ABSTRACT
Biliary tract cancer (BTC) is a highly aggressive malignancy with limited second-line therapy. We conducted this phase 2 trial to evaluate the efficacy and safety of second-line nab-paclitaxel plus sintilimab in advanced BTC. Histologically confirmed advanced BTC patients with documented disease progression after first-line chemotherapy were enrolled. Subjects received nab-paclitaxel 125 mg/m2 on days 1 and 8 plus sintilimab 200 mg on day 1, administered every 3 weeks. The primary end point was the objective response rate (ORR). The secondary end points were progression-free survival (PFS), overall survival (OS), and adverse reactions. Simultaneously, next-generation sequencing, programmed cell death ligand 1 immunohistochemistry and multiplex immunofluorescence of tumor-infiltrating lymphocytes were applied to explore potential biomarkers. Twenty-six subjects were consecutively enrolled. The ORR was 26.9% (7/26), including two complete responses and five partial responses, which met the primary end point. The disease control rate was 61.5% (16/26). The median PFS was 169 days (about 5.6 months, 95% confidence interval [CI] 60-278 days). The median OS was 442 days (about 14.7 months, 95% CI 298-586 days). Grade 3 treatment-related adverse events (TRAEs) were mainly anemia (27%), leukopenia (23%), neutropenia (19%), and peripheral sensory neuropathy (8%). No grade 4 or 5 TRAEs occurred. Biomarker analysis suggested that positive PD-L1 and high proportions of CD8+ T-cell infiltration were correlated with improved clinical outcome. Nab-paclitaxel plus sintilimab is a potentially effective and tolerable second-line regimen for advanced BTC that deserves to be studied in large-scale trials. PD-L1 status and CD8+ T cell infiltration might be promising biomarkers for efficacy prediction.
Subject(s)
Albumins , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Biliary Tract Neoplasms , Biomarkers, Tumor , Paclitaxel , Humans , Paclitaxel/administration & dosage , Paclitaxel/therapeutic use , Male , Female , Middle Aged , Albumins/administration & dosage , Albumins/therapeutic use , Aged , Biliary Tract Neoplasms/drug therapy , Biliary Tract Neoplasms/pathology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Adult , B7-H1 Antigen , Lymphocytes, Tumor-Infiltrating/immunology , Progression-Free Survival , Treatment OutcomeABSTRACT
BACKGROUND: Immune checkpoint inhibitors (ICIs) have demonstrated promising outcomes in small cell lung cancer (SCLC), but not all patients benefit from it. Thus, developing precise treatments for SCLC is a particularly urgent need. In our study, we constructed a novel phenotype for SCLC based on immune signatures. METHODS: We clustered patients with SCLC hierarchically in 3 publicly available datasets according to the immune signatures. ESTIMATE and CIBERSORT algorithm were used to evaluate the components of the tumor microenvironment. Moreover, we identified potential mRNA vaccine antigens for patients with SCLC, and qRT-PCR were performed to detect the gene expression. RESULTS: We identified 2 SCLC subtypes and named Immunity High (Immunity_H) and Immunity Low (Immunity_L). Meanwhile, we obtained generally consistent results by analyzing different datasets, suggesting that this classification was reliable. Immunity_H contained the higher number of immune cells and a better prognosis compared to Immunity_L. Gene-set enrichment analysis revealed that several immune-related pathways such as cytokine-cytokine receptor interaction, programmed cell death-Ligand 1 expression and programmed cell death-1 checkpoint pathway in cancer were hyperactivated in the Immunity_H. However, most of the pathways enriched in the Immunity_L were not associated with immunity. Furthermore, we identified 5 potential mRNA vaccine antigens of SCLC (NEK2, NOL4, RALYL, SH3GL2, and ZIC2), and they were expressed higher in Immunity_L, it indicated that Immunity_L maybe more suitable for tumor vaccine development. CONCLUSIONS: SCLC can be divided into Immunity_H and Immunity_L subtypes. Immunity_H may be more suitable for treatment with ICIs. NEK2, NOL4, RALYL, SH3GL2, and ZIC2 may be act as potential antigens for SCLC.
Subject(s)
Lung Neoplasms , Small Cell Lung Carcinoma , Humans , Small Cell Lung Carcinoma/pathology , Lung Neoplasms/pathology , Vaccines, Synthetic , Prognosis , Tumor Microenvironment , NIMA-Related Kinases , mRNA VaccinesABSTRACT
BACKGROUND: Biliary tract cancer (BTC) is a relatively rare but highly aggressive malignancy. However, there is currently no satisfactory second-line regimen for patients without specific genetic mutations. Nanoparticle albumin-bound paclitaxel, also known as nab-paclitaxel (Abraxane, Bristol Myers Squibb), has shown activity in patients with BTC. Studies investigating the immunogenic features of BTC suggested that checkpoint inhibition may lead to antitumor immune responses. In recent years, improved survival has been observed in patients treated with chemotherapy combined with immunotherapy across multiple cancer types, including BTC. This clinical trial aims to evaluate the efficacy and safety of second-line sintilimab in combination with nab-paclitaxel in advanced BTC patients. METHODS: The NapaSinti trial is a prospective, nonrandomized, open-label, phase 2 study conducted at a tertiary hospital in Chengdu, China. Eligible patients are those with histologically or cytologically confirmed locally advanced non-resectable or metastatic adenocarcinoma in the biliary tract (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer), aged between 18 and 75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, who have experienced disease progression after prior gemcitabine- or fluorouracil-based chemotherapy and have not received taxane or immune checkpoint inhibitor treatment. Enrolled patients will receive intravenous administration of sintilimab 200 mg on day 1 and nab-paclitaxel 125 mg/m2 on days 1 and 8, every three weeks. The primary endpoint is the objective response rate (ORR), while the secondary endpoints include overall survival (OS), progression-free survival (PFS), and safety. Exploratory objectives aim to identify biomarkers and molecular signatures for predicting response or prognosis. Using Simon's two-stage design, a total of 63 participants will be enrolled in the study. This trial was initiated in March 2022 in China. DISCUSSION: The NapaSinti trial evaluates the efficacy and safety of second-line sintilimab plus nab-paclitaxel for advanced biliary tract cancer. Additionally, the trial provides an opportunity for translational research. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100052118. Registered October 19, 2021.
Subject(s)
Bile Duct Neoplasms , Biliary Tract Neoplasms , Cholangiocarcinoma , Humans , Adolescent , Young Adult , Adult , Middle Aged , Aged , Deoxycytidine , Prospective Studies , Paclitaxel , Albumins , Bile Duct Neoplasms/drug therapy , Biliary Tract Neoplasms/drug therapy , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/etiology , Bile Ducts, Intrahepatic , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Clinical Trials, Phase II as TopicABSTRACT
LESSONS LEARNED: Bevacizumab combined with S-1 and raltitrexed demonstrated positive antitumor efficacy and acceptable toxicity. This combination might represent a treatment option for refractory metastatic colorectal cancer. BACKGROUND: In patients with metastatic colorectal cancer (mCRC) refractory to standard therapies, S-1 plus raltitrexed showed a good objective response rate (ORR) and significant survival benefit in our previous study. In the present study, we assessed the activity and safety of bevacizumab combined with S-1 and raltitrexed. METHODS: This investigator-initiated, open-label, single-arm, phase II trial was performed at West China Hospital in China. Patients with mCRC who had disease progression after fluoropyrimidine, irinotecan, and oxaliplatin and had at least one measurable lesion were eligible for this trial. Anti-epidermal growth factor receptor (EGFR) (for tumors with wild-type RAS) and anti-vascular endothelial growth factor (VEGF) therapy in the first or second line was allowed, but patients who had been treated with bevacizumab across two consecutive chemotherapy regimens were excluded. Patients received bevacizumab (7.5 mg/kg on day 1), oral S-1 (80-120 mg per day for 14 days), and raltitrexed (3 mg/m2 on day 1) every 3 weeks. The primary endpoint was ORR. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: From September 2015 to November 2019, 44 patients were enrolled. Tumor response evaluation was available in 44 patients at the time of the analysis. There were no complete responses; the ORR was 15.9%, and the disease control rate was 54.5%. Median PFS and OS were 110 days (95% confidence interval [CI], 65.0-155.0) and 367 days (95% CI, 310.4-423.6), respectively. The combination was well tolerated. CONCLUSION: Bevacizumab combined with S-1 and raltitrexed showed promising antitumor activity and safety in refractory mCRC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Colorectal Neoplasms , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bevacizumab/therapeutic use , Colorectal Neoplasms/drug therapy , Fluorouracil/therapeutic use , Humans , Leucovorin/therapeutic use , Quinazolines/therapeutic use , ThiophenesABSTRACT
BACKGROUND: With local recurrence of rectal cancer continuing to decrease, distant recurrence is becoming a major concern, especially for patients with low- and intermediate-risk stage II/III rectal cancer. Therefore, a new treatment strategy is warranted for these patients. This single-arm phase II trial aimed to assess the effect of neoadjuvant chemotherapy (NCT) in low- and intermediate-risk stage II/III rectal cancer and explore candidate radiological and clinical parameters for early prediction of tumour response after two cycles of CAPOX. METHODS: Patients with mid-low stage II/III rectal cancer with low and intermediate risk were examined. The primary outcome was defined as a clinicopathological response by integrating tumour longitudinal length reduction (TLLR) on MRI into pathological tumour regression grade (TRG). After completing NCT, patients with TRG0-2 and TRG3 with a TLLR rate greater than 30 per cent were considered to be responders. Secondary outcomes included pathological complete response (pCR), adverse events and local and distant recurrence. RESULTS: This study enrolled 61 eligible patients. No patient was converted to neoadjuvant chemoradiotherapy owing to tumour progression. The clinicopathological response and pCR rates were 78.7 and 21.3 per cent respectively. After two cycles of CAPOX, TLLR, TRG on MRI, and mucosal lesion regression grade on endoscopy had potential discriminative ability (area under the curve greater than 0.7) for predicting both clinicopathological and pathological response. CONCLUSION: NCT alone achieves good tumour response rates in patients with low- and intermediate-risk stage II/III rectal cancer, and predicting tumour response to NCT is feasible at an early treatment phase. REGISTRATION NUMBER: NCT03666442 (http://www.clinicaltrials.gov).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Capecitabine/therapeutic use , Neoadjuvant Therapy/methods , Oxaliplatin/therapeutic use , Rectal Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Capecitabine/administration & dosage , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Neoplasm Recurrence, Local/diagnostic imaging , Neoplasm Recurrence, Local/epidemiology , Oxaliplatin/administration & dosage , Rectal Neoplasms/diagnostic imaging , Rectal Neoplasms/pathology , Rectal Neoplasms/surgery , Remission Induction/methods , Risk Factors , Treatment OutcomeABSTRACT
The efficacy of chimeric antigen receptor T (CAR-T) cell therapy in solid tumors is far from satisfactory. In this study, we investigated the influence of epithelial-mesenchymal transition (EMT) on the antitumor effect of CAR-T cells and explored the potential efficacy of combining CAR-T cells with inhibitors targeting EMT. We successfully induced EMT in tumor cells with TGF-ß1, and the antitumor effect of HER2-directed CAR-T cells was significantly suppressed by EMT. Upregulation of PD-L1 was observed in tumor cells undergoing EMT, and change in PD-L1 expression during the EMT process was dependent on the MEK/ERK and PI3K/Akt pathways. Inhibition of the TGF-ß1 pathway could block the EMT process in tumor cells and restore their susceptibility to HER2-directed CAR-T cells in vitro. In addition, targeting the TGF-ß1 pathway significantly enhanced the antitumor effect of HER2-directed CAR-T cells in vivo. Our findings suggest that blocking EMT could potently enhance the antitumor effect of CAR-T cells, which provides a promising approach to improving the therapeutic efficacy of CAR-T cell therapy in solid tumors.
Subject(s)
Antineoplastic Agents/immunology , Epithelial-Mesenchymal Transition/immunology , Neoplasms/immunology , Neoplasms/therapy , Receptor, ErbB-2/immunology , Receptors, Chimeric Antigen/immunology , T-Lymphocytes/immunology , A549 Cells , Animals , B7-H1 Antigen/immunology , Cell Line , Cell Line, Tumor , Female , HCT116 Cells , HEK293 Cells , HT29 Cells , Humans , Immunotherapy, Adoptive/methods , Mice , Mice, Inbred NOD , Mice, SCID , Signal Transduction/immunology , Transforming Growth Factor beta1/immunology , Xenograft Model Antitumor Assays/methodsABSTRACT
Interleukin-18 (IL-18) has been demonstrated to augment the antitumor capacity of chimeric antigen receptor-T cells (CAR-T) but the underlying mechanisms are largely unknown. Here we explored the effects and mechanisms of exogenous IL-18 on the antitumor response of CAR-T cells. IL-18 boosted the cytotoxicity of human epidermal growth factor receptor-2 (HER2)-specific CAR-T cells ex vivo and enhanced the antitumor efficacy of the CAR-T cells in immunodeficient mice, moreover, IL-18 improved the antitumor capacity of OVA-specific T cells in immunocompetent mice, indicating the universal enhancing function of IL-18 for adoptive cell therapy. To address the roles of IL-18 receptor (IL-18R) in the enhancing function, we evaluated the effects of IL-18R knockout (IL-18R-/-) condition in immunocompetent host and CAR-T cells on the IL-18-enhanced antitumor activities. Interestingly, IL-18 persisted to improve the antitumor ability of IL-18R intact CAR-T cells in IL-18R-/- mice. For IL-18R-/- CAR-T cells, however, IL-18 still holds the enhancing ability to boost the antitumor efficacy in IL-18R-/- mice, albeit the ex vivo tumor-killing ability was lower than that of IL-18R intact CAR-T cells, indicating that IL-18R-independent pathway is involved in the enhancement. Furthermore, tagged IL-18 binded to the membrane of IL-18R-/- splenic and lymph node cells and IL-18R intact and IL-18R-/- CAR-T cells showed distinct transcriptomic profiles when stimulated by IL-18. These data demonstrate that IL-18R-independent pathways contribute to functions of IL-18.
Subject(s)
Antineoplastic Agents/metabolism , Interleukin-18/metabolism , Receptors, Antigen, T-Cell/metabolism , Receptors, Interleukin-18/metabolism , Signal Transduction/physiology , T-Lymphocytes/metabolism , Animals , Cell Line , Female , HEK293 Cells , Humans , Immunotherapy, Adoptive/methods , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, SCID , Xenograft Model Antitumor Assays/methodsABSTRACT
LESSONS LEARNED: The upregulation of dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) are important mechanisms of resistance to 5-fluorouracil (5-FU) in metastatic colorectal cancer (mCRC) after long exposure to 5-FU.S-1 (containing a DPD inhibitor) combined with raltitrexed (a TS inhibitor) showed a moderate effect, which needs further study as a third- or later-line therapy in mCRC. BACKGROUND: 5-fluorouracil (5-FU) is a fundamental drug in the treatment of metastatic colorectal cancer (mCRC). Patients with mCRC are often exposed to 5-FU and/or its analogues for a long time because of its central role in treatment regimens. The upregulation of dihydropyrimidine dehydrogenase (DPD) and/or thymidylate synthase (TS) are important mechanisms of resistance of 5-FU. To evaluate the efficacy and safety of S-1 (containing a DPD inhibitor) and raltitrexed (a TS inhibitor) for refractory mCRC, a one-center, single-arm, prospective phase II trial was conducted. METHODS: Patients who had mCRC that had progressed after treatment with fluoropyrimidine, irinotecan, and oxaliplatin and who had at least one measurable lesion were eligible for this trial. Patients received oral S-1 (80-120 mg for 14 days every 3 weeks) plus an intravenous infusion of raltitrexed (3 mg/m2 on day 1 every 3 weeks). The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: In total, 46 patients were enrolled. Three patients did not complete the first assessment because of adverse events and unwillingness, leaving tumor response evaluation available in 43 patients. Of 43 evaluable patients, the ORR was 13.9% and disease control rate was 58.1%. In the intention-to-treat population (n = 46), the ORR was 13.0% and disease control rate was 54.3%. Median PFS and median OS were 107 days (95% confidence interval [CI], 96.3-117.7) and 373 days (95% CI, 226.2-519.8), respectively. Most of the adverse effects were mild to moderate. CONCLUSION: S-1 combined with raltitrexed for refractory mCRC showed moderate effect, and it is worthy of further study as third- or later-line therapy in mCRC.
Subject(s)
Colorectal Neoplasms/drug therapy , Oxonic Acid/therapeutic use , Quinazolines/therapeutic use , Tegafur/therapeutic use , Thiophenes/therapeutic use , Adult , Aged , Colorectal Neoplasms/pathology , Drug Combinations , Female , Humans , Male , Middle Aged , Neoplasm Metastasis , Oxonic Acid/pharmacology , Quinazolines/pharmacology , Tegafur/pharmacology , Thiophenes/pharmacologyABSTRACT
This study aimed to explore the correlation between survival and tumor calcification in patients with metastatic colorectal cancer who received cetuximab combined with chemotherapy. The study was a single-center retrospective analysis that enrolled 111 patients who had received therapy between April 2011 and October 2016. Tumor calcification and treatment efficacy were evaluated independently by radiologists on the basis of computed tomography scans. Clinical characteristics and follow-up data were collected from electronic medical records. Correlations between tumor calcification and clinical characteristics, tumor response rate, and patient survival were analyzed. Among the 111 enrolled patients, 27 had tumor calcification [27/111 (24.3%)]. The median progression-free survival was significantly longer for patients with tumor calcification than for those without calcification (9.3 vs. 6.2 months, P=0.022). Patients with tumor calcification also had a higher objective response rate (55.6 vs. 31%, P=0.021) and better overall survival (21.9 vs. 16.5 months, P=0.084). The correlation between calcification features and prognosis showed that patients with an increasing number of calcifications after treatment had a significantly longer median overall survival (22.9 vs. 9.1 months, P=0.033). Simultaneously, new liver metastases and multiple calcifications also showed a trend toward better overall survival. There were also no significant correlations between clinical characteristics (sex, age, gene mutation, primary tumor location, pathological type, blood test result) and survival (Supplementary Table 1, Supplemental digital content 1, http://links.lww.com/ACD/A280). Tumor calcification is associated with a better treatment outcome and is a potential prognostic marker.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Calcinosis/mortality , Colorectal Neoplasms/mortality , Liver Neoplasms/mortality , Adult , Aged , Aged, 80 and over , Calcinosis/drug therapy , Calcinosis/pathology , Cetuximab/administration & dosage , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Female , Fluorouracil/administration & dosage , Follow-Up Studies , Humans , Irinotecan/administration & dosage , Leucovorin/administration & dosage , Liver Neoplasms/drug therapy , Liver Neoplasms/secondary , Male , Middle Aged , Oxaliplatin/administration & dosage , Prognosis , Retrospective Studies , Survival RateABSTRACT
Mesenchymal stem cells (MSCs), well-studied adult stem cells in various tissues, possess multi-lineage differentiation potential and anti-inflammatory properties. MSCs have been approved to regenerate lineage-specific cells to replace injured cells in tissues. MSCs are approved to treat inflammatory diseases. With the discovery of genes important for the repair of damaged tissues, MSCs genetically modified by such genes hold improved therapeutic potential. In this review, we summarised the uses of genetically modified MSCs to treat different diseases, including bone diseases, cardiovascular diseases, autoimmune diseases, central nervous system disorders, and cancer. To better understand the exact role of genetically modified MSCs, key mechanisms determining, which genes are selected to be used for modifying MSCs and improvements in post-genetic modification are discussed. Therapeutic benefits enhanced by genetic modifications are to be documented by further clinical studies.
Subject(s)
Genetic Therapy/methods , Mesenchymal Stem Cell Transplantation/methods , Animals , Gene Transfer Techniques , Humans , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolismABSTRACT
The tumor suppressor, p53, plays a critical role in suppressing osteosarcoma. Bone marrow stromal cells (BMSCs, also known as bone marrow-derived mesenchymal stem cells) have been suggested to give rise to osteosarcomas. However, the role of p53 in BMSCs has not been extensively explored. Here, we report that p53 regulates the lineage choice of mouse BMSCs (mBMSCs). Compared to mBMSCs with wild-type p53, mBMSCs deficient in p53 have enhanced osteogenic differentiation, but with similar adipogenic and chondrogenic differentiation. The role of p53 in inhibiting osteogenic lineage differentiation is mainly through the action of Runx2, a master transcription factor required for the osteogenic differentiation of mBMSCs. We find that p53 indirectly represses the expression of Runx2 by activating the microRNA-34 family, which suppresses the translation of Runx2. Since osteosarcoma may derive from BMSCs, we examined whether p53 has a role in the osteogenic differentiation of osteosarcoma cells and found that osteosarcoma cells with p53 deletion have higher levels of Runx2 and faster osteogenic differentiation than those with wild-type p53. A systems biology approach reveals that p53-deficient mBMSCs are more closely related to human osteosarcoma while mBMSCs with wild-type p53 are similar to normal human BMSCs. In summary, our results indicate that p53 activity can influence cell fate specification of mBMSCs, and provide molecular and cellular insights into the observation that p53 loss is associated with increased osteosarcoma incidence.
Subject(s)
Cell Differentiation/physiology , Mesenchymal Stem Cells/metabolism , Osteogenesis/physiology , Tumor Suppressor Protein p53/deficiency , Animals , Cell Line, Tumor , Cells, Cultured , Humans , Mice , Mice, KnockoutABSTRACT
BACKGROUND: To evaluate the safety and efficacy of a concurrent three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT) plus oxaliplatin, 5-fluorouracil and leucovorin (FOLFOX) regimen in completely resected gastric cancer patients with D2 lymph node dissection. MATERIALS AND METHODS: Patients with stage IB-IIIC gastric cancer (per the AJCC, 7th edition) who had undergone R0 and D2 gastrectomy were recruited. Two cycles of FOLFOX with concurrent 3D-CRT or IMRT (50.4 Gy/28f) were administered. One and an additional five cycles of FOLFOX were delivered before and after concurrent chemoradiotherapy, respectively. Primary endpoints were relapse-free survival (RFS) and overall survival (OS), with adverse events as secondary endpoints. RESULTS: From 2008 to 2011, 110 patients were evaluable. The 1-, 2- and 3-year RFS and OS were 86.2, 72.2, 67.8 and 94.7, 87.2, 77.6%, respectively. On multivariate analysis, stage (≤ IIIA vs. >IIIA) was a statistically significant factor affecting both RFS and OS. Additionally, the T-category (≤ T4a vs. = T4b) was a statistically significant factor affecting only the RFS. The most commonly observed grade 3 or 4 adverse events were nausea and vomiting, decreased appetite, leukopenia/neutropenia and fatigue, each of which occurred in 14.5, 11.8, 9.1 and 6.4% patients, respectively. CONCLUSIONS: Adjuvant 3D-CRT/IMRT to a dose of 50.4 Gy/28f with concurrent FOLFOX is safe and effective in patients following radical gastrectomy with D2 lymph node dissection.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Radiotherapy, Conformal/methods , Stomach Neoplasms/therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Chemoradiotherapy/methods , Chemoradiotherapy, Adjuvant/methods , Female , Fluorouracil/administration & dosage , Fluorouracil/therapeutic use , Gastrectomy/methods , Humans , Leucovorin/administration & dosage , Leucovorin/therapeutic use , Lymph Node Excision , Male , Middle Aged , Organoplatinum Compounds/administration & dosage , Organoplatinum Compounds/therapeutic use , Oxaliplatin , Radiotherapy, Intensity-Modulated , Stomach Neoplasms/pathology , Survival Rate , Treatment Outcome , Young AdultABSTRACT
Our previous study showed that the features of epidermal growth factor receptor (EGFR)-RAS signaling in penile squamous cell carcinoma (SCC) suggested potential benefits of anti-EGFR monoclonal antibodies (mAbs) for penile SCC. Here, we report, for the first time, a combination of nimotuzumab (an EGFR mAb) with chemotherapy that resulted in a partial response in a 44-year-old patient with penile SCC, who developed bilateral inguinal node metastasis after primary partial penile amputation. The literature of case reports of anti-EGFR mAbs in penile SCC was also reviewed.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Squamous Cell/drug therapy , ErbB Receptors/immunology , Penile Neoplasms/drug therapy , Adult , Antibodies, Monoclonal, Humanized/administration & dosage , Carcinoma, Squamous Cell/secondary , Cisplatin/administration & dosage , Fatal Outcome , Humans , Male , Paclitaxel/administration & dosage , Penile Neoplasms/pathologyABSTRACT
Lymphoma and leukemia are both hematological system tumors with complex etiology, and mainly treated with chemotherapeutic drugs. However, therapeutic drugs can interrupt curative effect due to different side effects. Therefore, it is worthwhile to develop a novel therapeutic for providing insights for clinical tumor treatment. In this study, we developed a fisetin nanoparticles (Fisetin NPs) through a self-assembled method, and investigated the activity and potential mechanism of Fisetin NPs against lymphoma and leukemia. The spherical and uniformly distributed Fisetin NPs effectively inhibited both tumor cells proliferation, arrested EL4 cells G0/G1 phase and K562 cells G2/M phase, and induced apoptosis in vitro. In vivo, Fisetin NPs exhibited excellent tumor growth inhibition, effective inhibition of cell proliferation and angiogenesis, significant induction of apoptosis and ideal safety. Mechanically, fisetin upregulated genes (Fas, Pidd, Puma, Apaf1, and p21) in the p53 signaling pathway and bound to N-acetyltransferase 10 (NAT10), ribosomal protein L34 (RPL34) and GTP binding protein 4 (GTPBP4). Collectively, Fisetin NPs have promising therapeutic effects on lymphoma and leukemia, which are of great significant for clinical implications.
Subject(s)
Leukemia , Lymphoma , Humans , Flavonoids/pharmacology , Flavonols/pharmacology , Apoptosis , Cell Proliferation , Leukemia/drug therapy , Lymphoma/drug therapy , Cell Line, Tumor , Nuclear Proteins/pharmacology , GTP-Binding Proteins/pharmacology , N-Terminal AcetyltransferasesABSTRACT
INTRODUCTION: Accurate baseline clinical staging is critical to inform treatment decision-making for patients with gastric cancers. Peritoneal metastasis (PM) is the most common form of metastasis in gastric cancer and mainly diagnosed by diagnostic laparoscopy and peritoneal lavage evaluation. However, diagnostic laparoscopy is invasive and less cost-effective. It is urgent to develop a safe, fast and non-invasive functional imaging method to verify the peritoneal metastasis of gastric cancer. The aim of our study was to evaluate the proportion of patients in whom 68Ga-FAPI-04 positron emission tomography/CT (PET/CT) led to a change in treatment strategy and to assess the diagnostic accuracy of 68Ga-FAPI-04 PET/CT for the detection of occult peritoneal metastasis compared with laparoscopic exploration. METHODS AND ANALYSIS: In this single-centre, prospective diagnostic test accuracy study, a total of 48 patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma (cT4a-b, N0-3, M0, based on CT images) who are considering radical tumour surgery will be recruited. All participants will undergo 68Ga-FAPI-04 PET/CT before the initiation of laparoscopic exploration. The primary outcome is the proportion of patients with occult peritoneal metastatic lesions detected by 68Ga-FAPI-04 PET/CT, leading to a change in therapy strategy. The secondary outcomes include the diagnostic performance of 68Ga-FAPI-04 PET/CT for occult peritoneal metastasis, including sensitivity, specificity, accuracy, positive predictive value and negative predictive value. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of West China Hospital, Sichuan University (2022-1484). Study results will be presented at public and scientific conferences and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ChiCTR2300067591.
Subject(s)
Laparoscopy , Peritoneal Neoplasms , Quinolines , Stomach Neoplasms , Humans , Stomach Neoplasms/diagnostic imaging , Gallium Radioisotopes , Prospective Studies , Peritoneal Neoplasms/diagnostic imaging , Positron Emission Tomography Computed Tomography , Positron-Emission Tomography , Fluorodeoxyglucose F18ABSTRACT
BACKGROUND: The purpose of this study was to explore the dynamic changes of genomic mutations and their correlations with the efficacy in metastatic colorectal cancer (mCRC) patients treated with cetuximab plus mFOLFOX as the first-line treatment. METHODS: We included mCRC patients from January 2018 to October 2020 as a studied cohort which were treated with cetuximab plus mFOLFOX as first line therapy. Blood samples were collected for circulating tumor DNA (ctDNA) test at three timepoints: before the first-line therapy(baseline), at the time of first-line progression and at the time of second-line progression. Progression-free survival was considered as the primary endpoint while objective response rate and overall survival were determined as the secondary endpoints. RESULTS: Totally 39 patients received first-line treatment, of which 25 patients entered the second-line treatment, while 10 patients entered the third-line treatment. The median follow-up time was 16.4 months (95 %CI, 14.8-19.3). Along the treatment from first-line progress disease (PD) to second-line PD, proportions of TP53 (12/18, 67 %), APC (10/18, 56 %), FBXW7 (3/18, 17 %), and AMER1 (2/18, 11 %) were gradually increased according to results of single nucleotide variation (SNV). CONCLUSIONS: Resistant gene mutations caused by anti-EGFR drugs in RAS/BRAF wild-type mCRC patients can be observed by dynamic ctDNA analysis. TP53 and AMER1 mutations, tumor mutational burden (TMB) levels, and TP53/AMER1 co-mutation may predict the efficacy of the first-line cetuximab-contained treatment. Situations of genetic mutations were differentiated from first-line PD to second-line PD, which indicated that mutation detection may contribute to predict prognosis of mCRC patients.
Subject(s)
Colonic Neoplasms , Colorectal Neoplasms , Rectal Neoplasms , Humans , Cetuximab/therapeutic use , Proto-Oncogene Proteins B-raf/genetics , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Colonic Neoplasms/drug therapy , Rectal Neoplasms/drug therapy , Mutation , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
PURPOSE: Patients with advanced biliary tract cancer (BTC) have a poor survival. We aim to evaluate the efficacy and safety of nab-paclitaxel plus gemcitabine and cisplatin regimen in Chinese advanced BTC patients. MATERIALS AND METHODS: Eligible patients with locally advanced or metastatic BTC administrated intravenous 100 mg/m2 nab-paclitaxel, 800 mg/m2 gemcitabine, and 25 mg/m2 cisplatin every 3 weeks. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS) and adverse events, while exploratory endpoint was the association of biomarkers with efficacy. RESULTS: After the median follow-up of 25.0 months, the median PFS and OS of 34 enrolled patients were 7.1 months (95% confidence interval [CI], 5.4 to 13.7) and 16.4 months (95% CI, 10.9 to 23.6), respectively. The most common treatment-related adverse events at ≥ 3 grade were neutropenia (26.5%) and leukopenia (26.5%). Survival analyses demonstrated that carcinoembryonic antigen (CEA) levels could monitor patients' survival outcomes. A significant increase in the number of infiltrating CD4+ cells (p=0.008) and a decrease in programmed death-1-positive (PD-1+) cells (p=0.032) were observed in the response patients. CONCLUSION: In advanced BTC patients, nab-paclitaxel plus gemcitabine and cisplatin regimen showed therapeutic potential. Potential prognostic factors of CEA levels, number of CD4+ cells and PD-1+ cells may help us maximize the efficacy benefit.
Subject(s)
Albumins , Bile Duct Neoplasms , Paclitaxel , Pancreatic Neoplasms , Humans , Gemcitabine , Cisplatin/adverse effects , Deoxycytidine/adverse effects , Carcinoembryonic Antigen/therapeutic use , Programmed Cell Death 1 Receptor , Bile Duct Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Pancreatic Neoplasms/pathologyABSTRACT
We identified clinical characteristics of 30 pulmonary metastasis (PM) patients and 29 second primary lung cancer (SPLC) patients with feature of solitary pulmonary mass (SPM) after radical treatment of prior cancers. 6.7% and 44.8% patients presented with centrally located SPM and the median event-free durations were 33 and 72 months in PM and SPLC groups, respectively. PM was more likely to be found in prior cancers with stage III. In conclusion, the location of SPM, the event-free duration and the prior tumor staging were important features for differentiating SPLC from PM among patients with SPM after prior cancers.
Subject(s)
Colorectal Neoplasms/diagnosis , Lung Neoplasms/diagnosis , Neoplasms, Second Primary/diagnosis , Adult , Aged , Aged, 80 and over , Breast Neoplasms/diagnosis , Breast Neoplasms/pathology , Breast Neoplasms/therapy , Colorectal Neoplasms/pathology , Colorectal Neoplasms/therapy , Diagnosis, Differential , Disease-Free Survival , Female , Head and Neck Neoplasms/diagnosis , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/therapy , Humans , Kidney Neoplasms/diagnosis , Kidney Neoplasms/pathology , Kidney Neoplasms/therapy , Lung Neoplasms/secondary , Lung Neoplasms/therapy , Male , Middle Aged , Neoplasm Staging , Neoplasms, Second Primary/therapy , Uterine Cervical Neoplasms/diagnosis , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/therapyABSTRACT
OBJECTIVE: To investigate the expression of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) in penile cancer. METHODS: A total of 96 patients with penile cancer were included, the expression of TS and DPD in tumor tissues were examined by immunohistochemistry method, the relationship of TS and DPD expressions with the clinical characters were also analyzed. RESULTS: The expression of TS and DPD in penile cancer tissue were 41. 67% (40/96) and 33. 33% (32/96) respectively. There was a positive correlation between TS and DPD expression (Pearson C= 0. 362, P<0. 01). DPD was found to be more expressed in non-smoking patients (P = 0. 040). CONCLUSION: TS and DPD were moderately expressed in penile cancer and their expressions were positively correlated. This could be helpful for the application of fluorouracil in chemotherapy for the patients with penile cancer.
Subject(s)
Carcinoma, Squamous Cell/enzymology , Dihydrouracil Dehydrogenase (NADP)/metabolism , Penile Neoplasms/enzymology , Thymidylate Synthase/metabolism , Adult , Aged , Aged, 80 and over , Fluorouracil/therapeutic use , Humans , Male , Middle AgedABSTRACT
BACKGROUND: Fruquintinib has demonstrated significant improvement in overall survival (OS) among previously treated metastatic colorectal cancer (mCRC) patients. However, the utilization of fruquintinib has been constrained by various toxicities, such as hand-foot skin reaction (HFSR) and hypertension, particularly in elderly patients with reduced tolerance to the standard dosage. This study aims to investigate the efficacy and safety of fruquintinib dose-escalation strategy for elderly refractory mCRC patients. PATIENTS AND METHODS: This open-label, single-arm, phase II trial included patients aged 65 years or over with mCRC who had progressed after two or more lines of chemotherapy. Fruquintinib was administered for 21 consecutive days of a 28-day treatment cycle. The starting dose of fruquintinib was 3 mg/day and escalated to 4 mg/day in Week 2 and 5 mg/day in Week 3 if no significant drug-related toxicity was observed. The highest tolerated dose from Cycle 1 would be administered in Cycle 2 and all subsequent cycles. Before commencing treatment, all enrolled patients underwent a G8 questionnaire and comprehensive geriatric assessments. The primary endpoint of the study was progression-free survival (PFS). RESULTS: A total of 29 patients were enrolled and all started fruquintinib at 3 mg/day. Fifteen patients (51.7%) were subsequently escalated to 4 mg/day and 4 (13.8%) to 5 mg/day. Only four (13.8%) patients discontinued treatment due to adverse events (AEs). The median PFS was 3.8 months (95% CI, 2.7-4.9), and the median OS was 7.6 months (95% CI, 6.5-8.7). Treatment-related adverse events (TRAEs) were observed in all 29 patients (100%). The most frequently occurring (>10%) TRAEs greater than Grade 3 were HFSR (20.7%), hypertension (20.7%), and diarrhea (10.3%). CONCLUSION: Our study indicated that a dose of 4 mg/day was well tolerated by most elderly patients, suggesting that fruquintinib dose-escalation strategy during the first cycle could serve as a viable alternative to the standard 5 mg/day dosing.