Chemotherapy In Clinical Practice Research Articles

In Situ Mitochondrial Biomineralization for Drug-Free Cancer Therapy.

The common clinical chemotherapy often brings serious side effects to patients, mainly due to the off-target and leakage of toxic drugs. However, this is fatal for some specific clinical tumors, such as brain tumors and neuroma. This study performs a drug-free approach by encapsulating black phosphorus (BP) and calcium peroxide (CaO2) in liposomes with surface-modified triphenylphosphonium (BCLT) to develop mitochondria targeting calcification for cancer therapy without damaging normal cells. BCLT preferentially accumulates inside tumor mitochondria and then is activated by near-infrared (NIR) laser irradiation to produce abundant PO4 3- and Ca2+ to accelerate in situ mitochondrial mineralization, leading to mitochondrial dysfunction and cancer cell death. More importantly, both PO4 3- and Ca2+ are essential components of metabolism in the body, and random gradient diffusion or premature leakage does not cause damage to adjacent normal cells. This achievement promises to be an alternative to conventional chemotherapy in clinical practice for many specific tumor types.

Pathological response and tumor stroma immunogenic features predict long-term survival in non-small cell lung cancer after neoadjuvant chemotherapy.

Major pathological response (MPR) has become a surrogate endpoint for overall survival (OS) in non-small cell lung cancer (NSCLC) after neoadjuvant therapy, however, the prognostic histologic features and optimal N descriptor after neoadjuvant therapy are poorly defined. We retrospectively analyzed data from 368 NSCLC patients who underwent surgery after neoadjuvant chemotherapy (NAC) from January 2010 to December 2020. The percentage of residual viable tumors in the primary tumor, lymph nodes (LN), and inflammation components within the tumor stroma were comprehensively reviewed. The primary endpoint was OS. Of the 368 enrolled patients, 12.0% (44/368) achieved MPR in the primary tumor, which was associated with significantly better OS (HR, 0.36 0.17-0.77, p = 0.008) and DFS (HR = 0.59, 0.36-0.92, p = 0.038). In patients who did not have an MPR, we identified an immune-activated phenotype in primary tumors, characterized by intense tumor-infiltrating lymphocyte or multinucleated giant cell infiltration, that was associated with similar OS and DFS as patients who had MPR. Neoadjuvant pathologic grade (NPG), consisting of MPR and immune-activated phenotype, identified 30.7% (113/368) patients that derived significant OS (HR 0.28, 0.17-0.46, p < 0.001) and DFS (HR 0.44, 0.31-0.61, p < 0.001) benefit from NAC. Moreover, the combination of NPG and the number of positive LN stations (nS) in the multivariate analysis had a higher C-index (0.711 vs. 0.663, p < 0.001) than the ypTNM Stage when examining OS. NPG integrated with nS can provide a simple, practical, and robust approach that may allow for better stratification of patients when evaluating neoadjuvant chemotherapy in clinical practice.

Efficacy of second-line chemotherapy after treatment with gemcitabine plus nab-paclitaxel or FOLFIRINOX in patients with metastatic pancreatic cancer

First-line chemotherapy for patients with metastatic pancreatic cancer (MPC) includes gemcitabine plus nab-paclitaxel (GnP) and FOLFIRINOX (FFX). However, the efficacy of second-line chemotherapy and the role of combination chemotherapy in clinical practice is still unknown. Data was gathered from 14 hospitals in the Kyushu area of Japan from December 2013 to March 2017. The median overall survival (mOS) from second-line treatment was contrasted between patients who received second-line chemotherapy (CT group) and those who received the best supportive care (BSC group). Furthermore, the mOS of combination chemotherapy was compared to mono chemotherapy in the CT group. To control possible bias in the selection of treatment, we performed a propensity score-adjusted analysis. A total of 255 patients received GnP or FFX as first-line chemotherapy. There were 156 in the CT group and 77 in the BSC group of these. The CT group had a significantly longer mOS than the BSC group (5.2 vs. 2.6 months; adjusted hazard ratio (HR) 0.38; 95% CI 0.27–0.54). In the CT group, 89 patients received combination chemotherapy while 67 received mono chemotherapy. The mOS did not differ significantly between the combination and mono chemotherapy groups (5.5 vs. 4.8 months; adjusted HR 0.88; 95% CI 0.58–1.33). Among patients with MPC receiving second-line treatment, the CT group had a significantly longer mOS than the BSC group, but combination chemotherapy conferred no improvement in survival compared to mono chemotherapy.

Study on the Interactions Between Cisplatin and Cadherin by Fluorescence Spectrometry and Atomic Force Microscopy.

Cisplatin is an important platinum drug in cancer chemotherapy in clinical practice. It is well established that the main target of cisplatin is nuclear DNA. However, recent studies have demonstrated that platinum drugs may act on some important functional proteins in the human body. E-cadherin is a newly discovered glycoprotein that has been regarded as an important sign of the occurrence and development of some tumors. This study examines the interactions between cisplatin and E-cadherin by fluorescence spectrometry and atomic force microscopy (AFM). The fluorescence spectrometry results indicated that cisplatin can efficiently quench the fluorescence of E-cadherin. The calculated binding constant Kb was 3.20 × 106 (25 ℃), 1.36 × 106(31 ℃), and 8.22 × 105 L mol-1 (37 ℃). These results reveal that the fluorescence quenching effect of cisplatin on E-cadherin is static quenching. The obtained thermodynamic parameters ΔH < 0, ΔS < 0, and ΔG < 0, indicate that the binding of cisplatin on E-cadherin is a spontaneous process dominated by hydrogen bonds and Van der Waals forces. The AFM results revealed that E-cadherins are interlaced with each other to form a spherical-chain structure. The addition of cisplatin can significantly disrupt the interlaced structure of the E-cadherin molecules.

Ni-Catalyzed Protecting Group Free Diphenic Acid Analog Synthesis.

Severe side effects and drug resistance are major drawbacks of Pt-based chemotherapy in clinical practice, leading to the search for new Pt-based drugs through the tuning of coordination ligands. Therefore, seeking appropriate ligands has attracted significant interest in this area. In this study, we report a Ni-catalyzed coupling strategy for the divergent synthesis of diphenic acid derivatives and the application of these newly prepared acids in Pt(II) agent synthesis.

Homologous recombination repair gene mutations in colorectal cancer favors treatment of immune checkpoint inhibitors.

Immune checkpoint inhibitor (ICI) therapy is insensitive for Colorectal cancer (CRC)patients with microsatellite stable (MSS). Genomic data of three CRC cohort, n = 35), and the Cancer Genome Atlas (TCGA CRC cohort, n = 377), were analyzed. A cohort treated with ICIs from Memorial Sloan Kettering Cancer Center (MSKCC CRC cohort, n = 110) and two cases from the local hospital were characterized the impact of the HRR mutation on prognosis of CRC. Homologous recombination repair(HRR) gene mutations were more common in CN and HL cohorts (27.85%; 48.57%) than in TCGA CRC cohort (15.92%), especially in the MSS populations, the frequencies of HRR mutation were higher in CN and HL cohort (27.45%, 51.72%) than in TCGA cohort (6.85%). HRR mutations were associated with high tumor mutational burden (TMB-H). Although HRR mutation uncorrelated with an improved overall survival in the MSKCC CRC cohort (p = 0.97), HRR mutated patients had a significantly improved OS compared to the HRR wildtype population particularly in MSS subgroups (p = 0.0407) under ICI treatment. It probably contributed by a higher neoantigen and increased CD4+ T cell infiltration which found in the TCGA MSS HRR mutated CRC cohort. The similar phenomenon on cases was observed that MSS metastatic CRC patient with HRR mutation seemed more sensitive to ICI after multi-line chemotherapy in clinical practice than HRR wildtype. This finding suggests the feasibility of HRR mutation as an immunotherapy response predictor in MSS CRC, which highlights a potential therapeutic approach for these patients.

Adjuvant chemotherapy in patients with low-risk epithelial ovarian cancer: A Taiwanese cohort study

Background: Whether or not patients with stage I epithelial ovarian cancer (EOC) benefit from postoperative chemotherapy in the Asian population remains unclear. This retrospective cohort study was aimed at investigating the use of adjuvant chemotherapy in clinical practice to treat patients with early-stage EOC considering clinical factors. Materials and Methods: A total of 414 patients with the International Federation of Gynecology and Obstetrics (FIGO) stage IA–IC and grade 1 EOC were enrolled from the Taiwan Cancer Registry. We used multivariable Cox proportional-hazards models to control for clinical factors. The overall survival (OS) and disease-free survival (DFS) were estimated with the Kaplan–Meier method. Results: DFS did not improve significantly for patients with FIGO stage IA/IB EOC receiving adjuvant chemotherapy, with a 10-year DFS rate of 98% and 88% for those with and without adjuvant chemotherapy, respectively (hazard ratio [HR] = 0.41, 95% confidence interval [CI]: 0.05–3.36). OS did not improve significantly for patients with FIGO stage IA/IB EOC with adjuvant chemotherapy (HR = 0.86, 95% CI: 0.18–4.22) or stage IC (HR = 0.50, 95% CI: 0.10–2.45). OS did not differ significantly for patients with optimal (10-year OS: 92% with chemotherapy and 86% without chemotherapy in the log-rank test, P = 0.629) or nonoptimal staging (10-year OS: 73% with chemotherapy and 90% without chemotherapy in the log-rank test, P = 0.959). Conclusion: Adjuvant chemotherapy did not improve the prognosis of patients with low to intermediate-risk EOC and optimal/nonoptimal surgery. This result should be considered in clinical practice.

More than one-third of advanced non-small-cell lung cancer patients do not receive immunochemotherapy due to intolerance.

Combination therapy with immune checkpoint inhibitors (ICIs) and chemotherapy (ICI + chemotherapy) has become the standard first line treatment for driver oncogene-negative advanced non-small-cell lung cancer (NSCLC). However, it may be more toxic compared to monotherapy, which limits its use. Moreover, the feasibility of the combination therapy in clinical practice remains unknown. We conducted a cohort study to determine the implementation rate of ICI + chemotherapy in clinical practice. We retrospectively reviewed clinical data from advanced NSCLC patients who received systemic therapy at 13 institutions between December 2018 and December 2020. After excluding 154 patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) gene alterations, a total of 919 NSCLC patients were included. Among them, 442 were treated with ICI + chemotherapy (48%), whereas 477 were treated with other therapies (52%). Among these 477 patients, 340 did not receive ICI + chemotherapy because of intolerance (71%); thus, more than one-third of the advanced NSCLC patients do not benefit from the combination therapy due to intolerance. Among the 659 NSCLC patients for whom PD-L1 was < 50% or unknown, only 342 received the ICI + chemotherapy combination (52%) even though it is considered preferable to either therapy alone; the remaining 318 patients were treated with other therapies (48%). Among the 318 patients who did not receive ICI + chemotherapy, 274 were intolerant to it (86%). Our results revealed that a substantial proportion of advanced NSCLC patients did not benefit from ICI + chemotherapy due to intolerance. As treatments for NSCLC are moving toward combinations for greater efficacy, their feasibility in clinical practice must be taken into consideration.

Induction of P-glycoprotein expression by dandelion in tumor and heart tissues: Impact on the anti-tumor activity and cardiotoxicity of doxorubicin

BackgroundPreviously, we have investigated the anti-tumor activity and mechanism through which dandelion acts against triple-negative breast cancer (TNBC). However, traditional Chinese medicine is mostly accepted as an adjunct therapy during chemotherapy in clinical practice. So far, little is known about the effects of dandelion in conjunction with chemotherapeutic drugs. PurposeTo investigate the effects of dandelion on the anti-tumor activity and cardiotoxicity of doxorubicin (DOX), and to further explore the molecular mechanisms through which these effects occur. Study designAt the beginning of this study, dandelion was observed to alleviate DOX-induced cardiotoxicity and reduce the anti-tumor activity of DOX. Subsequently, we investigated whether the resistance to DOX mediated by P-glycoprotein was involved in the above effects. MethodsThe cardioprotective effect of dandelion was investigated on DOX-treated mice by histological analysis, myocardial enzyme assays, and an untargeted metabolomics study based on LC-Q-TOF/MS. TNBC cell lines and 4T1 tumor-bearing mice were employed to investigate the combined anti-tumor activity. Laser scanning confocal microscope and a flow cytometry analysis were employed to measure the intracellular accumulation of DOX. A specific, sensitive, and rapid LC–MS/MS method was developed to detect the efflux of DOX from cells. Expression of P-glycoprotein in mouse tumor and heart tissues was detected via Western blotting analysis. ResultsDandelion was found to significantly alleviate DOX-induced cardiotoxicity, as was evidenced by improved cardiomyocyte morphology, decreased LDH and CK-MB release, and adjusted metabolic biomarker levels. However, in vitro and in vivo studies showed that dandelion could reduce the anti-tumor activity of DOX. This counteraction was achieved by activating of the drug efflux transporter P-glycoprotein, thereby promoting the efflux of DOX from cells and reducing the intracellular accumulation of DOX. Moreover, the activation of P-glycoprotein by dandelion in mouse heart tissue was also observed, thus suggesting that the decrease of cardiac DOX accumulation plays an important role in the cardioprotective effect of dandelion. ConclusionDandelion can activate the P-glycoprotein in heart and tumor tissues, which ameliorates DOX-induced cardiotoxicity but attenuates DOX cytotoxicity toward TNBC. Our findings have important implications for the correct clinical use of dandelion.

A prospective, open-label, multicenter phase IV clinical trial on the safety and efficacy of lobaplatin-based chemotherapy in advanced breast cancer

Since lobaplatin (LBP) has been approved to treat metastatic breast cancer in China, this study aimed to evaluate the safety and efficacy of LBP-based chemotherapy in clinical practice. This trial was a prospective, open-label, multicenter phase IV clinical trial that enrolled patients with unresectable locally advanced or recurrent/metastatic breast cancer from 34 sites between July 2013 and March 2017. Patients were treated with LBP monotherapy or in combination for four to six cycles. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). A total of 1179 patients were analyzed; 59 (5.0%) were treated with LBP alone, 134 (11.4%) with LBP plus paclitaxel, 263 (22.3%) with LBP plus docetaxel, 237 (20.1%) with LBP plus gemcitabine, 403 (34.2%) with LBP plus vinorelbine, and 83 (7.0%) with other LBP-based regimens. The overall incidence of adverse events (AEs) was 95.2%, and 57.9% of patients had grade >3 AEs. The most common grade >3 AEs were neutropenia (43.9%), leukopenia (39.4%), anemia (17.8%), and thrombopenia (17.7%). LBP monotherapy showed the lowest incidence of grade >3 AEs (39.0%), followed by LBP plus docetaxel (52.9%), LBP plus paclitaxel (59.0%), LBP plus vinorelbine (62.5%), and LBP plus gemcitabine (62.9%). The ORR and DCR were 36.8 and 77.0%, respectively. The median PFS was 5.5 months (95% confidence interval: 5.2-5.9). LBP-based chemotherapy shows favorable efficacy in patients with advanced breast cancer, with manageable safety profile. This trial was registered with ChiCTR.org.cn, ChiCTR-ONC-13003471.

Synergetic effects of the combined action of carbon ions and the chemotherapy drug doxorubicin on HeLa cancer cells

Proton and carbon beam therapy is currently recognized as the most effective and highly accurate form of radiation therapy for deeply located tumors, including radioresistant ones. This is due to the fact that they have all the advantages of spatial dose distribution and, at the same time, are densely ionizing radiations capable of effectively affecting hypoxic, slow-growing tumors and other neoplasms that are insensitive to traditional types of radiation. It is well known that one of the main methods for treating neoplasms is chemotherapy. The predominant mechanism of action of anti-tumor drugs is the induction of DNA damage with the subsequent impossibility of repair. In our study, we used an anti-tumor antibiotic of the anthracycline series, doxorubicin. The assessment of the potential significance of the synergistic interaction of ionizing radiation with chemical preparations in medical radiology remains an urgent and unresolved problem. It is possible to achieve the maximum effect of the combined action of two agents when they act simultaneously. The phenomenon of synergy can be used to optimize the combined use of radiation and chemotherapy in clinical practice. In this regard, it seems relevant to conduct a study for HeLa cancer cells exposed to ionizing radiation, an antitumor drug, as well as their combination. In the course of the study, results were obtained on the manifestation of the synergistic nature of the agents used, which is of great practical and theoretical importance for understanding the mechanism of the combined effect of ionizing radiation and the chemotherapy drug (doxorubicin). The obtained data can be helpful in optimizing the combined effects in order to achieve maximum synergistic interaction.

Jadomycins: A potential chemotherapy for multi-drug resistant metastatic breast cancer.

Breast cancer causes the most cancer fatalities in women worldwide. Approximately one‐third of breast cancers metastasize, or spread from primary tumors to other tissues, and have a 70% 5‐year mortality rate. Current breast cancer treatments like doxorubicin and paclitaxel become ineffective when breast cancer cells develop multi‐drug resistance and overexpress ATP‐binding cassette transporters, as the transporters cause a substantial efflux of the chemotherapies. Jadomycins, a group of molecules isolated from Streptomyces venezuelae ISP5230, are shown to be cytotoxic against a variety of cancers, especially breast cancer. Furthermore, jadomycins retain their cytotoxic properties in multi‐drug resistant breast cancer cells, as they are not expelled through ATP‐binding cassette transporters. Here, we describe the research that supports the potential use of jadomycins as a novel chemotherapy in the treatment of multi‐drug resistant, metastatic breast cancer. We present the supportive findings, as well as the mechanisms of action investigated thus far. These include copper‐mediated reactive oxygen species generation, aurora B kinase inhibition, and topoisomerase IIα and IIβ inhibition. We also suggest future directions of jadomycin research, which will help to determine if jadomycins can be used as a breast cancer chemotherapy in clinical practice.

Nuclear Factor Erythroid 2-Related Factor 2 Depletion Sensitizes Pancreatic Cancer Cells to Gemcitabine via Aldehyde Dehydrogenase 3a1 Repression.

As the central regulator of the oxidative stress response, nuclear factor erythroid 2-related factor 2 (Nrf2) is attracting great interest as a therapeutic target for various cancers, and the possible clinical applications of novel Nrf2 inhibitors have been explored in Nrf2-activated cancers. In the present study, we specifically investigated halofuginone, which is derived from a natural plant alkaloid. We found that halofuginone administration decreased the number of pancreatic intraepithelial neoplasias in pancreas-specific Kras and p53 mutant (KPC) mice. In Nrf2-activated pancreatic cancer cell lines established from KPC mice, halofuginone rapidly depleted Nrf2 in Nrf2-activated cancer cells. Both in vitro and in vivo, it sensitized Nrf2-activated pancreatic cancer cells to gemcitabine, which is the first-line chemotherapy in clinical practice. In our mechanistic study, we found that halofuginone downregulated aldehyde dehydrogenase 3a1 (ALDH3A1) in mouse pancreatic cancer cells. The Nrf2 inducer diethyl maleate upregulated ALDH3A1, and knockdown of Aldh3a1 sensitized Nrf2-activated cancer cells to gemcitabine, strongly suggesting that ALDH3A1 is regulated by Nrf2 and that it contributes to gemcitabine resistance. The current study demonstrated the therapeutic benefits of halofuginone in Nrf2-activated pancreatic cancers. SIGNIFICANCE STATEMENT: We identified nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target aldehyde dehydrogenase 3a1 (ALDH3A1) as novel therapeutic targets in pancreatic cancer. They negatively affect the efficacy of a conventional chemotherapeutic agent, gemcitabine. We confirmed that Nrf2 plays a pivotal role in the induction of ALDH3A1.

Real-World Clinical Outcomes in Patients with Locally Advanced or Metastatic Merkel Cell Carcinoma Treated in U.S. Oncology Clinical Practices: Results from SPEAR-Merkel.

BackgroundImmunotherapy (IO) has been associated with improved outcomes in patients with locally advanced Merkel cell carcinoma (laMCC) and metastatic Merkel cell carcinoma (mMCC). The primary objective of SPEAR‐Merkel was to explore treatment patterns, clinical outcomes, and health care resource utilization (HCRU) in patients with laMCC or mMCC initiating first‐line (1L) treatment with avelumab, non‐avelumab IO, or chemotherapy in a U.S. community oncology setting.MethodsAdult patients with laMCC or mMCC initiating 1L avelumab, non‐avelumab IO, or chemotherapy from January 1, 2015, to March 31, 2019, were identified from the U.S. Oncology Network electronic health care record database and followed up through September 30, 2019. Baseline characteristics and HCRU were analyzed descriptively, including physician‐stated overall response rate in the real‐world clinical setting. Kaplan‐Meier methods were used to measure duration of response, real‐world progression‐free survival (rwPFS), and overall survival (OS).ResultsAmong the overall population (n = 94), 28 received 1L avelumab (9 laMCC, 19 mMCC), 26 received 1L non‐avelumab IO (8 laMCC, 18 mMCC), and 40 received 1L chemotherapy (10 laMCC, 30 mMCC). The real‐world overall response rate was 64.3%, 61.5%, and 42.5%, respectively. From 1L treatment initiation, median rwPFS was 11.4, 8.1, and 6.1 months, and median OS was 20.2 months, not reached, and 14.7 months for the respective cohorts.ConclusionSPEAR‐Merkel showed that patients with laMCC or mMCC treated with IO had improved outcomes compared with chemotherapy in clinical practice. The study provides insight on utilization and clinical outcomes associated with newer, more innovative therapies in clinical practice, which may help clinicians understand the variety of newer treatment options for both laMCC and mMCC.Implications for PracticeTo the authors’ knowledge, SPEAR‐Merkel is the first study to evaluate real‐world clinical outcomes in patients with locally advanced Merkel cell carcinoma (laMCC) and metastatic Merkel cell carcinoma (mMCC) receiving first‐line (1L) avelumab, non‐avelumab immuno‐oncology therapies, or chemotherapy in a real‐world setting. SPEAR‐Merkel showed clinical benefit for immuno‐oncology therapies compared with chemotherapy. The study provides insight on uses and clinical outcomes associated with innovative therapies in clinical practice, which may help clinicians understand the variety of newer treatment options for both laMCC and mMCC. The study is of particular importance as it shows that chemotherapy is still being used as 1L treatment despite its inferior clinical and safety profile.

The incidence of thrombocytopenia in adult patients receiving chemotherapy for solid tumors or hematologic malignancies.

ObjectivesTo estimate the risk of thrombocytopenia in various cancers and chemotherapy regimens.MethodsStructured patient‐level data from the Flatiron Health Electronic Health Record database were used to identify adult patients who received chemotherapy for a solid tumor or hematologic malignancy from 2012 to 2017. Three‐month cumulative incidence of thrombocytopenia was assessed based on platelet counts, overall and by grade of thrombocytopenia. Co‐occurrence of anemia, neutropenia, and leukopenia was evaluated.ResultsOf 15,521 patients with solid tumors, 13% had thrombocytopenia within 3 months (platelet count < 100 × 109/L); 4% had grade 3 (25 to < 50 × 109/L), and 2% grade 4 (<25 × 109/L) thrombocytopenia. Of 2537 patients with hematologic malignancies, 28% had any thrombocytopenia, 16% with grade 3, and 12% with grade 4. Among patients with thrombocytopenia, it occurred without another cytopenia in 18% of solid tumors and 7% of hematologic malignancies.ConclusionsIn a large, US‐representative sample of patients undergoing chemotherapy in clinical practice, thrombocytopenia incidence varied across tumor and regimen types. Despite recommendations to alter chemotherapy to avoid severe thrombocytopenia, 4% of patients with solid tumors and 16% with hematologic malignancies experienced grade 3 thrombocytopenia. Prediction and prevention of thrombocytopenia may help oncologists avoid dose modifications and their adverse effects on survival.

Do irinotecan (IRI) dose reductions driven by UGT1A1*28 genotyping prevent IRI-related severe neutropenia? A real-world study.

e16116 Background: IRI is widely used in the treatment of gastrointestinal cancers. Consistent with current guidelines, UGT1A1 genotyping may drive IRI dose reductions, but the usefulness of this approach is still unclear. We assessed potential clinical variables that may predict grade ≥3 neutropenia and more specifically the upfront genotyping of UGT1A1 polymorphisms associated with IRI toxicity, according to predefined IRI dose reductions. Methods: We genotyped UGT1A1*28 polymorphisms in 247 patients with metastic colorectal, gastric and pancreatic cancers who received second or third-line IRI-based chemotherapy in clinical practice at a single academic center. Concomitant DPYD sequencing was undertaken in 179 patients receiving also fluoropyrimidines. We compared the incidence of severe neutropenia with full-dose IRI in UGT1A1 6/6 and 6/7 carriers, and in UGT1A1 7/7 carriers who underwent initial IRI dose reductions by at least 30%. Results: The incidence of UGT1A1 7/7, 6/7, 6/6 genotypes was 11.3%, 51.4%, and 37.2%, respectively. IRI dose reductions were significantly more frequent with UGT1A 7/7 and 6/7 genotypes (odds ratio [OR] = 9.5; 95% confidence interval [CI]: 4.3-21.7), and combination chemotherapy (OR = 3.8; 95%CI: 1.3 – 11.1). Other clinical parameters, including sex, cancer type, baseline neutrophils levels, performance status were not significantly associated with IRI dose reductions. Despite initial IRI reductions driven by the UGT1A1 panel, patients with UGT1A1 7/7 genotype had an increased, albeit non-significant, risk of grade ≥3 neutropenia, compared to patients with UGT1A1 6/6 and 6/7 genotypes who received full dose IRI (incidence: 39% versus 21%; OR = 2.4; 95%CI: 0.85 – 7.03). Conclusions: UGT1A1 testing is a determinant of IRI dose reductions, however this strategy does not reduce the burden of grade ≥3 neutropenia in UGT1A1 7/7 carriers. Further studies beyond the UGT1A1*28 genotype are needed to fully understand the increased risk of neutropenia in patients candidate to IRI-based chemotherapy.

Evidence mapping of interactions on concomitant use of Chinese medicine and platinum-based chemotherapy: a scoping review protocol

BackgroundThe utilization of Chinese herbal medicine (CHM) has gained popularity and acceptance worldwide. Increasing use of CHM either as a stand-alone or an adjunctive treatment for cancers has given rise to increasing concern on potential herbal-drug reactions. Possible combinatory effects are important to be explored in evaluating the rationality of integrating CHM and chemotherapy in clinical practice. This study aims to update the current knowledge on herbal-drug interactions (HDI) of the commonly used platinum-based chemotherapy (PtC) in cancer patients. MethodsSystemic searches will perform on online databases (English and Chinese) to identify papers from inception until December 2019 for inclusion into the review. The search strategy will be following PRISMA Scoping Reviews Checklist as a quality assurance step. All records retrieved will be screened by 2 independent reviewers. The preclinical studies and clinical studies that involve in assessing the concurrent use of CHM and PtC will be considered. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses will be used as scoping review framework. DiscussionThis scoping review will explore the compatibility or combination rule of CHM-PtC and assist in understanding HDI in CHM-PtC co-treatment. Identification of active properties in CHM’s HDI and understanding pharmacokinetics and pharmacodynamic of the CHM alone or as co-treatment are essential for patients’ safety profile. It will provide a new insight for future practice in cancer treatment. Study registrationThis protocol has been registered in the Research Register (https://www.researchregistry.com/) with an unique registration number: reviewregistry790.

Early relapse on adjuvant gemcitabine associated with an exceptional response to 2nd line capecitabine chemotherapy in a patient with pancreatic adenosquamous carcinoma with strong intra-tumoural expression of cytidine deaminase: a case report

BackgroundPancreatic adenosquamous carcinoma has a poor prognosis, with limited prospective trial data to guide optimal treatment. The potential impact of drug metabolism on the treatment response of patients with pancreatic adenosquamous carcinoma is largely unknown.Case presentationWe describe the case of a 51 year old woman with pancreatic adenosquamous carcinoma who, following surgical resection, experienced early disease relapse during adjuvant gemcitabine therapy. Paradoxically, this was followed by an exceptional response to capecitabine therapy lasting 34.6 months. Strong expression of cytidine deaminase was detected within the tumour.ConclusionsThis case study demonstrates that early relapse during adjuvant chemotherapy for pancreatic adenosquamous carcinoma may be compatible with a subsequent exceptional response to second line chemotherapy, an important observation given the poor overall prognosis of patients with adenosquamous carcinoma. Cytidine deaminase is predicted to inactivate gemcitabine and, conversely, catalyze capecitabine activation. We discuss strong intra-tumoural expression of cytidine deaminase as a potential mechanism to explain this patient’s disparate responses to gemcitabine and capecitabine therapy, and highlight the benefit that may be gained from considering similar determinants of response to chemotherapy in clinical practice.

Protein-Based Drug Delivery in Brain Tumor Therapy.

Despite the use of active surgeries, radiotherapy, and chemotherapy in clinical practice, brain tumors are still a difficult health problem due to their rapid development and poor prognosis. To treat brain tumors, various nanoparticles can be used to target effective physiological conditions based on continuously changing vascular characteristics and microenvironments to promote effective brain tumor-targeting drug delivery. In addition, a brain tumor-targeting drug delivery system that increases drug accumulation in the brain tumor area and reduces toxicity in the normal brain and peripheral tissues is needed. However, the blood-brain barrier ​​is a big obstacle for drug delivery to the brain. In this chapter, we provide a broad overview of brain drug delivery and current strategies over the last few years. In addition, several questions have been reconsidered, such as whether nanoparticles believed to be delivered to the brain can pass through the blood-brain barrier, whether the drug is delivered to the target site, and what brain tumor treatment is possible.

Anti-CD47 antibody eliminates bone tumors in rats.

Bone tumor is a rare heterogeneous malignancy. Osteosarcoma is the most common bone tumor with no apparent underlying pathogenesis, and its peak incidence often occurs during puberty. The intensive application of chemotherapy rarely alters the poor prognosis of the patients in advanced stage. Despite intensive chemotherapy in clinical practice, patients still suffer from the poor prognosis, or even progression of bone tumor. We identified integrin-associated protein (IAP) Cluster of Differentiation 47 (CD47) as a target for monoclonal antibody, and use anti-CD47 antibody to block its expression in bone tumors. CD47 was highly expressed in the bone tumor rats when comparing to the healthy rats. Likewise, Western blotting assay revealed a higher protein expression of CD47 in the bone tumor cells when compared to the normal osteoblasts. Further studies have shown the association between the mRNA expression of CD47 and the disordered bone tumors development and decreased rate of overall survival of diseased rats. In addition, blocking the CD47 monoclonal antibody has been shown to drive macrophages to engulf bone tumor cells in vitro and thus inhibiting tumor metastasis in rats. Taken together, the results of this study suggested that CD47 is a key regulator of bone tumor cell metastasis and that targeting inhibition of anti-CD47 may be a new immunotherapy for bone tumors.