Adherence to National Comprehensive Cancer Network ALK Testing Guidelines for Patients with Advanced Non-Small Cell Lung Cancer in U.S. Community Medical Centers

BackgroundNational Comprehensive Cancer Network (NCCN) guidelines recommend biomarker testing as the first step in the management of patients with advanced non‐small cell lung cancer (aNSCLC). We assessed anaplastic lymphoma kinase (ALK) testing rates and factors related to underuse in community medical systems between 2012 and 2019 to understand guideline adoption.MethodsA retrospective observational study using a nationwide electronic health record (EHR)‐derived deidentified database was conducted. Patients with aNSCLC diagnosed in community medical centers from January 2012 to May 2019 were included to describe the ALK testing trend. This cohort was further restricted to patients diagnosed after 2015 to understand factors associated with testing underuse using mixed‐effects multivariable logistic regression models.ResultsTrends for increased ALK testing rates by year were observed in both NCCN guideline‐eligible patients (59.5% in 2012 to 84.1% in 2019) and ‐ineligible patients (15.6% to 50.8%) in a cohort of 41,728 patients. Histology type and smoking status had the greatest impact on test use. Compared with patients with nonsquamous histology and no smoking history, patients with squamous histology and no smoking history (adjusted odds ratio [aOR], 7.6; 95% confidence interval [CI], 5.6–10.4), NSCLC histology not otherwise specified (NOS) with smoking history (aOR, 3.4; 95% CI, 2.8–4.2); NSCLC NOS/nonsmoker (aOR, 1.8; 95% CI, 1.1–3.2), and nonsquamous/smoker (aOR, 1.5; 95% CI, 1.3–1.7) were less likely to be tested. Factors related to underuse also included Eastern Cooperative Oncology Group performance status, stage at initial diagnosis, and demographics.ConclusionThis analysis of real‐world data shows increasing test use by year; however, one fifth of patients eligible for ALK testing still remain untested and potentially missing therapeutic options.Implications for PracticeAdvancement in treatment of lung cancer is accompanied by an increasing number of tests that should be run to determine potential therapy options for each patient. This study assessed adoption of testing recommendations for anaplastic lymphoma kinase rearrangements in a national database. Although test use increased over the time period studied (2012–2019), there is still room for improvement. Efforts are needed to increase test use in undertested groups, thus enabling eligible patients to benefit from novel lung cancer therapies.     

Pharmacokinetics of intramuscularly administered ertapenem

Ertapenem (INVANZ) is a new once-a-day parental beta-lactam antimicrobial agent that has been shown to be highly effective as a single agent for treatment of various community-acquired and mixed infections. The plasma pharmacokinetics of a 1-g intramuscular (i.m.) dose was compared with those of a 1-g intravenous (i.v.) dose infused over 30 min, the recommended rate of i.v. infusion for comparison, and over 120 min, which more closely mimicked the time course for absorption of the i.m. form. In a three-period crossover study (Part A), 26 healthy subjects received single doses of ertapenem administered i.m., i.v. infused over 30 min, and i.v. infused over 120 min. Blood for ertapenem analysis was collected over 24 h postdose for each treatment. In Part B, these fasted subjects received a 1-g i.m. dose of ertapenem once daily for 7 days. Following a 1-g i.m. dose and a 1-g i.v. dose infused over 120 min, the geometric mean area under the concentration curve from hour 0 to infinity (AUC(0- infinity )) was 541.8 micro g. hr/ml following i.m. administration and 591.4 micro g. hr/ml following a 120-min infusion; the geometric mean ratio was 0.92 with a 90% confidence interval of 0.88 to 0.95. The geometric mean AUC(0- infinity ) was nearly identical when 1-g doses were infused over 30 or 120 min. Although the maximum concentration of drug in serum was somewhat lower following i.m. administration than following i.v. administration, the shape of the plasma concentration profiles was roughly comparable at later time points. Ertapenem did not accumulate after multiple 1-g i.m. daily doses over 7 days. The geometric mean ratio for AUC(0-24) (day 7/day 1) was 0.98 with a 90% confidence interval of 0.94 to 1.02. Thus, the relative bioavailability of the 1-g i.m. dose was 92%. Ertapenem does not accumulate following multiple daily 1-g i.m. doses over 7 days.     

Evaluation of lung recruitment maneuvers in acute respiratory distress syndrome using computer simulation

IntroductionDirect comparison of the relative efficacy of different recruitment maneuvers (RMs) for patients with acute respiratory distress syndrome (ARDS) via clinical trials is difficult, due to the heterogeneity of patient populations and disease states, as well as a variety of practical issues. There is also significant uncertainty regarding the minimum values of positive end-expiratory pressure (PEEP) required to ensure maintenance of effective lung recruitment using RMs. We used patient-specific computational simulation to analyze how three different RMs act to improve physiological responses, and investigate how different levels of PEEP contribute to maintaining effective lung recruitment.MethodsWe conducted experiments on five ‘virtual’ ARDS patients using a computational simulator that reproduces static and dynamic features of a multivariable clinical dataset on the responses of individual ARDS patients to a range of ventilator inputs. Three recruitment maneuvers (sustained inflation (SI), maximal recruitment strategy (MRS) followed by a titrated PEEP, and prolonged recruitment maneuver (PRM)) were implemented and evaluated for a range of different pressure settings.ResultsAll maneuvers demonstrated improvements in gas exchange, but the extent and duration of improvement varied significantly, as did the observed mechanism of operation. Maintaining adequate post-RM levels of PEEP was seen to be crucial in avoiding cliff-edge type re-collapse of alveolar units for all maneuvers. For all five patients, the MRS exhibited the most prolonged improvement in oxygenation, and we found that a PEEP setting of 35 cm H₂O with a fixed driving pressure of 15 cm H₂O (above PEEP) was sufficient to achieve 95% recruitment. Subsequently, we found that PEEP titrated to a value of 16 cm H₂O was able to maintain 95% recruitment in all five patients.ConclusionsThere appears to be significant scope for reducing the peak levels of PEEP originally specified in the MRS and hence to avoid exposing the lung to unnecessarily high pressures. More generally, our study highlights the huge potential of computer simulation to assist in evaluating the efficacy of different recruitment maneuvers, in understanding their modes of operation, in optimizing RMs for individual patients, and in supporting clinicians in the rational design of improved treatment strategies.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-014-0723-6) contains supplementary material, which is available to authorized users.     

MOLECULAR CHARACTERIZATION AND SEQUENCE PHYLOGENETIC ANALYSIS OF SURFACE ANTIGEN 3 (SAG3) GENE OF LOCAL INDIAN ISOLATES (CHENNAI AND IZATNAGAR) OF Toxoplasma gondii

Context and objective:

The molecular characterization of local isolates of Toxoplasma gondii is considered significant so as to assess the homologous variations between the different loci of various strains of parasites.

Design and setting:

The present communication deals with the molecular cloning and sequence analysis of the 1158 bp entire open reading frame (ORF) of surface antigen 3 (SAG3) of two Indian T. gondii isolates (Chennai and Izatnagar) being maintained as cryostock at the IVRI.

Method:

The surface antigen 3 (SAG3) of two local Indian isolates were cloned and sequenced before being compared with the available published sequences.

Results:

The sequence comparison analysis revealed 99.9% homology with the standard published RH strain sequence of T. gondii. The strains were also compared with other established published sequences and found to be most related to the P-Br strain and CEP strain (both 99.3%), and least with PRU strain (98.4%). However, the two Indian isolates had 100% homology between them.

Conclusion:

Finally, it was concluded that the Indian isolates were closer to the RH strain than to the P-Br strain (Brazilian strain), the CEP strain and the PRU strains (USA), with respect to nucleotide homology. The two Indian isolates used in the present study are known to vary between themselves, as far as homologies related to other genes are concerned, but they were found to be 100% homologous as far as SAG3 locus is concerned. This could be attributed to the fact that this SAG3 might be a conserved locus and thereby, further detailed studies are thereby warranted to exploit the use of this particular molecule in diagnostics and immunoprophylactics. The findings are important from the point of view of molecular phylogeny.     

Squamous cell carcinoma in exstrophic unreconstructed urinary bladder in an adult

Bladder exstrophy is rare and associated with an increased incidence of bladder cancer. Unreconstructed bladder extrophy presenting in an adult is very rare as most of the patients undergo repair in childhood. Most of the cancers are adenocarcinomas. We report a rare case of squamous cell carcinoma occurring in exstrophic unreconstructed bladder in a 58-year-old male patient.     

Raised plasma levels of H<Subscript>2</Subscript>S and nitrate predict intrapulmonary vascular dilations: A preliminary report in patients with cryptogenic cirrhosis

Background and Aims

The role of vasoactive chemicals in the pathogenesis of hepatopulmonary syndrome (HPS), a disorder characterized by intrapulmonary vascular dilation (IPVD), is only vaguely elucidated. We aimed to study the association between plasma H₂S, nitrate levels, and presence and severity of IPVD and HPS.

Methods

Consecutive adult patients with cryptogenic cirrhosis were evaluated for IPVD (by contrast echocardiography) and for hypoxemia (by arterial blood gas analysis). Plasma H₂S and nitrate levels were measured in these patients.

Results

Fifty-eight patients with cryptogenic cirrhosis (male, 45; median age, range, 45, 16–74 years; Child’s class; A, 30; B, 18; C, 10) were enrolled in this study. Thirty-four of the 58 (59%) patients had IPVD and 13 (22%) had HPS (mild, 4; moderate, 5; severe, 2; very severe, 2). Plasma H₂S levels were significantly higher in patients with IPVD (19.6, 5.7–83 μmol/L) as compared to patients who had no IPVD (12.3, 0–47 μmol/L; p-value 0.03) with an area under receiver operating characteristic curve of 0.68 (95% CI 0.53–0.84). Plasma H₂S levels were higher in patients with IPVD irrespective of liver disease severity. There was a trend for higher plasma nitrate levels in patients with IPVD (47, 15.8–126.4 nmol/mL) as compared to patients who had no IPVD (32.3, 6.9–51.4 nmol/mL; p-value 0.1). Raised plasma H₂S and nitrate levels had an additive effect on the presence of IPVD. Neither plasma H₂S nor plasma nitrate levels correlated with the degree of hypoxemia.

Conclusion

Raised plasma H₂S and nitrate levels predict the presence of IPVD in patients with cryptogenic cirrhosis.