By means of programs GTMPAC based- on generalized triangle method,analy-sis and synthesis of mechanism design in accordance with absolutely graphicalmethod(absolutely germetrical method) is developed. In this paper we...By means of programs GTMPAC based- on generalized triangle method,analy-sis and synthesis of mechanism design in accordance with absolutely graphicalmethod(absolutely germetrical method) is developed. In this paper we make a specialstudy about Five- Position graphical synthesis.展开更多
Overexpression of human epidermal growth factor receptor 2 (HER2) occurs in approximately 15–20% of breast cancer cases. HER2 is a member of the epidermal growth factor receptor (EGFR) family with tyrosinase kinase a...Overexpression of human epidermal growth factor receptor 2 (HER2) occurs in approximately 15–20% of breast cancer cases. HER2 is a member of the epidermal growth factor receptor (EGFR) family with tyrosinase kinase activity, and its overexpression is linked to poor prognosis and shorter progression-free survival (PFS) and overall survival (OS). Among various treatment options, HER2-targeting monoclonal antibodies and tyrosine kinase inhibitors (TKIs) have mostly been applied in recent decades to treat HER2-positive (HER2^(+)) breast cancer patients. Although positive clinical outcomes were documented in both advanced disease and neoadjuvant settings, the development of resistance mechanisms to such approaches has been one of the major challenges with the continuous usage of these drugs. In addition, patients who experience disease progression after treatment with multiple HER2-targeted therapies often have limited treatment options. The Food and Drug Administration (FDA) has recently approved a new TKI (i.e., tucatinib) for use in combination with immunotherapy and/or chemotherapeutic agents for the treatment of advanced-stage/metastatic HER2^(+) breast cancer. This review highlights recent updates on the efficacy of tucatinib-based therapeutic approaches in experimental models as well as in the clinical settings of HER2^(+) breast cancer.展开更多
Objective: The aim of this study was to investigate the factors influencing pathological complete response(pCR)rate in early breast cancer patients receiving neoadjuvant dual-target [trastuzumab(H) + pertuzumab(P)] th...Objective: The aim of this study was to investigate the factors influencing pathological complete response(pCR)rate in early breast cancer patients receiving neoadjuvant dual-target [trastuzumab(H) + pertuzumab(P)] therapy combined with chemotherapy. Additionally, the consistency of the Miller-Payne and residual cancer burden(RCB)systems in evaluating the efficacy of neoadjuvant therapy for early human epidermal growth factor receptor-2(HER2)+ breast cancer was analyzed.Methods: The clinicopathological data of female patients with early-stage HER2+ breast cancer who received dual-target neoadjuvant therapy at 26 hospitals of the Chinese Society of Breast Surgery(CSBrS) from March 2019 to December 2021 were collected. Patients were allocated to four groups: the HER2 immunohistochemistry(IHC)3+/hormone receptor(HR)-, IHC3+/HR+, IHC2+ in situ hybridization(ISH)+/HR-and IHC2+ ISH+/HR+groups. The overall pCR rate for patients, the pCR rate in each group and the factors affecting the pCR rate were analyzed. The consistency between the Miller-Payne and RCB systems in assessing the efficacy of neoadjuvant therapy was analyzed.Results: From March 1, 2019, to December 31, 2021, 77,376 female patients with early-stage breast cancer were treated at 26 hospitals;18,853(24.4%) of these patients were HER2+. After exclusion of unqualified patients, 2,395 patients who received neoadjuvant dual-target(H+P) therapy combined with chemotherapy were included in this study. The overall pCR rate was 53.0%, and the patients' HR statuses and different HER2+ statuses were significantly correlated with the pCR rate(P<0.05). The consistency of the pathological efficacy assessed by the Miller-Payne and RCB systems was 88.0%(κ=0.717, P<0.001).Conclusions: Different HER2 expression statuses and HR expression statuses are correlated with the pCR rate after dual-target neoadjuvant therapy in HER2+ breast cancer patients. There is a relatively good consistency between Miller-Payne and RCB systems in evaluating the pathologic efficacy of neoadjuvant therapy for HER2+breast cancer.展开更多
A 62-year-old male was referred to our hospital because of liver dysfunction, diffuse pancreatic swelling, and trachelophyma. At admission, the patient was free of pain. Physical examination showed enlarged and palpab...A 62-year-old male was referred to our hospital because of liver dysfunction, diffuse pancreatic swelling, and trachelophyma. At admission, the patient was free of pain. Physical examination showed enlarged and palpable bilateral submandibular masses, but no palpable mass or organomegaly in the abdomen. Laboratory findings were as follows： total protein 90 g/L with γ-globulin of 37.3% （33 g/L）, total bilirubin 4 mg/L, aspartate aminotransferase 39 IU/L, alanine aminotransferase 67 IU/L,γ-glutamyl transpeptidase 1 647 IU/L, and amylase 135 IU/L. Autoantibodies were negative, and tumor markers were within the normal range. Serum IgG4 level was markedly elevated （18 900 rag/L）. Computed tomography （CT） showed diffuse swelling of the pancreas and dilatation of both common and intra-hepatic bile ducts. Endoscopic retrograde pancreatography （ERP） revealed diffuse irregular and narrow main pancreatic duct and stenosis of the lower common bile duct. Biopsy specimens from the pancreas, salivary gland and liver showed marked periductal IgG4-positive plasma cell infiltration with fibrosis. We considered this patient to be autoimmune pancreatitis （AIP） with fibrosclerosis of the salivary gland and biliary tract, prescribed prednisolone at an initial dose of 40 mg/d. Three months later, the laboratory data improved almost to normal. Abdominal CT reflected prominent improvement in the pancreatic lesion. Swelling of the salivary gland also improved. At present, the patient is on 10 mg/d of prednisolone without recurrence of the pancreatitis. We present here a case of AIP with fibrosclerosis of salivary gland and biliary tract.展开更多
Objective:This study aimed to compare the efficacy of anti-CD19 chimeric antigen receptor T cells(CAR-T cells)versus chemotherapy plus donor lymphocyte infusion(chemo-DLI)for treating relapsed CD 19-positive B-cell ac...Objective:This study aimed to compare the efficacy of anti-CD19 chimeric antigen receptor T cells(CAR-T cells)versus chemotherapy plus donor lymphocyte infusion(chemo-DLI)for treating relapsed CD 19-positive B-cell acute lymphoblastic leukemia(B-ALL)after allogeneic hematopoietic stem cell transplantation(allo-HSCT).Methods:Clinical data of 43 patients with B-ALL who relapsed after allo-HSCT were retrospectively analyzed.Twenty-two patients were treated with CAR-T cells(CAR-T group),and 21 with chemotherapy plus DLI(chemo-DLI group).The complete remission(CR)and minimal residual disease(MRD)-negative CR rates,leukemia-free survival(LFS)rate,overall survival(OS)rate,and incidence of acute graft-versus-host disease(aGVHD),cytokine release syndrome(CRS)and immune effector cell-associated neurotoxicity syndrome(ICANS)were compared between the two groups.Results:The CR and MRD-negative CR rates in the CAR-T group(77.3%and 61.5%)were significantly higher than those in the chemo-DLI group(38.1%and 23.8%)(P=0.008 and P=0.003).The 1-and 2-year LFS rates in the CAR-T group were superior to those in the chemo-DLI group:54.5%and 50.0%vs.9.5%and 4.8%(P=0.0001 and P=0.00004).The 1-and 2-year OS rates in the CAR-T versus chemo-DLI group were 59.1%and 54.5%vs.19%and 9.5%(P=0.011 and P=0.003).Six patients(28.6%)with grade 2-4 aGVHD were identified in the chemo-DLI group.Two patients(9.1%)in the CAR-T group developed grade 1-2 aGVHD.Nineteen patients(86.4%)developed CRS in the CAR-T group,comprising grade 1-2 CRS in 13 patients(59.1%)and grade 3 CRS in 6 patients(27.3%).Two patients(9.1%)developed grade 1-2 ICANS.Conclusion:Donor-derived anti-CD19 CAR-T-cell therapy may be better,safer,and more effective than chemo-DLI for B-ALL patients who relapse after allo-HSCT.展开更多
Objective: Despite cardiotoxicity overlap, the trastuzumab/pertuzumab and anthracycline combination remains crucial due to significant benefits. Pegylated liposomal doxorubicin(PLD), a less cardiotoxic anthracycline, ...Objective: Despite cardiotoxicity overlap, the trastuzumab/pertuzumab and anthracycline combination remains crucial due to significant benefits. Pegylated liposomal doxorubicin(PLD), a less cardiotoxic anthracycline, was evaluated for efficacy and cardiac safety when combined with cyclophosphamide and followed by taxanes with trastuzumab/pertuzumab in human epidermal growth factor receptor-2(HER2)-positive early breast cancer(BC).Methods: In this multicenter, phase II study, patients with confirmed HER2-positive early BC received four cycles of PLD(30-35 mg/m^(2)) and cyclophosphamide(600 mg/m^(2)), followed by four cycles of taxanes(docetaxel,90-100 mg/m^(2) or nab-paclitaxel, 260 mg/m^(2)), concomitant with eight cycles of trastuzumab(8 mg/kg loading dose,then 6 mg/kg) and pertuzumab(840 mg loading dose, then 420 mg) every 3 weeks. The primary endpoint was total pathological complete response(tp CR, yp T0/is yp N0). Secondary endpoints included breast p CR(bp CR),objective response rate(ORR), disease control rate, rate of breast-conserving surgery(BCS), and safety(with a focus on cardiotoxicity).Results: Between May 27, 2020 and May 11, 2022, 78 patients were treated with surgery, 42(53.8%) of whom had BCS. After neoadjuvant therapy, 47 [60.3%, 95% confidence interval(95% CI), 48.5%-71.2%] patients achieved tp CR, and 49(62.8%) achieved bp CR. ORRs were 76.9%(95% CI, 66.0%-85.7%) and 93.6%(95% CI,85.7%-97.9%) after 4-cycle and 8-cycle neoadjuvant therapy, respectively. Nine(11.5%) patients experienced asymptomatic left ventricular ejection fraction(LVEF) reductions of ≥10% from baseline, all with a minimum value of >55%. No treatment-related abnormal cardiac function changes were observed in mean N-terminal pro-BNP(NT-pro BNP), troponin I, or high-sensitivity troponin.Conclusions: This dual HER2-blockade with sequential polychemotherapy showed promising activity with rapid tumor regression in HER2-positive BC. Importantly, this regimen showed an acceptable safety profile,especially a low risk of cardiac events, suggesting it as an attractive treatment approach with a favorable risk-benefit balance.展开更多
BACKGROUND Superficial CD34-positive fibroblast tumors(SCPFTs)are newly recognized fibroblast and myofibroblast tumors representing intermediate tumors.To the best of our knowledge,fewer than 50 cases have been report...BACKGROUND Superficial CD34-positive fibroblast tumors(SCPFTs)are newly recognized fibroblast and myofibroblast tumors representing intermediate tumors.To the best of our knowledge,fewer than 50 cases have been reported.Perianal SCPFT has not been previously reported.CASE SUMMARY A 55-year-old man was hospitalized upon discovering a painless perianal lump 10 d prior.Physical examination showed a lump of approximately 3 cm×4 cm in the 7 to 8 o’clock direction in the perianal area.Perianal abscess was considered the primary diagnosis.Lump removal surgery was performed under epidural anesthesia.Postoperative pathology showed a well-circumscribed,soft tissuederived,spindle-cell tumor with strong CD34 positivity by immunohistochemistry.The final diagnosis was perianal SCPFT.There were no complications,and the patient was followed for more than 8 mo without recurrence or metastasis.CONCLUSION We report a case of perianal superficial CD34-positive fibroblast tumor.This rare mesenchymal neoplasm has distinctive histomorphology,which is important for diagnosis.Comprehensive consideration of clinical information,imaging,histology,and immunohistochemistry is important for diagnosis.展开更多
Purpose:To investigate the density, distribution and morphology of macrophages and MHC class II -positive dendritic cells in the iris and ciliary body of lewis rats. Methods:Immunohistochemistry was performed using mo...Purpose:To investigate the density, distribution and morphology of macrophages and MHC class II -positive dendritic cells in the iris and ciliary body of lewis rats. Methods:Immunohistochemistry was performed using monoclonal antibodies specific to monocytes and macrophages (ED1,ED2) and MHC class II -positive cells (OX6) on wholemounts of the iris-ciliary body complex isolated form normal lewis rats.Results:A well developed network of macrophages was present in the iris and ciliary body of normal lewis rats. These cells, morphologically displaying dendriti-form or pleiomorphic appearance, were more densely arranged in mid-iris (950 + 189 cells/mm2) than in iris base (482 ± 78 cells/mm2) and pupil margin (595 ± 92 cells/mm2). A similar network of MHC class II -positive cells with a cell density 452 ± 78 cells/mm2 was almost uniformly distributed in the iris of normal lewis rats.Conclusions : A network of macrophages and MHC class II -positive cells was established in the iris and ciliary body of展开更多
Trastuzumab has improved survival rates in human epidermal growth factor receptor 2(HER2)-positive breast cancer(BC),but drug resistance leads to treatment failure.Natural killer(NK)cell-mediated antibody-dependent ce...Trastuzumab has improved survival rates in human epidermal growth factor receptor 2(HER2)-positive breast cancer(BC),but drug resistance leads to treatment failure.Natural killer(NK)cell-mediated antibody-dependent cell cytotoxicity(ADCC)represents an essential antitumor immune mechanism of trastuzumab.Traditional Chinese medicine(TCM)has been used for centuries to treat diseases because of its capacity to improve immune responses.Xianling Lianxia formula(XLLXF),based on the principle of“strengthening body and eliminating toxin”,exhibits a synergistic effect in the trastuzumab treatment of patients with HER2-positive BC.Notably,this synergistic effect of XLLXF was executed by enhancing NK cells and ADCC,as demonstrated through in vitro co-culture of NK cells and BC cells and in vivo intervention experiments.Mechanistically,the augmented impact of XLLXF on NK cells is linked to a decrease in cytokine inducible Src homology 2(SH2)containing protein(CISH)expression,which in turn activates the Janus kinase 1(JAK1)/signal transducer and activator of transcription 5(STAT5)pathway.Collectively,these findings suggested that XLLXF holds promise for enhancing NK cell function and sensitizing patients with HER2-positive BC to trastuzumab.展开更多
Objective: Hemay022 is a novel small-molecule and an irreversible tyrosine kinase inhibitor with the target of epidermal growth factor receptor(EGFR)/human epidermal growth factor receptor 2(HER2), which demonstrated ...Objective: Hemay022 is a novel small-molecule and an irreversible tyrosine kinase inhibitor with the target of epidermal growth factor receptor(EGFR)/human epidermal growth factor receptor 2(HER2), which demonstrated anti-tumor activity in preclinical studies. This first-in-human study evaluated the safety, pharmacokinetics,tolerability and preliminary anti-tumor activity of Hemay022 in HER2-positive advanced breast cancer patients.Methods: Heavily pretreated patients with HER2-positive advanced breast cancer were assigned to eight dose cohorts in a 3+3 dose-escalation pattern at doses of 50-600 mg QD and 300 mg BID. Eligible patients were given a single dose of Hemay022 on d 1 in week 0, followed by once daily continuous doses for four weeks in 28-day cycles.Pharmacokinetic samples were obtained on d 1 and d 28. Clinical responses were assessed every eight weeks.Results: Twenty-eight patients with advanced breast cancer were treated with Hemay022. The most frequently reported drug-related adverse events were diarrhoea(85.7%), vomiting(28.6%), nausea(25.0%) and decreased appetite(17.9%). No grade 4 drug-related adverse events were reported. At 50-600 mg doses, steady state areas under the concentration-time curve and peak concentrations increased with doses. One patient achieved complete response(CR), and three achieved partial response(PR). The objective response rate(ORR) and disease control rate(DCR) were 14.3% and 46.4% in 28 patients, respectively. The median progression-free survival(PFS) was3.98 months.Conclusions: Hemay022 at the dose of 500 mg once daily was well tolerated. The pharmacokinetic properties and encouraging anti-tumor activities of Hemay022 in advanced breast cancer patients warranted further evaluation of Hemay022 for treating breast cancer patients in the current phase Ⅲ trial(No. NCT05122494).展开更多
BACKGROUND Patients with human epidermal growth factor receptor 2(HER2)-positive advanced gastric cancer have poor outcomes.Trastuzumab combined with chemotherapy is the first-line standard treatment for HER2-positive...BACKGROUND Patients with human epidermal growth factor receptor 2(HER2)-positive advanced gastric cancer have poor outcomes.Trastuzumab combined with chemotherapy is the first-line standard treatment for HER2-positive advanced gastric cancer.Inetetamab is a novel anti-HER2 drug,and its efficacy and safety in gastric cancer have not yet been reported.AIM To evaluate the efficacy and safety of the S-1 plus oxaliplatin(SOX)regimen combined with inetetamab as a first-line treatment for HER2-positive advanced gastric cancer.METHODS Thirty-eight patients with HER2-positive advanced gastric cancer or gastroeso-phageal junction adenocarcinoma were randomly divided into two groups:One group received inetetamab combined with the SOX regimen,and the other group received trastuzumab combined with the SOX regimen.After 4-6 cycles,patients with stable disease received maintenance therapy.The primary endpoints were progression-free survival(PFS)and overall survival(OS),and the secondary endpoints were the objective response rate,disease control rate,and adverse events(AEs).RESULTS Thirty-seven patients completed the trial,with 18 patients in the inetetamab group and 19 patients in the trastuzumab group.In the inetetamab group,the median PFS was 8.5 months,whereas it was 7.3 months in the trastuzumab group(P=0.046);this difference was significant.The median OS in the inetetamab group vs the trastuzumab group was 15.4 months vs 14.3 months(P=0.33),and the objective response rate was 50%vs 42%(P=0.63),respectively;these differences were not significant.Common AEs included leukopenia,thrombocytopenia,nausea,and vomiting.The incidence rates of grade≥3 AEs were 56%in the inetetamab group and 47%in the trastuzumab group(P=0.63),with no significant difference.CONCLUSION In the first-line treatment of HER2-positive advanced gastric cancer,inetetamab and trastuzumab showed comparable efficacy.The inetetamab group showed superior PFS,and both groups had good safety.展开更多
Trastuzumab resistance is one of the causes of poor prognosis in patients with human epidermal growth factor receptor 2(HER2)-positive(HER2+)breast cancer(BC).The truncated isoform of dopamine-and cAMPregulated phosph...Trastuzumab resistance is one of the causes of poor prognosis in patients with human epidermal growth factor receptor 2(HER2)-positive(HER2+)breast cancer(BC).The truncated isoform of dopamine-and cAMPregulated phosphoprotein(t-DARPP)has been reported to be involved in trastuzumab therapy resistance and promoting tumor progression.To evaluate the t-DARPP expression in BC,paired tumors and surrounding normal tissues were analyzed by real-time polymerase chain reaction and confirmed higher DARPP-32 kDa family mRNA expression in HER2+BC tumor tissues.We established 2 patient-derived xenografts(PDX)mice models to test the efficacy of trastuzumab,named model 1(non-responder)and model 2(responder).t-DARPP and p95-HER2 protein-protein interactions were detected in PDX tumor tissue from non-responders using Förster resonance energy transfer assays.Instead,there is no response from the responder.Furthermore,mechanistic studies using transwell and western blot assays demonstrated that t-DARPP could upregulate epithelial-mesenchymal transition signaling proteins,enhance p95-HER2 expression and promote cell migration.We found that quercetin effectively reduced t-DARPP expression in HER2+BC cells.In t-DARPP ShRNA-suppressed cells,quercetin synergistically enhanced trastuzumab-induced apoptotic cell death and G2/M phase arrest.In conclusion,the combination of quercetin and trastuzumab treatment by targeting t-DARPP in HER2+BC patients has the potential as a biomarker for mitigating drug resistance.展开更多
Introduction:Although many studies have shown the vast potential of circulating tumor cells(CTCs)detection in cancer diagnosis and prognosis,our understanding of their clinical significance is still far from complete....Introduction:Although many studies have shown the vast potential of circulating tumor cells(CTCs)detection in cancer diagnosis and prognosis,our understanding of their clinical significance is still far from complete.A major obstacle arises from the lack of well-established tumor or tissue-specific markers to detect CTCs by immunocytochemical staining after immunomagnetic enrichment(IE).Methods:We have established the utility of cytokeratin 20(CK20),a gastrointestinal tract specific marker,for the specific detection and identification of colorectal cancer(CRC)CTCs.This breakthrough was successfully validated in spike-in experiments using CRC cell line models followed by a pilot study which recruited 32 metastatic CRC patients,25 benign colorectal diseases patients and 27 normal subjects.Results:CK20-positive CTCs were detected in 90%metastatic CRC patients but not in benign colorectal diseases patients and normal subjects using this refined assay.Conclusions:These impressive results have laid the foundation for further development of CK20-positive CTCs as a promising marker in diagnosis,prognostication and treatment monitoring of metastatic CRC.展开更多
Adult stem cells have been identified in a variety of mammalian organs including skin, hair follicles, pancreas, and bone marrow （Kruse et al., 2004）. These stem cells reside in a specific cellular environment where...Adult stem cells have been identified in a variety of mammalian organs including skin, hair follicles, pancreas, and bone marrow （Kruse et al., 2004）. These stem cells reside in a specific cellular environment where they remain in an undifferentiated state （Theise, 2006）. In addition, they are generally considered to be mul- tipotent, possessing the capacity to generate multiple cell types within the tissue, and thus play an important role in tissue mainte- nance and regeneration.展开更多
Antibody drug conjugates (ADCs) are a new class of drugs that combine chemosynthetic drugs with antibody drugs through a linker. Antibody drug conjugates combine the targeting characteristics of traditional antibody d...Antibody drug conjugates (ADCs) are a new class of drugs that combine chemosynthetic drugs with antibody drugs through a linker. Antibody drug conjugates combine the targeting characteristics of traditional antibody drugs with the cytotoxic characteristics of small molecule drugs, while reducing the side effects of both drugs, making them a kind of “biological missile” and representing a relatively new and evolving class of anti-cancer drugs. Antibody-coupled drugs are currently used in many solid tumors, and this article reviews the clinical application of antibody-coupled drugs in HER2-positive gastric cancer.展开更多
Hormone receptor(HR)-positive breast cancer(BC)is the most common subtype of BC and some patients with such tumors experience recurrences.Endocrine-based therapy(ET)(e.g.,tamoxifen,aromatase inhibitors(AIs),and fulves...Hormone receptor(HR)-positive breast cancer(BC)is the most common subtype of BC and some patients with such tumors experience recurrences.Endocrine-based therapy(ET)(e.g.,tamoxifen,aromatase inhibitors(AIs),and fulvestrant)that has improved outcomes in such patients represents the initial therapy for women with HR-positive/human epidermal growth factor receptor 2(HER2)-negative BC(considering no evidence of visceral crisis).However,the resistance to ET can occur in almost 50%of HR-positive BCs.In order to improve outcomes of patients with HR-positive metastatic BC,new treatment strategies are required.One such therapy is the new class of medications,cyclin-dependent kinase(CDK)4/6 inhibitors,that have improved the outcomes in such patients(both endocrine-sensitive and endocrine-resistant).This article presents evidence from the main clinical trials,which led to the approval of palbociclib,ribociclib,and abemaciclib.These three CDK 4/6 inhibitors have shown a significant improvement of the progression-free survival(PFS)in patients with HR-positive/HER2-negative metastatic BC when used in combination with selected ETs.In addition,some important patient management considerations,when choosing a particular CDK 4/6 inhibitor for an individual patient are presented.Furthermore,a need to find biomarkers for CDK 4/6 inhibitor sensitivity,efficacy,and resistance,to be able to precisely select the best patientcandidates for this treatment is highlighted.展开更多
文摘By means of programs GTMPAC based- on generalized triangle method,analy-sis and synthesis of mechanism design in accordance with absolutely graphicalmethod(absolutely germetrical method) is developed. In this paper we make a specialstudy about Five- Position graphical synthesis.
文摘Overexpression of human epidermal growth factor receptor 2 (HER2) occurs in approximately 15–20% of breast cancer cases. HER2 is a member of the epidermal growth factor receptor (EGFR) family with tyrosinase kinase activity, and its overexpression is linked to poor prognosis and shorter progression-free survival (PFS) and overall survival (OS). Among various treatment options, HER2-targeting monoclonal antibodies and tyrosine kinase inhibitors (TKIs) have mostly been applied in recent decades to treat HER2-positive (HER2^(+)) breast cancer patients. Although positive clinical outcomes were documented in both advanced disease and neoadjuvant settings, the development of resistance mechanisms to such approaches has been one of the major challenges with the continuous usage of these drugs. In addition, patients who experience disease progression after treatment with multiple HER2-targeted therapies often have limited treatment options. The Food and Drug Administration (FDA) has recently approved a new TKI (i.e., tucatinib) for use in combination with immunotherapy and/or chemotherapeutic agents for the treatment of advanced-stage/metastatic HER2^(+) breast cancer. This review highlights recent updates on the efficacy of tucatinib-based therapeutic approaches in experimental models as well as in the clinical settings of HER2^(+) breast cancer.
基金supported by Beijing Science and Technology Innovation Medical Development Foundation (No. KC2021-JF-0167-01 and No. KC2021-JF-0167-24)。
文摘Objective: The aim of this study was to investigate the factors influencing pathological complete response(pCR)rate in early breast cancer patients receiving neoadjuvant dual-target [trastuzumab(H) + pertuzumab(P)] therapy combined with chemotherapy. Additionally, the consistency of the Miller-Payne and residual cancer burden(RCB)systems in evaluating the efficacy of neoadjuvant therapy for early human epidermal growth factor receptor-2(HER2)+ breast cancer was analyzed.Methods: The clinicopathological data of female patients with early-stage HER2+ breast cancer who received dual-target neoadjuvant therapy at 26 hospitals of the Chinese Society of Breast Surgery(CSBrS) from March 2019 to December 2021 were collected. Patients were allocated to four groups: the HER2 immunohistochemistry(IHC)3+/hormone receptor(HR)-, IHC3+/HR+, IHC2+ in situ hybridization(ISH)+/HR-and IHC2+ ISH+/HR+groups. The overall pCR rate for patients, the pCR rate in each group and the factors affecting the pCR rate were analyzed. The consistency between the Miller-Payne and RCB systems in assessing the efficacy of neoadjuvant therapy was analyzed.Results: From March 1, 2019, to December 31, 2021, 77,376 female patients with early-stage breast cancer were treated at 26 hospitals;18,853(24.4%) of these patients were HER2+. After exclusion of unqualified patients, 2,395 patients who received neoadjuvant dual-target(H+P) therapy combined with chemotherapy were included in this study. The overall pCR rate was 53.0%, and the patients' HR statuses and different HER2+ statuses were significantly correlated with the pCR rate(P<0.05). The consistency of the pathological efficacy assessed by the Miller-Payne and RCB systems was 88.0%(κ=0.717, P<0.001).Conclusions: Different HER2 expression statuses and HR expression statuses are correlated with the pCR rate after dual-target neoadjuvant therapy in HER2+ breast cancer patients. There is a relatively good consistency between Miller-Payne and RCB systems in evaluating the pathologic efficacy of neoadjuvant therapy for HER2+breast cancer.
文摘A 62-year-old male was referred to our hospital because of liver dysfunction, diffuse pancreatic swelling, and trachelophyma. At admission, the patient was free of pain. Physical examination showed enlarged and palpable bilateral submandibular masses, but no palpable mass or organomegaly in the abdomen. Laboratory findings were as follows： total protein 90 g/L with γ-globulin of 37.3% （33 g/L）, total bilirubin 4 mg/L, aspartate aminotransferase 39 IU/L, alanine aminotransferase 67 IU/L,γ-glutamyl transpeptidase 1 647 IU/L, and amylase 135 IU/L. Autoantibodies were negative, and tumor markers were within the normal range. Serum IgG4 level was markedly elevated （18 900 rag/L）. Computed tomography （CT） showed diffuse swelling of the pancreas and dilatation of both common and intra-hepatic bile ducts. Endoscopic retrograde pancreatography （ERP） revealed diffuse irregular and narrow main pancreatic duct and stenosis of the lower common bile duct. Biopsy specimens from the pancreas, salivary gland and liver showed marked periductal IgG4-positive plasma cell infiltration with fibrosis. We considered this patient to be autoimmune pancreatitis （AIP） with fibrosclerosis of the salivary gland and biliary tract, prescribed prednisolone at an initial dose of 40 mg/d. Three months later, the laboratory data improved almost to normal. Abdominal CT reflected prominent improvement in the pancreatic lesion. Swelling of the salivary gland also improved. At present, the patient is on 10 mg/d of prednisolone without recurrence of the pancreatitis. We present here a case of AIP with fibrosclerosis of salivary gland and biliary tract.
基金supported by grants from the National Natural Science Foundation of China(No.82020108004)the Hospital-level Clinical Innovation Military-Civilian Special Project of Army Medical University(No.2018JSLC0020)+1 种基金Chongqing Science and Technology Innovation Leading Talent(No.CSTCCXLJRC201718)Natural Science Foundation of Chongqing Innovation Group Science Program(No.cstc2021jcyj-cxttX0001).
文摘Objective:This study aimed to compare the efficacy of anti-CD19 chimeric antigen receptor T cells(CAR-T cells)versus chemotherapy plus donor lymphocyte infusion(chemo-DLI)for treating relapsed CD 19-positive B-cell acute lymphoblastic leukemia(B-ALL)after allogeneic hematopoietic stem cell transplantation(allo-HSCT).Methods:Clinical data of 43 patients with B-ALL who relapsed after allo-HSCT were retrospectively analyzed.Twenty-two patients were treated with CAR-T cells(CAR-T group),and 21 with chemotherapy plus DLI(chemo-DLI group).The complete remission(CR)and minimal residual disease(MRD)-negative CR rates,leukemia-free survival(LFS)rate,overall survival(OS)rate,and incidence of acute graft-versus-host disease(aGVHD),cytokine release syndrome(CRS)and immune effector cell-associated neurotoxicity syndrome(ICANS)were compared between the two groups.Results:The CR and MRD-negative CR rates in the CAR-T group(77.3%and 61.5%)were significantly higher than those in the chemo-DLI group(38.1%and 23.8%)(P=0.008 and P=0.003).The 1-and 2-year LFS rates in the CAR-T group were superior to those in the chemo-DLI group:54.5%and 50.0%vs.9.5%and 4.8%(P=0.0001 and P=0.00004).The 1-and 2-year OS rates in the CAR-T versus chemo-DLI group were 59.1%and 54.5%vs.19%and 9.5%(P=0.011 and P=0.003).Six patients(28.6%)with grade 2-4 aGVHD were identified in the chemo-DLI group.Two patients(9.1%)in the CAR-T group developed grade 1-2 aGVHD.Nineteen patients(86.4%)developed CRS in the CAR-T group,comprising grade 1-2 CRS in 13 patients(59.1%)and grade 3 CRS in 6 patients(27.3%).Two patients(9.1%)developed grade 1-2 ICANS.Conclusion:Donor-derived anti-CD19 CAR-T-cell therapy may be better,safer,and more effective than chemo-DLI for B-ALL patients who relapse after allo-HSCT.
基金supported by the National Natural Science Foundation of China (No. 82003311, No. 82061148016, No. 82230057 and No. 82272859)National Key R&D Program of China (No. 2022YFC2505101)+2 种基金Sun Yat-Sen Clinical Research Cultivating Program (No. SYS-Q202004)Beijing Medical Award Foundation (No. YXJL2020-0941-0760)Guangzhou Science and Technology Program (No. 202102010272 and No. 202201020486)。
文摘Objective: Despite cardiotoxicity overlap, the trastuzumab/pertuzumab and anthracycline combination remains crucial due to significant benefits. Pegylated liposomal doxorubicin(PLD), a less cardiotoxic anthracycline, was evaluated for efficacy and cardiac safety when combined with cyclophosphamide and followed by taxanes with trastuzumab/pertuzumab in human epidermal growth factor receptor-2(HER2)-positive early breast cancer(BC).Methods: In this multicenter, phase II study, patients with confirmed HER2-positive early BC received four cycles of PLD(30-35 mg/m^(2)) and cyclophosphamide(600 mg/m^(2)), followed by four cycles of taxanes(docetaxel,90-100 mg/m^(2) or nab-paclitaxel, 260 mg/m^(2)), concomitant with eight cycles of trastuzumab(8 mg/kg loading dose,then 6 mg/kg) and pertuzumab(840 mg loading dose, then 420 mg) every 3 weeks. The primary endpoint was total pathological complete response(tp CR, yp T0/is yp N0). Secondary endpoints included breast p CR(bp CR),objective response rate(ORR), disease control rate, rate of breast-conserving surgery(BCS), and safety(with a focus on cardiotoxicity).Results: Between May 27, 2020 and May 11, 2022, 78 patients were treated with surgery, 42(53.8%) of whom had BCS. After neoadjuvant therapy, 47 [60.3%, 95% confidence interval(95% CI), 48.5%-71.2%] patients achieved tp CR, and 49(62.8%) achieved bp CR. ORRs were 76.9%(95% CI, 66.0%-85.7%) and 93.6%(95% CI,85.7%-97.9%) after 4-cycle and 8-cycle neoadjuvant therapy, respectively. Nine(11.5%) patients experienced asymptomatic left ventricular ejection fraction(LVEF) reductions of ≥10% from baseline, all with a minimum value of >55%. No treatment-related abnormal cardiac function changes were observed in mean N-terminal pro-BNP(NT-pro BNP), troponin I, or high-sensitivity troponin.Conclusions: This dual HER2-blockade with sequential polychemotherapy showed promising activity with rapid tumor regression in HER2-positive BC. Importantly, this regimen showed an acceptable safety profile,especially a low risk of cardiac events, suggesting it as an attractive treatment approach with a favorable risk-benefit balance.
文摘BACKGROUND Superficial CD34-positive fibroblast tumors(SCPFTs)are newly recognized fibroblast and myofibroblast tumors representing intermediate tumors.To the best of our knowledge,fewer than 50 cases have been reported.Perianal SCPFT has not been previously reported.CASE SUMMARY A 55-year-old man was hospitalized upon discovering a painless perianal lump 10 d prior.Physical examination showed a lump of approximately 3 cm×4 cm in the 7 to 8 o’clock direction in the perianal area.Perianal abscess was considered the primary diagnosis.Lump removal surgery was performed under epidural anesthesia.Postoperative pathology showed a well-circumscribed,soft tissuederived,spindle-cell tumor with strong CD34 positivity by immunohistochemistry.The final diagnosis was perianal SCPFT.There were no complications,and the patient was followed for more than 8 mo without recurrence or metastasis.CONCLUSION We report a case of perianal superficial CD34-positive fibroblast tumor.This rare mesenchymal neoplasm has distinctive histomorphology,which is important for diagnosis.Comprehensive consideration of clinical information,imaging,histology,and immunohistochemistry is important for diagnosis.
基金a grant from Pubic Health Ministry of ChinaNatural Science Fundation of Guangdong Province
文摘Purpose:To investigate the density, distribution and morphology of macrophages and MHC class II -positive dendritic cells in the iris and ciliary body of lewis rats. Methods:Immunohistochemistry was performed using monoclonal antibodies specific to monocytes and macrophages (ED1,ED2) and MHC class II -positive cells (OX6) on wholemounts of the iris-ciliary body complex isolated form normal lewis rats.Results:A well developed network of macrophages was present in the iris and ciliary body of normal lewis rats. These cells, morphologically displaying dendriti-form or pleiomorphic appearance, were more densely arranged in mid-iris (950 + 189 cells/mm2) than in iris base (482 ± 78 cells/mm2) and pupil margin (595 ± 92 cells/mm2). A similar network of MHC class II -positive cells with a cell density 452 ± 78 cells/mm2 was almost uniformly distributed in the iris of normal lewis rats.Conclusions : A network of macrophages and MHC class II -positive cells was established in the iris and ciliary body of
基金This work was supported by the National Natural Science Foundation of China(Grant No.:81774308)the Multi-center Clinical Research Project for Major Diseases of Shanghai Shenkang Hospital Development Center,China(Grant No.:SHDC2020CR1050B)the High-level University Building Innovation Team,China(Grant No.:601521D).
文摘Trastuzumab has improved survival rates in human epidermal growth factor receptor 2(HER2)-positive breast cancer(BC),but drug resistance leads to treatment failure.Natural killer(NK)cell-mediated antibody-dependent cell cytotoxicity(ADCC)represents an essential antitumor immune mechanism of trastuzumab.Traditional Chinese medicine(TCM)has been used for centuries to treat diseases because of its capacity to improve immune responses.Xianling Lianxia formula(XLLXF),based on the principle of“strengthening body and eliminating toxin”,exhibits a synergistic effect in the trastuzumab treatment of patients with HER2-positive BC.Notably,this synergistic effect of XLLXF was executed by enhancing NK cells and ADCC,as demonstrated through in vitro co-culture of NK cells and BC cells and in vivo intervention experiments.Mechanistically,the augmented impact of XLLXF on NK cells is linked to a decrease in cytokine inducible Src homology 2(SH2)containing protein(CISH)expression,which in turn activates the Janus kinase 1(JAK1)/signal transducer and activator of transcription 5(STAT5)pathway.Collectively,these findings suggested that XLLXF holds promise for enhancing NK cell function and sensitizing patients with HER2-positive BC to trastuzumab.
文摘Objective: Hemay022 is a novel small-molecule and an irreversible tyrosine kinase inhibitor with the target of epidermal growth factor receptor(EGFR)/human epidermal growth factor receptor 2(HER2), which demonstrated anti-tumor activity in preclinical studies. This first-in-human study evaluated the safety, pharmacokinetics,tolerability and preliminary anti-tumor activity of Hemay022 in HER2-positive advanced breast cancer patients.Methods: Heavily pretreated patients with HER2-positive advanced breast cancer were assigned to eight dose cohorts in a 3+3 dose-escalation pattern at doses of 50-600 mg QD and 300 mg BID. Eligible patients were given a single dose of Hemay022 on d 1 in week 0, followed by once daily continuous doses for four weeks in 28-day cycles.Pharmacokinetic samples were obtained on d 1 and d 28. Clinical responses were assessed every eight weeks.Results: Twenty-eight patients with advanced breast cancer were treated with Hemay022. The most frequently reported drug-related adverse events were diarrhoea(85.7%), vomiting(28.6%), nausea(25.0%) and decreased appetite(17.9%). No grade 4 drug-related adverse events were reported. At 50-600 mg doses, steady state areas under the concentration-time curve and peak concentrations increased with doses. One patient achieved complete response(CR), and three achieved partial response(PR). The objective response rate(ORR) and disease control rate(DCR) were 14.3% and 46.4% in 28 patients, respectively. The median progression-free survival(PFS) was3.98 months.Conclusions: Hemay022 at the dose of 500 mg once daily was well tolerated. The pharmacokinetic properties and encouraging anti-tumor activities of Hemay022 in advanced breast cancer patients warranted further evaluation of Hemay022 for treating breast cancer patients in the current phase Ⅲ trial(No. NCT05122494).
基金Supported by China Scientific Research Fund for HER2 Target from China Anti-Cancer Association,No.CORP-239-M9.
文摘BACKGROUND Patients with human epidermal growth factor receptor 2(HER2)-positive advanced gastric cancer have poor outcomes.Trastuzumab combined with chemotherapy is the first-line standard treatment for HER2-positive advanced gastric cancer.Inetetamab is a novel anti-HER2 drug,and its efficacy and safety in gastric cancer have not yet been reported.AIM To evaluate the efficacy and safety of the S-1 plus oxaliplatin(SOX)regimen combined with inetetamab as a first-line treatment for HER2-positive advanced gastric cancer.METHODS Thirty-eight patients with HER2-positive advanced gastric cancer or gastroeso-phageal junction adenocarcinoma were randomly divided into two groups:One group received inetetamab combined with the SOX regimen,and the other group received trastuzumab combined with the SOX regimen.After 4-6 cycles,patients with stable disease received maintenance therapy.The primary endpoints were progression-free survival(PFS)and overall survival(OS),and the secondary endpoints were the objective response rate,disease control rate,and adverse events(AEs).RESULTS Thirty-seven patients completed the trial,with 18 patients in the inetetamab group and 19 patients in the trastuzumab group.In the inetetamab group,the median PFS was 8.5 months,whereas it was 7.3 months in the trastuzumab group(P=0.046);this difference was significant.The median OS in the inetetamab group vs the trastuzumab group was 15.4 months vs 14.3 months(P=0.33),and the objective response rate was 50%vs 42%(P=0.63),respectively;these differences were not significant.Common AEs included leukopenia,thrombocytopenia,nausea,and vomiting.The incidence rates of grade≥3 AEs were 56%in the inetetamab group and 47%in the trastuzumab group(P=0.63),with no significant difference.CONCLUSION In the first-line treatment of HER2-positive advanced gastric cancer,inetetamab and trastuzumab showed comparable efficacy.The inetetamab group showed superior PFS,and both groups had good safety.
基金The National Science and Technology Council of Taiwan funded this study.
文摘Trastuzumab resistance is one of the causes of poor prognosis in patients with human epidermal growth factor receptor 2(HER2)-positive(HER2+)breast cancer(BC).The truncated isoform of dopamine-and cAMPregulated phosphoprotein(t-DARPP)has been reported to be involved in trastuzumab therapy resistance and promoting tumor progression.To evaluate the t-DARPP expression in BC,paired tumors and surrounding normal tissues were analyzed by real-time polymerase chain reaction and confirmed higher DARPP-32 kDa family mRNA expression in HER2+BC tumor tissues.We established 2 patient-derived xenografts(PDX)mice models to test the efficacy of trastuzumab,named model 1(non-responder)and model 2(responder).t-DARPP and p95-HER2 protein-protein interactions were detected in PDX tumor tissue from non-responders using Förster resonance energy transfer assays.Instead,there is no response from the responder.Furthermore,mechanistic studies using transwell and western blot assays demonstrated that t-DARPP could upregulate epithelial-mesenchymal transition signaling proteins,enhance p95-HER2 expression and promote cell migration.We found that quercetin effectively reduced t-DARPP expression in HER2+BC cells.In t-DARPP ShRNA-suppressed cells,quercetin synergistically enhanced trastuzumab-induced apoptotic cell death and G2/M phase arrest.In conclusion,the combination of quercetin and trastuzumab treatment by targeting t-DARPP in HER2+BC patients has the potential as a biomarker for mitigating drug resistance.
文摘Introduction:Although many studies have shown the vast potential of circulating tumor cells(CTCs)detection in cancer diagnosis and prognosis,our understanding of their clinical significance is still far from complete.A major obstacle arises from the lack of well-established tumor or tissue-specific markers to detect CTCs by immunocytochemical staining after immunomagnetic enrichment(IE).Methods:We have established the utility of cytokeratin 20(CK20),a gastrointestinal tract specific marker,for the specific detection and identification of colorectal cancer(CRC)CTCs.This breakthrough was successfully validated in spike-in experiments using CRC cell line models followed by a pilot study which recruited 32 metastatic CRC patients,25 benign colorectal diseases patients and 27 normal subjects.Results:CK20-positive CTCs were detected in 90%metastatic CRC patients but not in benign colorectal diseases patients and normal subjects using this refined assay.Conclusions:These impressive results have laid the foundation for further development of CK20-positive CTCs as a promising marker in diagnosis,prognostication and treatment monitoring of metastatic CRC.
基金supported by National Nature Science Foundation(Nos. 31671554, 31672423 and 31471346)National Basic Research Program of China (973 Program, 2012CB944401)
文摘Adult stem cells have been identified in a variety of mammalian organs including skin, hair follicles, pancreas, and bone marrow （Kruse et al., 2004）. These stem cells reside in a specific cellular environment where they remain in an undifferentiated state （Theise, 2006）. In addition, they are generally considered to be mul- tipotent, possessing the capacity to generate multiple cell types within the tissue, and thus play an important role in tissue mainte- nance and regeneration.
文摘Antibody drug conjugates (ADCs) are a new class of drugs that combine chemosynthetic drugs with antibody drugs through a linker. Antibody drug conjugates combine the targeting characteristics of traditional antibody drugs with the cytotoxic characteristics of small molecule drugs, while reducing the side effects of both drugs, making them a kind of “biological missile” and representing a relatively new and evolving class of anti-cancer drugs. Antibody-coupled drugs are currently used in many solid tumors, and this article reviews the clinical application of antibody-coupled drugs in HER2-positive gastric cancer.
文摘Hormone receptor(HR)-positive breast cancer(BC)is the most common subtype of BC and some patients with such tumors experience recurrences.Endocrine-based therapy(ET)(e.g.,tamoxifen,aromatase inhibitors(AIs),and fulvestrant)that has improved outcomes in such patients represents the initial therapy for women with HR-positive/human epidermal growth factor receptor 2(HER2)-negative BC(considering no evidence of visceral crisis).However,the resistance to ET can occur in almost 50%of HR-positive BCs.In order to improve outcomes of patients with HR-positive metastatic BC,new treatment strategies are required.One such therapy is the new class of medications,cyclin-dependent kinase(CDK)4/6 inhibitors,that have improved the outcomes in such patients(both endocrine-sensitive and endocrine-resistant).This article presents evidence from the main clinical trials,which led to the approval of palbociclib,ribociclib,and abemaciclib.These three CDK 4/6 inhibitors have shown a significant improvement of the progression-free survival(PFS)in patients with HR-positive/HER2-negative metastatic BC when used in combination with selected ETs.In addition,some important patient management considerations,when choosing a particular CDK 4/6 inhibitor for an individual patient are presented.Furthermore,a need to find biomarkers for CDK 4/6 inhibitor sensitivity,efficacy,and resistance,to be able to precisely select the best patientcandidates for this treatment is highlighted.
