Pralsetinib in patients with RET fusion-positive non-small-cell lung cancer: A plain language summary of the ARROW study.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a research study called ARROW, which tested a medicine called pralsetinib in patients with non-small cell lung cancer (NSCLC), thyroid cancer, and other advanced solid tumours caused by a change in a gene called RET. For the purposes of this summary, only patients with NSCLC with a change in RET called fusion (RET fusion+) are highlighted. WHAT WERE THE RESULTS?: In total, 281 patients with RET fusion+ NSCLC had taken part in this study across the USA, Europe, and Asia. Patients were asked to take four pills (adding up to 400 mg) of pralsetinib each day and were checked for any changes in their tumours, as well as for any side effects. After an average of 8 months of treatment with pralsetinib, 72% of previously untreated patients and 59% of patients who had previously received chemotherapy had considerable shrinkage of their tumours. Among 10 patients with tumours which had spread to the brain (all of whom had received previous treatments), 70% had their tumours shrink greatly in the brain after treatment with pralsetinib. On average, patients lived with little to no tumour growth for 16 months. In previously untreated patients, the most common severe side effects that were considered related to pralsetinib treatment were decreased white blood cells (neutrophils and lymphocytes), increased blood pressure, and an increase in a blood protein called creatine phosphokinase. In previously treated patients, the severe side effects were decreased white blood cells (neutrophils, lymphocytes, and leukocytes), increased blood pressure, and low levels of red blood cells. In both untreated and previously treated patients, the most common severe side effects that required hospital attention were lung inflammation/swelling causing shortness of breath (pneumonitis) and lung infection (pneumonia). WHAT DO THE RESULTS MEAN?: Overall, the ARROW study showed that pralsetinib was effective in shrinking tumours in patients with RET fusion+ NSCLC regardless of previous treatment history. The recorded side effects were expected in patients receiving this type of medicine. Clinical Trial Registration: NCT03037385 (ARROW) (ClinicalTrials.gov).

The Leukocyte Esterase Strip Test has Practical Value for Diagnosing Periprosthetic Joint Infection After Total Knee Arthroplasty: A Multicenter Study.

BACKGROUND: Leukocyte esterase (LE) was recently reported to be an accurate marker for diagnosing periprosthetic joint infection (PJI) as defined by the Musculoskeletal Infection Society (MSIS) criteria. However, the diagnostic value of the LE test for PJI after total knee arthroplasty (TKA), the reliability of the subjective visual interpretation of the LE test, and the correlation between the LE test results and the current MSIS criteria remain unclear. METHODS: This study prospectively enrolled 60 patients undergoing revision TKA for either PJI or aseptic failure. Serological marker, synovial fluid, and histological analyses were performed in all cases. The PJI group comprised 38 cases that met the MSIS criteria and the other 22 cases formed the aseptic group. All the LE tests were interpreted using both visual judgment and automated colorimetric reader. RESULTS: When "++" results were considered to indicate a positive PJI, the sensitivity, specificity, positive and negative predictive value, and diagnostic accuracy were 84, 100, 100, 79, and 90%, respectively. The visual interpretation agreed with the automated colorimetric reader in 90% of cases (Cronbach α = 0.894). The grade of the LE test was strongly correlated with the synovial white blood cell count (ρ = 0.695) and polymorphonuclear leukocyte percentage (ρ = 0.638) and moderately correlated with the serum C-reactive protein and erythrocyte sedimentation rate. CONCLUSION: The LE test has high diagnostic value for diagnosing PJI after TKA. Subjective visual interpretation of the LE test was reliable and valid for the current battery of PJI diagnostic tests according to the MSIS criteria.

Trisomy 8 Defines a Distinct Subtype of Myeloproliferative Neoplasms Driven by the MYC-Alarmin Axis.

Despite advances in understanding the genetic abnormalities in myeloproliferative neoplasms (MPN) and the development of JAK2 inhibitors, there is an urgent need to devise new treatment strategies, particularly for patients with triple-negative (TN) myelofibrosis (MF) who lack mutations in the JAK2 kinase pathway and have very poor clinical outcomes. Here we report that MYC copy number gain and increased MYC expression frequently occur in TN-MF and that MYC-directed activation of S100A9, an alarmin protein that plays pivotal roles in inflammation and innate immunity, is necessary and sufficient to drive development and progression of MF. Notably, the MYC-S100A9 circuit provokes a complex network of inflammatory signaling that involves numerous hematopoietic cell types in the bone marrow microenvironment. Accordingly, genetic ablation of S100A9 or treatment with small molecules targeting the MYC-S100A9 pathway effectively ameliorates MF phenotypes, highlighting the MYC-alarmin axis as a novel therapeutic vulnerability for this subgroup of MPNs. Significance: This study establishes that MYC expression is increased in TN-MPNs via trisomy 8, that a MYC-S100A9 circuit manifest in these cases is sufficient to provoke myelofibrosis and inflammation in diverse hematopoietic cell types in the BM niche, and that the MYC-S100A9 circuit is targetable in TN-MPNs.

The role of integrated 18F-FDG PET-CT as a staging tool for limited-stage small cell lung cancer: a retrospective study.

BACKGROUND: The aim of this study was to evaluate whether positron emission tomography-computed tomography (PET-CT) could be used as part of the staging work-up in patients with limited-stage disease (LD) small cell lung cancer (SCLC). PATIENTS AND METHODS: Between January 2002 and December 2007, a total of 73 patients with presumed LD on CT, who underwent a PET-CT scan, were included in this study. RESULTS: Conventional work-up revealed distant metastases in 12 patients. Out of 61 patients diagnosed as LD SCLC, PET-CT found unexpected distant metastases in 15 (24.6%) patients (LD/extensive-stage disease (ED)) of whom 13 (21.3%) were upstaged as a consequence. In 10 (76.9%) of the 13 upstaged patients, treatment was changed. The median survival of LD/LD SCLC patients who underwent concurrent chemoradiotherapy and chemotherapy only was 21.9 and 17.5 months, respectively. The median survival of LD/ED and ED/ED SCLC patients who received chemotherapy only was 17.4 and 14.1 months, respectively. The median survival of LD/LD SCLC patients who received concurrent chemoradiotherapy was superior to that of LD/ ED and ED/ED patients who received chemotherapy only (p = 0.037 and 0.004, respectively). CONCLUSION: The addition of PET-CT seems to allow more accurate staging and may thus protect a percentage of SCLC patients from potentially futile and toxic radiotherapy.

Osimertinib in Patients With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer and Leptomeningeal Metastases: The BLOOM Study.

PURPOSE: In this phase I study (BLOOM), osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was evaluated in patients with leptomeningeal metastases (LMs) from EGFR-mutated (EGFRm) advanced non-small-cell lung cancer (NSCLC) whose disease had progressed on previous EGFR-TKI therapy. PATIENTS AND METHODS: Patients with cytologically confirmed LM received osimertinib 160 mg once daily. Objectives were to assess confirmed objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), pharmacokinetics (PK), and safety. Additional efficacy evaluations included changes from baseline in CSF cytology and neurologic examination. Measurable lesions were assessed by investigator according to RECIST version 1.1. LMs were assessed by neuroradiologic blinded central independent review (BICR) according to Response Assessment in Neuro-Oncology LM radiologic criteria and by investigator. RESULTS: Forty-one patients were enrolled. LM ORR and DoR by neuroradiologic BICR were 62% (95% CI, 45% to 78%) and 15.2 months (95% CI, 7.5 to 17.5 months), respectively. Overall, ORR by investigator was 41% (95% CI, 26% to 58%), and median DoR was 8.3 months (95% CI, 5.6 to 16.5 months). Median investigator-assessed PFS was 8.6 months (95% CI, 5.4 to 13.7 months) with 78% maturity; median OS was 11.0 months (95% CI, 8.0 to 18.0 months) with 68% maturity. CSF tumor cell clearance was confirmed in 11 (28%; 95% CI, 15% to 44%) of 40 patients. Neurologic function was improved in 12 (57%) of 21 patients with an abnormal assessment at baseline. The adverse event and PK profiles were consistent with previous reports for osimertinib. CONCLUSION: Osimertinib showed meaningful therapeutic efficacy in the CNS and a manageable safety profile at 160 mg once daily in patients with EGFRm NSCLC and LM.

The routine use of surgical exposure approach for trans-femoral implantation of the balloon expandable aortic prosthesis is associated to a low rate of vascular complications.

BACKGROUND: The most frequent complications of transfemoral aortic valve implantation are vascular (15-25%) and are related to an increase in mortality. We sought to assess the rate of vascular complications, its treatment and outcomes using a surgical approach for transfemoral implantation of Edwards-SAPIEN (Edwards Lifescience, Irvine, CA, USA) aortic valve. METHODS: We have conducted a multicenter registry including 4 hospitals using a systematic surgical exposure approach. Vascular complications have been collected following the definitions of the Valve Academic Research Consortium. RESULTS: From 2008 to 2013 a total of 312 consecutive patients have been included. Vascular complications were reported in 22 (7%), among those 6 (1.9%) were major whereas 16 (5.1%) were minor. Patients suffering vascular complications had significantly more previous history of peripheral vascular disease. All but one major complications occurred in women, aged 82-88 and with chronic renal failure. Hospital stay was longer in cases suffering complications (17.8±11 days vs. 9±7 days; P<0.0001). The 30 days mortality was 13.6% in patients with vascular complications, 33.3% in patients with major complications and 5.5% in patients with no complications (P=0.05). CONCLUSIONS: In this registry, the systematic use of a surgical exposure of the femoral artery for TAVR has been associated with a lower rate of vascular complications.

Determination of irinotecan and its metabolite SN-38 in rabbit plasma and tumors using a validated method of tandem mass spectrometry coupled with liquid chromatography.

New tandem mass spectrometric method coupled with liquid chromatography (LC-MS/MS) has been developed to determine the total concentration of camptothecin derivatives (irinotecan and SN-38) regardless of inter-conversion phenomenon between carboxylate and lactone forms. At first, all sample solutions were acidified for 1h in order to completely convert CPT derivatives into their lactone forms and then CPT derivatives were extracted with organic solution containing diethyl ether and ethyl acetate (2:1, v/v) just after alkalization in the range pH 8.0-8.5 in acid-treated solutions. Analytes were separated on a reverse phase C18 column (150×2.1mm) and eluted isocratically with a mobile phase which consisted of acetonitrile-methanol-buffer (0.1% formic acid, 5mM ammonium formate) (3:4:3, v/v). CPT derivatives were monitored by tandem mass spectrometry in electrospay-positive ionization and multiple reaction mode programmed to the following transitions (m/z): '587.6→167.2' of CPT-11, '393.6→349.3' of SN-38 and '349.4→ 305.2' of CPT. The method was validated to have the proper linearity (r(2)>0.99) over the range of 5-1000ng/ml of CPT-11 and 1-250ng/ml of SN-38 with good accuracy (89.8-114.3%) and precision (less than 10%). In all stability tests, concentration of CPT-11 and SN-38 had been left in the acceptable range of 88.8-110.7% when sample solutions were acidified before determination of CPT derivatives. Newly developed LC-MS/MS method was suitable for the determination of CPT derivatives of both rabbit plasma and tumor tissues in the pharmacokinetic study.

A phase II study of irinotecan plus cisplatin for patients with advanced stage IIIB or IV NSCLC previously treated with nonplatinum-based chemotherapy.

BACKGROUND: Irinotecan (1) and cisplatin (P) are active chemotherapy agents with clinical synergy in non-small-cell lung cancer (NSCLC). We evaluated the efficacy of IP regimen as a salvage treatment of patients with NSCLC that progressed after nonplatinum-containing regimen(s). METHODS: Eligibility required histologically confirmed NSCLC, bidimensionally measurable disease, ECOG PS 0-2, and progressive disease after nonplatinum-based chemotherapy. Treatment consisted of I (65 mg/m2) and P (30 mg/m2) i.v. on Days 1 and 8 of a 21-day cycle, for a maximum of 6 cycles. An informed consent was obtained from all patients. RESULTS: Between August 2002 and May 2004, 32 patients with median age of 56 years (range, 42-74) were enrolled. Twenty-four (75%) patients were men, and 28 (88%) had ECOG PS 0 or 1. Twenty-five patients had adenocarcinoma and 6 had squamous-cell carcinoma. All patients were evaluated for response and toxicity, and the response rate was 40.6%. After a median follow-up of 18.5 months, the median survival time was found to be 9.3 months, with a 1-year survival rate of 43.8%. Toxicities were moderate and manageable, with 47% G3 and 9% G4 neutropenia, 19% G3 diarrhea, and 22% G3 asthenia. There was no G4 nonhematologic toxicity. CONCLUSIONS: The irinotecan and cisplatin combination is an active and well-tolerated regimen for the patients with advanced NSCLC that progressed after nonplatinum-containing regimen(s).