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ESMO Open Jun 2024Paclitaxel resistance limits durability of response in patients with initial clinical benefit. Overexpression of spleen tyrosine kinase (SYK) has been proposed as a...
BACKGROUND
Paclitaxel resistance limits durability of response in patients with initial clinical benefit. Overexpression of spleen tyrosine kinase (SYK) has been proposed as a possible resistance mechanism. This phase I trial evaluated the safety and preliminary activity of the SYK inhibitor TAK-659 combined with paclitaxel in patients with advanced taxane-refractory solid tumors.
PATIENTS AND METHODS
Patients with advanced solid tumors and prior progression on taxane-based therapy received intravenous infusion of paclitaxel on days 1, 8, and 15 plus oral TAK-659 daily in 28-day cycles. The dose-escalation phase included six cohorts treated at different dose levels; the dose-expansion phase included patients with ovarian cancer treated at the highest dose level. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Efficacy was evaluated using Response Evaluation Criteria in Solid Tumors version 1.1.
RESULTS
Our study included 49 patients. Maximum tolerated dose was not reached, but higher rates of adverse events were observed at higher dose levels. There were no treatment-related deaths. The most common treatment-related adverse events of any grade were increased aspartate aminotransferase (n = 31; 63%), increased alanine aminotransferase (n = 26; 53%), decreased neutrophil count (n = 26; 53%), and decreased white blood cell count (n = 26; 53%). Most adverse events were either grade 1 or 2. In the 44 patients with evaluable disease, 12 (27%) had stable disease as the best overall response, including three patients with prolonged stable disease, and 4 patients (9%) achieved a partial response.
CONCLUSIONS
The combination of paclitaxel and TAK-659 showed preliminary activity possibly overcoming resistance to taxane-based therapy as well as a tolerable safety profile in patients with advanced solid tumors.
Topics: Humans; Paclitaxel; Female; Middle Aged; Aged; Neoplasms; Male; Adult; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Taxoids; Maximum Tolerated Dose; Syk Kinase
PubMed: 38914452
DOI: 10.1016/j.esmoop.2024.103486 -
The Oncologist Jun 2024To describe reasons for deviations from planned chemotherapy treatments in women with nonmetastatic breast cancer that contribute to less-than-planned receipt of...
BACKGROUND
To describe reasons for deviations from planned chemotherapy treatments in women with nonmetastatic breast cancer that contribute to less-than-planned receipt of chemotherapy.
METHODS
Electronic medical records for patients receiving chemotherapy were reviewed for adverse events and treatment modifications. Log-binomial regression models were used to estimate relative risks (RRs) with 95% CIs to examine associations between chemotherapy modifications, patient characteristics, and treatment modalities.
RESULTS
Delays in chemotherapy initiation (7%) were for surgical complications (58%), personal reasons (16%), and other (26%; port malfunction, infections, and obtaining extra imaging). Delays during chemotherapy (38%) were for infections (20%), neutropenia (13%), and personal reasons (13%). Dose reductions (38%) were for neuropathy (36%), unknown causes (9%), anemia (9%), and neutropenia (8%). Early treatment discontinuations (23%) were for neuropathy (29%). Patients receiving paclitaxel/nab-paclitaxel (RR 2.05; 95% CI, 1.47-2.87) and an anthracycline (RR 1.89; 95% CI, 1.39-2.57) reported more dose delays during chemotherapy. Black race (RR 1.46; 95% CI, 1.07-2.00), stage 3 (RR 1.79; 95% CI, 1.09-2.93), and paclitaxel/nab-paclitaxel receipt (RR 1.39; 95% CI, 1.02-1.90) increased the likelihood of dose reduction. Both Black race (RR 2.06; 95% CI, 1.35-3.15) and receipt of paclitaxel/nab-paclitaxel (RR 1.93; 95% CI, 1.19-3.13) increased the likelihood of early discontinuation. Patients receiving anthracyclines had higher rates of hospitalizations during chemotherapy (RR: 1.79; 95% CI, 1.11-2.89).
CONCLUSION
Toxicities are the most common reason for treatment modifications and need close monitoring in high-risk groups for timely intervention. Dose reductions and early treatment discontinuations occurred more for Black patients and need further study.
PubMed: 38913986
DOI: 10.1093/oncolo/oyae150 -
Journal of Inflammation Research 2024Dermatomyositis (DM) represents a group of inflammatory myopathies, with TIF1-γ positive DM strongly associated with malignancies. Spontaneous muscular hematoma in DM...
BACKGROUND
Dermatomyositis (DM) represents a group of inflammatory myopathies, with TIF1-γ positive DM strongly associated with malignancies. Spontaneous muscular hematoma in DM patients is exceedingly rare and often prognosticates a severe clinical outcome, especially in the context of concurrent malignancy.
CASE PRESENTATION
We describe a novel survival case of a patient with TIF1-γ positive DM and an underlying ovarian tumor who developed a spontaneous muscular hematoma. Despite the traditionally poor prognosis of these conditions, the patient survived through a comprehensive treatment regimen. This included targeted chemotherapy for ovarian cancer (Carboplatin and Paclitaxel), alongside corticosteroids, immunoglobulins, and immunosuppressants for DM, as well as component blood transfusions, coagulation correction therapy to control hematoma, and integrated management: nutritional support, lung function exercise, volume management.
RESULTS
The integrated treatment strategy stabilized the patient's condition and resolved the hematoma, a significant achievement given the usual high mortality rate of such complications.
CONCLUSION
This case underscores the importance of a multidisciplinary approach in the early diagnosis and treatment of TIF1-γ positive DM with complex comorbidities, including spontaneous muscular hematoma and ovarian cancer. It highlights the potential for favorable outcomes with aggressive and coordinated treatment strategies.
PubMed: 38911988
DOI: 10.2147/JIR.S469401 -
Hepatobiliary Surgery and Nutrition Jun 2024The establishment of preoperative chemotherapy (PCT) with FOLFIRINOX and gemcitabine/nab-paclitaxel in recent years has enabled resectability in many patients with...
BACKGROUND
The establishment of preoperative chemotherapy (PCT) with FOLFIRINOX and gemcitabine/nab-paclitaxel in recent years has enabled resectability in many patients with initially locally advanced pancreatic cancer (LAPC). Nevertheless, information about the impact of PCT on surgical results is scarce.
METHODS
All patients with initial LAPC who received surgery after chemotherapy at the high-volume centre for pancreatic surgery of St. Josef-Hospital Bochum between 2015 and 2022 were included in this retrospective cohort analysis.
RESULTS
A total of 139 patients underwent surgery after pre-treatment with FOLFIRINOX (76.3%), gemcitabine/nab-paclitaxel (11.5%), both (5.8%) and other regimens (6.5%). Eighty-five tumors (61.2%) were resectable after PCT. R0 resection was achieved in 92.9%, R1 in 7.1% and R2 in 0% of cases. Fifty-four tumors were still not resectable at the time of surgery. Surgical results of the patients did not show increased postoperative mortality and morbidity compared to the literature data. Postoperative 30-day mortality was 1.4%. Rates for pancreas-specific complications [postoperative pancreatic fistula (POPF), delayed gastric emptying (DGE), postpancreatectomy hemorrhage (PPH), and others] were not increased. POPF occurred in 10.5% and DGE in 26.3% after pancreaticoduodenectomy. After distal pancreatectomy, POPF was detected in 37.5% and DGE in 12.5%. Median postoperative survival (31 13 months) and overall survival after initial diagnosis (40 20 months) were significantly longer in resected patients (P<0.001). Postoperative recurrence-free survival in resected patients amounted to 12 months.
CONCLUSIONS
This study underlines that PCT allows resectability of primarily unresectable patients with LAPC without increasing perioperative mortality and morbidity. It may lead to a significant prolongation of recurrence-free and overall survival in resected patients after PCT.
PubMed: 38911210
DOI: 10.21037/hbsn-23-426 -
Discover Oncology Jun 2024To develop a prognostic risk model for Bladder Cancer (BLCA) based on mitochondrial-related long non-coding RNAs (lncRNAs).
OBJECTIVE
To develop a prognostic risk model for Bladder Cancer (BLCA) based on mitochondrial-related long non-coding RNAs (lncRNAs).
METHODS
Transcriptome and clinical data of BLCA patients were retrieved from the TCGA database. Mitochondrial-related lncRNAs with independent prognostic significance were screened to develop a prognostic risk model. Patients were categorized into high- and low-risk groups using the model. Various methods including Kaplan-Meier (KM) analysis, ROC curve analysis, Gene Set Enrichment Analysis (GSEA), immune analysis, and chemotherapy drug analysis were used to verify and evaluate the model.
RESULTS
A mitochondrial-associated lncRNA prognostic risk model with independent prognostic significance was developed. High-risk group (HRG) patients exhibited significantly shorter survival periods compared to low-risk group (LRG) patients (P < 0.01). The risk score from the model was an independent predictor of BLCA prognosis, correlating with tumor grade, pathological stage, and lymph node metastasis (P < 0.05). The HRG showed significant positive correlations with high expressions of immune checkpoints (CTLA4, LAG3, PD-1, TIGIT, PD-L1, PD-L2, and TIM-3) and lower IC50 for chemotherapy drugs (cisplatin, docetaxel, paclitaxel, methotrexate, and vinblastine) (P < 0.001).
CONCLUSIONS
The mitochondrial-related lncRNA-based prognostic risk model effectively predicts BLCA prognosis and can guide individualized treatment for BLCA patients.
PubMed: 38907134
DOI: 10.1007/s12672-024-01108-8 -
BMJ (Clinical Research Ed.) Jun 2024
Nab-paclitaxel, cisplatin, and capecitabine versus cisplatin and gemcitabine as first line chemotherapy in patients with recurrent or metastatic nasopharyngeal carcinoma: randomised phase 3 clinical trial.
PubMed: 38906541
DOI: 10.1136/bmj.q1381 -
Frontiers in Pharmacology 2024Systemic chemotherapy is typically administered following radical gastrectomy for advanced stage. To attenuate systemic side effects, we evaluated the effectiveness of...
Systemic chemotherapy is typically administered following radical gastrectomy for advanced stage. To attenuate systemic side effects, we evaluated the effectiveness of regional chemotherapy using paclitaxel, albumin-paclitaxel, and liposome-encapsulated albumin-paclitaxel via subserosal injection in rat models employing nuclear medicine and molecular imaging technology. Nine Sprague Dawley rats were divided into three groups: paclitaxel ( = 3), albumin-paclitaxel nano-particles (APNs; = 3), and liposome-encapsulated APNs ( = 3). [I]Iodo-paclitaxel ([I]I-paclitaxel) was synthesized by conventional electrophilic radioiodination using -butylstannyl substituted paclitaxel as the precursor. Albumin-[I]iodo-paclitaxel nanoparticles ([I]APNs) were prepared using a desolvation technique. Liposome-encapsulated APNs (L-[I]APNs) were prepared by thin-film hydration using DSPE-PEG2000, HSPC, and cholesterol. The rats in each group were injected with each test drug into the subserosa of the stomach antrum. After predetermined times (30 min, 2, 4, 8 h, and 24 h), molecular images of nuclear medicine were acquired using single-photon emission computed tomography/computed tomography. Paclitaxel, APNs, and L-APNs showed a high cumulative distribution in the stomach, with L-APNs showing the largest area under the curve. Most drugs administered via the gastric subserosal route are distributed in the stomach and intestines, with a low uptake of less than 1% in other major organs. The time to reach the maximum concentration in the intestine for L-APNs, paclitaxel, and APNs was 6.67, 5.33, and 4.00 h, respectively. These preliminary results imply that L-APNs have the potential to serve as a novel paclitaxel preparation method for the regional treatment of gastric cancer.
PubMed: 38904000
DOI: 10.3389/fphar.2024.1381406 -
Frontiers in Immunology 2024Drug-induced immune thrombocytopenia is an adverse reaction marked by accelerated destruction of blood platelets. In cancer therapy, thrombocytopenia has many other... (Review)
Review
Drug-induced immune thrombocytopenia is an adverse reaction marked by accelerated destruction of blood platelets. In cancer therapy, thrombocytopenia has many other causes including bone marrow suppression induced by chemotherapeutic agents, infection, and progression of cancer; drug-induced thrombocytopenia can easily be misdiagnosed or overlooked. Here, we present a case of an ovarian cancer patient with a history of mixed connective tissue disease who underwent surgery followed by treatment with paclitaxel, cisplatin, and bevacizumab. The patient developed acute isolated thrombocytopenia after the sixth cycle. Serum antiplatelet antibody testing revealed antibodies against glycoprotein IIb. After we analyzed the whole therapeutic process of this patient, drug-induced immune thrombocytopenia was assumed, and bevacizumab was conjectured as the most probable drug. Thrombocytopenia was ultimately successfully managed using recombinant human thrombopoietin, prednisone, and recombinant human interleukin-11. We provide a summary of existing literature on immune thrombocytopenia induced by bevacizumab and discuss related mechanisms and triggers for drug-induced immune thrombocytopenia. The present case underscores the potential of bevacizumab to induce immune-mediated thrombocytopenia, emphasizing the need for heightened vigilance towards autoimmune diseases or an autoimmune-activated state as plausible triggers for rare drug-induced immune thrombocytopenia in cancer therapy.
Topics: Humans; Female; Bevacizumab; Ovarian Neoplasms; Purpura, Thrombocytopenic, Idiopathic; Mixed Connective Tissue Disease; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Antineoplastic Agents, Immunological
PubMed: 38903494
DOI: 10.3389/fimmu.2024.1382964 -
The Oncologist Jun 2024Oxaliplatin- and fluoropyrimidine-based triplet regimens have demonstrated feasibility and efficacy in the treatment of upper gastrointestinal (UGI) cancers. Herein, we...
BACKGROUND
Oxaliplatin- and fluoropyrimidine-based triplet regimens have demonstrated feasibility and efficacy in the treatment of upper gastrointestinal (UGI) cancers. Herein, we evaluate the feasibility and preliminary efficacy of biweekly nab-paclitaxel plus oxaliplatin and S-1/leucovorin (SOLAR) in chemonaïve UGI cancers.
METHODS
A 3 + 3 phase 1 study was conducted to determine the maximal tolerated dose (MTD) of oxaliplatin in SOLAR (nab-paclitaxel [150 mg/m2 in D1], oxaliplatin [60, 75, or 85 mg/m2 in D1], and oral S-1/leucovorin [35 mg/m2 and 30 mg bid from D1 to D7]). The secondary endpoints were overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety.
RESULTS
Thirteen and 6 accruals were in the dose-escalation and MTD expansion cohorts, respectively. One of 6 patients at level III experienced dose-limiting toxicity (grade 3 diarrhea), which revealed that the MTD of oxaliplatin was 85 mg/m2. After a mean of 15.9 cycles of treatment, the most common treatment-related grade 3/4 toxicities were neutropenia (57.9%) and diarrhea (21.1%). The ORR was 63.2%. The median PFS and OS were 12.5 and 24.7 months, respectively.
CONCLUSION
The current study revealed the MTD of oxaliplatin and demonstrated the preliminary efficacy of SOLAR in UGI cancers, which deserves further investigation.
CLINICALTRIALS.GOV IDENTIFIER
NCT03162510.
PubMed: 38902994
DOI: 10.1093/oncolo/oyae109