Afatinib overcoming resistance to icotinib and osimertinib in NSCLC with leptomeningeal metastasis in patients with acquired EGFR L858R/T790M or L858R/S768I mutations: Two case reports.

Background: Advanced non-small cell lung cancer (NSCLC) is often complicated by leptomeningeal metastases (LMs), especially in patients carrying EGFR mutations. EGFR tyrosine kinase inhibitors (TKIs) are the first-line drug for patients with specific gene mutations, such as EGFR exon 19 deletion or exon 21 L858R mutation. However, after long-term TKI use, patients eventually develop drug resistance and acquire new mutations. Acquiring the EGFR T790 M mutation during TKI treatment is a marker for first/second generation TKI resistance. Osimertinib (a third-generation TKI) could overcome this resistance, especially for patients who have already developed NSCLC-LM. Treating NSCLC patients with osimertinib resistance is challenging. Our aim was to investigate whether afatinib is effective in NSCLC-LM patient who showed resistance to osimertinib. Herein, we report two patients with resistance to first- and third-generation TKIs who benefited from second-generation TKI. Case summary: Case one: A 43-year-old man was diagnosed with stage 3A NSCLC with EGFR exon 19 deletion. He underwent surgery and received 4 rounds of chemotherapy (oxaliplatin combined with liposomal paclitaxel), after which the disease was controlled by icotinib (a first-generation TKI) for 4 years. Then, he showed poor drug response and bone metastasis. A liquid biopsy was carried out, and the EGFR L858R/T790 M compound mutation was found. The patient was given osimertinib (a third-generation TKI). The patient was in a stable condition for 2 years and then he developed bilateral peripheral facial palsy. Brain MRI showed enhancement in the left temporal lobe and meninges, and cerebrospinal fluid (CSF) cytology detected tumour cells in the CSF. NSCLC-LM was diagnosed. His performance status (PS) score was 3-4. Liquid biopsy and next-generation sequencing were performed again. Different gene mutations and copy number alterations were found this time, including EGFR L858R, but without the EGFR T790 M mutation. His disease was controlled with intrathecal methotrexate and oral afatinib (a second generation TKI). The patient has shown clinical remission (PS score: 1-2) until now, which is longer than 10 months. Case two: A 50-year-old man was diagnosed with NSCLC in May 2020. He underwent one round of chemotherapy before thoracoscopic partial lobectomy of the right upper lung. Histological study of the lung tissue showed lung adenocarcinoma with the EGFR L858R mutation. Then, the disease was controlled with icotinib. One year later, he was diagnosed with NSCLC-LM. Liquid biopsy and sequencing showed an EGFR L858R/S768I compound mutation. The patient was treated with osimertinib. His condition was stable for 5 months before his central nervous system (CNS) symptoms were exacerbated. Liquid biopsy and sequencing were carried out again, and his gene mutation profile had not changed much. Then, the patient was given afatinib, and his condition has remained stable for 11 months. Conclusion: Afatinib might be suitable for NSCLC-LM patients with EGFR compound mutations who show resistance to icotinib and osimertinib, since it might help overcome first- and third-generation TKI resistance.

Molecular characteristics and prognostic factors of leptomeningeal metastasis in non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer with leptomeningeal metastasis (NSCLC-LM) is emerging as a new management challenge for oncologists and is associated with poor prognosis. This study aimed to investigate the molecular characteristics and prognostic factors of NSCLC-LM. METHODS: This retrospective study included 97 patients with NSCLC-LM between January 2015 and October 2021. Progression-free survival (PFS) and overall survival (OS) were evaluated. Gene mutations were detected by next-generation sequencing (NGS). RESULTS: The median PFS and OS were 8.4 (95 % confidence interval [CI]: 4.839-11.901) and 14.0 (95 % CI: 9.254-18.746) months, respectively. Sixty-seven patients harboured epidermal growth factor receptor-mutated (EGFRm): L858R (34), 19del (29), T790M (13), and G719C with L861Q (1). Other mutations included ALK (5), ROS1 (3), KRAS (1), TP53 (14), MET amplification (6). The detection rate and types of circulating tumour DNA (ctDNA) in the cerebrospinal fluid (CSF) samples were higher than the paired plasma samples. Patients with EGFR mutations had a longer median OS than those without mutations (19.0 vs. 13.0 months, P = 0.015). Patients with gene mutations had shorter median OS than those without mutations, such as ALK (11.8 vs. 19.9 months, P = 0.014), ROS1 (12.7 vs. 19.8 months, P = 0.014), KRAS (4.0 vs. 19.0 months, P = 0.005), TP53 (15.0 vs. 19.0 months, P = 0.014), and MET amplification (6.0 vs. 19.0 months, P = 0.003). Multivariate analysis indicated that MET amplification was an independent predictor of poor survival. Along with Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 3, LM accompanied with brain parenchymal metastasis (BPM), extracranial disease, and seizures were independent predictors of poor survival, whereas intrathecal chemotherapy, and third-generation EGFR-TKIs were independent predictors of favorable survival. CONCLUSIONS: CSF ctDNA detected using NGS had a high sensitivity for NSCLC-LM, showing high potential in detecting driver and drug-resistant gene mutations. Genomic profiles, combined with clinically relevant prognostic factors, will guide individualised treatments and improve the outcomes of NSCLC-LM patients.

Cerebrospinal fluid ctDNA testing shows an advantage over plasma ctDNA testing in advanced non-small cell lung cancer patients with brain metastases.

Background: Brain metastases (BM), including brain parenchyma metastases (BPM) and leptomeningeal metastases (LM), are devastating metastatic complications in advanced cancer patients. Next-generation sequencing (NGS) is emerging as a new promising tool for profiling cancer mutation, which could facilitate the diagnosis of cancer. This retrospective study aimed to investigate the molecular genetic characteristics of non-small cell lung cancer (NSCLC) patients with BPM and LM using NGS. Methods: Cerebrospinal fluid (CSF) samples and paired plasma samples were collected from 37 patients of NSCLC-BM. We profiled genetic mutation characteristics using NGS from NSCLC-BM by comparing CSF circulating tumour DNA (ctDNA) with plasma ctDNA and primary tumour tissues. Results: Among the 37 patients with NSCLC-BM, 28 patients had LM with or without BPM, while 9 patients only had BPM. Driver and drug-resistant mutations in primary tumours with LM included: EGFR L858R (10, 35.7%), EGFR 19del (6, 21.4%), EGFR L858R+MET (1, 3.6%), EGFR L858R+S768I (1, 3.6%), ALK (2, 7.1%), ROS1 (1, 3.6%), negative (5, 17.9%), and unknown (2, 7.1%). In patients with NSCLC-LM, the detection rate and abundance of ctDNA in the CSF were significantly higher than those in paired plasma. The main driver mutations of NSCLC-LM remained highly consistent with those of the primary tumours, along with other unique mutations. Circulating tumour DNA was negative in the CSF samples of BPM patients. Patients with BMP had a higher ratio of EGFR 19del than L858R mutation (55.6% vs 11.1.%), whereas NSCLC patients with LM had a higher ratio of EGFR L858R than 19del mutation (50.0% vs 25.0%). Most patients with positive plasma ctDNA results were male (p = 0.058) and in an unstable state (p = 0.003). Conclusion: Our study indicated that the CSF ctDNA detected by NGS may reflect the molecular characteristics and heterogeneity of NSCLC-LM. Timely screening of patients with NSCLC for CSF ctDNA, especially for patients with positive plasma ctDNA, may facilitate the early detection of LM. Furthermore, patients with the EGFR 19del may have a higher risk of developing BPM.

Interpreting light guidance in antiresonant and photonic bandgap waveguides and fibers by light scattering: analytical model and ultra-low guidance.

Here, we introduce a quasi-analytic model that allows studying mode formation in low refractive index core waveguides through solely focusing on the cladding properties. The model isolates the reflection properties of the cladding from the modes via correlating the complex amplitude reflection coefficient of the cladding to the complex effective index of the fundamental core mode. The relevance and validity of the model are demonstrated by considering a single-ring anti-resonant fiber, revealing unexpected situations of exceptionally low loss. Our model explains mode formation by light scattering, which conceptually provides deep insights into the relevant physics.

Removable retropubic uterine compression suture for controlling postpartum hemorrhage.

OBJECTIVE: To minimize the adverse events of uterine compression suture in controlling postpartum hemorrhage (PPH) and to search for a prophylactic approach to potential PPH. METHODS: A retrospective analysis was performed in 39 women with removable retropubic uterine compression suture (RRUCS) to stop PPH due to uterine atony during cesarean section (CS). The procedure was to suspend and compress the uterus to the retropubic abdominal wall using an absorbable suture. RESULTS: The technique was sufficient to stanch bleeding immediately in 36 patients (92.31%, 36/39). No morbidity or abnormalities occurred in women who underwent RRUCS. Subsequent pregnancies occurred in 10 cases, but the others lacked the desire for future pregnancy. CONCLUSION: RRUCS is a simple, safe, and effective technique in controlling atonic PPH; it is also used as a prophylactic application in patients with potential PPH after CS.

An improved spectrophotometric method tests the Einstein-Smoluchowski equation: a revisit and update.

Theoretical prediction and experimental measurements of light attenuation in chemically pure and optically transparent solvents have attracted continuous attention, due in part to their curious nature, and in part to the increasing requirements of solvent-related applications. Yet hitherto, a majority of accurate spectrophotometric measurements of transparent solvents upon visible light radiation often end up using long-path-length cells, usually over dozens of cm, rendering the measure costly and complex; meanwhile, the guidance for choosing the Einstein-Smoluchowski equation or its variants as the best formula to predict the light scattering in solvents has remained elusive. Here we demonstrate a simple, versatile and cost-effective spectrophotometric method, enabling a sensitivity of 10-4 dB cm-1 over a 0.5 cm differential path length based on using standard double-beam spectrophotometer. We prove that this method reduces the path length by a factor of 100 while still making its closest approach to the record-low measurement of solvent extinction. We also validate that all the present equations used for predicting the light scattering in the solvent possess similar capacities, suggesting that the criterion for the choice of the appropriate formula simply depends on the equation's practicability. Following the elucidation of the wavelength range where the light scattering dominates the extinction, we further identify differences between scattering coefficients via the theoretical predictions and experimental measures, exposing the need for an improved theory to account for the solvent scattering phenomenon.

Connexin 30 Deficiency Attenuates Chronic but Not Acute Phases of Experimental Autoimmune Encephalomyelitis Through Induction of Neuroprotective Microglia.

Glial connexins (Cxs) form gap junction channels through which a pan-glial network plays key roles in maintaining homeostasis of the central nervous system (CNS). In multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), expression of astrocytic Cx43 is lost in acute lesions but upregulated in chronic plaques, while astrocytic Cx30 is very low in normal white matter and changes in its expression have not been convincingly shown. In Cx30 or Cx43 single knockout (KO) mice and even in Cx30/Cx43 double KO mice, acute EAE is unaltered. However, the effects of Cx30/Cx43 deficiency on chronic EAE remains to be elucidated. We aimed to clarify the roles of Cx30 in chronic neuroinflammation by studying EAE induced by myelin oligodendrocyte glycoprotein peptide 35-55 in Cx30 KO mice. We found that Cx30 deficiency improved the clinical symptoms and demyelination of chronic but not acute EAE without influencing CD3+ T cell infiltration. Furthermore, increased ramified microglia in the naïve state and induced earlier and stronger microglial activation in the acute and chronic phases of EAE was observed. These activated microglia had an anti-inflammatory phenotype, as shown by the upregulation of arginase-1 and brain-derived neurotrophic factor and the downregulation of nitric oxide synthase 2. In the naïve state, Cx30 deficiency induced modest enlargement of astrocytic processes in the spinal cord gray matter and a partial reduction of Cx43 expression in the spinal cord white matter. These astrocytes in Cx30 KO mice showed earlier and stronger activation during the acute phase of EAE, with upregulated A2 astrocyte markers and a significant decrease in Cx43 in the chronic phases. Spinal cord neurons and axons were more preserved in Cx30 KO mice than in littermates in the chronic phase of EAE. These findings suggest that Cx30 deficiency increased ramified microglia in the CNS in the naïve state and improved chronic EAE through redirecting microglia toward an anti-inflammatory phenotype, suggesting a hitherto unknown critical role of astrocytic Cx30 in regulating microglial number and functional state.

Ring compression suture for controlling post-partum hemorrhage during cesarean section.

AIM: To avoid complications associated with uterine compression sutures, we devised a ring compression suture (RCS). METHODS: The RCS was performed on 12 patients with post-partum hemorrhage (PPH) during cesarean section. The suture was inserted 0.5 cm below the attachment point of the uterosacral ligament into the uterine cavity and pushed downward through the cervical canal into the vagina. The other end of the stitch was threaded through the lower abdominal wall, from the inside of the abdomen cavity to the outside of the abdominal wall, emerging at the external surface of the lower abdomen 2 cm lateral to the ventral median line and 1 cm above the symphysis pubis. Then, the two ends of the suture (the end in the vagina had been pulled out in advance) were tied tightly on the pudendum. The same stitch was repeated on the contralateral side. After 48 h postoperatively, the suture was removed through the vagina under sterilization. RESULTS: All 12 women with PPH who underwent RCS achieved hemostasis, and complications related to RCS were not seen. Two of them had successful pregnancies postoperatively. The remaining women had no desire for a further pregnancy. CONCLUSION: The procedure can be used as an alternative to peripartum hysterectomy and also as a prophylactic application in PPH.

Novel disease-modifying anti-rheumatic drug iguratimod suppresses chronic experimental autoimmune encephalomyelitis by down-regulating activation of macrophages/microglia through an NF-κB pathway.

We aimed to elucidate the effects of iguratimod, a widely used anti-rheumatic drug with no severe side effects, on chronic experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Iguratimod was orally administered to mice immunised with myelin oligodendrocyte glycoprotein peptide 35-55. Preventive administration of iguratimod from the time of immunisation was found to markedly reduce the clinical severity of acute and chronic EAE. Pathologically, iguratimod treatment significantly reduced demyelination and infiltration of CD3+ T, F4/80+, and CD169+ cells into the spinal cord, and suppressed macrophage/microglia activation in the parenchyma at the acute and chronic stages compared with vehicle treatment. Therapeutic administration of iguratimod after the onset of clinical symptoms significantly ameliorated the clinical severity of chronic EAE and reduced demyelination, T helper (Th)1/Th17 cell infiltration, macrophage/microglia activation, and nuclear factor (NF)-κB p65 and cyclooxygenase-2 expression in the spinal cord. In vitro, iguratimod treatment inhibited nuclear translocation of NF-κB p65 and down-regulated pro-inflammatory responses in macrophages and microglia. Our results suggest that iguratimod ameliorates acute and chronic EAE by suppressing inflammatory cell infiltration and immune cell activation, partly through inhibition of NF-κB p65, supporting the therapeutic potential of this drug for not only acute, but also chronic MS.

Guiding light in a water core all-solid cladding photonic band gap fiber - an innovative platform for fiber-based optofluidics.

We present a single-channel photonic band gap fiber design allowing for guiding light inside a water core, which is surrounded by solid microstructured cladding, consisting of an array of high refractive index strands in silica. We address all relevant properties and show that the microstructure substantially reduces loss. We also introduce a ray reflection model, matching numerical modelling and allowing for time-effective large-scale parameter sweeps. Our single channel fiber concept is particularly valuable for applications demanding fast and reliable injection of liquids into the core, with potential impact in fields such as optofluidics, spectroscopy or bioanalytics.

Identification of zero density of states domains in band gap fibers using a single binary function.

Here we introduce a new calculation method to find the domains of zero density of states for photonic band gap guiding fibers consisting of arrays of high refractive index strands in a low refractive index cladding. We find an analytic expression that associates any combination of geometric parameter, effective index, material and wavelength with a single binary function which allows direct determination whether the density of cladding states is zero or not. The method neither requires the typically used root finding procedure for dispersion tracking nor simulation volume discretization. We verify the validity of our approach on well-established results and reveal as example that band gap regions are mainly determined by the two lowest order Bessel function orders. Our method allows for extensive parameter scans and evaluation of photonic band gap structures against structural and material inaccuracies with substantially reduced simulation effort.

Longitudinal parallel compression suture to control postopartum hemorrhage due to placenta previa and accrete.

OBJECTIVE: To assess the efficacy and safety of longitudinal parallel compression suture to control heavy postpartum hemorrhage (PPH) in patients with placenta previa/accreta. MATERIALS AND METHODS: Fifteen women received a longitudinal parallel compression suture to stop life-threatening PPH due to placenta previa with or without accreta during cesarean section. The suture apposed the anterior and posterior walls of the lower uterine segment together using an absorbable thread A 70-mm round needle with a Number-1 absorbable thread was used. The point of needle entry was 1 cm above the upper margin of the cervix and 1 cm from the right lateral border of the lower segment of the anterior wall. The suture was threaded through the uterine cavity to the serosa of the posterior wall. Then, it was directed upward and threaded from the posterior to the anterior wall at ∼1-2 cm above the upper boundary of the lower uterine segment and 3-cm medial to the right margin of the uterus. Both ends of the suture were tied on the anterior aspect of uterus. The left side was sutured in the same way. RESULTS: The success rate of the procedure was 86.7% (13/15). Two of 15 cases were concurrently administered gauze packing and achieved satisfactory hemostasis. All patients resumed a normal menstrual flow, and no postoperative anatomical or physiological abnormalities related to the suture were observed. Three women achieved further pregnancies after the procedure. CONCLUSION: Longitudinal parallel compression suture is a safe, easy, effective, practical, and conservative surgical technique to stop intractable PPH from the lower uterine segment, particularly in women who have a cesarean scar and placenta previa/accreta.

Uterine folding hemostasis: a simpler and safer technique for controlling atonic postpartum hemorrhage.

OBJECTIVE: To observe the efficacy and safety of a uterine folding hemostatic technique in controlling atonic postpartum hemorrhage (PPH) during cesarean delivery. METHODS: Thirty-nine women with severe postpartum bleeding from uterine inertia, which did not react to conventional initial management protocols, underwent a uterine folding hemostasis. The procedure was to fold the uterine fundus onto the anterior wall of the corpus uterus using an absorbable suture that thread tautly through the inner myometrial layer of the uterus 1-3 cm below the fundus (not entered into uterine cavity) and 1-2 cm above and below the CS incision (entered into uterine cavity 2-4 cm medal to bilateral border of the uterus). RESULTS: The technique was sufficient to stanch bleeding immediately in 32 patients (82.1 %). Seven women underwent hypogastric arteries ligation (1 case) or uterine arterial embolization (6 cases) because of continuous bleeding after the procedure. There were no morbidities or abnormalities of the uterus in these 32 patients. Eight women had pregnancies after this hemostasis and the others lacked the desire for future pregnancy. CONCLUSION: Uterine folding hemostasis is a simple, safe and effective technique to control the atonic PPH.

[A randomized, placebo controlled study on Fangfeng Tongsheng granule in treatment of sub-acute eczema].

The clinical study was conducted to further evaluation the effectiveness and safety of Fangfeng Tongsheng granule in the treatment of sub-acute eczema (superficial cold and interior heat syndrome, exterior and interior sthenic syndrome). In the block randomized, multi-centered study, totally 108 patients were enrolled and assigned to two groups: 72 patients in the test group and 36 patients in the placebo control group. Those in the test group took Fangfeng Tongsheng granule with the dose of 3 g, twice a day, while those in the control group were give simulated agent granules with the same dose. The therapeutic course lasted for 14 days. Their efficacies in TCM syndrome, dermal symptoms and adverse events were observed. According to the test results, except for the one exit case, all of the remaining 108 cases, including 71 in the test group, and 36 in the control group, completed the clinical trial. As for the efficacy of TCM syndrome, after the medication for 2 weeks, the cure rate was 33.81% (24/71) in the test group and 0% (0/36) in the control group (P < 0.01), with a statistical difference between the two groups. Regarding the TCM score, after the medication for 2 weeks, the test group decreased by (12.82 +/- 7.96), while the control group decreased by (3.67 +/- 4.12), indicating a statistical difference between the two groups. As for the efficacy of dermal symptoms, after the medication for 2 weeks, the cure rate was 25.35% (18/71) in the test group and 0% (0/36) in the control group, with a statistical difference between the two groups. Regarding the dermal symptom score, after the medication for 2 weeks., the test group decreased by (10.04 +/- 7.17), while the control group decreased by (2.33 +/- 3.57), indicating a statistical difference between the two groups. There was no significant adverse event caused by Fangfeng Tongsheng granule. In conclusion, Fangfeng Tongsheng granule was effective and safe in treating subcute eczema (superficial cold and interior heat syndrome, exterior and interior sthenic syndrome).

Nonlinear stability of traveling wavefronts in an age-structured reaction-diffusion population model.

The paper is devoted to the study of a time-delayed reaction- diffusion equation of age-structured single species population. Linear stability for this model was first presented by Gourley [4], when the time delay is small. Here, we extend the previous result to the nonlinear stability by using the technical weighted-energy method, when the initial perturbation around the wavefront decays to zero exponentially as x--> -infinity, but the initial perturbation can be arbitrarily large on other locations. The exponential convergent rate (in time) of the solution is obtained. Numerical simulations are carried out to confirm the theoretical results, and the traveling wavefronts with a large delay term in the model are reported.