Interstitial lung disease (ILD) is the most frequent cause of drug-related mortality from EGFR tyrosine kinase inhibitors (TKIs). Yet, for patients with symptomatic osimertinib-induced ILD, the risk ...of recurrent ILD associated with EGFR TKI rechallenge, either with osimertinib or another TKI, such as erlotinib, is unclear.
Retrospective study of 913 patients who received osimertinib treatment for EGFR mutation-positive NSCLC. Clinical characteristics, ILD treatment history, and subsequent anticancer therapy of patients with symptomatic osimertinib-induced ILD were collated. The primary end point was to compare the incidence of recurrent ILD with osimertinib versus erlotinib rechallenge.
Of 913 patients, 35 (3.8%) had symptomatic osimertinib-induced ILD, of which 12 (34%), 15 (43%), and eight (23%) had grade 2, 3 to 4, and 5 ILD, respectively. On ILD recovery, 17 patients had EGFR TKI rechallenge with eight received osimertinib and nine received erlotinib. The risk of recurrent ILD was higher with osimertinib rechallenge than erlotinib (p = 0.0498). Of eight, five (63%) developed recurrent ILD on osimertinib rechallenge, including three patients with fatal outcomes. In contrast, only one of nine patients (11%) treated with erlotinib had recurrent ILD. Median time to second ILD occurrence was 4.7 (range 0.7–12) weeks. Median time-to-treatment failure of patients with erlotinib rechallenge was 13.2 months (95% confidence interval: 8.6–15.0).
The risk of recurrent ILD was considerably higher with osimertinib rechallenge than erlotinib. Osimertinib rechallenge should be avoided, whereas erlotinib may be considered in patients with symptomatic osimertinib-induced ILD.
•Addition of pemetrexed-platinum on first-line osimertinib progression is effective.•Patients with L858R and baseline CNS metastases also benefit from this approach.•Early initiation of chemotherapy ...after osimertinib failure improves outcomes.
First-line pemetrexed-platinum chemotherapy + osimertinib(Pem-Plat-Osi) improves progression-free survival as compared to osimertinib alone in advanced epidermal growth factor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, many patients are hesitant to commence chemotherapy upfront. We describe outcomes to Pem-Plat-Osi after first-line osimertinib failure.
Patients with advanced EGFR-mutated (ex19del/L858R) NSCLC who had Pem-Plat-Osi between 1/7/2018–30/9/2023 after progression on first-line osimertinib at National Cancer Centre Singapore, Prince of Wales Hospital and Chinese University of Hong Kong were identified. Key endpoints were time to treatment failure (TTF) and overall survival (OS).
A total of 60 patients were included. Median age at diagnosis was 62, 53.3 % (32/60) were male and 76.7 % (46/60) were never smokers. Ex19del comprised 56.7 % (34/60) and L858R 43.3 % (26/60). Baseline central nervous system (CNS) metastases were present in 66.7 % (40/60). Median TTF on osimertinib (TTF1) was 14.4 months(m) and median time to initiation of Pem-Plat-Osi was 41 days(d) (range 0–652) after progression on osimertinib.
Partial response (PR) or stable disease to Pem-Plat-Osi was achieved in 81.7 %(49/60). Intracranial disease control was achieved in 90.6 % (29/32) of patients with measurable CNS metastases, including those who did not undergo brain radiotherapy. At median follow up of 31.2 m, median TTF on Pem-Plat-Osi (TTF2) was 6.6 m. Median TTF1 + TTF2 was 23.4 m and median OS was 34.2 m. Survival outcomes were similar comparing ex19del and L858R (median TTF1 + TTF2 21.8 m vs 23.5 m, p = 0.90; median OS 34.2 m vs 36.8 m, p = 0.37) and in patients without/with baseline CNS metastases (median TTF1 + TTF2 21.8 m vs 23.4 m, p = 0.44; median OS 36.2 m vs 31.9 m, p = 0.65).
TTF1 duration was not significantly associated with TTF2 (p = 0.76). Patients who started Pem-Plat-Osi within 20d of progression on osimertinib had significantly longer TTF2 as compared to patients who started after 20d (median 8.4 m versus 6.0 months, p = 0.03), which remained statistically significant on multivariable analysis.
Our real-world data supports the efficacy of Pem-Plat-Osi after progression on first-line osimertinib, including L858R and baseline CNS metastases. Chemotherapy initiation within 20d of Osi progression was predictive of superior TTF2.
•First study to explore droplet digital PCR for HPV-associated E7 and L1 in plasma of patients with cervical cancer.•Presence of such plasma-based viral gene sequences was correlated with ...disease-free and overall survival.•Findings could lead to development of a sensitive tumor marker or “liquid biopsy” for cervical cancer.
A blood test to serve as a tumor marker for cervical cancer would be useful to clinicians to guide treatment and provide an early signal for recurrence. The development of droplet digital PCR has enabled the detection of HPV DNA in patient serum, providing a potential marker for cervical cancer.
To report on a blood-based test for HPV-specific E7 and L1 genes, which may serve as a tumor marker to guide treatment and detect early recurrence in cervical cancer.
Pre-treatment plasma samples were investigated from 138 Hong Kong Chinese women with primary invasive squamous cell carcinoma and adenocarcinoma of the cervix with tumor samples expressing HPV16 or HPV18. Two genes specific to the human papillomavirus, E7 and L1, were measured in cell free DNA (cfDNA) extracted from plasma using droplet digital PCR. Analysis of detectable E7 and L1 levels was performed to investigate the potential of liquid biopsy of E7 and L1 as a clinically useful molecular biomarker.
The majority of patients had HPV16 (71.7%), squamous cell carcinoma (78.3%) and stage IB-II disease (82.6%). HPV E7 and L1 sequences were detected in plasma cfDNA from 61.6% (85/138) of patients. Patients with high viral load (defined as ≥20 E7 or L1 copies per 20 μL reaction volume) had increased risk of recurrence and death at 5 years on univariate analysis but not multivariate analysis.
HPV DNA can be quantitatively detected with the use of cfDNA. This has the potential to provide a clinically useful tumor marker for patients with cervical cancer that can aid in post-treatment surveillance and estimating the risk of disease relapse.
Spinocerebellar ataxias (SCAs) are a group of clinically and genetically diverse and autosomal-dominant disorders characterised by neurological deficits in the cerebellum. At present, there is no ...cure for SCAs. Of the different distinct subtypes of autosomal-dominant SCAs identified to date, causative genes for only a fraction of them are currently known. In this study, we investigated the cause of an autosomal-dominant SCA phenotype in a family that exhibits cerebellar ataxia and pontocerebellar atrophy along with a global reduction in brain volume.
Whole-exome analysis revealed a missense mutation c.G1391A (p.R464H) in the coding region of the coiled-coil domain containing 88C (CCDC88C) gene in all affected individuals. Functional studies showed that the mutant form of CCDC88C activates the c-Jun N-terminal kinase (JNK) pathway, induces caspase 3 cleavage and triggers apoptosis.
This study expands our understanding of the cause of autosomal-dominant SCAs, a group of heterogeneous congenital neurological conditions in humans, and unveils a link between the JNK stress pathway and cerebellar atrophy.
Acute pain services have received widespread acceptance and formal support from institutions and organizations, but available evidence on their costs and benefits is scarce. Although there is good ...agreement on the provision of acute pain services after many major surgical procedures, there are other procedures for which the benefits are unclear. Data are required to justify any expansion of acute pain services. In this randomized, controlled clinical trial we compared the costs and effects of acute pain service care on clinical outcomes with conventional pain management on the ward. Patients included in the trial were considered by their anesthesiologist to have either arm be suitable for the procedure.
Four hundred twenty-three patients undergoing major elective surgery were randomized either to an anesthesiologist-led, nurse-based acute pain service group with patient-controlled analgesia or to a control group with IM or IV boluses of opioid analgesia. Both groups were treated with medications to treat opioid-related adverse effects and received the usual care from health professionals assigned to the ward. The main outcome measures were quality of recovery scores, pain intensity measures, global measure of treatment effectiveness, and overall pain treatment cost. Cost-effectiveness acceptability curves were drawn to detect a difference in the joint cost-effect relationship between groups.
There was no difference in quality of recovery score on postoperative day 1 between treatment and control groups (mean difference, 0; 95% confidence interval CI, -0.7 to 0.7; P = 0.94) or in the rate of improvement in quality of recovery score (mean difference, -0.1; 95% CI, -0.4 to 0.1; P = 0.34). The proportion of patients with 1 or more days of highly effective pain management was higher in the acute pain service group than in the control group (86% vs. 75%; P < 0.01). Costs were higher in the acute pain service group (mean difference, US$46; 95% CI, $44 to $48 per patient; P < 0.001). A cost-effectiveness acceptability curve showed that the acute pain service was more cost effective than was control for providing highly effective pain management if the decision maker was willing to pay more than US$546 per patient per 1 day with highly effective treatment.
In extending the role of the acute pain service to a specific group of major surgical procedures, the acute pain service was likely to be cost effective.
We previously reported that oroxylin A, a polyphenolic compound, was a potent inhibitor of lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 ...(COX-2). In the present study, three oroxylin A structurally related polyphenols isolated from the Chinese herb Huang Qui, namely baicalin, baicalein, and wogonin, were examined for their effects on LPS-induced nitric oxide (NO) production and iNOS and COX-2 gene expressions in RAW 264.7 macrophages. The results indicated that these three polyphenolic compounds inhibited LPS-induced NO production in a concentration-dependent manner without a notable cytotoxic effect on these cells. The decrease in NO production was in parallel with the inhibition by these polyphenolic compounds of LPS-induced
iNOS gene expression. However, these three compounds did not directly affect iNOS enzyme activity. In addition, wogonin, but not baicalin or baicalein, inhibited LPS-induced prostaglandin E
2 (PGE
2) production and
COX-2 gene expression without affecting COX-2 enzyme activity. Furthermore,
N-nitro-
l-arginine (NLA) and
N-nitro-
l-arginine methyl ester (L-NAME) pretreatment enhanced LPS-induced iNOS (but not COX-2) protein expression, which was inhibited by these three polyphenolic compounds. Wogonin, but not baicalin or baicalein, similarly inhibited PGE
2 production and COX-2 protein expression in NLA/LPS or L-NAME/LPS-co-treated RAW 264.7 cells. These results indicated that co-treatment with NOS inhibitors and polyphenolic compounds such as wogonin effectively blocks acute production of NO and, at the same time, inhibits expression of
iNOS and
COX-2 genes.
Phosphotyrosine (pTyr)-regulated protein complexes play critical roles in cancer signaling. The systematic characterization of these protein complexes in tumor samples remains a challenge due to ...their limited access and the transient nature of pTyr-mediated interactions. We developed a hybrid chemical proteomics approach, termed Photo-pTyr-scaffold, by engineering Src homology 2 (SH2) domains, which specifically bind pTyr proteins, with both trifunctional chemical probes and genetic mutations to overcome these challenges. Dynamic SH2 domain-scaffolding protein complexes were efficiently cross-linked under mild UV light, captured by biotin tag, and identified by mass spectrometry. This approach was successfully used to profile native pTyr protein complexes from breast cancer tissue samples on a proteome scale with high selectivity, achieving about 100 times higher sensitivity for detecting pTyr signaling proteins than that afforded by traditional immunohistochemical methods. Among more than 1,000 identified pTyr proteins, receptor tyrosine kinase PDGFRB expressed on cancer-associated fibroblasts was validated as an important intercellular signaling regulator with poor expression correlation to ERBB2, and blockade of PDGFRB signaling could efficiently suppress tumor growth. The Photo-pTyr-scaffold approach may become a generic tool for readily profiling dynamic pTyr signaling complexes in clinically relevant samples.
To evaluate the use of pars plana needle aspiration of retrolenticular fluid in the immediate management of an acute intraoperative rock-hard eye syndrome (AIRES).
Private practice, Sydney, ...Australia.
Retrospective case series.
Data over an 18-month period were collected to evaluate efficacy, complications, and visual outcomes in patients who had pars plana needle aspiration for management of AIRES, which is an acute intraoperative shallowing of the anterior chamber and a marked increase in intraocular pressure (IOP) during phacoemulsification cataract surgery but without evidence of a choroidal hemorrhage. Preoperative and postoperative (1 day, 1 week, and 1 month) data were evaluated. Resolution of AIRES and postoperative posterior segment status, IOP, and corrected distance visual acuity (CDVA) were the main outcome measures.
Acute intraoperative rock-hard eye syndrome occurred in 6 (1.45%) of 413 surgeries. All 6 patients were women with a mean age of 81 years. Four patients had dense nuclear cataracts. In each case, the anterior chamber depth and IOP normalized immediately after pars plana needle aspiration and the procedure concluded uneventfully. Mild vitreous hemorrhage was observed in 1 patient postoperatively. At 1 month, the IOP was normal in 5 of 6 cases, while the CDVA was 20/12 in 5 of 6 cases.
Although the etiology of AIRES is iatrogenic, immediate resolution was achieved uneventfully with pars plana needle aspiration, which appears to be a safe management technique with satisfactory outcomes.
Australia-wide population-based surveillance for scedosporiosis identified 180 cases, with 118 (65.6%) cases of colonization and 62 (34.4%) cases of infection. Predisposing factors for isolation of ...Scedosporium spp. included chronic lung disease in 37.8% and malignancy in 21.7% of cases. Predictors of invasive disease (n = 62) included haematological stem cell transplantation (n = 7), leukaemia (n = 16) and diabetes mellitus (n = 8). Of 183 phenotypically-speciated isolates, 75 (41%) were Scedosporium prolificans (risk factors: haematologic cancer (n = 17), neutropaenia (n = 14)) and 108 (59%) had Scedosporium apiospermum/Pseudallescheria boydii phenotype risk factor: diabetes (n = 15). Scedosporium prolificans (p 0.01) and leukaemia (p 0.03) independently predicted death. Epidemiological and antifungal susceptibility profiles of Scedosporium aurantiacum (prevalence ≥15.8%) and S. apiospermum were similar. No patient with S. aurantiacum infection (n = 6) died. This is the first description of clinical features associated with S. aurantiacum.
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