Successful therapy using high-dose furmonertinib for non-small cell lung cancer with leptomeningeal metastasis: a case report and literature review.

Background: Lung cancer is the second most common form of malignant tumor and has the highest mortality rate worldwide. Among its subtypes, lung adenocarcinoma is the most prevalent. Leptomeningeal metastasis (LM) is rare and is characterized by a dismal prognosis, with overall survival periods typically spanning 4 to 6 weeks without treatment. However, in specific cases, survival can be extended to 4 to 6 months with appropriate therapy. The recent approval of third-generation tyrosine kinase inhibitors (TKIs), such as osimertinib, aumolertinib, and furmonertinib, has introduced promising treatment options for individuals with non-small cell lung cancer (NSCLC) who develop LM after developing resistance to first- and second-generation TKIs. These third-generation TKIs exhibit an enhanced ability to penetrate the blood-brain barrier (BBB), opening up new avenues for managing this challenging condition. Case summary: We report the case of a 48-year-old Chinese man diagnosed with advanced NSCLC harboring an epidermal growth factor receptor (EGFR) mutation. Following a pulmonary lobectomy and postoperative adjuvant therapy with gefitinib, the patient was diagnosed with LM, which was confirmed by his neurologic symptoms, cerebrospinal fluid cytologic analysis, and cranial enhancement magnetic resonance imaging. Subsequently, he received oral treatment in the form of 160 mg of furmonertinib daily. After 5 days of furmonertinib therapy, the patient recovered from lethargy, with an obvious improvement in cognitive function. Follow-up visits revealed a 6-month survival period following the LM diagnosis. Patients with NSCLC and LM typically present with severe symptoms, and the efficacy of systemic treatment, intrathecal chemotherapy, and radiotherapy remains unsatisfactory. We hope that this specific case provide valuable insights into the management of patients with EGFR mutation-associated NSCLC with LM. Conclusion: Furmonertinib, a third-generation EGFR TKI with notable BBB penetration, shows promise in LM control and the rapid alleviation of intracranial symptoms. Further investigations into appropriate dosage and toxicity management are imperative.

The involvement of abscisic acid-insensitive mutants in low phosphate stress responses during rhizosphere acidification, anthocyanin accumulation and Pi homeostasis in Arabidopsis.

Phosphorus is an essential plant nutrient, used in the formation of macromolecules such as nucleic acids and phospholipids. Abscisic acid (ABA) may be involved in the process of low inorganic phosphate (Pi) responses. The phenotypes of ABA-insensitive Arabidopsis mutants (abi1/2/3/4/5) under low Pi stress were investigated to identify possible low Pi response mutant genes. The results showed enhanced rhizosphere acidification in the abi1-1/abi2-1/abi5-1 mutants under low Pi stress compared with wild-type (WT) seedlings. The abi1-1/abi2-1/ abi3-1/abi5-1 mutants accumulated less anthocyanin than the WT, while the abi4-1 mutant showed greater accumulation, implicating all the ABA-insensitive mutants in anthocyanin deposition under Pi deficiency. Alterations in the Pi contents of roots or shoots were also observed in the mutants in response to both Pi sufficiency and deficiency, indicating that the mutants were involved in Pi uptake or transportation. The primary root length and root-shoot ratio of abi3-1 and abi4-1 mutants decreased compared with WT seedlings under low Pi condition. Further research showed that ABI5 could regulate PHT1;5 and WRKY42 expression by combining with ACGT cis-acting elements of the PHT1;5 and WRKY42 promoters.

Continuous Low-Dose Apatinib Combined With WBRT Significantly Reduces Peritumoral Edema and Enhances the Efficacy of Symptomatic Multiple Brain Metastases in NSCLC.

BACKGROUND: Symptomatic multiple brain metastases with peritumoral brain edema (PTBE) occur in non-small cell lung cancer patients (NSCLC) who are without driver mutations or are resistant to epidermal growth factor tyrosine kinase (EGFR-TKI) are often associated with an unfavorable prognosis. Whole brain radiation therapy (WBRT) which comes with many complications and unsatisfactory effects, is the only option for the treatment. Previous studies have shown that bevacizumab can reduce the volume of PTBE and improve efficiency of radiotherapy. This study evaluated the effects and safety of apatinib combined with WBRT in NSCLC patients with symptomatic multiple brain metastases and PTBE. METHODS: We performed a retrospective review of 34 patients with symptomatic multiple brain metastases from NSCLC (number >4, and at least 1 measurable brain metastasis lesion with cerebral edema). Intracranial objective response rate (IORR), peritumoral edema and intracranial tumor volumetric measurement, Karnofsky performance status (KPS) and adverse events (AEs) were evaluated. Median intracranial progression-free survival (mIPFS) and median overall survival (mOS) were also analyzed. RESULTS: Thirteen cases received apatinib (125 mg or 250 mg, QD, oral) combined with WBRT and 21 cases received chemotherapy combined with WBRT were inclued. Apatinib combination group can better reduce the volume of intracranial tumors and PTBE and total steroid dosage used. It was associated with a better IORR (84.6% vs 47.6%, P = 0.067), longer mIPFS (6.97 vs 4.77months; P = 0.014). There was no significant difference in mOS(7.70 vs 6.67 months; P = 0.14) between the 2 groups. The most common adverse events of apatinib combination WBRT included grade 1/2 nausea (4/13), fatigue (3/13), hypertension (2/13) and white blood cell decrease (2/13). No grade 3/4 AEs were observed. CONCLUSION: Apatinib plus WBRT is well tolerated and may be a potential choice for relapsed or drug-resistant advanced NSCLC patients with symptomatic multiple brain metastases and PTBE.

Apatinib-induced Grade 3 hand-foot syndrome in advanced lung adenocarcinoma successful treated with thalidomide: A case report.

Hand-foot syndrome (HFS) is a specific cutaneous toxicity caused by a variety of antitumor drugs. The most common drugs include capecitabine, pegylated liposomal doxorubicin and fluorouracil (PLD), tyrosine kinase inhibitor. It is a dose-limiting cutaneous toxicity of these drugs. We reported an advanced lung adenocarcinoma female patient, who developed a Grade 3 HFS after a third-line treatment with apatinib of 250 mg for 10 days, the patient developed intolerable pain with pruritus. Large erythema on the skin of the hand, with local ulceratio, exudation, and desquamation of cutaneous lesions. After treatment with 100 mg of thalidomide every night for 1 week, the patient's HFS was significantly relieved, and the duration of the remission was about 2 months, which not only significantly improved the patient's quality of life, but also maintained the antitumor strength.

The volume of 99m Tc sulfur colloid SPET-defined active bone marrow can predict grade 3 or higher acute hematologic toxicity in locally advanced cervical cancer patients who receive chemoradiotherapy.

BACKGROUND: The purpose of the current study was to evaluate whether radiation dose-volume metrics to technetium-99m (99m Tc) sulfur colloid single-photon emission tomography (SPET)-defined active bone marrow (ABM) subregions can more accurately predict acute hematologic toxicity in locally advanced cervical cancer patients who receive chemoradiotherapy than conventional dosimetric parameters. METHODS AND MATERIALS: Thirty-nine patients with stage IB2-III cervical cancer who underwent 99m Tc sulfur colloid SPET imaging before treatment with cisplatin-based chemoradiation between January 2017 and March 2018 were analyzed. The total bone marrow (TBM) volume was defined as the external contours of all bones within the vertebral bodies from L4 to the coccyx, the pelvic bones, and the proximal femoral heads. The ABM volume was defined by SPET as the subregion of TBM with a nuclide uptake value greater than or equal to the mean total body nuclide uptake value. Student's t test was used to test for statistical significance between TBM and ABM dose-volume metrics. Receiver operating characteristic (ROC) curves were generated to compare the predictors of grade 3 or higher (grade 3+) hematologic toxicity. RESULTS: The mean ABM-V40 (23.22% ± 7.65%) and ABM-V30 (45.28% ± 9.20%) were significantly lower than the mean TBM-V40 (33.06% ± 6.72%) and TBM-V30 (53.08% ± 7.77%), respectively (t = 5.78, P = .001) (t = 4.13, P = .001). The ABM volume (<387.5 cm3 , AUC = 0.928, P = .001), ABM-V30 (>46.5%, AUC = 0.875, P = .001), and ABM-V40 (>23.5%, AUC = 0.858, P = .001) can predict the occurrence of grade 3+ hematologic toxicity. Among patients with an ABM volume < 387.5 cm3 , 16/19 (84.2%) had grade 3+ hematologic toxicity compared to 3/20 (15%) with an ABM volume > 387.5 cm3 . CONCLUSIONS: The ABM volume (<387.5 cm3 ) may be a better predictor of hematologic toxicity than conventional dose-volume metrics, but this finding needs to be further evaluated.

Significant response of low-dose apatinib monotherapy in brain metastases of triple-negative breast cancer: A case report.

RATIONALE: The potential efficacy of apatinib in patients with advanced triple-negative breast cancer (TNBC) has been observed in a previous phase II clinical study. However, there is no study to evaluate its efficacy and safety in TNBC patients with brain metastasis (BM). Here we report one case that apatinib exhibited excellent antitumor effects in a breast cancer patient with brain metastasis, with no serious treatment-associated with adverse event. PATIENT CONCERNS: In this case report, one Chinese woman who was diagnosed with stage IV TNBC with multiple bone, lung, and brain metastases was unable to tolerate chemotherapy and refused whole-brain radiation therapy (WBRT) due to her poor physical condition. She had previously undergone radical mastectomy and intravenous chemotherapy. DIAGNOSES: Triple-negative breast cancer. INTERVENTIONS: The patient underwent left radical mastectomy with ipsilateral axillary lymph node dissection, and the following adjuvant chemotherapy, but developed multiple bone, lung, and brain metastases. Due to her poor physical condition, chemotherapy was not eligible for her. And she refused WBRT and chose to take low-dose apatinib (250 mg, oral, daily) monotherapy. OUTCOMES: After 2 months of treatment, the symptom of headache and vomiting relieved and all the brain metastases (BMs) lesions disappeared. LESSONS: Low-dose apatinib monotherapy may be an alternative treatment for patients with poor physical condition. Preclinical and clinical studies should be conducted to further evaluate the mechanism and efficacy of apatinib in the treatment of BM from TNBC, as well as to explore the optimal dose of the drug.

Advantages with prophylactic PEG-rhG-CSF versus rhG-CSF in breast cancer patients receiving multiple cycles of myelosuppressive chemotherapy: an open-label, randomized, multicenter phase III study.

BACKGROUND: PEG-rhG-CSF reduces neutropenia and improves chemotherapy safety. In China's registration trial (CFDA: 2006L01305), we assessed its efficacy and safety against rhG-CSF, and prospectively explored its value over multiple cycles of chemotherapy. METHODS: In this open-label, randomized, multicenter phase 3 study, breast cancer patients (n = 569) were randomized to receive PEG-rhG-CSF 100 µg/kg, PEG-rhG-CSF 6 mg, or rhG-CSF 5 µg/kg/d after chemotherapy. The primary endpoints were the incidence and duration of grade 3/4 neutropenia during cycle 1. Secondary endpoints included the incidence and duration of grade 3/4 neutropenia during cycles 2-4, the incidence of febrile neutropenia, and the safety. RESULTS: A once-per-cycle PEG-rhG-CSF at either 100 µg/kg or 6 mg was not different from daily injections of rhG-CSF for either incidence or duration of grade 3/4 neutropenia. Interestingly, a substantial difference was noted during cycle 2, and the difference became bigger over cycles 3-4, reaching a statistical significance at cycle 4 in either incidence (P = 0.0309) or duration (P = 0.0289) favoring PEG-rhG-CSF. A significant trend toward a lower incidence of all-grade adverse events was noted at 129 (68.98%), 142 (75.53%), and 160 (82.47%) in the PEG-rhG-CSF 100 µg/kg and 6 mg and rhG-CSF groups, respectively (P = 0.0085). The corresponding incidence of grade 3/4 drug-related adverse events was 2/187 (1.07%), 1/188 (0.53%), and 8/194 (4.12%), respectively (P = 0.0477). Additionally, PFS in metastatic patients preferred PEG-rhG-CSF to rhG-CSF despite no significance observed by Kaplan-Meier analysis (n = 49, P = 0.153). CONCLUSIONS: PEG-rhG-CSF is a more convenient and safe formulation and a more effective prophylactic measure in breast cancer patients receiving multiple cycles of chemotherapy.

Continuous use of metformin can improve survival in type 2 diabetic patients with ovarian cancer: A retrospective study.

Evidence indicates that type 2 diabetes may stimulate the initiation and progression of several types of cancer. Metformin, a drug most commonly used to treat type 2 diabetes, may inhibit cancer cell growth and reduce the risk of cancer. However, evidence of the antitumor effects of metformin on ovarian cancer is still limited.In this study, we retrospectively examined the effects of metformin on ovarian cancer patients with diabetes at our institution.We identified 568 consecutive patients who were newly diagnosed with ovarian cancer and treated between January 2011 and March 2014. Patients with International Federation of Gynecology and Obstetrics (FIGO) stage I to IV epithelial ovarian, fallopian, or peritoneal cancer were included. Patients with type 1 diabetes, incomplete records (including medication records) and any other cancer before their ovarian cancer diagnosis, as well as those diagnosed with diabetes more than 6 months after their ovarian cancer diagnosis, were excluded. Out of 568 patients, 48 (8.5%) patients with type 2 diabetes continuously used metformin, 34 (5.9%) patients with type 2 diabetes did not take metformin, 22 (3.9%) patients with type 2 diabetes discontinued metformin, and 464 (81.7%) ovarian cancer patients were nondiabetic controls. Longer progression-free survival (PFS) and overall survival (OS) were observed in ovarian cancer patients with diabetes who were taking metformin than in diabetic patients not taking metformin, diabetic patients who discontinued metformin, and nondiabetic ovarian cancer patients (P = .001). After adjusting for possible confounders, metformin use was associated with a lower risk for disease relapse [hazard ratio (HR) = 0.34; 95% confidence interval (CI): 0.27-0.67; P < .01] and disease-related death (HR = 0.29; 95% CI: 0.13-0.58, P = .03) among ovarian cancer patients with diabetes.Metformin use may decrease the risk for disease recurrence and death in patients with ovarian cancer, but the drug treatment must be continuous.

miR156 modulates rhizosphere acidification in response to phosphate limitation in Arabidopsis.

Rhizosphere acidification is a general response to Pi deficiency, especially in dicotyledonous plants. However, the signaling pathway underlying this process is still unclear. Here, we demonstrate that miR156 is induced in the shoots and roots of wild type Arabidopsis plants during Pi starvation. The rhizosphere acidification capacity was increased in 35S:MIR156 (miR156 overexpression) plants, but was completely inhibited in 35S:MIM156 (target mimicry) plants. Both 35S:MIR156 and 35S:MIM156 plants showed altered proton efflux and H(+)-ATPase activity. In addition, significant up-regulation of H(+)-ATPase activity in 35S:MIR156 roots coupled with increased citric acid and malic acid exudates was observed. qRT-PCR results showed that most H(+)-ATPase and PPCK gene transcript levels were decreased in 35S:MIM156 plants, which may account for the decreased H(+)-ATPase activity in 35S:MIM156 plants. MiR156 also affect the root architecture system. Collectively, our results suggest that miR156 regulates the process of rhizosphere acidification in plants.

Modulation of the Phosphate-Deficient Responses by MicroRNA156 and its Targeted SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 3 in Arabidopsis.

The microRNA156 (miR156)-modulated SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) is involved in diverse biological processes that include growth, development and metabolism. Here, we report that the Arabidopsis miR156 and SPL3 as regulators play important roles in phosphate (Pi) deficiency response. MiR156 was induced during Pi starvation whereas SPL3 expression was repressed. Phenotypes of reduced rhizosphere acidification and decreased anthocyanin accumulation were observed in 35S:MIM156 (via target mimicry) transgenic plants under Pi deficiency. The content and uptake of Pi in 35S:MIM156 Arabidopsis plants were increased compared with wild-type (Col-0 ecotype) plants. 35S:rSPL3 seedlings showed similar anthocyanin accumulation and Pi content phenotypes to those of 35S:MIM156 plants. Chromatin immunoprecipitation and an electrophoretic mobility shift assay indicated that the SPL3 protein directly bound to GTAC motifs in the PLDZ2, Pht1;5 and miR399f promoters. The expression of several Pi starvation-induced genes was increased in 35S:MIM156 and 35S:rSPL3 plants, including high-affinity Pi transporters, Mt4/TPS1-like genes and phosphatases. Collectively, our results suggest that the miR156-SPL3-Pht1;5 (-PLDZ2 and -miR399f) pathways constitute a component of the Pi deficiency-induced regulatory mechanism of Arabidopsis.

Eyelash trichomegaly following treatment with erlotinib in a non-small cell lung cancer patient: A case report and literature review.

Inhibitors of epidermal growth factor receptor (EGFR), including tyrosine kinase inhibitors (TKIs), present significant clinical benefits in the treatment of non-small cell lung cancer (NSCLC), particularly in patients with an EGFR mutation. However, TKI treatment also results in unwanted cutaneous toxic side effects, such as a skin rash. Eyelash trichomegaly is rarely reported as a side effect; however, it causes cosmetic issues or eyeball irritation in patients, which may result in the early termination of TKI treatment. Therefore, although TKI-induced eyelash trichomegaly is rare, it should be considered carefully by lung cancer physicians. The present study reported a case of erlotinib-induced eyelash trichomegaly in a 65-year-old Chinese female patient suffering from NSCLC with an EGFR mutation. To the best of our knowledge, this is the first reported case of erlotinib-induced trichomegaly in a Chinese patient.

Transmembrane Topologies of Ca2+-permeable Mechanosensitive Channels MCA1 and MCA2 in Arabidopsis thaliana.

Sensing mechanical stresses, including touch, stretch, compression, and gravity, is crucial for growth and development in plants. A good mechanosensor candidate is the Ca(2+)-permeable mechanosensitive (MS) channel, the pore of which opens to permeate Ca(2+) in response to mechanical stresses. However, the structure-function relationships of plant MS channels are poorly understood. Arabidopsis MCA1 and MCA2 form a homotetramer and exhibit Ca(2+)-permeable MS channel activity; however, their structures have only been partially elucidated. The transmembrane topologies of these ion channels need to be determined in more detail to elucidate the underlying regulatory mechanisms. We herein determined the topologies of MCA1 and MCA2 using two independent methods, the Suc2C reporter and split-ubiquitin yeast two-hybrid methods, and found that both proteins are single-pass type I integral membrane proteins with extracellular N termini and intracellular C termini. These results imply that an EF hand-like motif, coiled-coil motif, and plac8 motif are all present in the cytoplasm. Thus, the activities of both channels can be regulated by intracellular Ca(2+) and protein interactions.