Higher-Order Demand-Driven Program Analysis (Artifact)

This artifact is a proof-of-concept implementation of DDPA, an on-demand program analysis for higher-order functional programs. The implementation, written in OCaml, includes a parser, evaluator, and DDPA analysis for the language defined in the companion paper (including the proper record semantics extension). The analysis may be performed using different levels of precision as specified by the user and is capable of rendering the control flow graphs and pushdown systems using the GraphViz language DOT. This artifact was used to verify the conclusions of the companion paper and produces visualizations matching those figures in the companion paper\u27s overview

Adding PD-1/PD-L1 inhibitors to chemotherapy for the first-line treatment of extensive stage small cell lung cancer (Sclc): A meta-analysis of randomized trials

Survival outcomes in extensive-stage small cell lung cancer (ES SCLC) are dismal, with median overall survival (OS) less than 12 months. The combination of PD-1/PD-L1 immune checkpoint inhibitors (ICIs) with first-line platinum-etoposide chemotherapy has been recently evaluated in randomized clinical trials. We performed a systematic literature review through PubMed and conference proceedings. Randomized trials evaluating chemotherapy +/− PD-1/PD-L1 ICIs were included in the meta-analysis. Efficacy (OS), activity [progression-free survival (PFS) and objective response rate (ORR)] outcomes and toxicities were analyzed. For selected endpoints, we focused on patients’ subgroups (OS) and on landmark analyses (OS, PFS). Four randomized trials were identified; globally, 1553 patients were randomized to receive chemotherapy +/− PD-1/PD-L1 ICIs. Adding a PD-1/PD-L1 ICI to chemotherapy led to a significant benefit in OS [hazard ratio (HR) 0.76, 95% confidence interval (CI) 0.68–0.85, p < 0.00001), PFS [HR 0.75, 95% CI 0.68–0.84, p < 0.00001] and ORR [odds ratio 1.28, 95% CI 1.04–1.57, p = 0.02]. No unexpected toxicity emerged. At 12, 18, 24 months for OS, and at 12, 18 months for PFS, experimental arms retained significant improvement in event-free rates, with absolute gain of approximately 10% compared with standard treatment. Albeit the magnitude of the benefit is less impacting compared to other settings of immunotherapy, the addition of PD-1/PD-L1 ICIs to chemotherapy in ES SCLC provided significant improvements in survival outcomes with the known toxicity profile. Biomarkers predicting which patients are suitable to derive long-term benefits are eagerly awaited

First-line immunotherapy in non-small cell lung cancer patients with poor performance status: A systematic review and meta-analysis

Background: Immune checkpoint inhibitors (ICIs) have become the standard of care for the first-line treatment of advanced non-small cell lung cancer patients (NSCLC), either as single agents or combined with chemotherapy. The evidence sustaining their role for poor performance status (ECOG PS ≥2) patients is limited. Methods: We search PubMed and the proceedings of international oncology meetings to perform a systematic review to assess the outcomes poor PS NSCLC patients who received ICIs as first-line treatment. A meta-analysis included retrospective studies focusing on pembrolizumab monotherapy in PD-L1 ≥50% NSCLC. We reported the global objective response rate (ORR), disease control rate (DCR) and landmark progression-free and overall survival (PFS and OS, respectively) in ECOG PS ≥2 and 0-1 patients, respectively. Results: Forty-one studies were included in the systematic review. Thirty-two retrospective studies focused on pembrolizumab monotherapy in PD-L1 ≥50% cases. In total, 1,030 out of 5,357 (19%) of patients across 30 studies presented with a PS ≥2 at pembrolizumab initiation. In 18 studies with detailed clinical information, worse outcomes in poor PS compared to good PS patients were documented. The meta-analysis revealed that ORR and DCR within the PS ≥2 patient population were 30.9% and 41.5% respectively (55.2% and 71.5% in PS 0-1 patients). The rates of PFS (at 3, 6, 12 and 18 months) and OS (at 6, 12, 18 and 24 months) were approximately double in the good PS compared to the poor PS group of patients. In the three prospective trials where of ICIs in PS 2 populations, the diverse strictness in PS definition likely contributed to the differential outcomes observed. Six retrospective studies dealt with chemo-immunotherapy combinations. Conclusions: Still with limited prospective evidence sustaining the role of immunotherapy in previously untreated NSCLC with poor PS, 19% of patients in retrospective series dealing with pembrolizumab in PDL1 ≥50% tumors had an ECOG PS ≥2. Clinical effort encompassing the definition of poor PS, of the factors conditioning it, and the development of dedicated treatment strategies is required to improve the outcomes in this patient population

The paradigm of norgestimate: a third-generation testosterone-derivative progestin with a peripheral anti-androgenic activity and the lowest risk of venous thromboembolism

Introduction: Norgestimate (NGM) is a testosterone derivative with peculiar receptor activities. Areas covered: This is a narrative review of the available data on the pharmacotherapy of NGM in combined hormonal contraceptives (CHCs) in terms of contraceptive efficacy, venous thromboembolism (VTE) risk, safety, tolerability and bleeding patterns. A comprehensive literature review was conducted in August 2020 using PubMed with the keyword ‘norgestimate’. Expert Opinion: NGM shows a mild estrogenic activity associated with anti-mineralocorticoid and anti-androgenic properties, largely responsible for the cardiovascular safety profile. The anti-androgenic property depends on the androgen receptor (AR) nuclear translocation (AR trafficking and its subnuclear distribution), the inhibition of 5α-reductase activity (it possesses higher activity compared to other available progestins), and the increase on sexual hormone binding globulin (SHBG) levels if combined with an estrogenic counterpart. NGM is one of the molecules that best modulates the power of ethinyl-estradiol on the thromboembolic risk, being associated with the lowest VTE risk between different CHCs. NGM has the advantage of retaining peripheral anti-androgenic activity, demonstrated by the impact on lipid and glucose metabolism, and it should be preferred if compared with other similar progestins of the same class of risk which are much more androgenic, such as levonorgestrel

Bilateral Severe Corneal Ulcer in a Patient with Lung Adenocarcinoma Treated with Gefitinib

We describe the case of Gefitinib-related bilateral corneal perforation. An 86-year-old female patient had bilateral painless and progressive vision loss due to neurotrophic corneal ulcer, following a 2-month treatment with Gefitinib, a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor for metastatic adenocarcinoma of the lung with confirmed EGFR gene mutation. She had no signs of ocular infection, inflammation, or lid problems to account for the development of corneal damage. Neurotrophic ulcer evolved into a frank perforation in one eye and an impending perforation on the other eye. EGFR inhibitors have been associated with dry eye, epithelial erosions, ulcerative keratitis, and corneal edema. However, to the best of our knowledge, this is the first case of bilateral severe corneal ulcer due to Gefitinib. The patient went on to have bilateral corneal graft surgery. This case aims to raise awareness among ophthalmologists and oncologists of the association between EGFR inhibitors, corneal neurotrophic ulcers, and possible evolution in corneal perforation

Prevalence of low antithrombin levels in preeclamptic women and perinatal outcome

Objective. The aim of this study is to evaluate the prevalence of low antithrombin levels in our population in order to assess an intervention trial feasibility. Methods. This is a retrospective study. A database was created by using queries to find out medical records of patients requiring hospitalization for preeclampsia or gestational hypertension or superimposed preeclampsia to chronic hypertension at Modena University Hospital between June 2015 and July 2019. Results. We screened 11845 deliveries. Overall, 221 (1.9%) cases of preeclampsia were identified. Antithrombin level was available for 201 women, thus included in the analysis. Median antithrombin value was 87% (IQ range: 77-98). The prevalence of low antithrombin levels was 9%. Antithrombin < 80% was found in 21% of the subjects. The remnant showed normal values. Median antithrombin was significantly lower in severe respect with mild preeclampsia (83% ± 14 vs 89% ± 14, p = 0.003). The rate of small for gestational age was significantly higher in low antithrombin levels group (44.4% vs 22.4%, p = 0.042). Considering mean values, antithrombin levels were also significantly lower in case of small for gestational age (84% ± 14 vs 89% ± 14; p = 0.040). Conclusions. In our population, low antithrombin levels (1 in 10 patients) were associated with severity of preeclampsia, namely with small for gestational age babies. Data suggest this subpopulation as a better target for trials assessing the efficacy of antithrombin supplementation