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Frontiers in Oncology 2023Uterine leiomyosarcoma is a rare and aggressive tumor known for its drug resistance and metastatic potential. The standard first-line treatment typically involves...
PURPOSE
Uterine leiomyosarcoma is a rare and aggressive tumor known for its drug resistance and metastatic potential. The standard first-line treatment typically involves anthracycline-based chemotherapy or a combination of gemcitabine and docetaxel; however, there is currently no established second-line treatment. Therefore, the aim of this study was to evaluate the efficacy and toxicity of doxorubicin plus ifosfamide as a potential second-line treatment for uterine leiomyosarcoma.
MATERIALS AND METHODS
This is a retrospective, single-center, single-arm study. We reviewed the tumor registry data from January 2010 to December 2022 and identified patients with uterine leiomyosarcoma who had previously received first-line salvage or adjuvant treatment involving gemcitabine and taxotere, and later experienced tumor recurrence. Patients who met these criteria were included in the study. The primary endpoint was the efficacy of doxorubicin and ifosfamide as a second-line treatment for uterine leiomyosarcoma, as measured by progression-free survival, 1-year overall survival, and response rate. The secondary endpoint was the adverse events associated with this regimen.
RESULTS
Fifty-two patients were diagnosed with uterine leiomyosarcoma during the study period, nine of whom were included in the data analysis. All patients had previously received gemcitabine-docetaxel as first-line adjuvant therapy, with a median progression-free survival period of 8.4 months. Doxorubicin-ifosfamide was administered as second-line treatment, with a median progression-free survival of 6.0 months (range: 2.7-79.9 months). The clinical benefit rate of the second-line treatment was 66.7%, with a median overall survival of 33.0 months, and a 1-year overall survival rate of 83.3%. Previous reports have shown that the median progression-free survival for second-line treatments using other regimens ranged from 1.4-5.6 months. The most common adverse event was myelosuppression, with five patients requiring granulocyte colony-stimulating factor and one patient requiring a blood transfusion. No patient discontinued treatment due to unmanageable adverse events.
CONCLUSION
Use of doxorubicin with ifosfamide may be a promising and reasonable second-line treatment with manageable adverse events for patients with uterine leiomyosarcoma.
PubMed: 38090488
DOI: 10.3389/fonc.2023.1282596 -
Frontiers in Immunology 2023This study aimed to evaluate the efficacy and safety of venetoclax in combination with hypomethylating agents and CAG (VEN-DCAG) regimens in patients with...
OBJECTIVE
This study aimed to evaluate the efficacy and safety of venetoclax in combination with hypomethylating agents and CAG (VEN-DCAG) regimens in patients with relapsed/refractory acute myeloid leukemia (R/R AML).
METHODS
The treatment response was analyzed by retrospective methods in R/R AML patients treated with the VEN-DCAG regimen at our institution. This included, but was not limited to, CR/CRi (complete remission/complete remission with incomplete hematologic recovery) rate, measurable residual disease (MRD) negative rate, and overall survival (OS).
RESULTS
20 patients with R/R AML were recruited, with a median age of 40 years (10-70), 11 of whom were male (55%), and a median follow-up of 10.4 months (0.7-21.8). The overall response rate (ORR) after receiving 1 course of VEN-DCAG was 90% (18/20), with 17 (85%) CR/CRi (10 MRD-CR), 1 (5%) PR, and 2 (10%) NR. Subsequently, 12 patients (7 MRD-CR, 4 MRD+CR, 1 NR) were treated with the VEN-DCAG regimen, and 3 MRD+CR patients turned negative, and 13 patients finally achieved MRD-CR. Among them, 7 patients were in the relapse group, all achieving CR/CRi (6 MRD-CR), and 13 patients in the refractory group, with 10 CR/CRi (7 MRD-CR). The ORR for patients in the relapse and refractory groups was 100% (7/7) and 84.6% (11/13), respectively. Further, all patients experienced adverse events (AEs) of varying degrees of severity, with hematologic AEs primarily consisting of myelosuppression, while non-hematologic AEs were more common in the form of fever, gastrointestinal distress, and infections. 11 patients were followed up with bridging allogeneic hematopoietic stem cell transplantation (allo-HSCT) therapy. At the last follow-up, 11 patients (7 MRD-CR, 4 MRD+CR) who received allo-HSCT, 1 (MRD+CR) died, and 9 patients (6 MRD-CR, 1 PR, 2 NR) who did not receive allo-HSCT, 5 (2 MRD-CR, 1 PR, 2 NR) died as well.
CONCLUSION
The VEN-DCAG regimen may be an effective treatment option for R/R AML patients, with high ORR and MRD negative remission rates in both the relapsed and refractory groups. It is recommend that patients should be bridged to allo-HSCT as soon as possible after induction to CR by the VEN-DCAG regimen, which can lead to a significant long-term survival benefit.
CLINICAL TRIAL REGISTRATION
https://www.chictr.org.cn/, identifier ChiCTR2300075985.
Topics: Humans; Male; Child; Adolescent; Young Adult; Adult; Middle Aged; Aged; Female; Retrospective Studies; Leukemia, Myeloid, Acute; Recurrence
PubMed: 38054008
DOI: 10.3389/fimmu.2023.1269163 -
Federal Practitioner : For the Health... Aug 2023Pruritus is a characteristic and often debilitating clinical manifestation reported by about 50% of patients with polycythemia vera (PV). Interventions for PV-associated...
BACKGROUND
Pruritus is a characteristic and often debilitating clinical manifestation reported by about 50% of patients with polycythemia vera (PV). Interventions for PV-associated pruritus include phlebotomy, antidepressants, antihistamines, phototherapy, interferon α, myelosuppression, and signaling pathway-specific agents.
CASE PRESENTATION
A 40-year-old man presented with Janus kinase 2 (Jak2)-positive PV complicated by intractable pruritus that was not alleviated by multimodal therapy and lifestyle modifications. Following the initiation of naltrexone, the patient experienced immediate relief that has persisted for 2 years.
CONCLUSIONS
This case demonstrates a novel approach to the management of PV-associated pruritus. Notably, naltrexone is an affordable, accessible, and potentially effective option for patients with intractable PV pruritus. Future directions involve consideration of case series or randomized clinical trials investigating the efficacy and pathophysiology of naltrexone in treating PV-associated pruritus.
PubMed: 38021098
DOI: 10.12788/fp.0396 -
JAMA Network Open Nov 2023Low-dose methotrexate is used to treat rheumatoid arthritis and psoriasis. Due to its kidney elimination, better evidence is needed to inform its safety in adults with...
IMPORTANCE
Low-dose methotrexate is used to treat rheumatoid arthritis and psoriasis. Due to its kidney elimination, better evidence is needed to inform its safety in adults with chronic kidney disease (CKD).
OBJECTIVES
To compare the 90-day risk of serious adverse events among adults with CKD who started low-dose methotrexate vs those who started hydroxychloroquine and to compare the risk of serious adverse events among adults with CKD starting 2 distinct doses of methotrexate vs those starting hydroxychloroquine.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective, population-based, new-user cohort study was conducted in Ontario, Canada (2008-2021) using linked administrative health care data. Adults aged 66 years or older with CKD (defined as an estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 but not receiving dialysis) who started low-dose methotrexate (n = 2309) were matched 1:1 with those who started hydroxychloroquine.
EXPOSURE
Low-dose methotrexate (5-35 mg/wk) vs hydroxychloroquine (200-400 mg/d).
MAIN OUTCOME AND MEASURE
The primary outcome was a composite of serious adverse events: a hospital visit with myelosuppression, sepsis, pneumotoxic effects, or hepatotoxic effects within 90 days of starting the study drug. Prespecified subgroup analyses were conducted by eGFR category. Propensity score matching was used to balance comparison groups on indicators of baseline health. Risk ratios (RRs) were obtained using modified Poisson regression, and risk differences (RDs) using binomial regression.
RESULTS
In a propensity score-matched cohort of 4618 adults with CKD (3192 [69%] women; median [IQR] age, 76 [71-82] years), the primary outcome was higher in patients who started low-dose methotrexate vs those who started hydroxychloroquine (82 of 2309 [3.55%] vs 40 of 2309 [1.73%]; RR, 2.05 (95% CI, 1.42-2.96); RD, 1.82% [95% CI, 0.91%-2.73%]). In subgroup analysis, the risks increased progressively at lower eGFR (eg, eGFR <45 mL/min/1.73 m2: RR, 2.79 [95% CI, 1.51-5.13]). In the secondary comparison with hydroxychloroquine, methotrexate users at 15 to 35 mg/wk had a higher risk of the primary outcome.
CONCLUSIONS AND RELEVANCE
In this cohort of 4618 older patients with CKD, the 90-day risk of serious adverse events was higher among those who started low-dose methotrexate than those who started hydroxychloroquine. If verified, these risks should be balanced against the benefits of low-dose methotrexate use.
Topics: Humans; Female; Aged; Male; Methotrexate; Hydroxychloroquine; Cohort Studies; Retrospective Studies; Renal Dialysis; Renal Insufficiency, Chronic; Ontario
PubMed: 38010652
DOI: 10.1001/jamanetworkopen.2023.45132 -
BMC Cancer Nov 2023In nasopharyngeal cancer (NPC), women have a lower incidence and mortality rate than men. Whether sex influences the prognosis of NPC patients remains debatable. We...
BACKGROUND
In nasopharyngeal cancer (NPC), women have a lower incidence and mortality rate than men. Whether sex influences the prognosis of NPC patients remains debatable. We retrospectively examined the influence of sex on treatment-related side effects and prognosis in NPC.
METHODS
Clinical data of 1,462 patients with NPC treated at the Southern Hospital of Southern Medical University from January 2004 to December 2015 were retrospectively examined. Statistical analysis was performed to assess differences in overall survival (OS), distant metastasis-free survival (DMFS), local recurrence-free survival(LRFS), and progression-free survival(PFS), as well as treatment-related adverse effects, including myelosuppression, gastrointestinal responses, and radiation pharyngitis and dermatitis, between men and women.
RESULTS
Women had better 5-year OS (81.5% vs. 87.1%, P = 0.032) and DMFS (76.2% vs. 83.9%, P = 0.004) than men. Analysis by age showed that the prognoses of premenopausal and menopausal women were better than those of men, whereas prognoses of postmenopausal women and men were not significantly different. Additionally, women had a better prognosis when stratified by treatment regimen. Furthermore, chemotherapy-related adverse effects were more severe in women than in men; however, the incidences of radiation laryngitis and dermatitis were not significantly different between the sexes. Logistic regression analysis revealed that the female sex was an independent risk factor for severe myelosuppression and gastrointestinal reactions.
CONCLUSIONS
Chemotherapy-related side effects are more severe but the overall prognosis is better in women with NPC than in men with NPC. Patients may benefit from a personalized treatment approach for NPC.
TRIAL REGISTRATION
This study was approved by the Medical Ethics Committee of Nanfang Hospital of the Southern Medical University (NFEC-201,710-K3).
Topics: Male; Humans; Female; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Carcinoma; Retrospective Studies; Prognosis; Dermatitis; Neoplasm Staging; Radiotherapy, Intensity-Modulated
PubMed: 38007428
DOI: 10.1186/s12885-023-11564-0 -
The Oncologist Apr 2024CDK4/6 inhibitors (CDK4/6i) have shown great efficacy in prolonging progression-free survival and is the current standard of care for hormone positive (HR(+)) metastatic...
BACKGROUND
CDK4/6 inhibitors (CDK4/6i) have shown great efficacy in prolonging progression-free survival and is the current standard of care for hormone positive (HR(+)) metastatic breast cancer (mBC). Despite well tolerability and ease of use, the most common side effect of CDK4/6i is myelosuppression, with neutropenia the most prevalent adverse effect. Studies show that the prevalence and severity of neutropenia are more marked in Asian patients, although details remain obscure.
METHODS
In this study, we retrospectively analyzed 105 Taiwanese patients who received palbociclib for HR(+) HER2(-) mBC at the Taipei Veterans General Hospital. To investigate a possible genetic association for high prevalence of neutropenia, we queried the Taiwan Biobank with publicly available germline databases (ALFA, gnomAD, ExAC, 1000 Genomes project, HapMap), for the allele frequencies of 4 neutropenia-related SNPs (ABCB1_rs1045642, ABCB1_rs1128503, ERCC1_rs3212986, ERCC1_rs11615) and compared between different ethnicities. In addition, one of the patients was a long-term patient with peritoneal dialysis. We quantified the levels of palbociclib in her serum and peritoneal fluid by liquid chromatography-mass spectrometry (LC-MS).
RESULTS
Interestingly, in our cohort, early neutropenia nadir (occurred within 56 days of start) was associated with worse treatment outcome, while occurrence of grade 3/4 neutropenia was associated with better outcome. We observed an extremely high incidence of neutropenia (96.2% any grade, 70.4% grade 3/4). In the analyzed germline databases, we discovered a higher SNP frequency of the T allele in ABCB1_rs1128503, a lower frequency of T allele in ABCB1_rs1045642, and a higher SNP frequency of G allele in ERCC1_rs11615. We observed that palbociclib levels in peritoneal dialysate ranged from around 20-50 ppb, and serum levels reached 100-110 ppb during drug administration and decreased to <10 ppb during discontinuation.
CONCLUSION
Our retrospective analysis of real world palbociclib use reveals an association with grade 3/4 neutropenia with better outcome and early neutropenia nadir with worse outcome. Our findings of Asian specific SNPs support a predisposition toward profound and prevalent neutropenia in Asian patients under CDK4/6i. We also report the first pharmacokinetics analysis on a patient with peritoneal dialysis receiving CDK4/6i. In summary, our study provides novel clinical and genotypic insights into CDK4/6i associated neutropenia.
Topics: Female; Humans; Retrospective Studies; Prevalence; Receptor, ErbB-2; Breast Neoplasms; Neutropenia; Antineoplastic Combined Chemotherapy Protocols; Cyclin-Dependent Kinase 4; Piperazines; Pyridines
PubMed: 37995303
DOI: 10.1093/oncolo/oyad304 -
Correlation of gut microbiota with leukopenia after chemotherapy in patients with colorectal cancer.BMC Microbiology Nov 2023The most common toxic side effect after chemotherapy, one of the main treatments for colorectal cancer (CRC), is myelosuppression.
BACKGROUND
The most common toxic side effect after chemotherapy, one of the main treatments for colorectal cancer (CRC), is myelosuppression.
OBJECTIVE
To analyze the correlation between gut microbiota and leukopenia after chemotherapy in CRC patients.
METHODS
Stool samples were collected from 56 healthy individuals and 55 CRC patients. According to the leukocytes levels in peripheral blood, the CRC patients were divided into hypoleukocytes group (n = 13) and normal leukocytes group (n = 42). Shannon index, Simpson index, Ace index, Chao index and Coverage index were used to analyze the diversity of gut microbiota. LDA and Student's t-test(St test) were used for analysis of differences. Six machine learning algorithms, including logistic regression (LR) algorithm, random forest (RF) algorithm, neural network (NN) algorithm, support vector machine (SVM) algorithm, catboost algorithm and gradient boosting tree algorithm, were used to construct the prediction model of gut microbiota with leukopenia after chemotherapy for CRC.
RESULTS
Compared with healthy group, the microbiota alpha diversity of CRC patients was significantly decreased (p < 0.05). After analyzing the gut microbiota differences of the two groups, 15 differential bacteria, such as Bacteroides, Faecalibacterium and Streptococcus, were screened. RF prediction model had the highest accuracy, and the gut microbiota with the highest predictive value were Peptostreptococcus, Faecalibacterium, and norank_f__Ruminococcaceae, respectively. Compared with normal leukocytes group, the microbiota alpha diversity of hypoleukocytes group was significantly decreased (p < 0.05). The proportion of Escherichia-Shigella was significantly decreased in the hypoleukocytes group. After analyzing the gut microbiota differences of the two groups, 9 differential bacteria, such as Escherichia-Shigella, Fusicatenibacter and Cetobacterium, were screened. RF prediction model had the highest accuracy, and the gut microbiota with the highest predictive value were Fusicatenibacte, Cetobacterium, and Paraeggerthella.
CONCLUSION
Gut microbiota is related to leukopenia after chemotherapy. The gut microbiota may provide a novel method for predicting myelosuppression after chemotherapy in CRC patients.
Topics: Humans; Gastrointestinal Microbiome; Colorectal Neoplasms; Microbiota; Bacteria; Leukopenia
PubMed: 37978347
DOI: 10.1186/s12866-023-03067-6 -
Research Square Oct 2023A multi-site Phase I trial was conducted to determine the safety, maximum tolerated dose, and pharmacokinetics (PK) of Veliparib, a Poly (ADP-ribose) polymerase [PARP]...
PURPOSE
A multi-site Phase I trial was conducted to determine the safety, maximum tolerated dose, and pharmacokinetics (PK) of Veliparib, a Poly (ADP-ribose) polymerase [PARP] enzyme inhibitor, when administered with temozolomide (TMZ) alone and then with temozolomide and radiation (RT) in patients with newly diagnosed glioblastoma.
METHODS
Given the potential for myelosuppression when a PARP inhibitor is combined with chemotherapy, the first 6 patients accrued were given Veliparib 10 mg bid and TMZ 75 mg/m2/d daily for six weeks. If this was well tolerated, the same doses of Veliparib and TMZ would be tested along with standard radiation with plans to dose escalate the Veliparib in subsequent patient cohorts. Once a maximal tolerated dose was determined, a 78 patient phase II study was planned. Peripheral blood pharmacokinetics were assessed.
RESULTS
Twenty-four patients were enrolled. In the first 6 patients who received 6 weeks of TMZ with Veliparib only one dose limiting toxicity (DLT) occurred. The next 12 patients received 6 weeks of RT + TMZ + veliparib and 4/12 (33%) had dose limiting hematologic toxicities. As a result, Veliparib was reduced by 50% to 10 mg BID every other week, but again 3/3 patients had dose limiting hematologic toxicities. The trial was then terminated. The mean clearance (± SD) CL/F of Veliparib for the initial dose (27.0 ± 9.0 L/h, n = 16) and at steady-state for 10 mg BID (23.5 ± 10.4 L/h, n = 18) were similar. Accumulation for BID dosing was 56% (± 33%).
CONCLUSIONS
Although Veliparib 10 mg BID administered with TMZ 75 mg/m2 for six weeks was well tolerated, when this regimen was combined with standard partial brain irradiation it was severely myelosuppressive even when the dose was reduced by 50%. This study again highlights the potential of localized cranial radiotherapy to significantly increase hematologic toxicity of marginally myelosuppressive systemic therapies.
PubMed: 37961385
DOI: 10.21203/rs.3.rs-3466927/v1 -
Journal of Clinical Medicine Oct 2023This study focuses on the use of thiopurines for treating inflammatory bowel diseases (IBD). These drugs undergo enzymatic changes within the body, resulting in active... (Review)
Review
This study focuses on the use of thiopurines for treating inflammatory bowel diseases (IBD). These drugs undergo enzymatic changes within the body, resulting in active and inactive metabolites that influence their therapeutic effects. The research examines the role of genetic polymorphisms in the enzyme thiopurine S-methyltransferase (TPMT) in predicting the therapeutic response and adverse effects of thiopurine treatment. The TPMT genotype variations impact the individual responses to thiopurines. Patients with reduced TPMT activity are more susceptible to adverse reactions (AEs), such leukopenia, hepatotoxicity, pancreatitis, and nausea, which are common adverse effects of thiopurine therapy. The therapeutic monitoring of the metabolites 6-thioguanine nucleotides (6-TGN) and 6-methyl mercaptopurine (6-MMP) is proposed to optimize treatment and minimize AEs. Patients with higher 6-TGN levels tend to have better clinical responses, while elevated 6-MMP levels are linked to hepatotoxicity. Genotyping for TPMT before or during treatment initiation is suggested to tailor dosing strategies and enhance treatment efficacy while reducing the risk of myelosuppression. In conclusion, this study highlights the importance of considering genetic variations and metabolite levels in optimizing thiopurine therapy for IBD patients, focusing on balance therapeutic efficacy with the prevention of adverse effects and contributing to personalized treatment and better patient outcomes.
PubMed: 37959208
DOI: 10.3390/jcm12216742 -
BMC Pharmacology & Toxicology Nov 2023Pertuzumab is widely used for the treatment of HER2 + breast cancer. But its safety in the real world should be continuously monitored. So, we evaluated the safety...
BACKGROUND
Pertuzumab is widely used for the treatment of HER2 + breast cancer. But its safety in the real world should be continuously monitored. So, we evaluated the safety of pertuzumab by pharmacovigilance analyze based on related adverse events (AEs) from the FDA Adverse Event Reporting System (FAERS) and find whether potential or uncertain adverse events were present.
METHODS
In disproportionality analysis, four algorithms were employed to detect the signals of pertuzumab from the FAERS between 2012 and 2022. In addition, we also used MYSQL 8.0, Navicat Premium 15, and Microsoft EXCEL 2019 to analyze the potential and high-ROR (reporting odds ratio) signals of pertuzumab. We also collected the onset times of pertuzumab-associated AEs.
RESULTS
From January 2012 to December 2022, there are 39,190,598 AEs reported from the FAERS database, of which 14,707 AEs listed pertuzumab as the 'primary suspected (PS)' drug. A total of 115 (46 potential) significant disproportionality preferred terms (PTs) conforming to the four algorithms were retained. Finally, we detected that the pertuzumab-induced AEs occurred in 12 organ systems. For pertuzumab, unexpected and significant PTs of AEs were found, including but not limited to below PTs: haematotoxicity, cardiotoxicity, cardiomyopathy, mitral valve incompetence, tachycardia, intestinal perforation, hemorrhoids, erysipelas, dehydration, pneumonitis, skin toxicity, onychomadesis, cyanosis, and circulatory collapse. We found there were 9 strong signals (5 potential safety signals) and 68 medium intensity signals (21 potential safety signals) according to IC (information component). The potential strong signals (IC > 3.0) were myelosuppression, cardiotoxicity, cardiac dysfunction, ejection fraction decreased, interstitial lung disease, and onychomadesis. Excluding unreported or unreasonable onset time reports, a total of 2016 AEs reported onset time and the median onset time was 117 days (4, 96), as median (Q1, Q3). Notably, most of the all AEs (n = 1133, 56%) and cardiac-related events (n = 405, 53%) all occurred within one month after pertuzumab therapy.
CONCLUSION
Analysis of FAERS data identified pertuzumab-associated AEs, and our findings supported continuous clinical monitoring, pharmacovigilance, and further studies of pertuzumab. A significant association was detected between pertuzumab and some potential adverse events which should be regarded with some care. We have to pay attention to the first month after pertuzumab therapy and prepare emergency measures, especially for the elderly and patients with cardiovascular diseases.
Topics: Humans; Aged; Female; Cardiotoxicity; Adverse Drug Reaction Reporting Systems; Antibodies, Monoclonal, Humanized; Pharmacovigilance; Breast Neoplasms
PubMed: 37957717
DOI: 10.1186/s40360-023-00702-w