Comparison between the effects of epidural and intravenous patient-controlled analgesia on postoperative disability-free survival in patients undergoing thoracic and abdominal surgery: A post hoc analysis.

BACKGROUND: Thoracic epidural analgesia (TEA) and intravenous patient-controlled analgesia (IV-PCA) are widely used to mitigate immediate postoperative pain; however, their effects on long-term disability-free survival are poorly documented. This study aimed to compare the effects of postoperative TEA and IV-PCA on disability-free survival in patients who underwent thoracic or abdominal surgery. METHODS: This post hoc analysis of a prospective observational study included 845 inpatients aged ≥55 years that underwent elective thoracic and abdominal surgery between 1 April 2016 and 28 December 2018 in a tertiary care hospital. Inverse probability of treatment weighted (IPTW) using stabilized inverse propensity scores was adopted to minimize bias. The primary outcome in this study was disability-free survival, defined as survival with a 12-item World Health Organization Disability Assessment Schedule 2.0 score of <16%, assessed at 3 months and 1 year after surgery. RESULTS: The final analysis included 601 patients who received TEA and 244 who received IV-PCA. After IPTW, the weighted incidence of disability-free survival at 3 months and 1 year was 60.5% and 61.4% in the TEA group and 78.3% and 66.2% in the IV-PCA group, respectively. The adjusted OR for disability-free survival at 3 months and 1 year was 0.84 (95% confidence interval [CI]: 0.50-1.39) and 1.21 (95% CI: 0.72-2.05), respectively, for the TEA group. CONCLUSION: No significant differences were observed in the disability-free survival at 3 months and 1 year after elective thoracic and abdominal surgery in patients aged ≥55 years who received TEA or IV-PCA. SIGNIFICANCE STATEMENT: This study is the first in our setting to document the long-term effects of patient-controlled analgesia. In a post hoc analysis of our prospective cohort study, we show that although differences in chronic postsurgical pain exist at 3 months post-surgery, disability-free survival rates at 1 year do not differ irrespective of the choice of patient-controlled analgesia. The findings of this study highlight the need for shared decision-making between clinicians and patients.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer (MBC) was published in 2021. A special, hybrid guidelines meeting was convened by ESMO and the Korean Society of Medical Oncology (KSMO) in collaboration with nine other Asian national oncology societies in May 2022 in order to adapt the ESMO 2021 guidelines to take into account the differences associated with the treatment of MBC in Asia. These guidelines represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with MBC representing the oncological societies of China (CSCO), India (ISMPO), Indonesia (ISHMO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO). The voting was based on the best available scientific evidence and was independent of drug access or practice restrictions in the different Asian countries. The latter were discussed when appropriate. The aim of these guidelines is to provide guidance for the harmonisation of the management of patients with MBC across the different regions of Asia, drawing from data provided by global and Asian trials whilst at the same time integrating the differences in genetics, demographics and scientific evidence, together with restricted access to certain therapeutic strategies.

Pimitespib in patients with advanced gastrointestinal stromal tumor (CHAPTER-GIST-301): a randomized, double-blind, placebo-controlled phase III trial.

BACKGROUND: Prognosis of advanced gastrointestinal stromal tumors (GIST) refractory to tyrosine kinase inhibitors (TKIs) is poor. This randomized, placebo-controlled, phase III trial evaluated the efficacy and safety of pimitespib, a novel heat shock protein 90 inhibitor, in advanced GIST refractory to standard TKIs. PATIENTS AND METHODS: Patients with histologically confirmed GIST refractory to imatinib, sunitinib, and regorafenib were randomized 2 : 1 to oral pimitespib 160 mg/day or placebo for 5 consecutive days per week in 21-day cycles. Following disease progression by blinded central radiological review (BCRR), cross-over to open-label pimitespib was permitted. The primary endpoint was progression-free survival (PFS) by BCRR in the full analysis set. Secondary endpoints included overall survival (OS) adjusted using the rank-preserving structural failure time (RPSFT) method to reduce the expected confounding impact of cross-over. RESULTS: From 31 October 2018 to 30 April 2020, 86 patients were randomized to pimitespib (n = 58) or placebo (n = 28). Median PFS was 2.8 months [95% confidence interval (CI) 1.6-2.9 months] with pimitespib versus 1.4 months (0.9-1.8 months) with placebo [hazard ratio (HR) 0.51 (95% CI 0.30-0.87); one-sided P = 0.006]. Pimitespib showed an improvement in cross-over-adjusted OS compared with placebo [HR 0.42 (0.21-0.85), one-sided P = 0.007]. Seventeen (60.7%) patients receiving placebo crossed-over to pimitespib; median PFS after cross-over was 2.7 months (95% CI 0.7-4.1 months). The most common (≥30%) treatment-related adverse events (AEs) with pimitespib were diarrhea (74.1%) and decreased appetite (31.0%); the most common (≥10%) grade ≥3 treatment-related AE was diarrhea (13.8%). Treatment-related AEs leading to pimitespib discontinuation occurred in three (5.2%) patients. CONCLUSIONS: Pimitespib significantly improved PFS and cross-over-adjusted OS compared with placebo and had an acceptable safety profile in patients with advanced GIST refractory to standard TKIs.

Diagnosis and management of tropomyosin receptor kinase (TRK) fusion sarcomas: expert recommendations from the World Sarcoma Network.

Sarcomas are a heterogeneous group of malignancies with mesenchymal lineage differentiation. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as tissue-agnostic oncogenic drivers has led to new personalized therapies for a subset of patients with sarcoma in the form of tropomyosin receptor kinase (TRK) inhibitors. NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry. The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians. To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions. We propose a diagnostic strategy that considers disease stage and histologic and molecular subtypes to facilitate routine testing for TRK expression and subsequent testing for NTRK gene fusions.

JSCO-ESMO-ASCO-JSMO-TOS: international expert consensus recommendations for tumour-agnostic treatments in patients with solid tumours with microsatellite instability or NTRK fusions.

A Japan Society of Clinical Oncology (JSCO)-hosted expert meeting was held in Japan on 27 October 2019, which comprised experts from the JSCO, the Japanese Society of Medical Oncology (JSMO), the European Society for Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO), and the Taiwan Oncology Society (TOS). The purpose of the meeting was to focus on what we have learnt from both microsatellite instability (MSI)/deficient mismatch repair (dMMR) biomarkers in predicting the efficacy of anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) immunotherapy, and the neurotrophic tyrosine receptor kinase (NTRK) gene fusions in predicting the efficacy of inhibitors of the tropomyosin receptor kinase (TRK) proteins across a range of solid tumour types. The recent regulatory approvals of the anti-PD-1 antibody pembrolizumab and the TRK inhibitors larotrectinib and entrectinib, based on specific tumour biomarkers rather than specific tumour type, have heralded a paradigm shift in cancer treatment approaches. The purpose of the meeting was to develop international expert consensus recommendations on the use of such tumour-agnostic treatments in patients with solid tumours. The aim was to generate a reference document for clinical practice, for pharmaceutical companies in the design of clinical trials, for ethics committees in the approval of clinical trial protocols and for regulatory authorities in relation to drug approvals, with a particular emphasis on diagnostic testing and patient selection.

Correction: Signal peptidase complex 18, encoded by SEC11A, contributes to progression via TGF-α secretion in gastric cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Amiodarone does not affect brain injury in a rat model of transient forebrain ischemia.

OBJECTIVES: Although amiodarone may cause neurotoxicity that can affect patient outcomes when used during cardiopulmonary resuscitation (CPR), it has been commonly prescribed during CPR. This study investigated the possible neurotoxic effects of amiodarone in a rat model of transient forebrain ischemia. DESIGN: A prospective laboratory animal study was carried out. SETTING: Animal laboratory. MATERIALS: Male Sprague-Dawley rats. INTERVENTION: Eight minutes of forebrain ischemia was induced in rats by bilateral carotid occlusion and hypotension (mean arterial pressure=35mmHg) under isoflurane (1.5%) anesthesia. Amiodarone (0, 50, 100 and 150mg/kg) with saline was injected intraperitoneally 10min after ischemia. Rats given 0mg/kg of amiodarone were used as saline-treated controls. Sham operated rats received no treatment. VARIABLES OF INTEREST: Animals were evaluated neurologically on postoperative days 4-7, and histologically after a one-week recovery period. RESULTS: The greatest improvement in water maze test performance corresponded to the sham operated group (p=0.015 vs. saline-treated controls). No differences in performance were seen in amiodarone-treated rats compared with saline-treated controls. In the control group, 45% of the CA1 hippocampal neurons survived, compared with 78% in the sham operated group (p=0.009). Neuron survival after ischemia in the amiodarone treatment groups (50, 100 and 150mg/kg) (58%, 40% and 36%, respectively) and in the control rats did not differ significantly. CONCLUSIONS: The administration of amiodarone immediately after transient forebrain ischemia did not worsen spatial cognitive function or neuronal survival in the hippocampal CA1 region in rats. The current results must be applied with caution in humans. However, they indicate that the potential neurotoxicity induced by amiodarone during resuscitation after cardiac arrest may be negligible.

SurePath® LBC improves the diagnostic accuracy of intrahepatic and hilar cholangiocarcinoma.

INTRODUCTION: The current study aimed to compare cytology using SurePath® (SP)-LBC and biliary tissue histology (BTH) for the diagnosis of biliary disease. METHODS: Between January 2014 and December 2016, 57 patients underwent endoscopic retrograde cholangiopancreatography for the diagnosis of biliary disease. Biliary cytological samples were processed using SP-LBC and subsequently BTH was performed. A final diagnosis was confirmed by surgery (23 malignant cases) and clinical follow-up (34 benign and malignant cases): 18 extrahepatic cholangiocarcinoma; 17 intrahepatic/hilar cholangiocarcinoma (intra/H-CC); eight other malignant disease; and 14 benign biliary disease. The diagnoses made using SP-LBC and BTH were classified into four categories: (1) benign; (2) indeterminate; (3) suspicious for malignancy/malignant; and (4) inadequate. In addition, diagnostic accuracy was compared between SP-LBC and BTH. RESULTS: Although 23% (13/57) of BTH samples were classified as inadequate, all SP-LBC cases were classified as adequate. Among 43 malignant cases, 11 normal, four indeterminate and 28 suspicious for malignancy/malignant were found using SP-LBC (26%, 9% and 65%, respectively), in contrast to 10 inadequate, nine normal, 10 indeterminate and 14 suspicious for malignancy/malignant observed using BTH (23%, 21%, 23%, and 33%, respectively). The identification of malignant cells was strikingly different between SP-LBC and BTH. Furthermore, limited to intra/H-CC, accuracy was significantly higher using SP-LBC than using BTH (P < .001). CONCLUSIONS: SP-LBC of the biliary tract is a useful and reliable method for diagnosing biliary malignant disease and has an advantage over BTH for detecting malignant cells and accurately diagnosing intra/H-CC.

A Combined test using both cell sediment and supernatant cell-free DNA in pleural effusion shows increased sensitivity in detecting activating EGFR mutation in lung cancer patients.

INTRODUCTION: The aim of this study was to examine whether a combined test using both cell sediment and supernatant cytology cell-free DNA (ccfDNA) is more useful in detecting EGFR mutation than using cell sediment DNA or supernatant ccfDNA alone in pleural effusion of lung cancer patients. METHODS: A total of 74 lung adenocarcinoma patients with paired samples between primary tumour and corresponding metastatic tumour with both cell sediment and supernatant ccfDNA of pleural effusion cytology were enrolled in this study. Cell sediment and supernatant ccfDNA were analysed separately for EGFR mutations by polymerase chain reaction. RESULTS: Out of 45 patients with mutant EGFR in primary tumours, EGFR mutations were detected in 23 cell sediments of corresponding metastases (sensitivity; 51.1%) and 20 supernatant ccfDNA corresponding metastases (sensitivity; 44.4%). By contrast, the combined test detected EGFR mutations in 27 corresponding metastases (sensitivity; 60.0%), and had a higher sensitivity than the cell sediment or the supernatant ccfDNA alone (P < .05). Out of 45 patients with mutant EGFR, 24, three and 18 were cytologically diagnosed as positive, atypical or negative, respectively. The detection rate in the combined test was highest (95.8%) in the positive group, and mutant EGFR was also detected in four of 18 samples (22.2%) in the negative group. CONCLUSIONS: A combined test using both cell sediment DNA and supernatant ccfDNA samples increases the concordance rate of EGFR mutations between primary tumour and corresponding metastases. Our findings indicate that supernatant ccfDNA is useful even in cases where the cytological diagnosis is negative.

Mucocutaneous inflammation in the Ikaros Family Zinc Finger 1-keratin 5-specific transgenic mice.

BACKGROUND: Our genomewide association study documented an association between cold medicine-related Stevens-Johnson syndrome/toxic epidermal necrolysis (CM-SJS/TEN) and Ikaros Family Zinc Finger 1 (IKZF1). Few studies examined biological and pathological functions of IKZF1 in mucosal immunity. We hypothesized that IKZF1 contributes to the mucocutaneous inflammation. METHODS: Human skin and conjunctival tissues were obtained for immunohistological studies. Primary human conjunctival epithelial cells (PHCjECs) and adult human epidermal keratinocytes (HEKa) also used for gene expression analysis. We also generated K5-Ikzf1-EGFP transgenic mice (Ikzf1 Tg) by introducing the Ik1 isoform into cells expressing keratin 5, which is expressed in epithelial tissues such as the epidermis and conjunctiva, and then examined them histologically and investigated gene expression of the epidermis. Moreover, Ikzf1 Tg were induced allergic contact dermatitis. RESULTS: We found that human epidermis and conjunctival epithelium expressed IKZF1, and in PHCjECs and HEKa, the expression of IKZF1 mRNA was upregulated by stimulation with polyI:C, a TLR3 ligand. In Ikzf1 Tg, we observed dermatitis and mucosal inflammation including the ocular surface. In contact dermatitis model, inflammatory infiltrates in the skin of Ikzf1 Tg were significantly increased compared with wild type. Microarray analysis showed that Lcn2, Adh7, Epgn, Ifi202b, Cdo1, Gpr37, Duoxa1, Tnfrsf4, and Enpp5 genes were significantly upregulated in the epidermis of Ikzf1 Tg compared with wild type. CONCLUSION: Our findings support the hypothesis that Ikaros might participate in mucocutaneous inflammation.