Disitamab Vedotin (RC48) for HER2-positive advanced breast cancer: a case report and literature review.

Background/aim: Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is associated with a higher risk of metastasis and poorer overall survival (OS) due to HER2 gene overexpression/amplification. Although anti-HER2 targeted therapy has shown survival benefits in HER2-positive advanced breast cancer (ABC) patients, long-term treatment often leads to drug resistance, complicating further treatment options. RC48, an antibody-drug conjugate (ADC), combines the benefits of antibody targeting with the cytotoxic effects of a small molecule drug. Case report: We present a case involving a female patient with HER2-positive ABC who developed drug resistance and disease progression following multi-line anti-HER2 targeted therapy. In this instance, RC48 exhibited anti-tumor activity in an ABC patient resistant to HER2-targeted therapy. After eight treatment cycles with 120 mg of RC48, the tumor size decreased and stabilized. Conclusion: This case report underscores the potential clinical value of RC48 as a promising treatment alternative for patients resistant to HER2 targeted therapies.

A multicentre single arm phase 2 trial of neoadjuvant pyrotinib and letrozole plus dalpiciclib for triple-positive breast cancer.

Current therapies for HER2-positive breast cancer have limited efficacy in patients with triple-positive breast cancer (TPBC). We conduct a multi-center single-arm phase 2 trial to test the efficacy and safety of an oral neoadjuvant therapy with pyrotinib, letrozole and dalpiciclib (a CDK4/6 inhibitor) in patients with treatment-naïve, stage II-III TPBC with a Karnofsky score of ≥70 (NCT04486911). The primary endpoint is the proportion of patients with pathological complete response (pCR) in the breast and axilla. The secondary endpoints include residual cancer burden (RCB)-0 or RCB-I, objective response rate (ORR), breast pCR (bpCR), safety and changes in molecular targets (Ki67) from baseline to surgery. Following 5 cycles of 4-week treatment, the results meet the primary endpoint with a pCR rate of 30.4% (24 of 79; 95% confidence interval (CI), 21.3-41.3). RCB-0/I is 55.7% (95% CI, 44.7-66.1). ORR is 87.4%, (95% CI, 78.1-93.2) and bpCR is 35.4% (95% CI, 25.8-46.5). The mean Ki67 expression reduces from 40.4% at baseline to 17.9% (P < 0.001) at time of surgery. The most frequent grade 3 or 4 adverse events are neutropenia, leukopenia, and diarrhoea. There is no serious adverse event- or treatment-related death. This fully oral, chemotherapy-free, triplet combined therapy has the potential to be an alternative neoadjuvant regimen for patients with TPBC.

The effect of toxic components on metabolomic response of male SD rats exposed to fine particulate matter.

PM2.5 pollution was associated with numerous adverse health effects. However, PM2.5 induced toxic effects and the relationships with toxic components remain largely unknown. To evaluate the metabolic toxicity of PM2.5 at environmentally relevant doses, investigate the seasonal variation of PM2.5 induced toxicity and the relationship with toxic components, a combination of general pathophysiological tests and metabolomics analysis was conducted in this study to explore the response of SD rats to PM2.5 exposure. The result of general toxicology analysis revealed unconspicuous toxicity of PM2.5 under environmental dose, but winter PM2.5 at high dose caused severe histopathological damage to lung. Metabolomic analysis highlighted significant metabolic disorder induced by PM2.5 even at environmentally relevant doses. Lipid metabolism and GSH metabolism were primarily influenced by PM2.5 exposure due to the high levels of heavy metals. In addition, high levels of organic compounds such as PAHs, PCBs and PCDD/Fs in winter PM2.5 bring multiple overlaps on the toxic pathways, resulting in larger pulmonary toxicity and metabolic toxicity in rats than summer.

Ubiquitin-specific protease 4 inhibits breast cancer cell growth through the upregulation of PDCD4.

Breast cancer is a common malignant tumor affecting women. The study of the association between breast cancer and molecular aberrations may lead to the development of novel diagnostic and therapeutic strategies for the disease. In the present study, we examined the role of ubiquitin-specific protease 4 (USP4) in breast cancer. We found that USP4 expression was significantly decreased in breast cancer tissue samples compared with paired normal breast tissue samples (P<0.001). USP4 was identified as a tumor suppressor. In addition, by inducing USP4 overexpression (using a USP4 overexpression plasmid) or the knockdown of USP4 (by transfection with a USP4 shRNA plasmid), we found that USP4 inhibited cell proliferation in vitro. We also found that USP4 suppressed tumor growth by using a mouse tumor xenograft model. Moreover, programmed cell death 4 (PCD4) was identified to be a target of USP4, which plays a role as a tumor suppressor. As a whole, our findings sugggest that USP4 acts as a tumor suppressor in breast cancer and that it may be an effective target for the treatment of breast cancer.

Clinicopathological and prognostic significance of FOXP3+ tumor infiltrating lymphocytes in patients with breast cancer: a meta-analysis.

BACKGROUND: The prognostic significance of FOXP3+ tumor-infiltrating lymphocytes (TILs) in patients with breast cancer remains controversial. The aims of our meta-analysis are to evaluate its association with clinicopathological characteristics and prognostic significance in patients with breast cancer. METHODS: PubMed, Embase, Cochrane Database and the Ovid Database were systematically searched (up to April 2015). The meta-analysis was performed using hazard ratio (HR), odds ratio (OR) and 95 % confidence intervals (CI) as effect measures. Using the random-effects model, statistical analysis was performed using Stata software, version 12.0. RESULTS: Seventeen studies including 8277 patients with breast cancer were analyzed. The meta-analysis indicated that the incidence difference of FOXP3+ TILs was significant when comparing the lymph node positive group to negative group (OR = 1.305, 95 % CI [1.071, 1.590]), the histological grade III group to the I-II group (OR = 3.067, 95 % CI [2.288, 4.111]), the ER positive group to the negative group (OR = 0.435, 95 % CI [0.287, 0.660]), the PR positive group to the negative group (OR = 0.493, 95 % CI [0.296, 0.822]), the HER2 positive group to the negative group (OR = 1.896, 95 % CI [1.335, 2.692]), the TNBC group to the non TNBC group (OR = 2.456, 95 % CI [1.801, 3.348]). The detection of FOXP3+ TILs was significantly correlated with the recurrence-free survival (RFS) of patients (HR = 1.752, 95 % CI [1.188-2.584]) and the overall survival (OS) of patients (HR =1.447, 95 % CI [1.037-2.019]). CONCLUSIONS: Our meta-analysis demonstrates that the presence of high levels of FOXP3+ TILs is associated with prognosis for breast cancer patients and predicts lymph node metastasis, hormone receptor and HER-2 status.

LC-ESI-MS/MS analysis and pharmacokinetics of jolkinolide B, a potential antitumor active component isolated from Euphorbia fischeriana, in rat plasma.

A simple, specific and reproducible liquid chromatography-electrospray ionization mass spectrometry was developed and validated for the determination of jolkinolide B, a potential antitumor active component isolated from Euphorbia fischeriana, in rat plasma. Chromatographic separation was achieved on a Venusil MP-C18 column using an isocratic elution. Jolkinolide B and osthole (internal standard) were monitored by positive electrospray ionization in the selected reaction monitoring mode. Good linearity (r(2) > 0.996) was achieved by a weighted (1/x(2) ) linear least-squares regression over a concentration range of 6.50-2600 ng/mL. The accuracy and precision of the assay were satisfactory and the method proved to be applicable to pharmacokinetics following a single intravenous bolus injection of jolkinolide B to rats.

OPN -443C>T genetic polymorphism and tumor OPN expression are associated with the risk and clinical features of papillary thyroid cancer in a Chinese cohort.

AIM: to test the possible association between the polymorphism of Osteopontin (OPN) gene with the risk and the clinical features of papillary thyroid cancer (PTC). METHODS: A total of 363 PTC patients and 413 healthy controls were enrolled. OPN expressions in tumor tissue were detected by immunohistochemistry. OPN gene polymorphisms, namely, -66T>G (rs28357094), -156G>GG (rs17524488), and -443C>T (rs11730582), were determined. RESULTS: We observed that the PTC patients had significantly higher rates of -443TT genotypes than controls (P<0.001). The multivariate logistic regression analysis showed a significantly increased risk for PTC for the -443CC genotype compared with the -443TT genotype (adjusted OR= 4.312, 95%CI: 2.747 -6.987, adjusted P < 0.001). OPN protein was not expressed in normal thyroid tissues while tumor samples from PTC patients were shown to have high expressions of OPN. Also, we found that the high OPN expressions were significantly more prevalent in -443CC carriers than TT carriers (P <0.001). Both the CC carriers and OPN expression were closely associated with the cervical lymph node metastasis and angiolymphatic invasion of PTC. CONCLUSION: This study provides evidence to support the connection between the OPN genetic polymorphism and tissue expression with risk as well as the invasiveness of PTC.

Aberrant elevated microRNA-146a in dendritic cells (DC) induced by human pancreatic cancer cell line BxPC-3-conditioned medium inhibits DC maturation and activation.

It has been shown that the function of dendritic cell (DC) is suppressed in pancreatic cancer patients; however, the detailed mechanism involved in it remains unclear. Here, we used medium conditioned by a highly metastatic human pancreatic cancer cell line BxPC-3 [BxPC-3-conditioned medium (BxCM)] to culture human CD14+ monocyte-derived DCs in vitro. Both DC differentiation and antigen presentation function were inhibited by BxCM. The microRNA-146a (miRNA-146a) expression is aberrantly up-regulated in BxCM-treated DCs. In addition, inhibition of aberrant miRNA-146a expression partly rescues the BxCM-induced defects in differentiation and function of DCs, which may be through regulation of Smad4 expression. Taken together, our findings indicate that aberrant miRNA-146a expression is one of main factors responsible for inhibition of DC maturation and antigen presentation function, and this inhibitory effect on DCs may be due to the repression of Smad4 mediated signal pathway by BxCM.

Induction of CTLs by DCs pulsed with K-ras mutant peptide on the surface of nanoparticles in the treatment of pancreatic cancer.

The aim of this study was to investigate the role of specific cytotoxic T lymphocytes (CTLs) activated by dendritic cells (DCs) presenting cationic nanoparticles with the K-ras (12-Val) mutant peptide in the killing of different pancreatic cancer cell lines in vivo and in vitro. Peripheral blood DCs were induced by rhGM-CSF and IL-4 and cultured. DCs were sensitized by whole antigen of PANC-1 with expression of K-ras mutant, K-ras mutant peptide (K-ras+peptide) and cationic nanoparticles with K-ras mutant peptide (K-ras+peptide-CNP), respectively. Cell surface markers were measured by flow cytometry. Lymphocyte proliferation was detected by the 3H-TdR test, and IL-12 and IFN­Î³ secretion was detected by ELISA. 125I-UdR was used to measure the killing effect of CTLs. The antitumor activity of CTLs in tumor-bearing nude mouse models prepared with PANC-1 and SW1990 cells was evaluated. Results showed that, compared with K-ras+peptide, low concentrations of K-ras+peptide-CNP were effectively presented by DCs (P<0.05). CTLs induced by DCs pulsed with whole tumor antigen had a significantly greater killing effect (P<0.05) on PANC-1 and SW1990 pancreatic cancer cells compared with K-ras+peptide- and K-ras+peptide-CNP-induced CTLs. CTLs induced by DCs pulsed with K-ras+peptide and K-ras+peptide- CNP had a specific killing effect (P<0.05) on PANC-1 cells and no effect (P>0.05) on SW1990 cells. In conclusion, cationic nanoparticles with the K-ras (12-Val) mutant peptide can be effectively presented by DCs at a low concentration. CTLs induced by K-ras+peptide-CNP had specific killing activity for the pancreatic cancer cell line with the K-ras mutant and significantly inhibited tumor growth and increased the survival time of tumor-bearing nude mice. Although this study confirmed that whole cell antigen induced a good antitumor immune response, the possibility of immune tolerance and autoimmunity which has been previously proven contribute to the difficulty in the application of this DC vaccine.