive condition, living situation, or were already receiving recommended care. Qualitative analysis found that team members considered standardized criteria to be a useful starting point but too broad to be relied on exclusively. Additional data collection through chart review and communication with the current primary care team was needed to adequately assess patient complexity. Qualitative analysis further found that differences in conceptualizing program goals led to conflicting opinions of which patients should be enrolled in PIM. ConclusionsA combined approach that includes clinical judgment, case review, standardized criteria, and targeted program goals are all needed to support appropriate patient selection processes.

Age Does Not Matter: Utilization of Veno-Arterial Extracorporeal Membrane Oxygenation for Massive Pulmonary Embolism in the Elderly Population

<h3>Purpose</h3> Management of massive and submassive pulmonary embolism (PE) remains a challenge. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a useful strategy in select patients with pulmonary emboli (PE) to provide hemodynamic support; however, age remains a relative contraindication based on prior literature as safety is controversial. <h3>Methods</h3> We retrospectively reviewed all patients with pulmonary emboli who were placed on peripheral VA-ECMO from 2015- 2021 at a single institution. Patients were identified and stratified into two groups with an age cutoff of 65 years of age. Demographics, pre-cannulation data, ECMO data, and echocardiographic results were obtained. Primary endpoints included 30-day, 6-month, and one-year survival. <h3>Results</h3> Sixty-nine patients <65 years of age (median age 58) and twenty patients ≥65 of age (median age 69) received VA-ECMO for PE. Hypertension incidence was higher in the ≥65 group; there were no differences in sex, BMI, pre-cannulation arrest, or in pre-cannulation ejection fraction or presence of right ventricular dysfunction. The median duration on ECMO was 5 days in both groups (p=0.503). 14.5% (10/69) of patients <65 and 25.0% (5/20) of patients ≥65 required surgical embolectomy after 5-7 days of VA-ECMO support (p=0.313). There was no difference in 30-day survival (91.3% (63/69, A) in <65 vs 90.0% (18/20) in ≥65, p=<0.999), 6-month survival (92.3% (60/65) in <65 vs 85% (17/20) in ≥65, p=0.385), and one-year survival (92.1% (58/63, B) in <65 vs 83.3% (15/18) in ≥65, p=0.367). There was no difference in ICU or hospital length of stay, need for renal replacement therapy, and rate of stroke between the groups. <h3>Conclusion</h3> There is no difference in 30-day, 6-month, or one-year survival in patients with a PE who are supported with VA-ECMO as compared to younger patients in our experience. As such, age should not be a contraindication for VA-ECMO use for cardiopulmonary support in management of pulmonary embolism.

Patient-activated anti-tachycardia pacing in adult congenital heart disease.

IntroductionIn adults with congenital heart disease, intra‐atrial reentrant tachycardia (IART) is a common arrhythmia that causes significant morbidity and mortality. One treatment option for IART is antitachycardia pacing. Atrial antitachycardia pacing algorithms deliver therapy for IART with ≥2:1 conduction, but most algorithms will not recognize IART with 1:1 conduction. Temporary Patient Activated Rx (TPARx) is Medtronic software that can be installed in antitachycardia pacemakers allowing patients to deliver therapies on demand for IART with 1:1 conduction.MethodsRetrospective chart review at a single institution of all patients who had TPARx installed into their pacemaker.ResultsFour adults with single ventricle congenital heart disease and IART underwent Fontan conversion, arrhythmia surgery, and placement of an epicardial dual‐chamber antitachycardia pacemaker. They had recurrent IART with a long cycle length and 1:1 conduction that failed to trigger antitachycardia pacing therapies. TPARx software was programmed into their pacemakers to allow recognition and treatment of IART with 1:1 conduction. Mean follow‐up duration after TPARx programming was 4.9 years. Each patient received at least one successful antitachycardia pacing therapy via TPARx – range 0.4–26 treated IART episodes per year. There were no atrial or ventricular arrhythmias induced with antitachycardia pacing. Two patients were able to discontinue anticoagulation after TPARx installation.ConclusionThis series demonstrates the use of TPARx software as part of a long‐term IART management strategy in select patients with IART who have failed more conventional therapies.

One-Year Outcomes With Venovenous Extracorporeal Membrane Oxygenation Support for Severe COVID-19

BackgroundSevere coronavirus disease 2019 (COVID-19) can cause acute respiratory failure requiring mechanical ventilation. Venovenous (VV) extracorporeal membrane oxygenation (ECMO) has been used in patients in whom conventional mechanical ventilatory support has failed. To date, published data have focused on survival from ECMO and survival to discharge. In addition to survival to discharge, this study reports 1-year follow-up data for patients who were successfully discharged from the hospital. MethodsA single-institution, retrospective review of all patients with severe COVID-19 who were cannulated for VV-ECMO between March 10, 2020 and May 1, 2020 was performed. A multidisciplinary ECMO team evaluated, selected, and managed patients with ECMO support. The primary outcome of this study was survival to discharge. Available 1-year follow-up data are also reported. ResultsA total of 30 patients were supported with VV-ECMO, and 27 patients (90%) survived to discharge. All patients were discharged home or to acute rehabilitation on room air, except for 1 patient (3.7%), who required supplemental oxygen therapy. At a median follow-up of 10.8 months (interquartile range [IQR], 8.9-14.4 months) since ECMO cannulation, survival was 86.7%, including 1 patient who underwent lung transplantation. Of the patients discharged from the hospital, 44.4% (12/27) had pulmonary function testing, with a median percent predicted forced expiratory volume of 100% (IQR, 91%-110%). For survivors, a 6-minute walk test was performed in 59.3% (16/27), with a median value of 350 m (IQR, 286-379 m). ConclusionsA well-defined patient selection and management strategy of VV-ECMO support in patients with severe COVID-19 resulted in exceptional survival to discharge that was sustained at 1-year after ECMO cannulation.

Active surveillance in favorable intermediate risk prostate cancer: outstanding questions and controversies.

Active surveillance has become the preferred management strategy for patients with low risk prostate cancer, but it is unclear if active surveillance can be safely extended to favorable intermediate risk (FIR) prostate cancer patients. Furthermore, defining a favorable intermediate risk prostate cancer population safe for active surveillance remains elusive due to paucity of high-level data in this population. This article serves to review relevant data, particularly the safety of active surveillance in grade group 2 patients, and what tools are available to aid in selecting a favorable subset of intermediate risk patients. Active surveillance studies with long-term data appear to report worsened survival outcomes in intermediate risk patients when compared to those undergoing definitive treatment, but there exists a subset of intermediate risk patients with nearly equivalent outcomes to low risk patients on active surveillance. Tools such as percentage and total length of Gleason pattern 4, tumor volume, prostate specific antigen density, magnetic resonance imaging, and genomic modifiers may help to select a favorable subset of intermediate risk prostate cancer appropriate for active surveillance. Active surveillance is a viable strategy in select patients with low volume group grade 2 (GG2) prostate cancer. Prospective and retrospective data in the FIR population appear to be mostly favorable in regards to survival outcomes, but there exists some heterogeneity with respect to long-term outcomes in this patient population.

Implantation of transjugular intrahepatic portosystemic shunt (TIPS): indication and patient selection.

This review summarizes indications and contraindications for implantation of transjugular intrahepatic portosystemic shunt (TIPS). Further, patient selection strategies are discussed. TIPS implantation is a highly effective treatment for portal hypertension. Main indications are ascites and variceal bleeding in patients with liver cirrhosis. There is growing evidence that early TIPS implantation after variceal bleeding is associated with an improved survival (preemptive TIPS).Preliminary data also suggest that an analogous concept of early TIPS implantation may be beneficial for patients with ascites. Further, well-selected patients with acute or chronic nonmalignant portal vein thrombosis can be effectively treated with TIPS implantation. In contrast, there is generally no recommendation for TIPS implantation in patients with hepatic veno-occlusive disease, noncirrhotic portal hypertension or prior before surgery to avoid complications of portal hypertension. Apart from evidence-based patient selection, the newly developed FIPS score can be an objective component in decision-making. Consideration of well-established indications and contraindications for TIPS implantation as well as concise patient selection criteria are essential for an optimal outcome after TIPS implantation.

PLK1 inhibition selectively induces apoptosis in ARID1A deficient cells through uncoupling of oxygen consumption from ATP production.

Inhibitors of the mitotic kinase PLK1 yield objective responses in a subset of refractory cancers. However, PLK1 overexpression in cancer does not correlate with drug sensitivity, and the clinical development of PLK1 inhibitors has been hampered by the lack of patient selection marker. Using a high-throughput chemical screen, we discovered that cells deficient for the tumor suppressor ARID1A are highly sensitive to PLK1 inhibition. Interestingly this sensitivity was unrelated to canonical functions of PLK1 in mediating G2/M cell cycle transition. Instead, a whole-genome CRISPR screen revealed PLK1 inhibitor sensitivity in ARID1A deficient cells to be dependent on the mitochondrial translation machinery. We find that ARID1A knock-out (KO) cells have an unusual mitochondrial phenotype with aberrant biogenesis, increased oxygen consumption/expression of oxidative phosphorylation genes, but without increased ATP production. Using expansion microscopy and biochemical fractionation, we see that a subset of PLK1 localizes to the mitochondria in interphase cells. Inhibition of PLK1 in ARID1A KO cells further uncouples oxygen consumption from ATP production, with subsequent membrane depolarization and apoptosis. Knockdown of specific subunits of the mitochondrial ribosome reverses PLK1-inhibitor induced apoptosis in ARID1A deficient cells, confirming specificity of the phenotype. Together, these findings highlight a novel interphase role for PLK1 in maintaining mitochondrial fitness under metabolic stress, and a strategy for therapeutic use of PLK1 inhibitors. To translate these findings, we describe a quantitative microscopy assay for assessment of ARID1A protein loss, which could offer a novel patient selection strategy for the clinical development of PLK1 inhibitors in cancer.

Cardiac computed tomographic angiography after abnormal ischemia test as a gatekeeper to invasive coronary angiography.

This study aimed to determine the impact of systematic coronary computed tomographic angiography (CCTA) use following an abnormal non-invasive ischemia test (NIST) on patient selection strategy for invasive coronary angiography (ICA).In patients with suspected stable coronary artery disease (CAD), NIST use frequently results in sub-optimal diagnostic and revascularization yields of ICA.This randomized clinical trial, conducted at a single academic tertiary center, selected 220 symptomatic patients with mild-to-moderately abnormal NIST results who were referred for ICA. Patients received either the originally intended ICA (n = 105) or CCTA (n = 115). The primary endpoint was the diagnostic yield of ICA in each group. Revascularization yield and major adverse cardiovascular events at 12 months were also assessed.The patients were 69 ± 9 years old, 60% were men, and 31% had typical angina. Mean pre-test probability of obstructive CAD was 34%. Overall prevalence of obstructive CAD was 37.7% on the index angiographic procedure. In the CCTA group, ICA was cancelled by referring physicians in 83 patients (72.2%) after receiving CCTA results. For those undergoing ICA, diagnostic (84.4% vs. 41.7%, p<0.001) and revascularization (71.9% vs. 38.8%, p = 0.001) yields were significantly higher for CCTA-guided ICA than for standard NIST-guided ICA. Mean cumulative radiation exposure was significantly lower in the CCTA-guided ICA arm than in the NIST-guided ICA arm (12 ± 9 vs. 16 ± 10 mSv, respectively, p = 0.024). There were no significant differences in the primary safety endpoint rates between the strategies (p = 0.439).In patients with suspected CAD and mild-to-moderately abnormal ischemia tests, a diagnostic strategy including CCTA as a gatekeeper is safe and effective and significantly improves diagnostic and revascularization yields of ICA.

Abstract P1-13-03: Radiotherapy vs. endocrine therapy for hormone receptor positive early stage breast cancer accounting for endocrine therapy adherence

Abstract Purpose/Objective(s):. Several trials have compared endocrine therapy (ET) alone vs. ET and radiotherapy (RT) in low risk early stage estrogen receptor (ER)-positive breast cancer and have shown that the addition of RT to ET modestly reduces the rate of loco-regional recurrence (LRR) without altering survival. ET may also yield modest reductions in contralateral breast events. ET alone has thus become a standard strategy in select patients. Data evaluating the efficacy of RT alone are scarce. However, the toxicity of ET is not trivial and its effectiveness is dependent upon treatment adherence. As RT courses become ever shorter and safer, a re-evaluation of the strategy of RT alone is warranted. This analysis reports on the treatment outcomes of ER-positive early stage breast cancer treated with adjuvant RT or ET alone at a multi-hospital health system. We hypothesized that adjuvant RT alone would yield loco-regional control comparable to that of ET alone and that ET adherence would influence outcomes. Materials/Methods:. The shared electronic health record of multiple facilities within a university health system was queried to identify women with pathologic T1-2 N0 breast cancer treated with breast-conserving surgery between 2007 and 2016. Data collection included demographic features, tumor characteristics, treatment type, and evidence of LRR. Analysis was restricted to those patients with ER positive disease who underwent either RT alone or ET alone. Five-year LRR were compared across groups using the Kaplan-Meier method. Results:. 240 patients met inclusion criteria. Of these, 86 were treated with RT alone and 154 with ET alone. Patient, tumor and ET variables are listed in the table below. ET adherence and duration information were available for 135 out of 154 patients who received ET alone. Patients who completed 5 years of ET or whose ET was discontinued due to the disease recurrence or death were categorized as ET-adherence (ET-A). Patients who discontinued ET before reaching 5 years due to other reasons were categorized as ET-non adherence (ET-NA). Median ET duration in ET-A was 60 months (range, 15-101 months) and in ET-NA was 13 months (range, 1-54 months). The 5-year rates of LRR for RT alone vs. ET alone were 4.1 % (95% CI 0-8.8) vs. 5.0 % (95% CI 1.1-8.9). The 5-year rates of LRR for ET-A vs. ET-NA were 2.0 % (95% CI 0-4.7) vs. 16.4 % (95% CI 1.1-31.7). While the difference in the LRR rates between RT alone vs. ET-A was not statistically significant (p= .481), ET-NA was associated with significantly higher LRR rate compared to RT alone or ET-A (p&amp;lt;.05). The rate of ET non-adherent rate was 21.4%. Conclusion:. RT yielded LRR equivalent to overall ET and superior to ET non-adherence. For patients with early stage ER+ breast cancer, a prospective randomized trial comparing RT to ET and evaluating quality of life (QoL) is needed. In light of emerging data, a five-day course of RT can be considered as an alternative to five years of ET, and RT should be strongly considered if ET adherence is in doubt. Table 1.Patient, tumor and treatment characteristicsRT alone (n=86)ET alone (n=154)Median follow-up (months)50.6 (1-135)48 (3-114)Age (median)63 (39-91)74 (50-87)StageT176 (88.4%)142 (92.2%)T210 (11.6%)12 (7.8%)HistologyGrade 38 (9.3%)9 (5.8%)+LVI5 (5.8%)3 (2.0%)Endocrine Therapy (ET)ET duration (median, months)-57 (1-101)ET-Adherent-102 (66.2%)ET-Non adherent-33 (21.4%)ET duration not available-19 (12.3%) Citation Format: Seung Won Seol, Travis Pflederer, Lauren Weller, Chelain Goodman, Eric D Donnelly, John P Hayes, Jonathan B Strauss. Radiotherapy vs. endocrine therapy for hormone receptor positive early stage breast cancer accounting for endocrine therapy adherence [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-13-03.

Immune targets for therapeutic development in depression: towards precision medicine.

Over the past two decades, compelling evidence has emerged indicating that immune mechanisms can contribute to the pathogenesis of major depressive disorder (MDD) and that drugs with primary immune targets can improve depressive symptoms. Patients with MDD are heterogeneous with respect to symptoms, treatment responses and biological correlates. Defining a narrower patient group based on biology could increase the treatment response rates in certain subgroups: a major advance in clinical psychiatry. For example, patients with MDD and elevated pro-inflammatory biomarkers are less likely to respond to conventional antidepressant drugs, but novel immune-based therapeutics could potentially address their unmet clinical needs. This article outlines a framework for developing drugs targeting a novel patient subtype within MDD and reviews the current state of neuroimmune drug development for mood disorders. We discuss evidence for a causal role of immune mechanisms in the pathogenesis of depression, together with targets under investigation in randomized controlled trials, biomarker evidence elucidating the link to neural mechanisms, biological and phenotypic patient selection strategies, and the unmet clinical need among patients with MDD.

Neoadjuvant therapy vs. upfront surgery for resectable pancreatic cancer: An update on a systematic review and meta-analysis.

The effectiveness of neoadjuvant therapy (NAT) remains controversial in the treatment of pancreatic cancer (PC). Therefore, this meta-analysis aimed to investigate the clinical differences between NAT and upfront surgery (US) in resectable pancreatic cancer (RPC). Eligible studies were retrieved from PubMed, Embase, and Cochrane Library. The endpoints assessed were R0 resection rate, pathological T stage < 2 rate, positive lymph node rate, and overall survival. A total of 4,588 potentially relevant studies were identified, and 13 studies were included in this study. In patients with RPC, this meta-analysis showed that NAT presented an increased R0 resection rate, pathological T stage < 2 rate, and a remarkably reduced positive lymph node rate compared to US. However, patients receiving NAT did not result in a significantly increased overall survival. These findings supported the application of NAT, especially as a patient selection strategy, in the management of RPC. Additional large clinical studies are needed to determine whether NAT is superior to US.

Association Between CRP/Albumin Ratio and Long-Term Mortality in Patients With cHronIc Limb-Threatening Ischemia Undergoing EndovaScular Therapy Below The Knee: The ACHILES-BTK Registry

Chronic limb-threatening ischemia (CLTI), which presents with ischemic rest pain, ulceration, or gangrene, is a complex form of peripheral artery disease that can cause mortality and amputation. C-reactive protein (CRP), an inflammatory marker, indicates vascular inflammation resulting from the cytokine-dependent inflammatory process in the arterial wall, and arterial atherosclerosis resulting from the inflammation. Lower albumin levels are also associated with peripheral artery disease. We investigated the association between CRP/Albumin ratio (CAR) and long-term mortality in patients with CLTI. A total of 172 patients who underwent endovascular treatment (EVT) for below the knee (BTK) lesions were enrolled in this study. Patients with acute infection requiring antibiotic therapy, chronic inflammatory disease, end-stage liver disease, malignancy were excluded from the study. Besides, patients with pre-follow-up intervention to the same vascular bed were also excluded from the study. The primary endpoint of the study was all-cause mortality. Patients were divided into 2 groups according to mortality. A total of 70 patients (40.6%) died during 32 ± 21 months of follow-up in the present study. The major amputation rate was 21.5%. The mortality (+) group was older and had higher rates of congestive heart failure, chronic kidney disease, history of stroke, and CRP levels. Moreover, statin and ACE inhibitor/angiotensin receptor blocker (ACE/ARB) use, GFR, and albumin levels were lower in the mortality (+) group. CAR was significantly higher in the mortality (+) group when comparing both groups (3.25 [1.46 - 7.86] vs. 9.75 [4.5 - 17.71], P < 0.001). CAR, congestive heart failure, chronic kidney disease, history of stroke, ACE/ARB, or statin use were independent predictors of all-cause mortality in multivariable Cox regression analysis. CAR was associated with mortality in CLTI patients undergoing EVT for BTK lesions. CAR may be a simple method to help patient selection, assessment, and intervention strategy for EVT and may improve patient outcomes.

Abstract P095: Isogenic CRISPR anchor screens identified actionable nodes to CHK1/2 inhibitor prexasertib in TP53 mutant cancer

Abstract TP53 is the most mutated tumor suppressor gene in human cancers and is a master regulator of a wide array of cellular processes including but not limited to cell cycle progression and DNA damage response. Due to its diverse functions, therapies specifically exploit the vulnerabilities created by TP53 loss remained elusive. We established a panel of TP53 isogenic pair cell line models by knocking out TP53 from WT cell lines and observed that CHK1/2 inhibitor prexasertib showed preferential selectivity toward TP53 KO cell lines. To thoroughly examine additional nodes which could further exploit this selective sensitivity, we carried out genome-wide prexasertib anchor screen in A549 isogenic lines employing CRISPRn, CRISPRi and CRISPRa platforms. From these functional genomics screens, we identified that targeting the anti-folate pathway genes (TYMS, DHFR) showed selective synergy with prexasertib specifically in TP53 KO cells. Secondly, a panel of iron metabolism genes was identified across different CRISPR platforms as candidate TP53 context specific synthetic lethal hits synergize with prexasertib. And lastly, additional sub-context was identified which may inform patient selection strategy for prexasertib as single agent. Citation Format: Teng Teng, Stephen Paik, Shan-chuan Zhao, Ashley Choi, Steven A. Lombardo, Shangtao Liu, Samuel R. Meier, Yi Yu, Jannik N. Anderson, Alan Huang, Fang Li, Xuewen Pan. Isogenic CRISPR anchor screens identified actionable nodes to CHK1/2 inhibitor prexasertib in TP53 mutant cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P095.

Abstract LBA011: Discovery of combination targets of CDK inhibitors from CRISPR screens

Abstract CRISPR/Cas9 functional genetic screens are a powerful tool to discover drug targets in cancer. While many screens have been performed for identification of intrinsic cancer vulnerabilities, synthetic lethalities of targeted therapies remain largely unexplored, despite the fact that they may provide a potential targets and pathways for potential combination therapies, advance understanding of target biology, and hone patient selection strategies. To discover novel combination targets of Palbociclib, a CDK2 inhibitor, and a CDK2,4,6 inhibitor, we have screened a genome-wide CRISPR library in priority tumors with genetic background of interest, including ER+ breast cancer (HCC1428, MCF7), cyclin E amplified breast (HCC1806) and/or ovarian cancer (OVCAR4), and pancreatic cancer cell lines (MIAPACA2, Hs766T, SU8686). We analyzed the samples by condition and compared using MAGeCK-MLE for gene-level drop out and enrichment to identify common sensitizers and resistors to different CDK inhibitors. Differential genes, complexes, and pathways were assessed, and we have found that genes involved in G1/S transition (CyclinE/CDK2) are top Palbo sensitizers and CDK1/CyclinA, CDC25A/B, MuvB complex (MYBL2 and FOXM1) are major CDK2 sensitizing genes. In addition to sensitizers, we have identified genes with strong signals of resistance to CDK inhibitors. Furthermore, we highlighted major mechanisms influencing response to CDK2 inhibitors; 1) Regulation of DREAM may influence response to CDK inhibitors, 2) Regulation of cell cycle check points mediated by CDC25. Our targeted CRISPR KO screens in different CDKi combinations have identified common sensitizers and mediators of resistance to CDK inhibitors, and highlighted biology worthy of deeper consideration and offers opportunities to consider new directions for therapeutic intervention into the cancer cell cycle Citation Format: Kimberly H Kim, Jonathan Almaden, vinu arunachalam, Todd VanArsdale, chaoting liu. Discovery of combination targets of CDK inhibitors from CRISPR screens [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA011.

Effectiveness of Specific Neck Exercise for Nonspecific Neck Pain; Usefulness of Strategies for Patient Selection and Tailored Exercise-A Systematic Review With Meta-Analysis.

Specific neck exercises (SNE) targeting deep cervical flexors and extensors are commonly used for the treatment of nonspecific neck pain (NSNP). However, whether SNE are more effective than alternative exercise interventions (AEI) remains unclear. Furthermore, it has been postulated that SNE may be most effective when they are tailored and targeted to patients with evidence of motor control dysfunction, yet this notion also remains unproven. The objectives of this study were to compare the effectiveness of SNE with that of AEI for reducing pain and disability in people with NSNP and to assess whether the effectiveness of SNE is increased when the exercises are tailored and provided to patients with evidence of motor control dysfunction. For this systematic review with meta-analysis, Medline, Web of Science, Scopus, and Physiotherapy Evidence Database were searched. Eligibility criteria included randomized controlled trials evaluating the effectiveness of SNE against that of AEI in people with NSNP. Meta-analysis included subgroup analyses to determine the effect of exercise tailoring and participant selection criteria on the effectiveness of SNE. Twelve studies were included. Meta-analysis revealed greater effectiveness of SNE in the short to medium term for reducing pain (pooled standardized mean difference [SMD] = -0.41; 95% CI = -0.76 to -0.06; P = .02) and disability (pooled SMD = -0.41; 95% CI = -0.78 to -0.04; P = .03) but no differences in the long term for pain (pooled SMD = -1.30; 95% CI = -3.35 to 0.75; P = .21) and disability (pooled SMD = -1.81; 95% CI = -4.29 to 0.67; P = .15), although evidence was limited for the latter. The effectiveness of SNE was not superior in studies that included only participants with motor control dysfunction or when exercises were tailored to each participant. Overall, the studies were of low quality. Grading of Recommendations Assessment, Development and Evaluation revealed low certainty, serious risk of bias, and inconsistency of findings for short- to medium-term effects and very low certainty, serious risk of bias, and very serious inconsistency for long-term effects. The preferential use of SNE may be recommended to achieve better short- to medium-term outcomes, although the low quality of evidence affects the certainty of these findings. Currently used strategies for selecting patients and tailoring SNE are not supported by the evidence and therefore cannot be recommended for clinical practice. SNE are more effective than AEI for reducing pain and disability in patients with NSNP in the short to medium term, but overall evidence is of low quality, affecting the certainty of the findings. Tests of muscle dysfunction (mostly the craniocervical flexion test) currently used in studies to select patients and tailor SNE do not result in greater effectiveness of these exercises. Evidence suggests SNE are more effective than other forms of exercise, although evidence is overall of low quality. Use of the craniocervical flexion test in isolation to select participants and/or tailor SNE cannot be recommended.