BACKGROUND: Poly adenosine-diphosphate-ribose polymerase (PARP) inhibitors (PARPi) have been approved to act as first-line maintenance (FL-M) therapy and as platinum-sensitive recurrent maintenance (PSR-M) therapy for ovarian cancer in China for >5 years. Herein, we have analyzed the clinical-application characteristics of olaparib and niraparib in ovarian cancer-maintenance therapy in a real-world setting to strengthen our understanding and promote their rational usage. METHODS: A retrospective chart review identified patients with newly diagnosed or platinum-sensitive recurrent ovarian cancer, who received olaparib or niraparib as maintenance therapy at Sichuan Cancer Hospital between August 1, 2018, and December 31, 2021. Patient medical records were reviewed. We grouped and analyzed patients based on the type of PARPi they used (the olaparib group and the niraparib group) and the line of PARPi maintenance therapy (the FL-M setting and the PSR-M setting). The primary endpoint was the 24-month progression-free survival (PFS) rate. RESULTS: In total, 131 patients (olaparib: n = 67, 51.1%; niraparib: n = 64, 48.9%) were enrolled. Breast cancer susceptibility genes ( BRCA ) mutations ( BRCA m) were significantly less common in the niraparib group than in the olaparib group [9.4% (6/64) vs . 62.7% (42/67), P <0.001], especially in the FL-M setting [10.4% (5/48) vs . 91.4% (32/35), P <0.001]. The 24-month progression-free survival (PFS) rates in the FL-M and PSR-M settings were 60.4% and 45.7%, respectively. In patients with BRCA m, the 24-month PFS rates in the FL-M and PSR-M settings were 62.2% and 72.7%, respectively. CONCLUSIONS Olaparib and niraparib were effective in patients with ovarian cancer without any new safety signals except for skin pigmentation. In patients with BRCA m, the 24-month PFS of the PARPi used in the PSR-M setting was even higher than that used in the FL-M setting.
Humans ; Female ; Ovarian Neoplasms/drug therapy* ; Piperazines/therapeutic use* ; Middle Aged ; Retrospective Studies ; Phthalazines/therapeutic use* ; Piperidines/therapeutic use* ; Indazoles/therapeutic use* ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use* ; Adult ; Aged ; China ; Neoplasm Recurrence, Local/drug therapy* ; Progression-Free Survival

Although olaparib has demonstrated substantial clinical benefits as maintenance therapy in BRCA mutation-carrying women with newly diagnosed advanced ovarian cancer, its effectiveness in patients without BRCA mutations remains poorly investigated. This study aims to provide the first evidence on the efficacy of mono-olaparib maintenance therapy in such context. Using real-world data from 11 high-volume tertiary care centers in China, a retrospective cohort study was conducted to assess the efficacy and safety of olaparib as first-line maintenance therapy in patients with BRCA wild-type ovarian cancer. The primary objective was 1-year progression-free survival rate. Safety was also evaluated. Fifty patients with a median age of 54 years were included, and all of them tested negative for BRCA mutations but positive for homologous recombination deficiency (HRD). The 1-year PFS rate was 75.2% (95% CI, 63.4 to 89.2), and the median PFS was 21.0 months (95% CI, 13.8 to 28.2). All the patients received olaparib at a starting dose of 300 mg twice daily, and none experienced serious adverse events (AEs). Eight (16%) patients had dose adjustment, but none discontinued olaparib treatment due to AEs. We provide the first evidence that mono-olaparib could be a safe and effective maintenance treatment option for patients newly diagnosed with HRD-positive/BRCA wild-type ovarian cancer.
Humans ; Female ; Phthalazines/adverse effects* ; Piperazines/administration & dosage* ; Middle Aged ; Ovarian Neoplasms/genetics* ; Retrospective Studies ; Adult ; Aged ; Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage* ; China ; Maintenance Chemotherapy ; BRCA2 Protein/genetics* ; Antineoplastic Agents/adverse effects* ; Progression-Free Survival ; BRCA1 Protein/genetics*

The common adverse reactions caused by poly (ADP-ribose) polymerase (PARP) inhibitors include hematological toxicity, gastrointestinal toxicity and fatigue. The main prevention and treatment of hematological toxicity include: regular blood tests, referral to hematology department when routine treatment is ineffective, and being alert of myelodysplastic syndrome/acute myeloid leukemia. The key points to deal with gastrointestinal toxicity include: taking medicine at the right time, light diet, appropriate amount of drinking water, timely symptomatic treatment, prevention of expected nausea and vomiting, and so on. For fatigue, full assessment should be completed before treatment because the causes of fatigue are various; the management includes massage therapy, psychosocial interventions and drugs such as methylphenidate and Panax quinquefolius according to the severity. In addition, niraparib and fluzoparib can cause hypertension, hypertensive crisis and palpitation. Blood pressure and heart rate monitoring, timely symptomatic treatment, and multidisciplinary consultation should be taken if necessary. When cough and dyspnea occur, high resolution CT and bronchoscopy should be performed to exclude pneumonia. If necessary, PARP inhibitors should be stopped, and glucocorticoid and antimicrobial therapy should be given. Finally, more attention should be paid to drug interaction management, patient self-management and regular monitoring to minimize the risk and harm of adverse reactions of PARP inhibitors.
Humans ; Poly(ADP-ribose) Polymerase Inhibitors/adverse effects* ; Phthalazines/pharmacology* ; Poly(ADP-ribose) Polymerases ; Fatigue/drug therapy*

This study explored the preservation effect of strigolactone analogs on Gastrodia elata tubers and screened out the suitable preservation measures of G. elata to provide a safer and more effective method for its storage and preservation. Fresh G. elata tubers were treated with 7FGR24, 2,4-D isooctyl ester, and maleic hydrazide, respectively. The growth of flower buds, the activities of CAT, and MDA, and the content of gastrodin and p-hydroxybenzyl alcohol were measured to compare the effects of different compounds on the storage and preservation of G. elata. The effects of different storage temperatures on the preservation of 7FGR24 were compared and analyzed. The gibberellin signal transduction receptor gene GeGID1 was cloned, and the effect of 7FGR24 on the expression level of GeGID1 was analyzed by quantitative polymerase chain reaction(qPCR). The toxicity of the G. elata preservative 7FGR24 was analyzed by intragastric administration in mice to evaluate its safety. The results showed that compared with 2,4-D isooctyl ester and maleic hydrazide, 7FGR24 treatment had a significant inhibitory effect on the growth of G. elata flower buds, and the CAT enzyme activity of G. elata was the highest, indicating that its preservation effect was stronger. Different storage temperatures had different effects on the preservation of G. elata, and the preservation effect was the strongest at 5 ℃. The open reading frame(ORF) of GeGID1 gene was 936 bp in length, and its expression level was significantly down-regulated after 7FGR24 treatment, indicating that 7FGR24 may inhibit the growth of flower buds by inhibiting the gibberellin signal of G. elata, thereby exerting a fresh-keeping effect. Feeding preservative 7FGR24 had no significant effect on the behavior and physiology of mice, indicating that it had no obvious toxicity. This study explored the application of the strigolactone analog 7FGR24 in the storage and preservation of G. elata and preliminarily established a method for the storage and preservation of G. elata, laying a foundation for the molecular mechanism of 7FGR24 in the storage and preservation of G. elata.
Animals ; Mice ; Gastrodia ; Gibberellins ; Maleic Hydrazide ; Esters

The mutation rate of anaplastic lymphoma kinase (ALK) in patients with non-small cell lung cancer is 3% to 7%. Due to its low mutation rate and better long-term survival compared with epidermal growth factor receptor-positive non-small cell lung cancer patients, therefore, it's called "diamond mutation". At present, there are three generations of ALK tyrosine kinase inhibitor (TKI) drugs in the world. The first-generation ALK-TKI drug approved in China is crizotinib, and the second-generation drugs are alectinib, ceritinib and ensartinib. Among them, ensartinib is an ALK-TKI domestically developed, and its efficacy is similar to that of alectinib. The main adverse event is transient rash, and compliance to ensartinib is better from the perspective of long-term survival of patients. The manifestation of rash caused by ensartinib is different from that of other ALK-TKI drugs. In order to facilitate clinical application and provide patients with more treatment options, under the guidance of the Committee of Cancer Rehabilitation and Palliative Care of China Anti-Cancer Association, this article collects and summarizes the common adverse reactions of ensartinib. Based on the clinical practice, a clear adverse classification and specific treatment plan are formulated, in order to provide a corresponding reference for clinicians to make more comprehensive clinical decisions.
Anaplastic Lymphoma Kinase ; Carbazoles/adverse effects* ; Carcinoma, Non-Small-Cell Lung/pathology* ; Consensus ; Exanthema/drug therapy* ; Humans ; Lung Neoplasms/pathology* ; Piperazines ; Protein Kinase Inhibitors/adverse effects* ; Pyridazines

OBJECTIVE: To investigate the antitumor effect of ponatinib on the growth of cholangiocarcinoma xenograft derived from a clinical patient in a mouse model expressing FGFR2-CCDC6 fusion protein. METHODS: Lung metastatic tumor tissue was collected from a patient with advanced intrahepatic cholangiocarcinoma and implanted subcutaneously a NOD/SCID/ Il2rg-knockout (NSG) mouse. The tumor tissues were harvested and transplanted in nude mice to establish mouse models bearing patient-derived xenograft (PDX) of cholangiocarcinoma expressing FGFR2-CCDC6 fusion protein. The PDX mouse models were divided into 4 groups for treatment with citrate buffer (control group), intragastric administration of 20 mg/kg ponatinib dissolved in citrate buffer (ponatinib group), weekly intraperitoneal injections of 50 mg/kg gemcitabine and 2.5 mg/ kg cisplatin (gemcitabine group), or ponatinib combined with gemcitabine and cisplatin at the same doses (10 mice in each group, and 9 mice were evaluated in ponatinib group). The expressions of p-FGFR, p-FRS2, p-AKT, p-ERK, CD31, and Ki-67 in the xenografts were evaluated with immunohistochemistry, and cell apoptosis was analyzed with cleaved caspase-3 (CC3) staining and TUNEL staining. Western blotting was used to detect the expressions of FGFR2, p-FGFR, AKT, p-AKT, ERK, p-ERK, FRS2 and p-FRS2 in the tumor tissues. RESULTS: Compared with those in the control group, the mice in ponatinib group showed a significantly reduced tumor volume ( CONCLUSIONS Ponatinib can regulate FGFR signaling to inhibit the proliferation and induce apoptosis of tumor cells in mice bearing patient-derived cholangiocarcinoma xenograft with FGFR2 fusion. FGFR inhibitor can serve as a treatment option for patients with cholangiocarcinoma with FGFR2 fusion.
Animals ; Bile Duct Neoplasms/genetics* ; Cell Line, Tumor ; Cell Proliferation ; Cholangiocarcinoma/genetics* ; Cytoskeletal Proteins ; Heterografts ; Humans ; Imidazoles ; Mice ; Mice, Inbred NOD ; Mice, Nude ; Mice, SCID ; Pyridazines ; Receptor, Fibroblast Growth Factor, Type 2 ; Xenograft Model Antitumor Assays

OBJECTIVE: To investigate the regulatory effects of Olaparib on natural killer cell activating receptor (NKG2D) ligands expression on human acute myeloid leukemia (AML) cell line HL-60, and to explore the molecular mechanism of Olaparib on HL-60 cells. METHODS: After HL-60 cells in logarithmic growth phase were treated with Olaparib at different concentrations for different times (24, 48 h), the expression of NKG2D ligand on the surface of HL-60 cells was detected by flow cytometry. Western blot was used to dectect the expression of ERK expression in HL-60 cells. The killing effect of NK cells to HL-60 cells was detected by CFSE/PI method. RESULTS: 10 μmol/L Olaparib could upregulate the expression of NKG2D ligand on the surface of HL-60 cell at 24 and 48 hours, while 5 μmol/L Olaparib could induce up-regulation of the expression of ULBP-2 and ULBP-3 at 48 hours. Western blot analysis showed that ERK phosphorylation of HL-60 cells was enhanced after treating with Olaparib. The killing effect of NK cells to HL-60 cells could be enhanced by Olaparib, however, ERK inhibitor could suppress the killing effect of NK cells to HL-60 cells. CONCLUSION Olaparib can upregulate NKG2D ligands expression on the surface of HL-60 cells and enhance the cytotoxicity of NK cell to HL-60 cells. The mechanism may be related to Olaparib promoting ERK phosphorylation expression.
Cell Line, Tumor ; Cytotoxicity, Immunologic ; HL-60 Cells ; Histocompatibility Antigens Class I ; Humans ; Ligands ; NK Cell Lectin-Like Receptor Subfamily K ; Phthalazines ; Piperazines ; Poly(ADP-ribose) Polymerase Inhibitors

OBJECTIVE: To analyze the clinical features of chronic myeloid leukemia (CML) with T315 I mutation (CML-T315I) and compare the effectiveness of different treatments. METHODS: We retrospectively analyzed the clinical data and outcomes of 19 patients with CML-T315I receiving different treatments. The T315 I mutations in these patients were detected by examination of BCR-ABL kinase domain (KD) mutation by RTQ-PCR and Sanger sequencing. The relapse following the treatments, defined as hematological, cytogenetic and molecular biological recurrences, were analyzed in these patients. RESULTS: Of the 19 patients with CML-T315I, 14 (73.7%) were in CML-CP stage at the initial diagnosis, and 13 (81.2%) were high-risk patients based on the Sokal scores. All the 19 patients were treated with TKI after the initial diagnosis, and during the treatment, 15 (78.9%) patients were found to have additional chromosomal aberrations, and 10 (52.6%) had multiple mutations; 13 (68.4%) of the patients experienced disease progression (accelerated phase/blast crisis) before the detection of T315I mutation, with a median time of 40 months (5-120 months) from the initial diagnosis to the mutation detection. After detection of the mutation, 12 patients were treated with ponatinib and 7 were managed with the conventional chemotherapy regimen, and their overall survival rates at 3 years were 83.3% and 14.2%, respectively ( < 0.001). CONCLUSIONS CML patients resistant to TKI are more likely to have T315I mutations, whose detection rate is significantly higher in the progressive phase than in the chronic phase. These patients often have additional chromosomal aberrations and multiple gene mutations with poor prognoses and a high recurrence rate even after hematopoietic stem cell transplantation. Long-term maintenance therapy with ponatinib may improve the prognosis and prolong the survival time of the patients.
Drug Resistance, Neoplasm ; Fusion Proteins, bcr-abl ; Humans ; Imidazoles ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; Mutation ; Pyridazines ; Retrospective Studies

ABSTRACT:

BACKGROUND: The Millennium Development Goal (MDG) for 2015 has a target MMR of 52/100,000 live births but this goal been difficult to achieve. In the Philippines, 11 mothers die everyday from pregnancy related complications, a bulk contributed by Hypertension. Public health midwives sometimes attend to these obsterical emergencies often in the absence of a physician. this led to the BEmONC program, which addresses the rising morbidities from far-flung areas where resources are scarce, and helps train midwives in essential obsterical emergency care. The midwives are our allies in providing the best standard of care every mother and child rightfully deserves. Only thru periodic evaluation can we help strengthen BEmONC program, making it crucial to evaluate the midwives' knowledge and management practices in hypertension to help identify the setbacks that have impeded our progress in achieving the MDG.

GENERAL OBJECTIVE: To access the knowledge and management practices of midwives in the management of hypertension in pregnancy in accourdance to the BEmONC protocol.

STUDY DESIGN: Descriptive Study

STUDY SETTING: The 69 public health centers of Cebu City

STUDY POPULATION: Public Health Midwives

METHODOLOGY:This is descriptive study where a survey questionnaire was used and convenience sampling was done. Chi square and Fischer exact tests were employed to compare proportions. Descriptive statistics was used to summarize the data in proportion.

RESULT: More than 70% of the midwives were knowledgeable regarding expected competencies, where BEmONC-trained midwives were 5-14x more likely to identity appropriate function. However, Only a dismal 22-36% will actually administer Magnesium Sulfate, which shows that knowledge is not translated into practice. Also, more than 70% were knowledgeable on the risk factors and danger signs of hypertension in pregnancy. It also showed that the midwives agreed to give antihypertensive medications- where Methyldopa was commonly given. Among those who agreed too give Methyldopa, majority were BEmONC-trained. A number also agreed to give hydralazine and diazepam in the setting of sever preeclampsia and eclampsia, where more non-BEmONC midwives agreed. Alarmlingly, only less than 50% will refer to a physician in the management og gestational hypertension and mild preeclampsia, and only 50%-60% agreed to facilitate hospital transport in the setting of severe preeclampsia and eclampsia.

CONCLUSION: The BEmONC manual must be updated to keep up with current guidelines and ensure the conversation of knowledge into practice. The BEmONCcoverage of training must also be expanded so that all practicing midwives know the protocol. However, the DOH must further strengthen their role in the active surveillance of public health midwives and review the retention of their skills and regular practice of knowledge. Midwives must also be certified proficient, not merely trained. The must also be consulted to explore their problems in the implementation of current guidelines so we can better understand their situation as to why knowledge is not put into practice. By identifying deficiencies, we can improve and address setbacks that have impeded our progress towards achieving the Millennium Development Goal.

Human ; Knowledge ; Methyldopa ; Antihypertensive Agents ; Eclampsia ; Hypertension, Pregnancy-induced ; Magnesium Sulfate ; Midwifery ; Pre-eclampsia ; Live Birth ; Diazepam ; Hydralazine ; Obstetrics

OBJECTIVE: To explore the relevance between nasal symptoms and laryngopharyngeal reflux disease in patients with allergic rhinitis. METHOD: Thirty patients of laryngopharyngeal reflux disease were diagnosed in ENT outpatient department in our hospital. All patients have symptoms of sneeze, nasal discharge as chief complaint and they responded no effect for other normal treatment for nasal-sinusitis at least three months. Orally before meals, a dose of 5 mg Mosapride citrate each time, three times a day for 7 days. Orally before meals, a dose of 20 mg Esomeprazole each time, two times a. day for 2-3 months. Nasal spray, one spray of azelastine hydrochloride once, two times a day for 2 month. RESULT: Laryngopharyngeal reflux symptom scores at four time points (the first visit, post treatment 15 days, 45 days, 75 days) were analyzed by repeated measures analysis of variance. There is a significant difference in four time points. CONCLUSION Laryngopharyngeal reflux disease has a strong association with allergic rhinitis. Patients who has allergic rhinitis nasal symptoms as chief complaint must be exclude, the laryngopharyngeal reflux disease first.
Benzamides ; therapeutic use ; Esomeprazole ; therapeutic use ; Humans ; Laryngopharyngeal Reflux ; complications ; drug therapy ; Morpholines ; therapeutic use ; Phthalazines ; therapeutic use ; Pilot Projects ; Rhinitis, Allergic ; drug therapy ; etiology