Intensive follo w-up after liver resection for colorectal liver metastases: results of combined serial tumour marker estimations and computed tomography of the chest and abdomen – a prospective study

The aim of the study was to prospectively evaluate an intensive follow-up programme using serial tumour marker estimations and contrast-enhanced computed tomography (CT) of the chest and abdomen in patients undergoing potentially curative resection of colorectal liver metastases. Seventy-six consecutive patients having undergone potentially curative resections of colorectal liver metastases in a single unit were followed up with a protocol of 3 monthly carcinoembryonic antigen and carbohydrate antigen 19-9 estimations and contrast-enhanced spiral CT of the chest, abdomen and pelvis for the first 2 years following surgery and 6 monthly thereafter. The median period of follow-up was 24 months (range 18–60). Recurrent tumour was classed as early if within 6 months of liver resection. Thirty-seven of the 76 patients (49%) developed recurrence on follow-up. Nineteen recurrences were in the liver alone (51%), 16 liver and extrahepatic (43%) and two extrahepatic alone (6%). Of the 19 patients with isolated liver recurrence, eight developed within 6 months of liver resection none of which were resectable. Of the 11 recurrences after 6 months, five (45%) were resectable. Of the 37 recurrences, CT indicated recurrence despite normal tumour markers in 19 patients. Tumour markers suggested recurrence before imaging in 12 and concurrently with imaging in 6. In the 12 patients who presented with elevated tumour markers before imaging, there was a median lag period of 3 months (range 1–21) in recurrence being detected on further serial imaging. Seventeen patients who developed recurrence had normal tumour markers before initial resection of their liver metastases. Of these 17, 10 (58%) had an elevation of tumour markers associated with recurrence. Over a median follow-up of 2 years following liver resection, the use of CT or tumour markers alone would have failed to demonstrate early recurrence in 12 and 18 patients respectively. A combination of tumour markers and CT detected significantly more (P<0.05) recurrence than either modality alone. Tumour markers and CT should be used in combination in the follow-up of patients with resected colorectal liver metatases, including patients whose markers are normal at the time of initial liver resection

Strong enhancement of phonon scattering through nanoscale grains in lead sulfide thermoelectrics

We present nanocrystalline PbS, which was prepared using a solvothermal method followed by spark plasma sintering, as a promising thermoelectric material. The effects of grains with different length scales on phonon scattering of PbS samples, and therefore on the thermal conductivity of these samples, were studied using transmission electron microscopy and theoretical calculations. We found that a high density of nanoscale grain boundaries dramatically lowered the thermal conductivity by effectively scattering long-wavelength phonons. The thermal conductivity at room temperature was reduced from 2.5 W m1K 1 for ingot-PbS (grain size 4200 lm) to 2.3 W m1K 1 for micro-PbS (grain size 40.4 lm); remarkably, thermal conductivity was reduced to 0.85 W m1 K 1 for nano-PbS (grain size B30 nm). Considering the full phonon spectrum of the material, a theoretical model based on a combination of first-principles calculations and semiempirical phonon scattering rates was proposed to explain this effective enhancement. The results show that the high density of nanoscale grains could cause effective phonon scattering of almost 61%. These findings shed light on developing high-performance thermoelectrics via nanograins at the intermediate temperature range.This contribution was supported primarily by the startup of the South University of Science and Technology of China, supported by the Shenzhen government, and the national 1000 plan for young scientists. This work was also partially supported by a grant-in-aid of ‘985 Project’ from Xi’an Jiaotong University, the National Natural Science Foundation of China (Grant No. 21201138 and 11204228), the National Basic Research Program of China (2012CB619402 and 2014CB644003) and the Fundamental Research Funds for the Central UniversitiesS

Tepotinib plus gefitinib in patients with EGFR-mutant non-small-cell lung cancer with MET overexpression or MET amplification and acquired resistance to previous EGFR inhibitor (INSIGHT study): an open-label, phase 1b/2, multicentre, randomised trial

Background We evaluated the efficacy and safety of tepotinib, a potent and highly selective oral MET inhibitor, plus gefitinib in patients with epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) with MET overexpression (immunohistochemistry [IHC]2+ or IHC3+) or MET amplification having acquired resistance to EGFR inhibition. Methods In this open-label, phase 1b/2, multicentre, randomised trial (the INSIGHT study), we enrolled adult patients (>= 18 years) with advanced or metastatic NSCLC, and Eastern Cooperative Oncology Group performance status of 0 or 1, from academic medical centres and community clinics in six Asian countries. In phase 1b, patients received oral tepotinib 300 mg or 500 mg plus gefitinib 250 mg once daily. In phase 2, patients with EGFR-mutant, T790M-negative NSCLC MET overexpression or MET amplification were randomly assigned (initially in a 1:1 ratio and then 2:1 following a protocol amendment) to tepotinib plus gefitinib at the recommended phase 2 dose or to standard platinum doublet chemotherapy. Randomisation was done centrally via an interactive voice-response system. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Subgroup analyses were preplanned in patients with high MET overexpression (IHC3+) or MET amplification (mean gene copy number >= 5 or MET to centromere of chromosome 7 ratio >= 2). Efficacy and patient characteristics were assessed on an intention-to-treat basis and safety was assessed for all patients who received at least one dose of study medication. Low recruitment led to early termination of phase 2, so all analyses are considered to be exploratory. This study is registered with ClinicalTrials.gov , NCT01982955, and the European Union Drug Regulating Authorities Clinical Trials Database, Eudra-CT 2016-001604-28. Findings From Dec 23,2013, to May 25,2017,18 patients were enrolled in phase 1b (n=6 in the 300 mg tepotinib group; n=12 in the 500 mg tepotinib group) and 55 patients in phase 2 (n=31 in the tepotinib plus gefitinib group; n=24 in the chemotherapy group). No dose-limiting toxicities were observed in phase lb, so tepotinib 500 mg was used as the recommended phase 2 dose. In phase 2, survival outcomes were similar between groups: median PFS was 4.9 months in the tepotinib plus gefitinib group (90% CI 3.9-6-9) versus 4.4 months in the chemotherapy group (90% CI 4-2-6.8; hazard ratio [HR] 0.67, 90% CI 0-35-1-28). Median OS was 17.3 months in the tepotinib plus gefitinib group (12.1-37.3) versus 18.7 months in the chemotherapy group (15.9-20-7; HR 0.69,0-34-1-41). PFS and OS were longer with tepotinib plus gefitinib than with chemotherapy in patients with high (IHC3+) MET overexpression (n=34; median PFS 8.3 months [44-16.6] vs 4.4 months [4.1-6.8]; HR O. 35,047-0.74; median OS 37.3 months [90% CI 24-2-37.3] vs 17.9 months [12.0-20-7]; HR 0.33, 0.14-0.76) or MET amplification (n=19; median PFS 16.6 months [8.3-not estimable] vs 4.2 months [1.4-7-0]; HR 0- 13,0- 04-0.43; median OS 37.3 months [90% CI not estimable] vs 13.1 months [3.25-not estimable]; HR 0.08,0-01-0.51) The most frequent treatment-related grade 3 or worse adverse events were increased amylase (5 [16%] of 31 patients) and lipase (4 [13%]) concentrations in the tepotinib plus gefitinib group and anaemia (7 [30%] of 23 patients) and decreased neutrophil count (3 [13%]) in the chemotherapy group. Interpretation Despite early study termination, in a preplanned subgroup analysis, our findings suggest improved anti activity for tepotinib plus gefitinib compared with standard chemotherapy in patients with EGFR-inu tarn NSCLC and MET amplification, warranting further exploration. Copyright (C) 2020 Elsevier Ltd. All rights reserved.

Unraveling the historical prevalence of the invasive chytrid fungus in the Bolivian Andes: implications in recent amphibian declines

We studied the historical prevalence of the invasive and pathogenic chytrid fungus Batrachochytrium dendrobatidis (Bd) among amphibians from the Bolivian Andes. Our aim was also to determine its geographic pattern of dispersion, and a potential host taxonomic signature. We collected frog tissue samples from nine museum collections covering a period from 1863 to 2005 and from the field during 2009–2016. Bd was diagnosed via quantitative PCR in 599 individuals of 17 genera and 54 species. We found an overall Bd prevalence of 41% among 44 species tested. The first incidence of Bd was from a Telmatobius culeus in 1863; this is the earliest report of detection for this pathogen in the world. Results reveal a non-random historical and geographical pattern of Bd occurrence and amphibian declines that suggests the presence of two different invasive strains, an ancient endemic and a more recent introduction. Prevalence of Bd increased significantly by the mid-1990s, particularly in the cloud-forests, and this is coincident with the timing of drastic amphibian declines. In contrast, amphibians occurring in drier altiplano habitats have persisted in spite of Bd presence. We hypothesize that the early 1990s, and the cloud-forests in central Bolivia were the center of an epidemic surge of Bd that took its toll on many species, especially in the genus Telmatobius. Further sampling of cloud-forest species, and ongoing genetic studies of Bd isolates from Bolivia should help resolve the history of this invasive pathogen and test hypotheses on the differential response of endangered hosts.This research was supported by Projects CGL2011-30393 and CGL2014-56160-P of the Spanish Government (PI, Ignacio De la Riva).Peer Reviewe