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Background: First‐line treatment in patients with acute myeloid leukemia (AML) unfit for intensive therapy is the combination of a hypomethylating agent (HMA) with venetoclax (VEN). However, retrospective data confirming the benefits of this regimen outside of clinical trials have shown conflicting results. Methods: We performed a multicenter retrospective analysis of outcomes with first‐line HMA–VEN versus HMA in AML patients unfit for intensive chemotherapy. Results: A total of 213 patients were included from three German hospitals (125 HMA–VEN, 88 HMA). Median overall survival in the HMA–VEN cohort was 7.9 months (95% confidence interval [CI], 5.1–14.7) versus 4.9 months (3.1–7.1) with HMA. After 1 year, 42% (95% CI, 33–54) and 19% (12–30) of patients were alive, respectively (hazard ratio [HR] for death, 0.64; 95% CI, 0.46–0.88). After adjusting for clinical and molecular baseline characteristics, treatment with HMA–VEN remained significantly associated with both prolonged survival (HR, 0.48; 95% CI, 0.29–0.77) and time to next treatment (HR, 0.63; 95% CI, 0.47–0.85). Patients who achieved recovery of peripheral blood counts had a favorable prognosis (HR for death, 0.52; 95% CI, 0.33–0.84). Discussion: These data align with findings from the pivotal VIALE‐A trial and support the use of HMA–VEN in patients unfit for intensive therapy. [ABSTRACT FROM AUTHOR]

Patients with lung cancer under treatment have been associated with a high risk of COVID‐19 infection and potentially worse outcome, but real‐world data on patient‐reported outcomes (PROs) are rare. We assess patients' characteristics and PROs before and during the COVID‐19 pandemic in an advanced non‐small cell lung cancer (NSCLC) cohort in Germany. Patients with locally advanced or metastatic NSCLC from the prospective, multicentre, observational CRISP Registry (NCT02622581) were categorised as pre‐pandemic (March 2019 to Feb 2020, n = 1621) and pandemic (March 2020 to Feb 2021, n = 1317). From baseline to month 15, patients' health‐related quality of life (HRQoL) was assessed by FACT‐L, anxiety and depression by PHQ‐4. Association of pandemic status with time to deterioration (TTD) in QoL scales adjusted for potential covariates was estimated using Cox modelling. PROs were documented for 1166 patients (72%) in the pre‐pandemic, 979 (74%) in the pandemic group. Almost 60% of patients were male, median age was 66 years, comorbidities occurred in 85%. Regarding HRQoL, mean‐change‐from‐baseline plots hardly differed between both samples. Approximately 15%–21% of patients reported anxiety, about 19%–27% signs of depression. For the pandemic group, TTD was slightly, but statistically significantly, worse for the physical well‐being‐FACT‐G subscale (HR 1.15 [95%CI 1.02–1.30]) and the anxiety‐GAD‐2 subscale (HR 1.14 [95%CI 1.01–1.29]). These prospectively collected real‐world data provide valuable insights into PROs before and during the COVID‐19 pandemic in advanced NSCLC. For the patients, the pandemic seemed to be less of a burden than the disease itself, as there was a considerable proportion of patients with anxiety and depression in both groups. [ABSTRACT FROM AUTHOR]

Aim: To investigate changes in treatment patterns in extensive-stage small-cell lung cancer (ES-SCLC) in France, Germany, Italy, Spain and the UK (EU5) between 2018 and 2021. Methods: Cross-sectional data from an oncology database were analyzed retrospectively. Results: Of 5832 eligible patients, 88.4% had stage IV disease at diagnosis. Among patients receiving first-line treatment, 91.8% (1079 /1176) received the platinum-etoposide (PE) combination in 2018 which decreased to 42.3% (509/1203) by 2021. Usage of the PE-atezolizumab combination increased from 0 to 41.2% during the same timeframe. Topotecan monotherapy remained the most widely used second-line treatment regardless of patients' platinum sensitivity. Conclusion: The first-line standard of care for ES-SCLC has evolved in EU5 with the PE-atezolizumab/durvalumab combination gradually superseding PE usage. Lung cancer is the leading cause of cancer-related deaths. Small-cell lung cancer (SCLC) is fast-growing type of lung cancer. New treatments for SCLC using medicines that stimulate the immune system to kill cancer cells (called immunotherapies) have recently been approved for use in Europe. The purpose of the study was to describe the type of treatments that patients received in five European countries before and after the introduction of these new treatments to determine how quickly these new treatments were adopted in a real-world setting. This study found that most patients treated between 2018 and 2020 still received a platinum-based chemotherapy as their first anticancer therapy, but immunotherapies were used more often in later years and became the most common first treatment in 2021 for patients who had never been treated for their cancer. Topotecan, a type of chemotherapy, was the most used treatment for patients whose cancer came back after treatment. There is still a clear unmet need for new, safe and effective therapies for the treatment of patients with SCLC whose cancer comes back again after treatment. Real-world data from 5,832 patients with extensive-stage small-cell lung cancer (ES-SCLC) who were treated in France, Germany, Italy, Spain and the UK (EU5) between 2018 and 2021 were analyzed to identify patient characteristics and changes in treatment patterns following the approval of atezolizumab and durvalumab in combination with platinum-etoposide chemotherapy for first-line treatment of ES-SCLC in Europe. Atezolizumab with platinum-etoposide chemotherapy was rapidly adopted as first-line treatment in France, Germany and the UK while the adoption was relatively slower in Italy and Spain. The country-specific differences in the adoption of immunotherapy were potentially related to the different time points at which reimbursement for anti-PD-L1 immunotherapy was initiated in these countries. Topotecan remained the most widely used second-line treatment for patients regardless of platinum sensitivity or the duration of the platinum-free interval after first-line therapy (3–6 months vs ≥6 months). This study highlights the presence of an unmet need for newer treatment options for ES-SCLC in the second-line and beyond. [ABSTRACT FROM AUTHOR]

Objective: Brain tumors and metastases account for approximately 10% of all status epilepticus (SE) cases. This study described the clinical characteristics, treatment, and short- and long-term outcomes of this population. Methods: This retrospective, multi-center cohort study analyzed all brain tumor patients treated for SE at the university hospitals of Frankfurt and Marburg between 2011 and 2017. Results: The 208 patients (mean 61.5 ± 14.7 years of age; 51% male) presented with adult-type diffuse gliomas (55.8%), metastatic entities (25.5%), intracranial extradural tumors (14.4%), or other tumors (4.3%). The radiological criteria for tumor progression were evidenced in 128 (61.5%) patients, while 57 (27.4%) were newly diagnosed with tumor at admission and 113 (54.3%) had refractory SE. The mean hospital length of stay (LOS) was 14.8 days (median 12.0, range 1–57), 171 (82.2%) patients required intensive care (mean LOS 8.9 days, median 5, range 1–46), and 44 (21.2%) were administered mechanical ventilation. All patients exhibited significant functional status decline (modified Rankin Scale) post-SE at discharge (p < 0.001). Mortality at discharge was 17.3% (n = 36), with the greatest occurring in patients with metastatic disease (26.4%, p = 0.031) and those that met the radiological criteria for tumor progression (25%, p < 0.001). Long-term mortality at one year (65.9%) was highest in those diagnosed with adult-type diffuse gliomas (68.1%) and metastatic disease (79.2%). Refractory status epilepticus cases showed lower survival rates than non-refractory SE patients (log-rank p = 0.02) and those with signs of tumor progression (log-rank p = 0.001). Conclusions: SE occurrence contributed to a decline in functional status in all cases, regardless of tumor type, tumor progression status, and SE refractoriness, while long-term mortality was increased in those with malignant tumor entities, tumor progressions, and refractory SE. SE prevention may preserve functional status and improve survival in individuals with brain tumors. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to characterize the fetal buccal fat pad (BFP) on magnetic resonance imaging (MRI) to determine the frequency and types of sequences on which the BFP demonstrates low signal intensity and determine any possible correlation with timing of the MRI during fetal development. Materials and Methods: A retrospective review of all fetal MR studies was performed, and a pediatric radiologist blinded to the referring and final fetal diagnosis as well as outcome evaluated the included cases. A positive buccal fat pad sign (BFS) was recorded as present if a round, symmetric, and bilateral area was seen in the submalar region of the face with the following signal characteristics: T1 hyperintensity, low signal on echo planar imaging (EPI), low signal on true fast imaging with steady-state free precession (TRUFI), and with restriction on diffusion-weighted imaging (DWI). Results: A total of one hundred sixty-seven (167) fetal MRI studies: one hundred fourteen (114) body (68%) and fifty-three (53) neuro (32%) scans were reviewed during the study period. The BFS was most commonly seen on EPI (63%) and TRUFI (49%) sequences. Substantial agreement between TRUFI and EPI (κ = 0.68; p < 0.01); moderate agreement between TRUFI and T1 (κ = 0.53; p < 0.01) as well as T1 and EPI (κ = 0.53; p < 0.01), and fair agreement between EPI and Diffusion (κ = 0.28; p < 0.01) was observed. The median gestational age (GA) was 24 weeks (IQR 22–30 weeks). The fetuses with a positive BFS were significantly older (mean GA of 27 weeks or higher) than those without, for each sequence. Conclusions: The focal low signal in the fetal buccal fat pad, termed the fetal BFS, is a commonly encountered normal finding in the majority of fetal MRI scans on TRUFI and EPI sequences. This finding may be related to the presence and development of brown adipose tissue in the buccal fat pad resulting in T2* effects, but further studies are needed in order to confirm this. Further work can incorporate any of the sensitive sequences demonstrating low signal in brown adipose tissue to map its distribution and development in the fetus and beyond. [ABSTRACT FROM AUTHOR]

Up to 20% of total knee arthroplasty (TKA) patients continue to experience chronic postsurgical pain. Various factors have been identified as potential contributors, including so-called "yellow flags", encompassing symptoms of depression, anxiety, and catastrophizing, which were examined in this study to assess their predictive value concerning functional outcomes after TKA. Methods: Fifty TKA patients were categorized into high-risk and low-risk groups based on clinical assessment, demographic data, medication, and patient-reported outcome measures (DN4, SF-36, WOMAC, NRS, Fibromyalgia Survey Questionnaire, Pain Catastrophizing Scale, and Hospital Anxiety and Depression Scale). Postoperative outcomes within six months after TKA were then compared. Results: Both groups exhibited significant (p < 0.001) improvements in all WOMAC and NRS subscales, as well as in the physical function, role physical, pain, and energy/fatigue subdomains of the SF-36 after six months, while the high-risk group showed lower WOMAC scores regarding stiffness (19.0 ± 18.3 vs. 27.2 ± 20.7, p < 0.001) and pain (13.5 ± 13.3 vs. 15.1 ± 16.3, p = 0.029). The high-risk group showed significantly worse preoperative DN4 scores (1.8 ± 1.3 vs. 3.0 ± 1.1, p = 0.002) than the low-risk group, which persisted for one day (2.3 ± 1.2 vs. 3.5 ± 1.5, p = 0.005) and six weeks (2.2 ± 1.9 vs. 3.6 ± 2.3, p = 0.041) postoperatively. Conclusions: Our results indicate that pre-existing yellow flags contribute to a more challenging early postoperative phase, underscoring the importance of considering individual patient characteristics and psychological factors to optimize TKA outcomes. [ABSTRACT FROM AUTHOR]

Background Neoadjuvant immunochemotherapy is currently being tested in pivotal trials for stage I to III nonsmall cell lung cancer (NSCLC). The impact of immunochemotherapy in patients with oligometastatic disease (OMD) remains undefined. This study aimed to compare the outcomes of radical treatment after the neoadjuvant course of immunochemotherapy versus chemotherapy. Methods We retrospectively analyzed patients with OMD who were treated with immunochemotherapy or chemotherapy combined with local ablation of metastases and radical primary tumor resection between 2017 and 2021. Group A included eight patients with immunochemotherapy; Group B included seven patients with chemotherapy. Descriptive statistical analysis included the characteristics of the patients, tumors, and outcomes. Results There was no difference in postoperative morbidity rates between the groups (p = 0.626). The 30-day mortality in both groups was 0%. The median overall survival for Group A was not reached, with a median follow-up time of 25 (range: 13–35) months; the median overall survival for Group B was 26 (range: 5–53) months. In Group A, all patients remained alive; in contrast, in Group B, four patients died (p = 0.026). There was no local thoracic recurrence in either group. In Group B, the recurrent disease was identified significantly more often (12.5 vs. 85.75%; p = 0.009). The rates of complete and major pathologic response were 37.5 and 0% in Group A and 42.85 and 14.25% in Group B, respectively. Conclusion Despite the small patient number and short-term results, the progression-free and overall survival in patients with OMD after local therapy for metastases and primary tumor resection following a neoadjuvant course of immunochemotherapy might be promising compared with chemotherapy. [ABSTRACT FROM AUTHOR]

This study aimed to analyse and compare the vancomycin elution kinetics of four biodegradable, osteoconductive antibiotic carriers used in clinical practice within a 42-day in vitro setting. Carriers A and D already contained vancomycin (1.1 g and 0.247 g), whereas carriers B and C were mixed with vancomycin according to the manufacturer's recommendations (B: 0.83 g and C: 0.305 g). At nine time points, 50% (4.5 mL) of the elution sample was removed and substituted with the same amount of PBS. Probes were analysed with a kinetic microparticle immunoassay. Time-dependent changes in vancomycin concentrations for each carrier and differences between carriers were analysed. Mean initial antibiotic levels were highest for carrier A (37.5 mg/mL) and lowest for carrier B (5.4 mg/mL). We observed time-dependent, strongly negative linear elution kinetics for carriers A (−0.835; p < 0.001), C (−0.793; p < 0.001), and D (−0.853; p < 0.001). Vancomycin concentrations increased from 48 h to 7 d and dropped thereafter in carriers C and D whilst constantly decreasing at any time point for carrier A. Carrier B showed a shallower decrease. Mean antibiotics levels at 42 d were 1.5 mg/mL, 2.6 mg/mL, 0.1 mg/mL, and 0.1 mg/mL for carriers A, B, C, and D. Differences in mean initial and final vancomycin concentrations for carrier A were significantly larger in comparison to C (p = 0.040). A carrier consisting of allogenic bone chips showed the highest vancomycin-to-carrier ratio and the largest elution over the study period. Whilst vancomycin concentrations were still measurable at 42 days for all carriers, carrier A provided a higher drug-to-carrier ratio and a more consistent antibiotic-releasing profile. [ABSTRACT FROM AUTHOR]

Introduction: Small cell lung cancer (SCLC) is a rapidly growing malignancy with early distant metastases. Up to 70% will develop brain metastases, and the poor prognosis of these patients has not changed considerably. The potential of checkpoint inhibitors (CPI) in treating recurrent (r/r) SCLC and their effect on brain metastases remain unclear. Methods: In this retrospective multicenter study, we analyzed r/r SCLC patients receiving second or further-line CPI versus chemotherapy between 2010 and 2020. We applied multivariable-adjusted Cox regression analysis to test for differences in 1-year mortality and real-world progression. We then used interaction analysis to evaluate whether brain metastases (BM) and/or cranial radiotherapy (CRT) modified the effect of CPI versus chemotherapy on overall survival. Results: Among 285 patients, 99 (35%) received CPI and 186 (65%) patients received chemotherapy. Most patients (93%) in the CPI group received nivolumab/ipilimumab. Chemotherapy patients were entirely CPI-naïve and only one CPI patient had received atezolizumab for first-line treatment. CPI was associated with a lower risk of 1-year mortality (adjusted Hazard Ratio [HRadj] 0.59, 95% CI 0.42 to 0.82, p=0.002). This benefit was modified by BM and CRT, indicating a pronounced effect in patients without BM (with CRT: HRadj 0.34, p=0.003; no CRT: HRadj 0.50, p=0.05), while there was no effect in patients with BM who received CRT (HRadj 0.85, p=0.59). Conclusion: CPI was associated with a lower risk of 1-year mortality compared to chemotherapy. However, the effect on OS was significantly modified by intracranial disease and radiotherapy, suggesting the benefit was driven by patients without BM. [ABSTRACT FROM AUTHOR]

Purpose: EGFR tyrosine kinase inhibitor (TKI) therapy in EGFR-mutated lung cancer is limited by acquired resistance. In half of the patients treated with first/second-generation (1st/2nd gen) TKI, resistance is associated with EGFR p.T790M mutation. Sequential treatment with osimertinib is highly active in such patients. Currently, there is no approved targeted second-line option for patients receiving first-line osimertinib, which thus may not be the best choice for all patients. The present study aimed to evaluate the feasibility and efficacy of a sequential TKI treatment with 1st/2nd gen TKI, followed by osimertinib in a real-world setting. Methods: Patients with EGFR-mutated lung cancer treated at two major comprehensive cancer centers were retrospectively analyzed by the Kaplan–Meier method and log rank test. Results: A cohort of 150 patients, of which 133 received first-line treatment with a first/second gen EGFR TKI, and 17 received first-line osimertinib, was included. Median age was 63.9 years, 55% had ECOG performance score of ≥ 1. First-line osimertinib was associated with prolonged progression-free survival (P = 0.038). Since the approval of osimertinib (February 2016), 91 patients were under treatment with a 1st/2nd gen TKI. Median overall survival (OS) of this cohort was 39.3 months. At data cutoff, 87% had progressed. Of those, 92% underwent new biomarker analyses, revealing EGFR p.T790M in 51%. Overall, 91% of progressing patients received second-line therapy, which was osimertinib in 46%. Median OS with sequenced osimertinib was 50 months. Median OS of patients with p.T790M-negative progression was 23.4 months. Conclusion: Real-world survival outcomes of patients with EGFR-mutated lung cancer may be superior with a sequenced TKI strategy. Predictors of p.T790M-associated resistance are needed to personalize first-line treatment decisions. [ABSTRACT FROM AUTHOR]

Background: This study aimed to compare local periarticular infiltration (LIA) with ultra-sound guided regional anesthesia (USRA) with ropivacaine and dexmedetomidine as an additive agent in primary total knee arthroplasty (TKA). Methods: Fifty patients were randomized into two groups in a 1:1 ratio. Patients in the LIA group received local periarticular infiltration into the knee joint. The USRA group received two single-shot USRA blocks. Functional outcomes and satisfaction (range of movement, Knee Society Knee Score, Western Ontario and McMaster Universities Osteoarthritis Index, Oxford Knee Score, and Forgotten Joint Score), including well-being, were analyzed preoperatively and at five days, six weeks, and one and two years postoperatively. Results: Functional outcomes did not significantly differ between the two groups at six weeks and one and two years after the implementation of TKA. A moderate correlation was observed in the LIA group regarding well-being and pain on day five. Six weeks postoperatively, the LIA group showed significantly superior well-being but worse pain scores. No differences between the groups in well-being and functional outcomes could be observed one and two years postoperatively. Conclusion: Patients treated with LIA had superior postoperative well-being in the early postoperative phase of up to six weeks. Furthermore, LIA patients had similar functionality compared to patients treated with USRA but experienced significantly more pain six weeks postoperatively. LIA leads to improved short-term well-being, which is potentially beneficial for faster knee recovery. We believe that LIA benefits fast-track knee recovery with respect to improved short-term well-being, higher practicability, and faster application. [ABSTRACT FROM AUTHOR]

This study assessed the quality of life (QOL) and the functional outcome in daily living in patients with a chronic, treatment-resistant periprosthetic joint infection (PJI) or osteomyelitis, living with a natural or iatrogenic sinus tract. Methods: A follow-up examination in three national reference centers for septic bone and joint surgery was performed utilizing the Hospital Anxiety and Depression Scale (HADS-D/A), the Visual Analogue Scale (VAS), and the Short Form-36 (SF-36) score, including patients with a chronic sinus tract due to treatment-resistant PJI or osteomyelitis. Results: In total, 48 patients were included, with a mean follow-up time of 43.1 ± 23.9 months. The mean SF-36 Mental Component Summary (MCS) was 50.2 (±12.3) and the Physical Component Summary (PCS) was 33.9 (±11.3). The mean HADS-D was 6.6 (±4.4) and HADS-A was 6.2 (±4.6), and the VAS was 3.4 (±2.6). The SF-36 MCS showed no significant differences between the study group and the standard population (47.0, p = 0.10), as well as the HADS-A. The PCS in the study population was significantly worse (50.0, p < 0.001), as was the HADS-D. Conclusions: A sinus tract represents a treatment option in selected cases with an acceptable QOL. The treatment should be considered for multimorbid patients with a high perioperative risk or if the bone or soft tissue quality prevents surgery. [ABSTRACT FROM AUTHOR]

Data on reconstruction of the femoral anteversion (FA) and the center of rotation after total hip arthroplasty (THA) are rare. We aimed to answer whether a short-stem fixation enables improved anatomical reconstruction of the FA compared to a straight-stem. Methods: One hundred and thirty patients who underwent short- (n = 89, group A, prospective) or straight-stem THA (n = 41, group B, retrospective) were included. CT scans of the hip, knee, and ankle were performed pre- and postoperatively in group A and in group B during the last follow-up. Femoral torsion was determined using three-dimensional models. Results: The mean preoperative FA was 22.4° ± 11.0°, and the mean postoperative FA was 23.4° ± 10.1°. The relative difference was −0.8° ± 8°, and the absolute difference was 6.4° ± 4.9°. Gender analysis revealed significant differences in preoperative FA between female (f) and male (m) patients (28.1° ± 11.2° (f) vs. 18.4° ± 8.3° (m); p > 0.001) as well as in postoperative FA (26.7° ± 23.5° (f) vs. 21.0° ± 9.7° (m); p < 0.007) in group A. Postoperative FA was higher in group A (mean 6.8°; 23.9° ± 10.1° (f) vs. 16.6° ± 8.6° (m); p < 0.001). Conclusions: The study's findings suggest that short-stem THA leads to improved anatomical FA reconstruction; however, a substantial postoperative gender-related FA difference was detectable, which may warrant consideration by surgeons when determining the final stem anteversion. It should be noted that the impact of the postoperative gender-related FA difference on clinical outcomes is not entirely clear, and further research is warranted to elucidate this relationship. [ABSTRACT FROM AUTHOR]

Introduction: Patients with advanced, epidermal growth factor receptor (EGFR)-mutated, non-small cell lung cancer (NSCLC) with Exon 20 insertion mutations (Exon20ins) have poor prognoses, exacerbated by a previous lack of specific treatment guidelines and unmet need for targeted therapies. Amivantamab, an EGFR and MET bispecific antibody, demonstrated efficacy and tolerability in patients with advanced EGFR-mutated NSCLC with Exon20ins following platinum-based therapy in CHRYSALIS (NCT02609776; Cohort D+). Since CHRYSALIS was single-arm, individual patient data (IPD)-based adjusted analyses versus similar patients in real-world clinical practice (RWCP) were conducted to generate comparative evidence. Methods: RWCP cohorts were derived from seven European and US real-world sources, comprising patients fulfilling CHRYSALIS Cohort D+ eligibility criteria. Amivantamab was compared with a basket of RWCP treatments. Differences in prognostic characteristics were adjusted for using inverse probability weighting (IPW; average treatment effect among the treated [ATT]). Balance between cohorts was assessed using standardized mean differences (SMDs). Overall response rate (ORR; investigator- [INV] and independent review committee-assessed [IRC]), overall survival (OS), progression-free survival (PFS; INV and IRC) and time-to-next treatment (TTNT) were compared. Binary and time-to-event endpoints were analyzed using weighted logistic regression and proportional hazards regression, respectively. Results: Pre-adjustment, baseline characteristics were comparable between cohorts. IPW ATT-adjustment improved comparability, giving closely matched characteristics. ORR (INV) was 36.8% for amivantamab versus 17.0% for the adjusted EU + US cohort (response rate ratio [RR]: 2.16). Median OS, PFS (INV) and TTNT were 22.77 versus 12.52 months (hazard ratio [HR]: 0.47; p < 0.0001), 6.93 versus 4.17 months (HR: 0.55; p < 0.0001) and 12.42 versus 5.36 months (HR: 0.44; p < 0.0001) for amivantamab versus the adjusted EU + US cohort, respectively. Results were consistent versus EU- and US-only cohorts, and when using IRC assessment. Conclusion: Adjusted comparisons demonstrated significantly improved outcomes for amivantamab versus RWCP, highlighting the value of amivantamab in addressing unmet need in patients with advanced EGFR Exon20ins NSCLC following platinum-based therapy. Trial Registration: CHRYSALIS: NCT02609776. [ABSTRACT FROM AUTHOR]

Aims: The use of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II-receptor blockers (ARBs) post-myocardial infarction (MI) is supported by evidence based on trials performed in the thrombolysis era. This was prior to primary percutaneous coronary intervention (PCI) being routine practice, and with little direct evidence for the use of these medications in patients with preserved left ventricular (LV) function. This study sought to determine whether there is an association between ACEi/ARB use after PCI for acute coronary syndrome (ACS) and long-term all-cause mortality, with a particular focus on patients with preserved LV function. Methods: This multicentre, observational study evaluated prospectively collected data of 21,388 patients (> 18 years old) that underwent PCI for NSTEMI and STEMI between 2005 and 2018, and were alive at 30 day follow-up. Results: In total, 83.8% of patients were using ACEi/ARBs. Kaplan–Meier analysis demonstrated ACEi/ARB use was associated with a significantly lower mortality in the entire cohort (15.0 vs. 22.7%; p < 0.001) with a mean follow-up of 5.58 years; and independently associated with 24% lower mortality by Cox proportional hazards modelling (HR 0.76, CI 0.67–0.85, p < 0.001). ACEi/ARB therapy was also associated with significantly lower mortality in patients with reduced or preserved LV function, with greater survival benefit with worse LV dysfunction. Conclusion: ACEi/ARB therapy post-PCI is associated with significantly lower long-term mortality in patients with reduced and preserved LV function. These findings provide contemporary evidence for using these agents in the current era of routine primary PCI, including those with preserved EF. [ABSTRACT FROM AUTHOR]

Objectives: Small-cell lung cancer (SCLC) is a lung malignancy with high relapse rates and poor survival outcomes. Treatment-resistant disease relapse occurs frequently and effective salvage therapies are urgently needed. Materials and Methods: We aimed to define efficacy and safety of checkpoint inhibitors (CPIs) in a heterogeneous population of relapsed and refractory SCLC patients in a large retrospective multicentric real-world cohort across German tertiary care centers. Results: A total of 111 patients from 11 treatment centers were included. Median age of all patients was 64 years, and 63% were male. Approximately one-third of all patients had poor performance status [Eastern Cooperative Oncology Group (ECOG) ⩾ 2], and 37% had known brain metastases. Patients were heavily pretreated with a median number of prior therapy lines of 2 (range, 1–8). Median follow-up of the entire cohort was 21.7 months. Nivolumab and Nivolumab/Ipilimumab were the most common regimens. Overall disease control rate was 27.2% in all patients and was numerically higher in CPI combination regimens compared with single-agent CPI (31.8% versus 23.8%; p = 0.16). Median overall survival (OS) was 5.8 months [95% confidence interval (CI), 1.7–9.9 months]. The 12- and 24-month survival rates were 31.8% and 12.7%, respectively. The 12-week death rate was 27.9%. Disease control and response rate were significantly lower in patients with liver metastases. Platinum sensitivity (to first-line treatment), metastatic burden, and lactate dehydrogenase (LDH) showed prognostic impact on survival in univariate analysis. Neutrophil-to-lymphocyte ratio (NLR) was a significant and independent predictor of survival in univariate (p = 0.01) and multivariate analyses [hazard ratio (HR), 2.1; 95% CI = 1.1–4.1; p = 0.03]. Conclusion: CPI in patients with relapsed or refractory (R/R) SCLC is of limited value in an overall patient cohort; however, long-term survival, in particular with CPI combination strategies, is possible. Clinical characteristics allow a more differentiated subgroup selection, in particular patients with low NLR showed less benefit from CPI in R/R SCLC. [ABSTRACT FROM AUTHOR]

Simple Summary: In this short communication, we present three cases of patients with symptomatic, synchronous brain metastases of otherwise locally limited non-small cell lung cancer. The patients received local ablative treatment of the brain metastases followed by neoadjuvant immunochemotherapy with pemetrexed, cisplatin, and pembrolizumab, and resection of the pulmonary lesion with curative intent. With two of the patients still alive and maintaining a good quality of life with a progression-free survival and overall survival of 28 and 35 months, respectively, this case series illustrates the potential of novel combinatorial treatment approaches. Brain metastases are a common finding upon initial diagnosis of otherwise locally limited non-small cell lung cancer. We present a retrospective case series describing three cases of patients with symptomatic, synchronous brain metastases and resectable lung tumors. The patients received local ablative treatment of the brain metastases followed by neoadjuvant immunochemotherapy with pemetrexed, cisplatin, and pembrolizumab. Afterwards, resection of the pulmonary lesion with curative intent was performed. One patient showed progressive disease 12 months after initial diagnosis, and passed away 31 months after initial diagnosis. Two of the patients are still alive and maintain a good quality of life with a progression-free survival and overall survival of 28 and 35 months, respectively, illustrating the potential of novel combinatorial treatment approaches. [ABSTRACT FROM AUTHOR]

Background: Recent clinical trials demonstrate the feasibility of neoadjuvant immuno(chemo)therapy and report high rates of pathological remission, a surrogate marker for overall survival. Patients and methods: This is a retrospective multicentre real-world analysis of patients with locally resectable NSCLC, including oligometastatic disease, who received neoadjuvant immuno(chemo)therapy and resection. Consolidating immunotherapy was applied following multidisciplinary board recommendation. Primary endpoint was the rate of complete pathological response (pCR, no residual vital tumour cells) or major pathological response (MPR, ⩽ 10% residual vital tumour cells). Secondary endpoints included the radiological response and survival. Results: Seven centres contributed 59 patients (56% stage IIB–IIIC, 44% in stage IVA–IVB with up to four oligometastatic sites). MPR was found in 68% including 53% with pCR. There were no radiological progressions. Median follow-up was 24.3 months. At 12 and 24 months, progression-free survival was 82.6% and 68.1%, and overall survival was 89.5% and 87.2%, respectively. Conclusion: To our knowledge, this study encompassed the largest NSCLC real-world cohort treated with neoadjuvant immuno(chemo)therapy to date. In routine clinical practice, resection after neoadjuvant immuno(chemo)therapy is feasible in patients with locally resectable NSCLC, including oligometastatic disease. In line with clinical trials, we found MPR in more than two-thirds of patients. Early data show encouraging survival. [ABSTRACT FROM AUTHOR]

Background: Information on the epidemiology of uncommon EGFR mutations including exon 20 insertions amongst non-small-cell lung cancer (NSCLC) is lacking. Objective: The objective of this pragmatic literature review (PLR) and meta-analysis was to generate robust prevalence and incidence estimates based on ranges of exon 20 insertion mutations reported in the literature. Materials and methods: Searches of MEDLINE, Embase, congresses and reference lists for articles published from 2013 in key European countries of interest (Belgium, France, Germany, Italy, The Netherlands, Spain, Sweden, Switzerland, United Kingdom) were performed. Articles were reviewed against pre-specified criteria and their quality was appraised using a published checklist. Prevalence estimates were synthesised by random-effects meta-analyses. Results: Eighty unique studies of moderate-to-high quality were included in the PLR. The meta-analysed prevalence for EGFR mutations was 12.5% (95% confidence interval [CI]: 11.0, 14.1) in any stage NSCLC and 14.8% (12.8, 17.1) in advanced/metastatic NSCLC. The prevalence of exon 20 insertions was 0.7% (0.4, 1.1) in any stage NSCLC and 6.1% (4.0, 9.4) in any stage EGFR-positive NSCLC. Mutation status was primarily measured using direct sequencing or a combination of methods. One study reporting exon 20 insertions in advanced/metastatic disease was identified, which reported a prevalence of 0.5% in overall NSCLC and 4.0% in EGFR-positive NSCLC. Conclusions: EGFR exon 20 insertion mutations are rare in NSCLC. There is a high unmet need in patients with exon 20 insertions, including effective therapies. Prospective cohort studies are needed to better clinically characterise these patients. [ABSTRACT FROM AUTHOR]

Hypothyroidism increases the incidence of gestational diabetes mellitus (GDM) but the mechanisms responsible are unknown. This study aimed to assess the pathophysiological mechanisms by which hypothyroidism leads to glucose intolerance in pregnancy. Hypothyroidism was induced in female Sprague-Dawley rats by adding methimazole (MMI) to drinking water at moderate (MOD, MMI at 0.005% w/v) and severe (SEV, MMI at 0.02% w/v) doses from 1 week before pregnancy and throughout gestation. A nonpregnant cohort received the same dose for the same duration but were not mated. On gestational day 16 (GD16), or nonpregnant day 16 (NP16), animals were subjected to an intraperitoneal glucose tolerance test. Tissues and blood samples were collected 4 days later. Hypothyroidism induced a diabetic-like phenotype by GD16 in pregnant females only. Pregnant MOD and SEV females had reduced fasting plasma insulin, less insulin following a glucose load, and altered expression of genes involved in insulin signaling within skeletal muscle and adipose tissue. Hypothyroidism reduced rat placental lactogen concentrations, which was accompanied by reduced percentage β-cell cross-sectional area (CSA) relative to total pancreas CSA, and a reduced number of large β-cell clusters in the SEV hypothyroid group. Plasma triglycerides and free fatty acids were reduced by hypothyroidism in pregnant rats, as was the expression of genes that regulate lipid homeostasis. Hypothyroidism in pregnant rats results in a diabetic-like phenotype that is likely mediated by impaired β-cell expansion in pregnancy. This pregnancy-specific phenomenon is likely due to reduced placental lactogen secretion. [ABSTRACT FROM AUTHOR]

Background: The inclusion of immune checkpoint inhibitors (ICIs) in therapeutic algorithms has led to significant survival benefits in patients with various metastatic cancers. Concurrently, an increasing number of neurological immune related adverse events (IRAE) has been observed. In this retrospective analysis, we examine the ICI-induced incidence of cerebral pseudoprogression and propose a classification system. Methods: We screened our hospital information system to identify patients with any in-house ICI treatment for any tumor disease during the years 2007-2019. All patients with cerebral MR imaging (cMRI) of sufficient diagnostic quality were included. cMRIs were retrospectively analyzed according to immunotherapy response assessment for neuro-oncology (iRANO) criteria. Results: We identified 12 cases of cerebral pseudoprogression in 123 patients treated with ICIs and sufficient MRI. These patients were receiving ICI therapy for lung cancer (n=5), malignant melanoma (n=4), glioblastoma (n=1), hepatocellular carcinoma (n=1) or lymphoma (n=1) when cerebral pseudoprogression was detected. Median time from the start of ICI treatment to pseudoprogression was 5 months. All but one patient developed neurological symptoms. Three different patterns of cerebral pseudoprogression could be distinguished: new or increasing contrast-enhancing lesions, new or increasing T2 predominant lesions and cerebral vasculitis type pattern. Conclusion: Cerebral pseudoprogression followed three distinct patterns and was detectable in 3.2% of all patients during ICI treatment and in 9.75% of the patients with sufficient brain imaging follow up. The fact that all but one of the affected patients developed neurological symptoms, which would be classified as progressive disease according to iRANO criteria, mandates vigilance in the diagnosis and treatment of ICI-induced cerebral lesions. [ABSTRACT FROM AUTHOR]

KRAS is one of the most commonly mutated oncogenes in cancer, enabling tumor proliferation and maintenance. After various approaches to target KRAS have failed over the past decades, the first specific inhibitor of the p.G12C mutation of KRAS was recently approved by the FDA after showing promising results in adenocarcinomas of the lung and other solid tumors. Lung cancer, the most common cancer worldwide, is a promising use case for these new therapies, as adenocarcinomas in particular frequently harbor KRAS mutations. However, in squamous cell carcinoma (SCC) of the lung, KRAS mutations are rare and their impact on clinical outcome is poorly understood. In this review, we discuss the current knowledge on the prevalence and prognostic and predictive significance of KRAS mutations in the context of SCC. [ABSTRACT FROM AUTHOR]

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Purpose: Superagers are older adults presenting excellent memory performance that may reflect resilience to the conventional pathways of aging. Our contribution aims to shape the evidence body of the known distinctive biomarkers of superagers and their connections with the Brain and Cognitive Reserve and Brain Maintenance concepts. Methods: We performed a systematic literature search in PubMed and ScienceDirect with no limit on publication date for studies that evaluated potential biomarkers in superagers classified by validated neuropsychological tests. Methodological quality was assessed using the QUADAS-2 tool. Results: Twenty-one studies were included, the majority in neuroimaging, followed by histological, genetic, cognition, and a single one on blood plasma analysis. Superagers exhibited specific regions of cortical preservation, rather than global cortical maintenance, standing out the anterior cingulate and hippocampus regions. Both superagers and controls showed similar levels of amyloid deposition. Moreover, the functional oscillation patterns in superagers resembled those described in young adults. Most of the quality assessment for the included studies showed medium risks of bias. Conclusion: This systematic review supports selective cortical preservation in superagers, comprehending regions of the default mode, and salience networks, overlapped by stronger functional connectivity. In this context, the anterior cingulate cortex is highlighted as an imaging and histologic signature of these subjects. Besides, the biomarkers included pointed out that the Brain and Cognitive Reserve and Brain Maintenance concepts are independent and complementary in the superagers' setting. [ABSTRACT FROM AUTHOR]

Aims: There is a paucity of evidence supporting routine beta blocker (BB) use in patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). The aim of this study was to evaluate BB use post PCI and its association with mortality. Furthermore, the study aimed to evaluate the association between BB and mortality in the subgroups of patients with left ventricular ejection fraction (LVEF) <35%, LVEF 35%-50% and LVEF >50%.Methods: Using a large PCI registry, data from patients with ACS between January 2005 and June 2017 who were alive at 30 days were analysed. Those patients taking BB at 30 days were compared with those who were not taking BB. The primary outcome was all-cause mortality. The mean follow-up was 5.3±3.5 years.Results: Of the 17 562 patients, 83.3% were on BB. Mortality was lower in the BB group (13.1% vs 19.5%, p=0.0001). Multivariable Cox proportional hazards model showed that BB use was associated with lower overall mortality (adjusted HR 0.87, 95% CI 0.78 to 0.97, p=0.014). In the subgroup analysis, BB use was associated with reduced mortality in LVEF <35% (adjusted HR 0.63, 95% CI 0.44 to 0.91, p=0.013), LVEF 35%-50% (adjusted HR 0.80, 95% CI 0.68 to 0.95, p=0.01), but not LVEF >50% (adjusted HR 1.03, 95% CI 0.87 to 1.21, p=0.74).Conclusion: BB use remains high and is associated with reduced mortality. This reduction in mortality is primarily seen in those with reduced ejection fraction, but not in those with preserved ejection fraction. [ABSTRACT FROM AUTHOR]

Background: Pemetrexed and cisplatin is a first-line standard in non-squamous non-small-cell lung cancer without targetable mutations. It became the backbone of checkpoint-inhibitor–chemotherapy combinations. Single high doses of cisplatin pose toxicity risks and require hyperhydration, potentially prolonging outpatient application. The aim of this study was to compare efficacy, safety and tolerability of split-dose cisplatin with the standard schedule. Methods: Patients with metastatic non-squamous non-small-cell lung cancer were randomly assigned to up to six 21-day cycles of pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1 (arm A), or pemetrexed 500 mg/m2 (day 1) and cisplatin 40 mg/m2 (day 1 + 8, arm B), followed by pemetrexed maintenance. Primary endpoint was objective response rate. Secondary objectives were overall survival, progression-free survival, time to progression, treatment compliance, toxicity profile, and quality of life. Results: We enrolled 130 patients (129 evaluable). Median cycle numbers in A and B were six (1–6) and five (1–6). Dose intensities were comparable between arms. More patients in A received pemetrexed maintenance (24.2% versus 11.1%). With 16 (24.2%) in A and 19 (30.2%) patients in B achieving objective responses [odds ratio 0.74 (0.34–1.62), p = 0.55] the primary endpoint was met. Overall survival was not different between arms (median 14.4 versus 14.9 months); [HR = 1.07; (0.68–1.68), p = 0.78]. Median progression-free survival was 7.0 months in A and 6.2 months in B [HR = 1.63; (1.17–2.38); p = 0.01]. Adverse events of CTCAE grade ⩾3, particularly hematological, were more frequent in B. No difference in grade 4 and 5 infections between arms was noted. Treatment-related asthenia and nausea/vomiting of any grade were more frequent in A. Global health status, fatigue and constipation measured on day 1 of cycle 4 demonstrated superior scores in B. Conclusion: Pemetrexed and split-dose cisplatin is safe and effective. Advantages of split-dose cisplatin with regard to specific toxicities allow personalization of this important chemotherapy backbone. Trial Registration: European Clinical Trials Database (EudraCT) number 2011-001963-37. [ABSTRACT FROM AUTHOR]

Background: Optimal secondary prevention pharmacotherapy is the cornerstone of post‐acute coronary syndrome (ACS) management. The prognostic impact of not receiving five guideline‐recommended therapies is poorly described. Aim: To ascertain the prognostic significance of suboptimal pharmacotherapy in ACS survivors. Methods: Consecutive patients with ACS from the Melbourne Interventional Group registry who were alive at 30 days following their index percutaneous coronary intervention were included. Patients were divided into three categories based on the number of secondary prevention medications prescribed. The optimal medical therapy (OMT), near‐optimal medical therapy (NMT), suboptimal medical therapy (SMT) groups were prescribed 5, 4 and ≤ 3 medications, respectively. Primary endpoint was long‐term mortality. Cox‐proportional hazard modelling was undertaken to assess independent predictors of survival. Results: Of the 9375 patients included, 5678 (60.6%) received OMT, 2903 (31.0%) received NMT and 794 (8.5%) received SMT. Patients receiving SMT were older, more likely to be female and had higher burden of comorbidities (renal impairment, congestive heart failure, diabetes, peripheral vascular disease; P < 0.01 for all). SMT was associated with higher long‐term mortality at 3.9 ± 2.2 years when compared to NMT and OMT (16.8% vs 10.5% vs 8.2%, P < 0.001). Compared to OMT, SMT was an independent predictor of long‐term mortality (hazard ratio, HR 1.62, 95% confidence interval, CI 1.30–2.02, P < 0.01) while NMT was associated with a clinically significant 14% mortality hazard (HR 1.14, 95% CI 0.97–1.34, P = 0.11). Conclusions: There is a graded long‐term hazard associated with not receiving OMT after an ACS. Improvements in secondary prevention pharmacotherapy models of care are warranted to further decrease the long‐term mortality. [ABSTRACT FROM AUTHOR]

Background: Pemetrexed and cisplatin is a first-line standard in non-squamous non-small-cell lung cancer without targetable mutations. It became the backbone of checkpoint-inhibitor–chemotherapy combinations. Single high doses of cisplatin pose toxicity risks and require hyperhydration, potentially prolonging outpatient application. The aim of this study was to compare efficacy, safety and tolerability of split-dose cisplatin with the standard schedule. Methods: Patients with metastatic non-squamous non-small-cell lung cancer were randomly assigned to up to six 21-day cycles of pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1 (arm A), or pemetrexed 500 mg/m2 (day 1) and cisplatin 40 mg/m2 (day 1 + 8, arm B), followed by pemetrexed maintenance. Primary endpoint was objective response rate. Secondary objectives were overall survival, progression-free survival, time to progression, treatment compliance, toxicity profile, and quality of life. Results: We enrolled 130 patients (129 evaluable). Median cycle numbers in A and B were six (1–6) and five (1–6). Dose intensities were comparable between arms. More patients in A received pemetrexed maintenance (24.2% versus 11.1%). With 16 (24.2%) in A and 19 (30.2%) patients in B achieving objective responses [odds ratio 0.74 (0.34–1.62), p = 0.55] the primary endpoint was met. Overall survival was not different between arms (median 14.4 versus 14.9 months); [HR = 1.07; (0.68–1.68), p = 0.78]. Median progression-free survival was 7.0 months in A and 6.2 months in B [HR = 1.63; (1.17–2.38); p = 0.01]. Adverse events of CTCAE grade ⩾3, particularly hematological, were more frequent in B. No difference in grade 4 and 5 infections between arms was noted. Treatment-related asthenia and nausea/vomiting of any grade were more frequent in A. Global health status, fatigue and constipation measured on day 1 of cycle 4 demonstrated superior scores in B. Conclusion: Pemetrexed and split-dose cisplatin is safe and effective. Advantages of split-dose cisplatin with regard to specific toxicities allow personalization of this important chemotherapy backbone. Trial Registration: European Clinical Trials Database (EudraCT) number 2011-001963-37. [ABSTRACT FROM AUTHOR]

Objectives: Multidrug-resistant organisms (MDRO) are considered an emerging threat worldwide. Data covering the clinical impact of MDRO colonization in patients with solid malignancies, however, is widely missing. We sought to determine the impact of MDRO colonization in patients who have been diagnosed with Non-small cell lung cancer (NSCLC) who are at known high-risk for invasive infections. Materials and methods: Patients who were screened for MDRO colonization within a 90-day period after NSCLC diagnosis of all stages were included in this single-center retrospective study. Results: Two hundred and ninety-five patients were included of whom 24 patients (8.1%) were screened positive for MDRO colonization (MDROpos) at first diagnosis. Enterobacterales were by far the most frequent MDRO detected with a proportion of 79.2% (19/24). MDRO colonization was present across all disease stages and more present in patients with concomitant diabetes mellitus. Median overall survival was significantly inferior in the MDROpos study group with a median OS of 7.8 months (95% CI, 0.0–19.9 months) compared to a median OS of 23.9 months (95% CI, 17.6–30.1 months) in the MDROneg group in univariate (p = 0.036) and multivariate analysis (P = 0.02). Exploratory analyses suggest a higher rate of non-cancer-related-mortality in MDROpos patients compared to MDROneg patients (p = 0.002) with an increased rate of fatal infections in MDROpos patients (p = 0.0002). Conclusions: MDRO colonization is an independent risk factor for inferior OS in patients diagnosed with NSCLC due to a higher rate of fatal infections. Empirical antibiotic treatment approaches should cover formerly detected MDR commensals in cases of (suspected) invasive infections. [ABSTRACT FROM AUTHOR]

Background: Stroke rates and risk factors may change as percutaneous coronary intervention practice evolves and no data are available comparing stroke incidence after percutaneous coronary intervention to the general population. Aims: This study aimed to identify the incidence and risk factors for inpatient and subsequent stroke following percutaneous coronary intervention with comparison to age-matched controls. Methods: Data were prospectively collected from 22,618 patients undergoing percutaneous coronary intervention in the Melbourne Interventional Group registry (2005–2015). The cohort was compared to the North-East Melbourne Stroke Incidence Study population-based cohort (1997–1999) and predefined variables assessed for association with inpatient or outpatient stroke. Results: Inpatient stroke occurred in 0.33% (65.3% ischemic, 28.0% haemorrhagic, and 6.7% cause unknown), while outpatient stroke occurred in 0.55%. Inpatient and outpatient stroke were associated with higher rates of in-hospital major adverse cardiovascular outcomes (p < 0.0001) and mortality (p < 0.0001), as well as 12-month mortality (p < 0.0001). Factors independently associated with inpatient stroke were renal impairment, ST-elevation myocardial infarction, previous stroke, left ventricular ejection fraction 30–45%, and female sex, while those associated with outpatient stroke were previous stroke, chronic lung disease, previous myocardial infarction, rheumatoid arthritis, female sex, and older age. Compared to the age-standardized population-based cohort, stroke rates in the 12 months following discharge were higher for percutaneous coronary intervention patients <65 years old, but lower for percutaneous coronary intervention patients ≥65 years old. Conclusions: Risk of inpatient stroke following percutaneous coronary intervention appears to be largely associated with clinical status at presentation, while outpatient stroke relates more to age and chronic disease. Compared to the general population, outpatient stroke rates following percutaneous coronary intervention are higher for younger, but not older, patients. [ABSTRACT FROM AUTHOR]

Background: Glycoprotein IIb/IIIa inhibitors (GPIs) are a treatment option in the management of acute coronary syndromes (ACSs). Evidence supporting the use of GPIs predates trials establishing the benefits of P2Y12 inhibitors, routine early invasive therapy, and thrombectomy devices in patients with ACS. Objective: The aim of this study was to determine trends in GPI use and their associated outcomes in contemporary practice. Methods: We assessed GPI use in patients with ACS undergoing percutaneous coronary intervention (PCI) from the Melbourne Interventional Group registry (2005-2013). The primary endpoint was the 30-day incidence of major adverse cardiovascular events (MACE). The safety endpoint was in-hospital major bleeding. Results: GPIs were used in 40.5% of 12 357 patients with ACS undergoing PCI. GPI use decreased over the study period (P for trend <0.0001). Patients were more likely to receive GPIs if they were younger, presented with a ST-elevation myocardial infarction (STEMI), had more complex (B2/C-type) lesions, and when thrombectomy devices were used (all P < 0.0001). MACE were higher in patients receiving GPI (4.9% vs 4.1%, P = 0.03). Propensity score matching revealed no difference in 30-day mortality and 30-day MACE (odds ratio [OR] = 1.00; 95% CI = 0.99-1.004 and OR = 1.01; 95% CI = 0.99-1.02, respectively). GPI use was associated with more bleeding complications (3.6% vs 1.8%, P < 0.0001). Conclusion and Relevance: GPI use in ACS patients undergoing PCI has declined, and use appears to be dictated by ACS type and lesion complexity, as opposed to high-risk comorbidities. GPI use was associated with a doubling in bleeding complications. [ABSTRACT FROM AUTHOR]

Background: Preclinical studies demonstrate synergism between cancer immunotherapy and local radiation, enhancing anti-tumor effects and promoting immune responses. BI1361849 (CV9202) is an active cancer immunotherapeutic comprising protamine-formulated, sequence-optimized mRNA encoding six non-small cell lung cancer (NSCLC)-associated antigens (NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, and MUC-1), intended to induce targeted immune responses. Methods: We describe a phase Ib clinical trial evaluating treatment with BI1361849 combined with local radiation in 26 stage IV NSCLC patients with partial response (PR)/stable disease (SD) after standard first-line therapy. Patients were stratified into three strata (1: non-squamous NSCLC, no epidermal growth factor receptor (EGFR) mutation, PR/SD after ≥4 cycles of platinum- and pemetrexed-based treatment [n = 16]; 2: squamous NSCLC, PR/SD after ≥4 cycles of platinum-based and non-platinum compound treatment [n = 8]; 3: non-squamous NSCLC, EGFR mutation, PR/SD after ≥3 and ≤ 6 months EGFR-tyrosine kinase inhibitor (TKI) treatment [n = 2]). Patients received intradermal BI1361849, local radiation (4 x 5 Gy), then BI1361849 until disease progression. Strata 1 and 3 also had maintenance pemetrexed or continued EGFR-TKI therapy, respectively. The primary endpoint was evaluation of safety; secondary objectives included assessment of clinical efficacy (every 6 weeks during treatment) and of immune response (on Days 1 [baseline], 19 and 61). Results: Study treatment was well tolerated; injection site reactions and flu-like symptoms were the most common BI1361849-related adverse events. Three patients had grade 3 BI1361849-related adverse events (fatigue, pyrexia); there was one grade 3 radiation-related event (dysphagia). In comparison to baseline, immunomonitoring revealed increased BI1361849 antigen-specific immune responses in the majority of patients (84%), whereby antigen-specific antibody levels were increased in 80% and functional T cells in 40% of patients, and involvement of multiple antigen specificities was evident in 52% of patients. One patient had a partial response in combination with pemetrexed maintenance, and 46.2% achieved stable disease as best overall response. Best overall response was SD in 57.7% for target lesions. Conclusion: The results support further investigation of mRNA-based immunotherapy in NSCLC including combinations with immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

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CV9201 is an RNActive®-based cancer immunotherapy encoding five non-small cell lung cancer-antigens: New York esophageal squamous cell carcinoma-1, melanoma antigen family C1/C2, survivin, and trophoblast glycoprotein. In a phase I/IIa dose-escalation trial, 46 patients with locally advanced (n = 7) or metastatic (n = 39) NSCLC and at least stable disease after first-line treatment received five intradermal CV9201 injections (400–1600 µg of mRNA). The primary objective of the trial was to assess safety. Secondary objectives included assessment of antibody and ex vivo T cell responses against the five antigens, and changes in immune cell populations. All CV9201 dose levels were well-tolerated and the recommended dose for phase IIa was 1600 µg. Most AEs were mild-to-moderate injection site reactions and flu-like symptoms. Three (7%) patients had grade 3 related AEs. No related grade 4/5 or related serious AEs occurred. In phase IIa, antigen-specific immune responses against ≥ 1 antigen were detected in 63% of evaluable patients after treatment. The frequency of activated IgD+CD38hi B cells increased > twofold in 18/30 (60%) evaluable patients. 9/29 (31%) evaluable patients in phase IIa had stable disease and 20/29 (69%) had progressive disease. Median progression-free and overall survival were 5.0 months (95% CI 1.8–6.3) and 10.8 months (8.1–16.7) from first administration, respectively. Two- and 3-year survival rates were 26.7% and 20.7%, respectively. CV9201 was well-tolerated and immune responses could be detected after treatment supporting further clinical investigation. [ABSTRACT FROM AUTHOR]

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Purpose: Osimertinib, a third-generation irreversible mutant-selective inhibitor of EGFR kinase activity was clinically evaluated in the AURA trials, where it showed high clinical efficacy and a favorable toxicity profile in patients with acquired exon 20-EGFR pT790M mutation. We provide the clinical data of the German expanded access program that further characterizes the efficacy and safety of osimertinib in a heterogeneous patient population outside clinical trials.Methods: We performed a retrospective data analysis on patients who were included into the German osimertinib EAP.Results: Of 81 patients enrolled, 51 patients (62.9%) with sufficient case report form data were available for efficacy and safety analysis. Unconfirmed overall response rate was 80.0% with 2 patients (3.9%) achieving a complete remission and 37 patients (72.5%) having a partial remission. Disease control rate was 95.9% and only two patients showed refractory disease. Disease control rate did not correlate with clinical characteristics and was independent of number as well as type of the previous therapy line(s). Estimated progression-free survival was 10.1 months (95% CI 9.2-11.0 months). Osimertinib showed a favorable toxicity profile with no dose reductions in our observation period, even in patients with low performance status. Median survival from first diagnosis to data cut-off was 47.3 months (95% CI 43.3-51.9 months). Repeated tissue/liquid biopsy of three patients in our cohort who showed disease progression revealed an amplification of MET.Conclusions: We confirm safety and efficacy of osimertinib with high response rates among all subgroups, including patients with poor performance status and multiple prior therapy lines. Amplification of MET might mediate acquired resistance to osimertinib. [ABSTRACT FROM AUTHOR]

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Background: Polo like kinase 1 (PLK1) is frequently upregulated in tumors and is thus viewed as a promising therapeutic target in various cancers. Several PLK1 inhibitors have recently been developed and clinically tested in solid cancers, albeit with limited success. So far, no predictive biomarkers for PLK1 inhibitors have been established. To this end, we conducted a post-hoc biomarker analysis of tumor samples from non-small cell lung cancer (NSCLC) patients treated with the PLK1 inhibitor BI2536 in a phase II study. Methods: We analyzed formalin-fixed paraffin-embedded surplus tumor tissue from 47 study patients using immunohistochemistry (IHC) and DNA sequencing of KRAS, EGFR, BRAF, and PIK3CA. Results: KRAS-mutated patients showed numerically prolonged progression-free survival, but statistical significance was not established. Interestingly, when pathways rather than single genes were analyzed, a positive correlation between IHC staining of activated ERK (p-ERK) and mutated KRAS was detected, whereas KRAS mutation status was found to be negatively correlated with activated AKT (p-AKT). Conclusion: With this hypothesis-generating study in BI2531-treated patients, we could not establish a correlation between KRAS mutations and relevant clinical endpoints. Future clinical trials with concomitant systematic biosampling and comprehensive molecular analyses are required to identify biomarkers predictive for response to PLK1 inhibitors. [ABSTRACT FROM AUTHOR]

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Background. Afatinib, an irreversible ErbB family blocker, is approved for treatment of patients with previously untreated non-small cell lung cancer (NSCLC) harboring activating epidermal growth factor receptor (EGFR) mutations. Efficacy of afatinib in EGFR tyrosine kinase inhibitor-naï ve (TKI-naïve) patients with uncommon EGFR mutations (other than exon 19 deletions or exon 21 point mutations) has been reported; however, efficacy in TKI-pretreated patients with uncommon EGFR mutations is unknown. Materials and Methods. In the afatinib compassionate use program (CUP), patients with advanced or metastatic, histologically confirmed NSCLC progressing after at least one line of chemotherapy and one line of EGFR-TKI treatment were enrolled. Demographic data, mutation type, response rates, time to treatment failure (TTF), and safety in patients harboring uncommon EGFR mutations were reported. Results. In 60 patients (63% female, median age 63 years [range: 30-84 years]), a total of 66 uncommon EGFR mutations including 30 T790M mutations were reported (18.4% and 11%, respectively, of known EGFR mutations within the CUP). Most patients (67%) received afatinib as third- or fourth-line treatment. Median TTF was 3.8 months (range: 0.2 to >24.6 months; p = .244) in patients with uncommon mutations compared with 5.1 months (range: 0.1 to >21.1 months) in patients with common mutations (n = 165). Pronounced activity was observed with E709X mutations (TTF >12 months). No new safety signals were detected. Conclusion. Afatinib is clinically active and well tolerated in many TKI-pretreated NSCLC patients harboring uncommon EGFR mutations. Compared with results reported in TKI-naTve patients, activity was also indicated in patients with T790M and exon 20 insertion mutations. [ABSTRACT FROM AUTHOR]

Background: Advanced non-small cell lung cancer (NSCLC) represents a significant unmet medical need. Despite advances with targeted therapies in a small subset of patients, fewer than 20% of patients survive for more than two years after diagnosis. Cancer vaccines are a promising therapeutic approach that offers the potential for durable responses through the engagement of the patient's own immune system. CV9202 is a self-adjuvanting mRNA vaccine that targets six antigens commonly expressed in NSCLC (NY-ESO-1, MAGEC1, MAGEC2, 5 T4, survivin, and MUC1). Methods/Design: The trial will assess the safety and tolerability of CV9202 vaccination combined with local radiation designed to enhance immune responses and will include patients with stage IV NSCLC and a response or stable disease after first-line chemotherapy or therapy with an EGFR tyrosine kinase inhibitor. Three histological and molecular subtypes of NSCLC will be investigated (squamous and non-squamous cell with/without EGFR mutations). All patients will receive two initial vaccinations with CV9202 prior to local radiotherapy (5 GY per day for four successive days) followed by further vaccinations until disease progression. The primary endpoint of the study is the number of patients experiencing Grade >3 treatment-related adverse events. Pharmacodynamic analyses include the assessment of immune responses to the antigens encoded by CV9202 and others not included in the panel (antigen spreading) and standard efficacy assessments. Discussion: RNActive self-adjuvanted mRNA vaccines offer the potential for simultaneously inducing immune responses to a wide panel of antigens commonly expressed in tumors. This trial will assess the feasibility of this approach in combination with local radiotherapy in NSCLC patients. [ABSTRACT FROM AUTHOR]