Impact of Enterococcus faecalis Endocarditis Treatment on Risk of Relapse.

BACKGROUND: Enterococcus faecalis infective endocarditis (EFIE) is characterized by a higher frequency of relapses than other infective endocarditis. The role of the treatment on its occurrence remains poorly understood. The aim of this study was to investigate whether the antibiotic regimen could impact the risk of relapse in EFIE. MATERIALS: This was a multicenter retrospective study of patients diagnosed with definite EFIE between 2015 and 2019 in 14 French hospitals. The primary endpoint was the occurrence of relapses within the year following endocarditis diagnosis. As death was a competing risk for relapse, Fine and Gray models were used for studying risk factors and impact of treatment. RESULTS: Of the 279 patients included, 83 (29.7%) received the amoxicillin-gentamicin (A-G) combination, 114 (40.9%) amoxicillin-ceftriaxone (A-C), 63 (22.6%) A-G and A-C (A-G/A-C) sequentially, 9 (3.2%) amoxicillin (A), and 10 received other treatments. One-year-relapse rate was 9.3% (26 patients). Relapse occurred after a median delay of 107 days from EFIE diagnosis; 6 occurred after 6 months, and 6 were diagnosed by blood cultures in asymptomatic patients. In multivariate analysis, surgery during treatment was a protective factor against one-year relapse and death.The cumulative incidence of relapse 1 year after endocarditis was 46.2% for patients treated with amoxicillin, 13.4% with A-G, 14.7% with A-C, and 4.3% with A-G/A-C (P≥.05 in multivariate analysis). CONCLUSIONS: Relapses after treatment of EFIE are frequent, frequently asymptomatic, and may occur more than 6 months after the initial episode.

Pembrolizumab, radiotherapy, and an immunomodulatory five-drug cocktail in pretreated patients with persistent, recurrent, or metastatic cervical or endometrial carcinoma: Results of the phase II PRIMMO study.

A phase II study (PRIMMO) of patients with pretreated persistent/recurrent/metastatic cervical or endometrial cancer is presented. Patients received an immunomodulatory five-drug cocktail (IDC) consisting of low-dose cyclophosphamide, aspirin, lansoprazole, vitamin D, and curcumin starting 2 weeks before radioimmunotherapy. Pembrolizumab was administered three-weekly from day 15 onwards; one of the tumor lesions was irradiated (8Gyx3) on days 15, 17, and 19. The primary endpoint was the objective response rate per immune-related response criteria (irORR) at week 26 (a lower bound of the 90% confidence interval [CI] of > 10% was considered efficacious). The prespecified 43 patients (cervical, n = 18; endometrial, n = 25) were enrolled. The irORR was 11.1% (90% CI 2.0-31.0) in cervical cancer and 12.0% (90% CI 3.4-28.2) in endometrial cancer. Median duration of response was not reached in both cohorts. Median interval-censored progression-free survival was 4.1 weeks (95% CI 4.1-25.7) in cervical cancer and 3.6 weeks (95% CI 3.6-15.4) in endometrial cancer; median overall survival was 39.6 weeks (95% CI 15.0-67.0) and 37.4 weeks (95% CI 19.0-50.3), respectively. Grade ≥ 3 treatment-related adverse events were reported in 10 (55.6%) cervical cancer patients and 9 (36.0%) endometrial cancer patients. Health-related quality of life was generally stable over time. Responders had a significantly higher proportion of peripheral T cells when compared to nonresponders (p = 0.013). In conclusion, PRIMMO did not meet its primary objective in both cohorts; pembrolizumab, radiotherapy, and an IDC had modest but durable antitumor activity with acceptable but not negligible toxicity.Trial registration ClinicalTrials.gov (identifier NCT03192059) and EudraCT Registry (number 2016-001569-97).

Refined risk stratification, current treatment, and new therapeutic approaches in pulmonary arterial hypertension.

The 2022 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines for pulmonary hypertension have introduced a refined risk stratification to guide both initial and subsequent treatment of pulmonary arterial hypertension (PAH). The risk stratification at PAH diagnosis still comprises three risk categories (low, intermediate, high) and lists some new parameters. As the estimated 1­year mortality is more than 20% in high-risk patients after diagnosis, an initial triple-combination therapy including parenteral prostacyclin analogues is recommended for this group. All other patients should receive a dual-combination therapy with an endothelin receptor antagonist and a phosphodiesterase­5 inhibitor. However, this approach of initial combination therapy is only recommended for classic PAH, while monotherapy followed by regular follow-up and individualized therapy should be used for patients with cardiopulmonary comorbidities. For PAH patients without cardiopulmonary comorbidities, it is recommended to assess their risk at follow-up with a new 4­strata classification, where the intermediate-risk group is split on the basis of three noninvasive parameters. Importantly, changes from intermediate-high to intermediate-low risk have been shown to be associated with a better prognosis. In addition, the recommendations on treatment escalation became more precise with the addition of a prostacyclin receptor agonist or switching a phosphodiesterase­5 inhibitor to a soluble guanylate cyclase stimulator for intermediate-low risk and proceeding to triple-combination therapy with parenteral prostacyclin analogues already for intermediate-high risk. With sotatercept, the first non-vasodilator PAH treatment will become available in the near future to further enrich our treatment options for this chronic and still severe disease.

Onset of efficacy and adverse events during Cenobamate titration period.

OBJECTIVES: Cenobamate is an antiseizure medication (ASM) approved in Europe as adjunctive therapy for adults with inadequately controlled focal seizures. This post hoc analysis reports onset of efficacy and characterizes time to onset, duration, and severity of the most common treatment-emergent adverse events (TEAEs) during cenobamate titration. MATERIALS & METHODS: Adult patients with uncontrolled focal seizures taking 1 to 3 concomitant ASMs were randomized to receive adjunctive cenobamate or placebo (double-blind studies C013 and C017) or cenobamate (open-label study C021). Outcome assessments included efficacy (median percentage change in seizure frequency and onset [studies C013 and C017]) and safety (onset, duration, and severity of TEAEs [all studies]). RESULTS: Onset of efficacy was observed by Weeks 1 to 4 of titration in studies C013 and C017 which used a faster titration schedule than study CO21. In study C013, the median percentage seizure frequency reduction was 36.7% in patients receiving cenobamate versus 16.3% in those taking placebo (p = .002); in study C017, significant differences in seizure frequency emerged in Week 1 and continued throughout titration between all cenobamate groups and placebo (p < .001). The most commonly reported TEAEs were somnolence, dizziness, fatigue, and headache, with first onset of each reported as early as Week 1; however, the majority resolved. CONCLUSIONS: Reductions in seizure frequency occurred during titration with initial efficacy observed prior to reaching the target dose. These reductions were regarded as clinically meaningful because they may indicate early efficacy at lower doses than previously expected and had a considerable impact on patient quality of life. Long-term treatment with adjunctive cenobamate was generally safe and well-tolerated.

[Personalized systemic treatment of metastatic colorectal cancer]. / Personalisierte Systemtherapie beim metastasierten kolorektalen Karzinom.

This article deals with the treatment of metastatic colorectal cancer (stage IV). The treatment goals and approaches are determined by the resectability status of the metastases: resectable liver and lung metastases are primarily resected and perioperative chemotherapy appears to be dispensable. In potentially resectable metastases, a conversion therapy is attempted to enable a potentially curative resection. In the case of nonresectability the treatment goal is palliative. Induction and maintenance therapy as well as drug holidays are suggested in an attempt to achieve extended survival while maintaining the quality of life, beginning with the best possible individual treatment. For some patients with stage IV, molecular targeted therapies are available. The study situation and approval status are dealt with in detail. With improved molecular characterization of tumors the treatment can be further individualized.

[Immunotherapy for malignant melanoma]. / Immuntherapie beim malignen Melanom.

Although cutaneous melanoma accounts for only about 4% of all skin cancers (including nonmelanocytic skin cancer), it is responsible for 80% of all deaths caused by skin cancer. The introduction of immune checkpoint inhibitors led to a significant improvement in long-term survival of patients in an advanced stage regardless of BRAF mutation status. In addition to targeted therapy for patients with BRAF-mutated melanoma, immunotherapies are the therapies of choice in advanced stages and, since 2018, also in the adjuvant setting. The effectiveness of combination therapies and sequences of targeted and immunotherapies are currently being tested.

Managing Pharmacotherapy in People Living With HIV and Concomitant Malignancy.

Objective: To describe data with selected malignancies in people living with HIV (PLWH) and HIV in individuals affected by both conditions and to summarize drug-drug interactions (DDIs) with clinical recommendations for point-of-care review of combination therapies. Data Sources: Literature searches were performed (2005 to December 2018) in MEDLINE and EMBASE to identify studies of malignancies in PLWH in the modern era. Study Selection and Data Extraction: Article bibliographies and drug interaction databases were reviewed. Search terms included HIV, antiretroviral therapy, antineoplastic agents, malignancies, and drug interactions. Data Synthesis: In the pre-antiretroviral therapy (ART) era, malignancies in PLWH were AIDS-defining illnesses, and life expectancy was shorter. Nowadays, PLWH are living longer and developing malignancies, including lung, anal, and prostate cancers. Concurrently, the oncology landscape has evolved, with novel oral targeted agents and immunotherapies becoming routine elements of care. The increased need for and complexity with antineoplastics in PLWH has led to recommendations for multidisciplinary care of this unique population. Evaluation of DDIs requires review of metabolic pathways, absorption mechanisms, and various drug transporters associated with antineoplastics and ART. Relevance to Patient Care and Clinical Practice: This review summarizes available data of non-AIDS-defining malignancies, principles of HIV care in the patient with malignancy, and guidance for assessing DDIs between antineoplastics and ART. Summary DDI tables provide point-of-care recommendations. Conclusions: The availability of ART has transformed AIDS into a chronic medical condition, and PLWH are experiencing age-related malignancies. Pharmacists play an important role in the management of this patient population.

[Jinghuaweikang capsules combined with Quadruple therapy in the treatment of Helicobacter pylori infection:a multicenter,randomized,controlled,clinical study].

Objective: To explore the efficacy of Jinghuaweikang capsules combined with Quadruple therapy in the treatment of Helicobacter pylori (H.pylori)infection. Methods: Patients who were infected with H.pylori in 7 centers in Gansu Province were recruited in this prospective simple randomized study. All the patients are divided into four groups randomly: patients in Group A1 were treated with esomeprazole (20 mg, twice a day) + pectin bismuth (200 mg, three times a day) + amoxicillin (1 000 mg, twice a day) + clarithromycin (500 mg, twice a day), while Group A2 with Jinghuaweikang capsules(160 mg, three times a day) based on group A2, Group B1 with esomeprazole (20 mg, twice a day) + bismuth pectin (200 mg, three times a day) + amoxicillin (1 000 mg, twice a day) + furazolidone (100 mg, twice a day) and Group B2 with Jinghuaweikang capsules(160 mg, three times a day) based on group B2. The treatment time was 14 days for all 4 groups. In the course of treatment, abdominal pain, acid reflux, abdominal distension, belching, hiccups were observed at the time before treatment, 14 days and 30 days after treatment and were scored. Finally, all patients received (13)C or (14)C for H.pylori at the time of 30 days after the treatment. Result: A total of 455 patients were included in 7 hospitals from February 2016 to May 2017 in Gansu province, and there were 189 male patients. Group A1 included 129 cases, group A2 96 cases, group B1 112 cases and group B2 118 cases. The eradication rates that accorded with program data analysis (PP) were A1[46.9%(60/128)], A2[63.8%(60/94)], B1[60.7%(68/112)], B2[68.6%(81/118)] (P<0.004). Compared with group A1, the eradication rate of H.pylori in group B1 and group A2 increased (P<0.001, P=0.032), there was no statistical difference between group B2 and group A2, group B1 and group B2 (P=0.208, P=0.461). According to intentional analysis (ITT), the eradication rates of H.pylori in group A1 were 46.5% (60/129),group A2 were 62.5% (60/96),group B1 were 60.7% (68/112),and group B2 were 68.6% (81/118).The radical rate of A2 was higher than A1 (P=0.017), group B2 was not higher than group B1 (P=0.208), and there was no significant difference among the other groups. The symptoms of abdominal pain, abdominal distention, acid reflux, belching and hiccup in the group A2 and group B2 were improved than those in group A1 and group B1 (P<0.05). No serious adverse reactions occurred in all groups. Conclusion: Jinghuaweikang capsules can improve the eradication rate of Helicobacter pylori, and improve the symptoms of patients.

[The clinical focus and prospect of medical treatments in genitourinary tract tumors].

In recent years, the field of medical treatment of genitourinary tract tumors has made rapid progress. Precision medicine has provided important role in selecting the potential patients. Immunotherapy is a new choice for metastatic disease. The combination therapy has also brought the light for better tumor control. This article briefly introduces these progresses and provides new conception and research directions for treatment of genitourinary tract tumors.

Intensified preoperative chemoradiation by adding oxaliplatin in locally advanced, primary operable (cT3NxM0) rectal cancer : Impact on long-term outcome. Results of the phase II TAKO 05/ABCSG R­02 trial.

PURPOSE: The major goals of preoperative treatment for locally advanced rectal cancers (LARCs) are improvement of local tumor control, tumor downsizing, and downstaging. Modifications with respect to standardized chemoradiation protocol, e. g., integrating oxaliplatin, are realized with the aim of improving primary tumor response and patient outcome. PATIENTS AND METHODS: In this phase II multicenter study, patients with LARC of the mid- or lower rectum, cT3cNxcM0 as staged by MRI, were included and treated preoperatively with a combination of capecitabine and oxaliplatin following a standardized protocol during radiation. The focus of this long-term analysis was overall (OS) and disease-free survival (DFS). RESULTS: A total of 60 patients (19 women, 41 men, median age 60.5 years) were initially enrolled, 1 patient was excluded (violation of study protocol), and 1 was patient lost of follow-up, leading to a total of 58 patients for long-term analysis. The 3­year OS was 85.5%; 3­year DFS 71.2%. Over time, 15 patients (25.9%) developed tumor recurrence (1 locoregional, 6.7%; 11 distant, 73.3%; 3 locoregional+distant, 20%). Recurrence-specific therapy was planned in the majority of patients, in 9 of 15 patients (60%) with a radical surgical approach. Of these, 4 patients (44.4%) are again tumor-free at the end of investigation. While tumor downsizing (T level) or pathologically complete response did not influence patient survival, lymph node negativity (LNneg) after preoperative chemoradiation showed significant influence. CONCLUSION: LNneg after preoperative treatment for LARC significantly influences patient survival. A radical surgical approach for recurrent LARC (locoregional, distant) should be contemplated when possible as we were able to clearly demonstrate its importance and efficacy.

[Clinical value of (125)I radioactive seed implantation plus transcatheter arterial chemoembolization combined with radiofrequency ablation in treating patient with sub-capsular hepatocellular carcinoma].

Objective: To analyze the clinical efficacy and safety of (125)I radioactive seed implantation in the treatment of sub-capsular hepatocellular carcinoma (sub-HCC) with sequential radiofrequency ablation and transcatheter arterial chemoembolization (TACE). Methods: The clinical data of 76 cases with advanced HCC with sub-capsular nodules including 68 males and 8 females, with an average age of (58±9) years, ranging from 33 to 78 years, enrolled in Lishui Central Hospital from January 2010 to December 2016 were collected.The average maximum diameter of tumor is (5.7±2.3) cm, ranging from 3.1 cm to 12.0 cm.The patients were divided into TACE+ RFA group and (125)I + TACE+ RFA group with 38 cases in each group.The overall survival (OS) and progression free survival(PFS) were calculated.The clinical efficiency and adverse events were evaluated. Results: The disease control rate were 84.2%(32/38) in (125)I + TACE+ RFA group and 63.2% (24/38) in TACE+ RFA group, χ(2)=4.34, P= 0.04.The median PFS were 18 months in (125)I + TACE+ RFA group and 11 months in TACE+ RFA group, χ(2)=4.84, P=0.03.The FPS cumulative rate in (125)I + TACE+ RFA group were higher than that in TACE+ RFA group at 6 months (94.7%±3.6% vs 81.3%±6.4%, Z=24.1>2.58, P=0.00), 1 year (89.2%±5.1% vs 40.7%±8.3%, Z=13.3>2.58, P=0.00) and 2 year (55.9%±8.6% vs 29.6%±8.2%, Z=7.2>2.58, P=0.00). The median OS were 42 months in (125)I + TACE+ RFA group and 30 months in TACE+ RFA group, χ(2)=4.76, P=0.029.The survival cumulative rate in (125)I+ TACE+ RFA group were higher than that in TACE+ RFA group at 1 year (92.1%±4.4% vs 83.8%±6.1%, Z=23.5>2.58, P=0.00), 2 year (75.8%±7.0% vs 59.8%±8.4%, Z=12.43>2.58, P=0.00), 3 year (59.0%±8.2% vs 41.7%±8.9%, Z=8.3>2.58, P=0.00), 5 year (34.2%±8.2% vs 18.2%±8.1%, Z=5.5>2.58, P=0.00). In addition, there was no statistical difference in liver function and complications between TACE+ RFA group and (125)I+ TACE+ RFA group. Conclusion: (125)I radioactive seed implantation plus TACE combined with RFA treatment is an effective and safe treatment for sub-capsular hepatocellular carcinoma.

[Impact of first-line chemotherapy on renal function in patients with advanced upper tract urothelial carcinoma].

Objective: To observe the impact of first-line chemotherapy on renal function in patients with unresectable/metastatic upper tract urothelial carcinoma(UTUC). Methods: A total of 222 (130 males and 92 females) unresectable/metastatic upper tract urothelial carcinoma patients were included in the study between January 2005 and May 2017, with age of 29 to 87 (62.4±10.1) years old. The serum creatinine level and estimated glomerular filtration rate (eGFR) were compared before and after first-line chemotherapy. And predictive factors for decreased renal function were analyzed in logistic regression model. Results: After the first-line chemotherapy, the average serum creatinine level increased, with a median changing value of 1.5 µmol/L. Howerver, the eGFR improved, with a median changing value of 0.5 ml·min-1· (1.73 m2)-1, but the differences were not statistically significant (all P>0.05). In 149 patients who were treated with cisplatin-based chemotherapy, the average serum creatinine level increased by 1.31 µmol/L and eGFR improved by 0.14 ml·min-1·(1.73 m2)-1, but the differences were not statistically significant (P>0.05). In multivariate logistic regression model, age more than and equal to 60 years old (OR=0.88, P=0.745) and cisplatin-based chemotherapy (OR=0.95, P=0.893) did not increase the risk of renal dysfunction after first-line chemotherapy. If the time interval between surgery and first-line chemotherapy was more than 1 year, the risk of renal dysfunction due to chemotherapy decreased (OR=0.54, P=0.196). Eastern Cooperative Oncology Group Performance Status (ECOG PS) Scale≥1 (OR=1.81, P=0.131), anemia before treatment (OR=1.14, P=0.764), the cycles of first-line chemotherapy (OR=1.41, P=0.398) may lead to increase the risk of renal dysfunction, but the differences were not statistically significant. However in the patients who accepted nephrectomy, the risk of renal dysfunction after chemotherapy increased, but the difference was still not statistically significant (OR=3.06, P=0.089). Conclusions: First-line chemotherapy, especially the cisplatin-based regimen, had no significant impact on renal function in the patients with UTUC. Nephrectomy maybe a predictive risk factor for decreased renal function after chemotherapy. Adequate assessment of renal function before treatment, hydration and close monitoring during chemotherapy can effectively protect renal function of the patients.

[Chronic hepatitis C : Standard treatment and remaining challenges]. / Chronische Hepatitis C : Standardtherapie und verbliebene Herausforderungen.

BACKGROUND: Among patients with chronic hepatitis C, 20-30% develop cirrhosis and its complications within 30 years. The antiviral treatment of hepatitis C has become interferon-free, with resulting improvements in sustained virological response rates, safety and tolerability and a shorter duration of treatment. OBJECTIVE: The mechanism of action of available drugs and current treatment recommendations. MATERIAL AND METHODS: This review is based on relevant publications retrieved by a selective literature search and particularly on studies and reviews concerning the course and treatment of hepatitis C. RESULTS: The available drugs for interferon-free antiviral treatment of hepatitis C include inhibitors of the RNA-dependent RNA polymerase, NS3/4A protease, and NS5A protein of the hepatitis C virus (HCV), and ribavirin. Typically, two specific inhibitors are given in combination and the usual duration of treatment is 8-12 weeks. The antiviral drugs differ in their genotypic effectiveness and resistance barriers. The appropriate drug(s) should be chosen in consideration of the patient's hepatic and renal function and potential drug-drug interactions. All approved anti-HCV drugs are safe and well-tolerated and result in sustained virological response rates above 95%. CONCLUSION: All patients with hepatitis C, whatever their disease stage, can achieve a sustained eradication of HCV using a combination of drugs with direct antiviral activity. Viral eradication is associated with a better quality of life and with lower morbidity and mortality.

[Analysis on the medication of the outpatients diagnosed with glaucoma at West China Hospital of Sichuan University].

Objective: To retrospectively investigate the medication structures and characteristics among the outpatients diagnosed with glaucoma at West China Hospital of Sichuan University in 2015. Methods: Based on retrospective study method, the data of glaucoma patients (6 236 people, and 13 693 person-times) who received medication at the outpatient department of West China Hospital in 2015 were collected from hospital information system, such data include date, doctor's advice date, doctor's advice ID, diagnosis, western medicine fee, Chinese medicine fee, etc. Excel 2011 software was used to analyze the drug use of glaucoma outpatients. Results: (1) The total of outpatients with glaucoma medication were 13 693 person-times, of which 4 247 persons-times patients who did not take intraocular pressure (IOP)-lowering drugs accounted for 31.02%. (2) There were 7 types of IOP-lowering drugs used, including 14 kinds of different drugs. The top three most frequently used drugs were prostaglandin analogs (PGA, 36.98%, 5 847 cases), ß-adrenergic receptor blockers (26.61%, 4 207 cases), and carbonic anhydrase inhibitor (CAI, 20.95%,3 312cases). (3) Among all the patients who have taken IOP-lowering drugs, the patients that received single-drug treatment accounted for 62.41% (5 895/9 446), and the most frequently used single IOP-lowering drug is PGA(44.94%,2 649/5 895). Patients that received two-drugs combined treatment accounted for 28.03% (2 648/9 446), and the most frequently used combined treatment is "ß-adrenergic receptor blockers+ PGA" (27.57%,730/2 648). Patients that received three-drugs combined treatment accounted for 7.88% (744/9 446), and the most frequently used combined treatment is "ß-adrenergic receptor blockers+ PGA+ CAI" (46.24%,344/744). Patients that received four-drugs combined treatment accounted for 1.57% (149/9 446), and the most frequently used combined treatment is "ß-adrenergic receptor blockers+α-adrenergic receptor agonist +PGA + CAI" (87.25%,130/149). And patients that received five-druges combined treatment accounted for 0.11% (10/9 446). Conclusions: The most frequently used single IOP-lowering drug for outpatients with glaucoma at West China Hospital of Sichuan University in 2015 is PGA. The most frequently used combined medications are "ß-adrenergic receptor blockers+ PGA" for two-drugs combined treatment and "ß-adrenergic receptor blockers+ PGA + CAI" for three-drugs combined treatment.(Chin J Ophthalmol, 2018, 54: 189-193).

[Safety and efficacy of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) in Chinese patients with advanced colorectal cancer].

Objective: To establish the maximum tolerated dose (MTD) of 5-fluorouracil, leucovorin, oxaliplatin and irinotecan (FOLFOXIRI), and to evaluate the safety and efficacy in Chinese patients with advanced colorectal cancer. Methods: Patients were treated with a regimen consisting of infusional 5-fluorouracil (2 400 mg/m(2) on day 1), leucovorin (200 mg/m(2) on day 1), oxaliplatin (85 mg/m(2) on day 1), and irinotecan (at doses from 150 to 180 mg/m(2) on day 8) according to the dose-escalation schema. Treatment was repeated every 14 days. The UDP-glucuronosyl transferase (UGT) 1A1 genotypes were analyzed in the patients with dose-limiting toxicity (DLT). Results: A total of 12 patients with advanced colorectal cancer were included. The MTD of FOLFOXIRI in these patients was oxaliplatin 85 mg/m(2) day 1, leucovorin 200 mg/m(2) day 1, 5-fluorouracil 2 400 mg/m(2) day 1, and irinotecan 150 mg/m(2) day 8 every 2 weeks. The most common toxicities were nausea, diarrhea, leukopenia, neutropenia and fatigue. The DLTs were febrile neutropenia and diarrhea. The objective response rate was 66.7%. Conclusions: Our results indicate that FOLFOXIRI regimen is considered safe and effective in Chinese patients with advanced colorectal cancer, and the MTD of FOLFOXIRI regimen for Chinese patients with advanced colorectal cancer is recommended.

[Effect of rapamycin and chloroquine on osteosarcoma].

Objective: To investigate the combination effect of anti-tumor agent rapamycin and anti-autophagy agent chloroquine on osteosarcoma. Methods: The inhibition effect of rapamycin or chloroquine and combination of both on human osteosarcoma cell line 143B measured with CCK-8 box.The combination index at different concentration was calculated, and the synergism effect range was analysed.The effect of combined therapy on cell cycle and apoptosis via flow cytometric was analyzted.Setting up murine subcutaneous xenograft model, the combination effect of antitumor in vivo observed. Results: Either of them, rapamycin or chloroquine had an antitumor effect in vitro (RAPA: IC50=1.5 nmol/L; CQ: IC50=400 µmol/L). When the inhibition rate 40%

First-generation antipsychotics and QTc: any role for mediating variables?

OBJECTIVE: Corrected QT (QTc) interval prolongation is often associated with use of first-generation antipsychotics (FGAs). However, other factors require appropriate consideration, including age and gender, the role of other known medications associated with QTc prolongation, and severe comorbid conditions, such as co-occurring alcohol abuse/dependence. We aimed to study potential mediating roles of different, related, candidate variables on QTc. METHODS: We capitalized on data from a large (N = 2366), cross-sectional, national survey, the STAR Network QTc study, using a representative sample of people taking FGAs, and recruited from mental health services across Italy. RESULTS: About one-third of the sample was treated with FGAs, and almost one-tenth of the subjects took a different, additional, drug known to cause QTc prolongation. Our findings confirmed that there is an impact from FGAs, age, gender, alcohol misuse, and concurrent risky drugs on QTc. However, comorbid alcohol abuse/dependence and concurrent risky drugs did not mediate the effect of FGAs on QTc. CONCLUSIONS: Our findings showed that FGAs, concurrent risky drugs, and alcohol use disorders prolonged QTc. FGAs had a direct effect on QTc, confirming the need for clinicians to monitor a risk that could lead to sudden unexplained death. Copyright © 2016 John Wiley & Sons, Ltd.

[Treatment of tuberculosis. Current standards]. / Therapie der Tuberkulose. Was ist gesichert?

The treatment of drug-sensitive tuberculosis consists of 2 months of isoniazid, rifampin, pyrazinamide and ethambutol, followed by 4 months of isoniazid and rifampin. These drugs are well tolerated and cure rate are above 95 %. In contrast the treatment of drug-resistent tuberculosis is difficult, mostly due to side effects of the drugs used under these circumstances. Therefore, any treatment of drug-resistant tuberculosis has to be done by experts.

Effects of tissue plasminogen activator and annexin A2 combination therapy on long-term neurological outcomes of rat focal embolic stroke.

BACKGROUND AND PURPOSE: Tissue-type plasminogen activator (tPA) in combination with recombinant annexin A2 (rA2) is known to reduce acute brain damage after focal ischemia. Here, we ask whether tPA-plus-rA2 combination therapy can lead to sustained long-term neurological improvements as well. METHODS: We compared the effects of intravenous high-dose tPA alone (10 mg/kg) versus a combination of low-dose tPA (5 mg/kg) plus 10 mg/kg rA2 in a model of focal embolic cerebral ischemia in rats. All rats were treated at 3 hours after embolization. Brain tissue and neurological outcomes were assessed at 1 month. Surrogate biomarkers for endogenous neurovascular remodeling in peri-infarct area were analyzed by immunohistochemistry. RESULTS: Compared with high-dose tPA alone, low-dose tPA-plus-rA2 significantly decreased infarction and improved neurological function at 1-month poststroke. In peri-infarct areas, tPA-plus-rA2 combination therapy also significantly augmented microvessel density, vascular endothelial growth factor, and synaptophysin expression. CONCLUSIONS: Compared with conventional high-dose tPA alone, combination low-dose tPA plus rA2 therapy may provide a safe and effective way to improve long-term neurological outcomes after stroke.

First-line treatment with camrelizumab plus famitinib in advanced or metastatic NSCLC patients with PD-L1 TPS ≥1%: results from a multicenter, open-label, phase 2 trial.

BACKGROUND: The combination of immune-checkpoint inhibitors and antiangiogenic agents can synergistically modulate the tumor microenvironment and represents a promising treatment option. Here, we evaluated the efficacy and safety of camrelizumab plus famitinib (a receptor tyrosine kinase inhibitor) as a first-line treatment for advanced or metastatic NSCLC patients with a programmed death ligand-1 (PD-L1) tumor proportion score (TPS) of ≥1%, in an open-label, multicenter, phase 2 basket trial. METHODS: Eligible patients received camrelizumab (200 mg once every 3 weeks via intravenous infusion) plus oral famitinib at an initial dose of 20 mg once daily. The primary endpoint was the objective response rate (ORR), as assessed by the investigator per Response Evaluation Criteria in Solid Tumors V.1.1. Key secondary endpoints included disease control rate (DCR), duration of respons, progression-free survival (PFS), overall survival (OS), 12-month OS rate, and safety profile. RESULTS: Of the enrolled 41 patients, 21 (51.2%) had a PD-L1 TPS of 1-49%. As of the cut-off date on June 22, 2022, the combination regimen of camrelizumab and famitinib achieved an ORR of 53.7% (95% CI 37.4% to 69.3%) and a DCR of 92.7% (95% CI 80.1% to 98.5%). The median PFS was 16.6 months (95% CI 8.3 to not reached), and OS data were not yet mature, with an estimated 12-month OS rate of 76.8% (95% CI 60.0% to 87.3%). The most common treatment-related adverse events of grade 3 or higher included hypertension (22.0%), increased alanine aminotransferase (12.2%), decreased neutrophil count (9.8%), proteinuria (7.3%), decrease platelet count (7.3%), and hypokalemia (7.3%). One (2.4%) patient died from grade 5 hemoptysis, which was considered possibly related to the study treatment by the investigator. CONCLUSION: Camrelizumab plus famitinib demonstrated promising antitumor activity in advanced or metastatic NSCLC patients and had an acceptable safety profile. These findings suggest that this combination regimen could be an alternative therapeutic option and warrant further investigation. TRIAL REGISTRATION NUMBER: NCT04346381.