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1.
BMC Pulm Med ; 24(1): 307, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38956524

ABSTRACT

Liver-related side effects are a known complication of treatment with elexacaftor/tezacaftor/ivacaftor (ETI) for cystic fibrosis (CF). Gilbert's syndrome is caused by a genetic mutation that reduces activity of the enzyme UDP glucuronosyltransferase 1 polypeptide A1 (UGT1A1), causing elevated levels of unconjugated bilirubin in the blood and duodenal bile. The presence of Gilbert's syndrome and CF might represent additive risk factors for liver-related adverse events during ETI treatment. This case series describes six people with CF (pwCF) in whom previously unknown Gilbert's syndrome was unmasked after initiation of treatment with ETI. Although all patients had some level of hepatic dysfunction and/or elevated levels of bilirubin after initiation of ETI, the clinical course varied. Only one patient had to stop ETI therapy altogether, while the others were able to continue treatment (some at a reduced dosage and others at the full recommended daily dosage). All patients, even those using a lower dosage, experienced clinical benefit during ETI therapy. Gilbert's syndrome is not a contraindication for ETI therapy but may be mistaken for a risk factor for liver-related adverse events in pwCF. This is something that physicians need to be aware of in pwCF who show liver adverse events during ETI therapy.


Subject(s)
Aminophenols , Benzodioxoles , Cystic Fibrosis , Drug Combinations , Gilbert Disease , Hyperbilirubinemia , Indoles , Pyrazoles , Pyridines , Quinolones , Humans , Gilbert Disease/genetics , Gilbert Disease/drug therapy , Male , Aminophenols/adverse effects , Aminophenols/therapeutic use , Female , Adult , Cystic Fibrosis/drug therapy , Cystic Fibrosis/complications , Pyridines/adverse effects , Pyridines/therapeutic use , Indoles/adverse effects , Benzodioxoles/adverse effects , Benzodioxoles/therapeutic use , Quinolones/adverse effects , Quinolones/therapeutic use , Pyrazoles/adverse effects , Pyrazoles/therapeutic use , Hyperbilirubinemia/chemically induced , Young Adult , Pyrroles/adverse effects , Adolescent , Glucuronosyltransferase/genetics , Pyrrolidines , Quinolines
2.
Medicine (Baltimore) ; 103(27): e38459, 2024 Jul 05.
Article in English | MEDLINE | ID: mdl-38968520

ABSTRACT

BACKGROUND: Maintenance therapy could significantly improve the prognosis of patients with advanced non-small cell lung cancer (NSCLC) receiving chemotherapy. Anlotinib is effective, tolerable, and convenient in administration as a third-line treatment for NSCLC. This study aimed to evaluate the efficacy and safety of maintenance therapy with anlotinib after platinum-based induction chemotherapy for patients with advanced NSCLC. METHODS: This pooled analysis of 2 multicenter, open-label, single-arm, phase 2 clinical trials (ALTER-L014 and ALTER-L011) enrolled patients with locally advanced or metastatic NSCLC and without known sensitive mutations in China between September 2018 and January 2021. The primary outcome was progression-free survival. The secondary outcomes were objective response rate, disease control rate, overall survival, and safety. RESULTS: The data of 23 patients were pooled, with 15 from ALTER-L014 and 8 from ALTER-L011. At the cutoff date of June 13, 2021, the median progression-free survival since the start of maintenance therapy was 5.95 (95% confidence interval, 4.30-8.80) months. Nineteen patients had stable disease, 1 had a partial response and 3 had progressive disease. The objective response rate was 4.35%, while disease control rate was 86.96%. The median overall survival of the patients since the start of maintenance therapy was 18.60 (95% confidence interval, 6.87-22.80) months. The incidence of adverse events of grade ≥ 3 was 21.7%. CONCLUSION: Anlotinib might offer a new option for maintenance treatment in patients with locally advanced or metastatic NSCLC without known sensitive mutations after standard first-line platinum-based chemotherapy.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Indoles , Induction Chemotherapy , Lung Neoplasms , Quinolines , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/mortality , Indoles/therapeutic use , Indoles/administration & dosage , Indoles/adverse effects , Lung Neoplasms/drug therapy , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Female , Quinolines/therapeutic use , Quinolines/administration & dosage , Quinolines/adverse effects , Aged , Induction Chemotherapy/methods , Maintenance Chemotherapy/methods , Adult , Progression-Free Survival , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use
3.
Neurol India ; 72(3): 578-584, 2024 May 01.
Article in English | MEDLINE | ID: mdl-39041976

ABSTRACT

PURPOSE: Anlotinib is a multi-target TKI which has been used in different advanced tumors. However, its efficiency and safety in patients with glioblastoma are still not well discussed. This retrospective study aimed to discover the safety and efficiency of anlotinib in recurrent grade 4 glioma. METHODS: The clinical data of patients with recurrent grade 4 glioma treated with anlotinib in our center were collected and analyzed. The progression-free survival (PFS), overall survival (OS), and OS after recurrence were calculated by Kaplan-Meier method and compared by log-rank test. Sub-group analysis was used to find possible variables that affect survival. RESULTS: From October 2017 to December 2020, seventeen patients with recurrent grade 4 glioma treated with anlotinib were enrolled. The median age was 50 with 13 males. The median KPS was 70. All patients received standard STUPP mode treatment before recurrence. The median PFS was 7 months [95% confidence interval (CI) 5.3-8.6]. The median OS after first diagnosis was 17 months (95% CI 15.7-18.3). The median OS after recurrence was 10 months (95% CI 7.6-12.4). The objective response rate was 33.33% (5/15), and the disease control rate was 60% (9/15). The existence of target genes was identified as a variable affecting the survival after recurrence. The median OS after recurrence in patients with target genes was 12 months (95% CI 6.9-17.1), whereas for patients without targets, the median OS was 4 months (95% CI 1.9-6.1) and for patients with an unknown status, the median OS was 10 months (95% CI 8.4-11.6) (P = 0.013). CONCLUSION: For recurrent grade 4 glioma, anlotinib can be considered as a supplement to the standard STUPP treatment, especially for the patient with anlotinib target genes.


Subject(s)
Brain Neoplasms , Glioma , Indoles , Neoplasm Recurrence, Local , Quinolines , Humans , Male , Quinolines/therapeutic use , Quinolines/adverse effects , Middle Aged , Female , Retrospective Studies , Indoles/therapeutic use , Indoles/adverse effects , Glioma/drug therapy , Brain Neoplasms/drug therapy , Adult , Neoplasm Recurrence, Local/drug therapy , Aged , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/adverse effects , Treatment Outcome , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Progression-Free Survival
5.
Neoplasma ; 71(3): 297-305, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38958712

ABSTRACT

Currently, there is a lack of effective second-line and subsequent treatments for patients with extensive-stage small-cell lung cancer (ES-SCLC), and the establishment of a standardized treatment protocol is still underway. Considering the potential synergistic therapeutic effects of anti-angiogenic drugs and immune checkpoint inhibitors (ICIs), combination therapy could be a viable option for treating lung cancer. This research concentrates on assessing the efficacy and safety of anlotinib in combination with ICIs for the treatment of ES-SCLC. We undertook a retrospective analysis of patients with extensive-stage SCLC who received anlotinib in combination with ICIs as second-line and subsequent treatment at Zhejiang Cancer Hospital between April 2020 and April 2023. Survival rates were analyzed using the Kaplan-Meier method. Among the 43 patients who received combination therapy, there were no cases of complete response (CR), 16 patients who achieved partial response (PR), 21 patients who had stable disease (SD), and 6 patients who experienced disease progression (PD). This resulted in an overall response rate (ORR) of 37.2% (16/43) and a disease control rate (DCR) of 86.0% (34/43). The median progression-free survival (PFS) was 4.0 months (95% CI: 2.74-5.26), and the median overall survival (OS) time was 10 months (95% CI: 4.8-15.2). Cox multifactorial regression analysis disclosed that the performance score (PS) and the number of metastatic organs were independent factors influencing PFS in ES-SCLC (p<0.001). The combination therapy demonstrated acceptable toxicity, with a total grade 3/4 toxicity rate of 30.2%. The combination therapy showed a notable association with several adverse events, including hand-foot syndrome, hypertension, and fatigue, which were the most significant. Combining anlotinib with immune checkpoint inhibitors has demonstrated favorable efficacy and safety in the treatment of second-line and subsequent extensive-stage small-cell lung cancer.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Immune Checkpoint Inhibitors , Indoles , Lung Neoplasms , Quinolines , Small Cell Lung Carcinoma , Humans , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/pathology , Indoles/administration & dosage , Indoles/adverse effects , Indoles/therapeutic use , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/administration & dosage , Quinolines/therapeutic use , Quinolines/adverse effects , Quinolines/administration & dosage , Male , Female , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Middle Aged , Retrospective Studies , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Adult , Survival Rate , Progression-Free Survival , Neoplasm Staging , Aged, 80 and over
6.
Front Endocrinol (Lausanne) ; 15: 1403687, 2024.
Article in English | MEDLINE | ID: mdl-39015176

ABSTRACT

Background: Nintedanib is a triple-angiokinase inhibitor with potential activity in patients with advanced thyroid cancers, as radioiodine refractory differentiated thyroid cancer (RAIR DTC) and medullary thyroid cancer (MTC). Design: EORTC-1209 (NCT01788982) was a double-blind randomized (2:1 ratio) placebo-controlled phase II, multi-cohort study exploring the efficacy and safety of nintedanib in patients with progressive, locally advanced, and/or metastatic RAIR DTC and MTC. The primary endpoint was progression-free survival (PFS) in the per-protocol (PP) population for both cohorts. Secondary endpoints included response rate, duration of response, overall survival (OS), and safety. Results: RAIR DTC cohort: Seventy out of the 75 planned patients with RAIR DTC (median age, 66 years; 39 women) who had progressed after one (76%) or two lines (24%) of previous systemic therapy were randomized to receive either nintedanib (N = 45) or placebo (N = 25). Of these, 69 patients started treatment and 56 met all inclusion criteria (PP). At data cutoff, the median duration of follow-up was 26.3 months in the nintedanib arm and 19.8 months in the placebo arm. In the PP population, the median PFS was 3.7 months [80% confidence interval (CI), 1.9-6.5] in the nintedanib arm and 2.9 months (80% CI, 2.0-5.6) in the placebo arm (HR = 0.65; 80% CI, 0.42-0.99; one-sided log-rank test P = 0.0947). No objective response was observed. The median OS was 29.6 months [80% CI, 15.2-not reached (NR)] in the nintedanib arm and not reached in the placebo arm. Grade 3-4 adverse events of any attribution occurred in 50% of patients receiving nintedanib and in 36% of patients receiving placebo. MTC cohort: Thirty-one out of the 67 planned patients with MTC (median age, 57 years; eight women) who had progressed after one (68%) or two (32%) lines of previous systemic therapy were randomized to receive either nintedanib (N = 22) or placebo (N = 9). Of these, 20 patients (15 in the nintedanib arm and five in the placebo arm) started treatment and met all inclusion criteria (PP). The median PFS was 7.0 months (80% CI, 1.9-8.7) in the nintedanib arm and 3.9 months (80% CI, 3.0-5.5) in the placebo arm (HR = 0.49; 95% CI, 0.16-1.53). No objective response was reported. The median OS was 16.4 months (80% CI, 12.1-24.9) in the nintedanib arm and 12.3 months (80% CI, 7.1-NR) in the placebo arm. Grade 3-4 adverse events of any attribution during the blinded period occurred in 59.1% of patients receiving nintedanib and in 33.3% of patients receiving placebo. Conclusion: This study did not suggest a clinically significant improvement of PFS with nintedanib over placebo in patients with pretreated RAIR DTC and MTC.


Subject(s)
Carcinoma, Neuroendocrine , Indoles , Thyroid Neoplasms , Humans , Thyroid Neoplasms/drug therapy , Thyroid Neoplasms/pathology , Female , Male , Indoles/therapeutic use , Indoles/adverse effects , Indoles/administration & dosage , Middle Aged , Aged , Double-Blind Method , Carcinoma, Neuroendocrine/drug therapy , Carcinoma, Neuroendocrine/pathology , Adult , Disease Progression , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/adverse effects , Treatment Outcome
7.
N Engl J Med ; 391(3): 224-234, 2024 Jul 18.
Article in English | MEDLINE | ID: mdl-39018532

ABSTRACT

BACKGROUND: Clinical trials of treatments for coronavirus disease 2019 (Covid-19) have not shown a significant benefit of postexposure prophylaxis. METHODS: We conducted a phase 2-3 double-blind trial to assess the efficacy and safety of nirmatrelvir-ritonavir in asymptomatic, rapid antigen test-negative adults who had been exposed to a household contact with Covid-19 within 96 hours before randomization. The participants were randomly assigned in a 1:1:1 ratio to receive nirmatrelvir-ritonavir (300 mg of nirmatrelvir and 100 mg of ritonavir) every 12 hours for 5 days or for 10 days or matching placebo for 5 or 10 days. The primary end point was the development of symptomatic SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection, confirmed on reverse-transcriptase-polymerase-chain-reaction (RT-PCR) or rapid antigen testing, through 14 days in participants who had a negative RT-PCR test at baseline. RESULTS: A total of 2736 participants were randomly assigned to a trial group - 921 to the 5-day nirmatrelvir-ritonavir group, 917 to the 10-day nirmatrelvir-ritonavir group, and 898 to the placebo group. Symptomatic, confirmed SARS-CoV-2 infection developed by day 14 in 2.6% of the participants in the 5-day nirmatrelvir-ritonavir group, 2.4% of those in the 10-day nirmatrelvir-ritonavir group, and 3.9% of those in the placebo group. In each nirmatrelvir-ritonavir group, the percentage of participants in whom symptomatic, confirmed SARS-CoV-2 infection developed did not differ significantly from that in the placebo group, with risk reductions relative to placebo of 29.8% (95% confidence interval [CI], -16.7 to 57.8; P = 0.17) in the 5-day nirmatrelvir-ritonavir group and 35.5% (95% CI, -11.5 to 62.7; P = 0.12) in the 10-day nirmatrelvir-ritonavir group. The incidence of adverse events was similar across the trial groups, with dysgeusia being the most frequently reported adverse event (in 5.9% and 6.8% of the participants in the 5-day and 10-day nirmatrelvir-ritonavir groups, respectively, and in 0.7% of those in the placebo group). CONCLUSIONS: In this placebo-controlled trial, postexposure prophylaxis with nirmatrelvir-ritonavir for 5 or 10 days did not significantly reduce the risk of symptomatic SARS-CoV-2 infection. (Funded by Pfizer; ClinicalTrials.gov number, NCT05047601.).


Subject(s)
COVID-19 Drug Treatment , COVID-19 , Post-Exposure Prophylaxis , Ritonavir , SARS-CoV-2 , Humans , Ritonavir/therapeutic use , Ritonavir/adverse effects , Ritonavir/administration & dosage , Double-Blind Method , Male , Female , Adult , Middle Aged , COVID-19/prevention & control , Administration, Oral , Indazoles/adverse effects , Indazoles/therapeutic use , Drug Combinations , Antiviral Agents/therapeutic use , Antiviral Agents/adverse effects , Antiviral Agents/administration & dosage , Indoles/adverse effects , Indoles/therapeutic use , Indoles/administration & dosage , Young Adult , Drug Therapy, Combination , Lactams , Leucine , Nitriles , Proline
8.
Medicine (Baltimore) ; 103(28): e38920, 2024 Jul 12.
Article in English | MEDLINE | ID: mdl-38996147

ABSTRACT

Nintedanib, a multi-intracellular tyrosine kinase inhibitor, reduces progression of idiopathic pulmonary fibrosis (IPF) and has been approved to use in other progressive fibrosing interstitial lung diseases (ILD) recently. However, the factors that affect the discontinuation of treatment due to adverse events is uncertain. The dorsal muscle group area at the T12 vertebral level (T12DMA) assessed on computed tomography (CT) images has been reported to be associated with mortality in chronic obstructive pulmonary disease (COPD) and other diseases. The relationship between T12DMA and the discontinuation of nintedanib remains unclear. METHODS: 39 patients with IPF or other progressive fibrosing ILDs who started nintedanib at a regular dose (300 mg/day) were enrolled. We compared the characteristics between patients who stopped nintedanib at a regular dose before 6 months and/or continue to take nintedanib at a low dose (150 mg/day) and patients who were still taking nintedanib at a regular dose over 6 months. This study retrospectively investigated clinical parameters including T12DMA index (T12DMA/height2) to evaluate whether these parameters might serve as risk factor for the tolerability of nintedanib in patients with IPF and other progressive fibrosing ILDs. RESULTS: Discontinuation or dose reductions of nintedanib due to adverse events were observed in 14 (35.8%) patients. A multiple logistic regression model showed T12DMA index to be the only significant risk factor for predicting for the early termination of nintedanib (odd rate, 0.549; 95% confidence interval, 0.327-0.922; P = .023). CONCLUSIONS: This study revealed that T12DMA index was a risk factor for the early termination of nintedanib. The initial dose of nintedanib adjusted to the differences in skeletal muscle mass and careful management of adverse events may contribute to the longer nintedanib treatment, which would lead to a better clinical outcome.


Subject(s)
Idiopathic Pulmonary Fibrosis , Indoles , Humans , Indoles/adverse effects , Indoles/administration & dosage , Indoles/therapeutic use , Male , Female , Aged , Idiopathic Pulmonary Fibrosis/drug therapy , Risk Factors , Retrospective Studies , Middle Aged , Lung Diseases, Interstitial/drug therapy , Tomography, X-Ray Computed , Disease Progression , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/therapeutic use , Aged, 80 and over
9.
Sci Rep ; 14(1): 17422, 2024 07 29.
Article in English | MEDLINE | ID: mdl-39075279

ABSTRACT

Modulators of cystic fibrosis transmembrane conductance regulator (CFTR) improved cystic fibrosis (CF) patients' outcome. The elexacaftor/tezacaftor/ivacaftor (ETI) combination was safe and effective improving lung function in patients with different CFTR genotypes, including at least one F508del mutation. However, cases with liver damage were reported. We describe 105 CF patients heterozygous for F508del in trans with another CFTR mutation, treated for 1 year with ETI. We analyzed liver biochemical parameters and cholesterol metabolism, including lathosterol and phytosterols, surrogate markers of cholesterol de-novo synthesis and absorption, respectively. The treatment significantly improved sweat chloride, body mass index and forced expiratory volume in 1 s, whereas it caused a significant increase of total and conjugated bilirubin, ALT and GGT, even if no patients developed CF liver disease. Such alterations were less relevant than those previously observed in ETI-treated F508del homozygous patients. Furthermore, ETI treatment significantly increased serum cholesterol by enhancing its absorption (correlation between serum cholesterol and phytosterols). Whereas, we observed a normalization of de-novo biosynthesis (lathosterol reduction) that was not observed in homozygous patients. These data suggest that the second mutation in trans with the F508del contributes to reduce the liver cholesterol accumulation and thus, the triggering of liver inflammation. However, no differences in the alteration of biochemical indexes were observed between CF patients with and without liver steatosis, and between patients with different mutations in trans with the F508del. Such data suggest to further investigate the effects of ETI therapy on liver function indexes and new predictive biomarkers.


Subject(s)
Aminophenols , Benzodioxoles , Cholesterol , Cystic Fibrosis Transmembrane Conductance Regulator , Cystic Fibrosis , Genotype , Indoles , Liver , Quinolones , Humans , Cystic Fibrosis/drug therapy , Cystic Fibrosis/genetics , Cystic Fibrosis/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Female , Male , Cholesterol/metabolism , Cholesterol/blood , Benzodioxoles/therapeutic use , Aminophenols/therapeutic use , Adult , Indoles/therapeutic use , Indoles/adverse effects , Liver/metabolism , Liver/drug effects , Adolescent , Quinolones/therapeutic use , Quinolones/adverse effects , Young Adult , Pyrazoles/therapeutic use , Pyrazoles/pharmacology , Mutation , Child , Drug Combinations , Pyridines/therapeutic use , Pyridines/administration & dosage , Pyridines/adverse effects , Pyrrolidines/therapeutic use , Pyrrolidines/pharmacology , Pyrrolidines/administration & dosage
10.
Zhonghua Zhong Liu Za Zhi ; 46(7): 696-702, 2024 Jul 23.
Article in Chinese | MEDLINE | ID: mdl-39034805

ABSTRACT

Objectives: To investigate the efficacy and safety of anlotinib combined with niraparib in treating patients with platinum-resistant ovarian cancer. Methods: Thirty-five patients with pathological confirmed platinum-resistant ovarian cancer who experienced progression after receiving at least two lines of standard treatment were eligible. All of them were treated with anlotinib combined with niraparib between September 2019 and October 2021. The primary endpoint was progression-free survival (PFS). The second endpoints included overall survival, objective response rate (ORR), disease control rate (DCR) and safety. Survival analysis was performed using the Kaplan-Meier method and Log-rank test, and influence factor analysis was performed using Cox proportional risk regression models. Results: The best overall response showed that partial response was observed in 14 patients, stable disease was noted within 13 patients, and progressive disease was found in 8 patients. Therefore, the ORR and DCR of these 35 patients were 40.0% (95% CI:22.9%-57.1%) and 77.1% (95% CI:62.9%-91.4%), respectively. The median follow-up duration was 18.9 months (6.9-32.2). The median PFS was 6.5 months (95% CI:5.35-7.66). Multivariate Cox regression analysis for PFS indicated that age, Eastern Cooperative Oncology Group performance status (ECOG PS) score, International Federation of Gynecology and Obstetrics (FIGO) stage, and BRCA mutation status were independent factors influencing PFS (P<0.05). Additionally, the PFS in patients with BRCA mutation who have never received PARP inhibitor treatment was significantly longer than that in patients without BRCA mutation who have been exposed to prior PARPi treatment (15.0 vs 6.0 month, P=0.029). The most common treatment-related adverse reactions were fatigue (85.7%), hematologic toxic (85.7%) and hypertension (74.3%). There were no treatment-related deaths. Conclusion: Anlotinib combined with niraparib shows a promising efficacy and tolerable safety in platinum-resistant ROC patients.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Drug Resistance, Neoplasm , Indazoles , Indoles , Neoplasm Recurrence, Local , Ovarian Neoplasms , Piperidines , Quinolines , Humans , Female , Indazoles/adverse effects , Indazoles/therapeutic use , Ovarian Neoplasms/drug therapy , Indoles/adverse effects , Indoles/administration & dosage , Indoles/therapeutic use , Piperidines/adverse effects , Piperidines/administration & dosage , Piperidines/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Quinolines/adverse effects , Quinolines/therapeutic use , Quinolines/administration & dosage , Neoplasm Recurrence, Local/drug therapy , Platinum/therapeutic use , Progression-Free Survival , Adult , Middle Aged , Aged , BRCA1 Protein/genetics , Poly(ADP-ribose) Polymerase Inhibitors/adverse effects , Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , BRCA2 Protein/genetics
12.
Medicine (Baltimore) ; 103(30): e39075, 2024 Jul 26.
Article in English | MEDLINE | ID: mdl-39058831

ABSTRACT

INTRODUCTION: Pneumatosis cystoides intestinalis (PCI) is a rare condition characterized by multiple gas-filled cysts in the gastrointestinal tract and is associated with numerous conditions. Benign PCI can occur secondary to certain medications, such as anticancer-targeted therapies. Here, we report a rare case of PCI that developed following sunitinib therapy for metastatic RCC and was successfully managed with conservative treatment without surgery. PATIENT CONCERNS: A 57-year-old woman with a medical history of metastatic renal cell carcinoma (RCC) referred to the Department of General Surgery after completion of the 16th cycle of sunitinib because of abnormal findings on abdominopelvic computed tomography (CT), suggesting necrotizing enteritis with pneumoperitoneum involving the ileum. At the time of presentation to the Department of General Surgery, she was asymptomatic and had no abnormal findings on examination other than the imaging findings. DIAGNOSIS: Sunitinib-induced PCI, metastatic RCC, liver cirrhosis, and diabetes mellitus. INTERVENTIONS: She was admitted to the general ward for conservative treatment, and sunitinib was discontinued. Conservative treatments included nil per os, total parenteral nutrition, antibiotics, H2-blockers, and oxygen therapy. OUTCOMES: On the fifth day of hospitalization, the PCI showed moderate resolution on plain radiography, and she was discharged on the seventh day. Follow-up CT imaging 3 months later demonstrated complete resolution of PCI. CONCLUSION: This case emphasizes that the decision between conservative versus surgical treatment for PCI should be based not solely on radiological findings but rather on a comprehensive assessment, including the underlying condition, vital signs, physical examinations, and blood tests.


Subject(s)
Antineoplastic Agents , Carcinoma, Renal Cell , Kidney Neoplasms , Pneumatosis Cystoides Intestinalis , Sunitinib , Humans , Sunitinib/adverse effects , Female , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/secondary , Pneumatosis Cystoides Intestinalis/chemically induced , Middle Aged , Kidney Neoplasms/drug therapy , Kidney Neoplasms/pathology , Antineoplastic Agents/adverse effects , Indoles/adverse effects , Indoles/therapeutic use , Tomography, X-Ray Computed , Pyrroles/adverse effects
13.
BMJ Case Rep ; 17(6)2024 Jun 17.
Article in English | MEDLINE | ID: mdl-38885996

ABSTRACT

Drug-induced pleural effusion is one of the rare causes of exudative pleural effusion and a high index of suspicion is necessary to lead to early diagnosis. We hereby present the case of a young male in his late 30s, known case of metastatic gastrointestinal stromal tumour on sunitinib therapy, who presented with right-sided mild pleural effusion. Diagnostic thoracentesis showed the effusion to be a monomorphic exudate with low adenosine deaminase, which was negative for malignant cells on cytopathology. A contrast-enhanced CT chest revealed an enlarged lymph node (LN) at the 4R station, cytological analysis of which was suggestive of reactive lymphoid hyperplasia. Infective workup of the LN aspirate and bronchoalveolar lavage taken from the right middle lobe was negative. After systematically excluding the usual causes of exudative pleural effusion, sunitinib was considered to be a possible cause and was, therefore, withheld. A repeat chest X-ray after 3 weeks of stopping the drug showed resolution of the pleural effusion.


Subject(s)
Antineoplastic Agents , Pleural Effusion , Sunitinib , Humans , Male , Sunitinib/adverse effects , Sunitinib/therapeutic use , Pleural Effusion/chemically induced , Pleural Effusion/diagnostic imaging , Adult , Antineoplastic Agents/adverse effects , Gastrointestinal Stromal Tumors/drug therapy , Tomography, X-Ray Computed , Thoracentesis , Indoles/adverse effects , Indoles/therapeutic use
14.
BMC Cancer ; 24(1): 715, 2024 Jun 11.
Article in English | MEDLINE | ID: mdl-38862908

ABSTRACT

BACKGROUND: Resistance to immune checkpoint inhibitors (ICIs) represents a major unmet medical need in non-small cell lung cancer (NSCLC) patients. Vascular endothelial growth factor (VEGF) inhibition may reverse a suppressive microenvironment and recover sensitivity to subsequent ICIs. METHODS: This phase Ib/IIa, single-arm study, comprised dose-finding (Part A) and expansion (Part B) cohorts. Patients with ICIs-refractory NSCLC were enrolled to receive anlotinib (a multi-target tyrosine kinase inhibitor) orally (from days 1 to 14 in a 21-day cycle) and nivolumab (360 mg every 3 weeks, intravenously) on a 21-day treatment cycle. The first 21-day treatment cycle was a safety observation period (phase Ib) followed by a phase II expansion cohort. The primary objectives were recommended phase 2 dose (RP2D, part A), safety (part B), and objective response rate (ORR, part B), respectively. RESULTS: Between November 2020 and March 2022, 34 patients were screened, and 21 eligible patients were enrolled (6 patients in Part A). The RP2D of anlotinib is 12 mg/day orally (14 days on and 7 days off) and nivolumab (360 mg every 3 weeks). Adverse events (AEs) of any cause and treatment-related AEs (TRAEs) were reported in all treated patients. Two patients (9.5%) experienced grade 3 TRAE. No grade 4 or higher AEs were observed. Serious AEs were reported in 4 patients. Six patients experienced anlotinib interruption and 4 patients experienced nivolumab interruption due to TRAEs. ORR and disease control rate (DCR) was 19.0% and 76.2%, respectively. Median PFS and OS were 7.4 months (95% CI, 4.3-NE) and 15.2 months (95% CI, 12.1-NE), respectively. CONCLUSION: Our study suggests that anlotinib combined with nivolumab shows manageable safety and promising efficacy signals. Further studies are warranted. TRIAL REGISTRATION: NCT04507906 August 11, 2020.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Non-Small-Cell Lung , Immune Checkpoint Inhibitors , Lung Neoplasms , Nivolumab , Protein Kinase Inhibitors , Adult , Aged , Female , Humans , Male , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/mortality , Drug Resistance, Neoplasm , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Inhibitors/administration & dosage , Immune Checkpoint Inhibitors/therapeutic use , Indoles/administration & dosage , Indoles/adverse effects , Indoles/therapeutic use , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Nivolumab/administration & dosage , Nivolumab/adverse effects , Nivolumab/therapeutic use , Prospective Studies , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Quinolines/administration & dosage , Quinolines/adverse effects , Quinolines/therapeutic use , Adolescent
15.
JCO Precis Oncol ; 8: e2300494, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38865673

ABSTRACT

PURPOSE: Combining poly ADP-ribose polymerase (PARP) and topoisomerase I inhibitors has demonstrated synergistic effects in in vivo models. This phase I trial evaluated rucaparib and irinotecan in metastatic solid tumors with homologous recombination deficiency. METHODS: This study enrolled patients in three cohorts to determine the tolerability and preliminary efficacy of (1) rucaparib 400 mg PO twice a day (days 1-7, 15-21) and irinotecan 65 mg/m2 intravenously once every 2 weeks; (2) rucaparib 400 mg PO twice a day (D1-7, 15-21) and irinotecan 100 mg/m2 once every 2 weeks; and (3) rucaparib 400 mg per os twice a day (D1-7) and irinotecan 100 mg/m2 once every 3 weeks. RESULTS: Twenty patients were enrolled: 95% with previous platinum, 40% with previous irinotecan, and 20% with previous PARP inhibitor. The maximally tolerated was determined as rucaparib 400 mg twice a day days 1-7 and irinotecan 100 mg/m2 once every 3 weeks. Four dose-limiting toxicities (all grade 3-4 neutropenia) occurred during dose escalation with only neutropenia as other grade 3-4 toxicities (25%; grade 3 [n = 3], grade 4 [n = 2]). Treatment-related grade 1-2 adverse events included neutropenia (45%), diarrhea (45%), nausea (40%), and fatigue (30%). Of 17 patients with evaluable disease, six patients (35%) derived clinical benefit (n = 2 with PR, n = 4 with stable disease for over 6 months). Three patients remained on study >1 year: two with ATM mutations (small bowel carcinoma and pancreatic neuroendocrine tumor) and one patient with a PALB2 mutation (primary peritoneal cancer). CONCLUSION: Pulse dosing of rucaparib and once every 3 weeks irinotecan was well tolerated for up to 18 months with durable responses in BRCA-, PALB2-, and ATM-mutated cancers despite progression on previous platinum.


Subject(s)
Indoles , Irinotecan , Neoplasms , Humans , Middle Aged , Female , Male , Irinotecan/therapeutic use , Irinotecan/administration & dosage , Indoles/therapeutic use , Indoles/administration & dosage , Indoles/adverse effects , Aged , Adult , Neoplasms/drug therapy , Neoplasms/genetics , Mutation , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , BRCA2 Protein/genetics , BRCA1 Protein/genetics , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Poly(ADP-ribose) Polymerase Inhibitors/adverse effects , Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage , Homologous Recombination , Neoplasm Metastasis
16.
BMC Cancer ; 24(1): 706, 2024 Jun 08.
Article in English | MEDLINE | ID: mdl-38851712

ABSTRACT

BACKGROUND: Poly (ADP- ribose) polymerase inhibitors (PARPi) has been increasingly adopted for metastatic castration-resistance prostate cancer (mCRPC) patients with homologous recombination repair deficiency (HRD). However, it is unclear which PARPi is optimal in mCRPC patients with HRD in 2nd -line setting. METHOD: We conducted a systematic review of trials regarding PARPi- based therapies on mCRPC in 2nd -line setting and performed a Bayesian network meta-analysis (NMA). Radiographic progression-free survival (rPFS) was assessed as primary outcome. PSA response and adverse events (AEs) were evaluated as secondary outcomes. Subgroup analyses were performed according to specific genetic mutation. RESULTS: Four RCTs comprised of 1024 patients (763 harbored homologous recombination repair (HRR) mutations) were identified for quantitative analysis. Regarding rPFS, olaparib monotherapy, rucaparib and cediranib plus olaparib showed significant improvement compared with ARAT. Olaparib plus cediranib had the highest surface under cumulative ranking curve (SUCRA) scores (87.5%) for rPFS, followed by rucaparib, olaparib and olaparib plus abiraterone acetate prednisone. For patients with BRCA 1/2 mutations, olaparib associated with the highest probability (98.1%) of improved rPFS. For patients with BRCA-2 mutations, olaparib and olaparib plus cediranib had similar efficacy. However, neither olaparib nor rucaparib showed significant superior effectiveness to androgen receptor-axis-targeted therapy (ARAT) in patients with ATM mutations. For safety, olaparib showed significantly lower ≥ 3 AE rate compared with cediranib plus olaparib (RR: 0.72, 95% CI: 0.51, 0.97), while olaparib plus cediranib was associated with the highest risk of all-grade AE. CONCLUSION: PARPi-based therapy showed considerable efficacy for mCRPC patients with HRD in 2nd -line setting. However, patients should be treated accordingly based on their genetic background as well as the efficacy and safety of the selected regimen. TRIAL REGISTRATION: CRD42023454079.


Subject(s)
Bayes Theorem , Mutation , Phthalazines , Poly(ADP-ribose) Polymerase Inhibitors , Prostatic Neoplasms, Castration-Resistant , Humans , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Poly(ADP-ribose) Polymerase Inhibitors/adverse effects , Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/pathology , Male , Phthalazines/therapeutic use , Phthalazines/adverse effects , Phthalazines/administration & dosage , Network Meta-Analysis , Piperazines/therapeutic use , Piperazines/adverse effects , Piperazines/administration & dosage , BRCA2 Protein/genetics , Recombinational DNA Repair/genetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Randomized Controlled Trials as Topic , Progression-Free Survival , Indoles/therapeutic use , Indoles/adverse effects , Indoles/administration & dosage , BRCA1 Protein/genetics , Treatment Outcome , Quinazolines
17.
PLoS One ; 19(6): e0305429, 2024.
Article in English | MEDLINE | ID: mdl-38870246

ABSTRACT

BACKGROUND: In real-world studies, the rate of discontinuation of nintedanib (NT) varies from 4% to 53%. Switching anti-fibrotic treatment in patients with idiopathic pulmonary fibrosis (IPF) has not been adequately investigated, and data on the tolerability and efficacy of changes in anti-fibrotic treatment is limited in clinical practice. OBJECTIVE: To identify factors associated with poor continuation of NT, efficacy and predictors of deterioration after switching from NT to pirfenidone (PFD) in patients with IPF. SUBJECTS AND METHODS: One hundred and seventy patients with IPF in whom NT was introduced between April 2017 and March 2022 were included to investigate NT continuation status and the effect of switching to PFD. RESULTS: A total of 123 patients (72.4%) continued NT for 1 year and had a significantly higher %forced vital capacity (FVC) at NT introduction than those who discontinued within 1 year (80.9% ± 16.3% vs. 71.9% ± 22.1%, P = 0.004). The determinant of poor NT continuation was the high GAP stage. On the other hand, 28 of 36 patients who discontinued NT because of disease progression switched to PFD. Consequently, FVC decline was suppressed before and after the change. The predictor of deterioration after the switch was a lower body mass index. CONCLUSIONS: In patients with IPF, early NT introduction increased continuation rates, and switching to PFD was effective when patients deteriorated despite initial NT treatment.


Subject(s)
Antifibrotic Agents , Idiopathic Pulmonary Fibrosis , Indoles , Pyridones , Humans , Idiopathic Pulmonary Fibrosis/drug therapy , Male , Pyridones/therapeutic use , Pyridones/adverse effects , Pyridones/administration & dosage , Female , Aged , Indoles/therapeutic use , Indoles/administration & dosage , Indoles/adverse effects , Vital Capacity/drug effects , Antifibrotic Agents/therapeutic use , Middle Aged , Treatment Outcome , Disease Progression , Drug Substitution , Aged, 80 and over , Retrospective Studies
18.
Anticancer Drugs ; 35(7): 680-685, 2024 Aug 01.
Article in English | MEDLINE | ID: mdl-38718190

ABSTRACT

Anlotinib is an antiangiogenic drug that shows good efficacy and safety in patients with advanced non-small-cell lung cancer (NSCLC). This study aimed to explore the efficacy and safety of anlotinib for consolidation therapy in patients with stage III locally advanced, unresectable NSCLC after concurrent chemoradiotherapy (cCRT). This was a randomized, parallel-controlled, open-label, multicenter, phase II trial of patients with unresectable/nonoperated NSCLC treated with cCRT. The participants were randomized 2:1 to the anlotinib or control group. The primary endpoint was progression-free survival (PFS). The secondary endpoints were the disease control rate (DCR) and overall survival. This study was terminated early due to poor recruitment. Nine and two participants were randomly assigned to the anlotinib and control groups, respectively. One participant in the control group was excluded due to taking prohibited medications before the first efficacy evaluation. In the anlotinib group, the median age was 63 (range, 37-74) years. Two participants achieved partial response, six stable disease, and one progressive disease as best response. The DCR was 88.9%. The median PFS was 11.5 months, and the 12-month PFS rate was 33.9%. All related adverse events were grade 1 or 2. Two participants had a dose adjustment during the study. The evaluable data suggest that anlotinib alone was effective and tolerable in consolidation therapy after cCRT in patients with stage III unresectable NSCLC. The results need to be confirmed by a large-sample trial. This clinical trial was registered on www.clinicaltrials.gov (NCT03743129). Registration date: 6 September 2018.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Chemoradiotherapy , Indoles , Lung Neoplasms , Quinolines , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/therapy , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lung Neoplasms/therapy , Middle Aged , Male , Female , Indoles/administration & dosage , Indoles/therapeutic use , Indoles/adverse effects , Aged , Quinolines/therapeutic use , Quinolines/administration & dosage , Quinolines/adverse effects , Chemoradiotherapy/methods , Adult , Consolidation Chemotherapy/methods , Neoplasm Staging , Progression-Free Survival , Survival Rate
19.
Zhongguo Zhen Jiu ; 44(5): 531-6, 2024 May 12.
Article in Chinese | MEDLINE | ID: mdl-38764103

ABSTRACT

OBJECTIVE: To compare the clinical efficacy of heat-sensitive moxibustion combined with tropisetron hydrochloride and tropisetron hydrochloride alone in the treatment of chemotherapy-induced nausea and vomiting (CINV). METHODS: Sixty CINV patients were randomly divided into an observation group and a control group, 30 cases in each group.The control group was treated with tropisetron hydrochloride. On the basis of the treatment in the control group, heat-sensitive acupoints were explored at Zhongwan (CV 12), Shenque (CV 8), Qihai (CV 6), Guanyuan (CV 4), Shangwan (CV 13), Xiawan (CV 10), Jianli (CV 11) and bilateral Zusanli (ST 36), Neiguan (PC 6), Tianshu (ST 25), Liangmen (ST 21) areas in the observation group,and heat-sensitive moxibustion was applied at heat-sensitive acupoints. The treatment started from the day of chemotherapy in both groups, once a day for 7 days. The occurrence and severity of nausea and vomiting after chemotherapy were recorded after each treatment on the 1st to 7th days of chemotherapy in the two groups, the complete remission rate was evaluated. The KPS score, quality of life scale score before and after treatment and incidence of myelosuppression were compared between the two groups. RESULTS: On the 2nd to 4th days of chemotherapy, the incidence and severity of nausea and vomiting in the observation group were lower than those in the control group (P<0.05), the complete remission rates of nausea and vomiting were higher than those in the control group (P<0.05). After treatment, the KPS score in the observation group was higher than those before treatment and in the control group (P<0.05). After treatment, the scores of emotional function and overall health status in the observation group were higher than those before treatment and in the control group (P<0.05), the scores of fatigue, pain, insomnia, loss of appetite and diarrhea were lower than those before treatment and in the control group (P<0.05). The incidence of myelosuppression in the observation group was 20.0% (6/30), which was lower than 46.7% (14/30) in the control group (P<0.05). CONCLUSION: Heat-sensitive moxibustion combined with tropisetron hydrochloride can effectively reduce nausea and vomiting after chemotherapy in patients with malignant tumor, improve the quality of life, relieve the myelosuppression caused by chemotherapy drugs.


Subject(s)
Acupuncture Points , Antineoplastic Agents , Moxibustion , Nausea , Tropisetron , Vomiting , Humans , Vomiting/therapy , Vomiting/chemically induced , Vomiting/drug therapy , Male , Middle Aged , Female , Nausea/therapy , Nausea/etiology , Adult , Aged , Antineoplastic Agents/adverse effects , Combined Modality Therapy , Indoles/adverse effects , Neoplasms/drug therapy , Neoplasms/therapy , Young Adult , Treatment Outcome
20.
Lasers Med Sci ; 39(1): 133, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38771549

ABSTRACT

BACKGROUND: Tooth discoloration is a common concern in antimicrobial photodynamic therapy (aPDT) using various photosensitizers (PS). Toluidine Blue (TB), Methylene Blue (MB), Phthalocyanine (Pc), and 2-mercaptopyridine-substituted zinc phthalocyanine (TM-ZnPc) are among those studied, but their relative impacts on tooth discoloration remain unclear. AIM: This study aimed to compare the effects of TB, MB, Pc, and TM-ZnPc in aPDT on tooth discoloration, utilizing a controlled experimental setup. MATERIALS AND METHODS: The study comprised seventy-five single-rooted incisors with root canals. Following meticulous preparation, a standardized area on the crown surface was designated for examination, and precise measurements of the initial tooth colors were recorded. Samples were randomly divided into five groups: Negative control, MB, TM, Pc, and TM-ZnPc. Photoactivation was performed using LED light, and color measurements were taken at multiple time points up to 90 days. Data were converted to Lab* color values of the CIE Lab* color system (International Commission on Illumination, Vienna, Austria), and ΔE values were calculated. Statistical analysis was performed using Two-way ANOVA and Post-Hoc Tukey tests (p < 0.05). RESULTS: At day 7 and 30, TM-ZnPc and Pc caused less discoloration compared to MB and TB. TM-ZnPc caused more tooth discoloration compared to Pc (p < 0.05). Compared to baseline, MB and TM-ZnPc caused more tooth discoloration at 30 days and TB caused more tooth discoloration at 90 days (p < 0.05). No significant difference was observed in terms of tooth discoloration at all periods evaluated after Pc application (p > 0.05). All photosensitizers tested in the study caused tooth coloration. CONCLUSION: All PS induced clinically detectable tooth discoloration, with TB and MB causing more significant discoloration compared to Pc and TM-ZnPc at certain time points. TM-ZnPc and Pc demonstrated more stable coloration levels over time, suggesting their potential reliability in aPDT applications. This study highlights the importance of selecting appropriate PS to minimize tooth discoloration in aPDT, with Pc showing promise in this regard.


Subject(s)
Isoindoles , Methylene Blue , Photochemotherapy , Photosensitizing Agents , Spectrophotometry , Tolonium Chloride , Tooth Discoloration , Photochemotherapy/methods , Photochemotherapy/adverse effects , Photosensitizing Agents/administration & dosage , Humans , Tooth Discoloration/chemically induced , Methylene Blue/administration & dosage , Zinc Compounds , Indoles/adverse effects , Indoles/administration & dosage , Organometallic Compounds/administration & dosage , Organometallic Compounds/adverse effects
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