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Cancer is caused by uncontrollable growth of neoplastic cells, leading to invasion of adjacent and distant tissues resulting in death. Cancer cells have specific nutrient(s) auxotrophy and have a much higher nutrient demand compared to normal tissues. Therefore, different metabolic inhibitors or nutrient-depleting enzymes have been tested for their anti-cancer activities. We review recent available laboratory and clinical data on using various specific amino acid metabolic pathways inhibitors in treating cancers. Our focus is on glutamine, asparagine, and arginine starvation. These three amino acids are chosen due to their better scientific evidence compared to other related approaches in cancer treatment. Amino acid-specific depleting enzymes have been adopted in different standard chemotherapy protocols. Glutamine starvation by glutaminase inhibitior, transporter inhibitor, or glutamine depletion has shown to have significant anti-cancer effect in pre-clinical studies. Currently, glutaminase inhibitor is under clinical trial for testing anti-cancer efficacy. Clinical data suggests that asparagine depletion is effective in treating hematologic malignancies even as a single agent. On the other hand, arginine depletion has lower toxicity profile and can effectively reduce the level of pro-cancer biochemicals in patients as shown by ours and others’ data. This supports the clinical use of arginine depletion as anti-cancer therapy but its exact efficacy in various cancers requires further investigation. However, clinical application of these enzymes is usually hindered by common problems including allergy to these foreign proteins, off-target cytotoxicity, short half-life and rapidly emerging chemoresistance. There have been efforts to overcome these problems by modifying the drugs in different ways to circumvent these hindrance such as (1) isolate human native enzymes to reduce allergy, (2) isolate enzyme isoforms with higher specificities and efficiencies, (3) pegylate the enzymes to reduce allergy and prolong the half-lives, and (4) design drug combinations protocols to enhance the efficacy of chemotherapy by drug synergy and minimizing resistance. These improvements can potentially lead to the development of more effective anti-cancer treatment with less adverse effects and higher therapeutic efficacy.

Background It is unknown whether transmediastinal esophagectomy (TME) is an acceptable surgical procedure for locally advanced esophageal squamous cell carcinoma (ESCC). Therefore, we investigated the feasibility of long-term survival after TME with neoadjuvant docetaxel, cisplatin, and 5-fluorouracil combination chemotherapy (DCF therapy). Methods This retrospective, observational study included locally advanced resectable ESCC. All patients received two cycles of preoperative DCF therapy (60 mg/m 2 of docetaxel and cisplatin on day 1 and 700 mg/m 2 /day of 5-FU on days 1–5 in each cycle) followed by radical TME. The main outcomes were survival and the rate of adverse events of chemotherapy and surgery. Results Sixteen patients were included in this study. All patients received two cycles of DCF therapy, followed by surgery. The median follow-up duration of the 16 patients was 35.4 months. The 2-year overall survival (OS) was 93.3% (95% confidence interval [CI], 61.3–99.0), and the 3-year OS was 78.8% (95% CI, 47.3–92.7). The 2-year and 3-year relapse-free survivals were both 73.3% (95% CI, 43.6–89.1). Leukopenia and neutropenia occurred in most patients; however, they were controllable. Fifteen patients completed TME, and one was converted to open transthoracic esophagectomy because of tracheal injury. Three-field dissection was performed for 12 of 16 patients (75%), and R0 resection was achieved in 15 of 16 patients (93.8%). Three cases of grade IIIb chylothorax were observed. There was no mortality in this study. Conclusion Combined neoadjuvant DCF and TME for locally advanced ESCC was safe and less invasive than traditional therapies and had a satisfactory long-term prognosis.

Background Schistosomiasis is a debilitating and neglected tropical disease for which praziquantel (PZQ) remains the first-choice drug for treatment and control of the disease. In our previous studies, we found that the patented compound DW-3-15 (patent no. ZL201110142538.2) displayed significant and stabilized antiparasitic activity through a mechanism that might be distinct from PZQ. Here, we investigated the antischistosomal efficacy of PZQ combined with DW-3-15 against schistosomula and adult worms of Schistosoma japonicum in vitro and in vivo, to verify whether there was a synergistic effect of the two compounds. Methods The antischistosomal efficacy of PZQ combined with DW-3-15 in comparison with an untreated control and monotherapy group against schistosomula and adult worms was assessed both in vitro and in vivo. Parasitological studies, scanning electron microscopy, combination index, and histopathological analysis were used for the assessment. Results The results showed significantly reduced viability of schistosomes, achieving 100% viability reduction for juveniles and males by combination chemotherapy using PZQ together with DW-3-15 in vitro. The combination index was 0.28, 0.27, and 0.53 at the higher concentration of PZQ combined with DW-3-15 against juveniles, males, and females, respectively, indicating that the two compounds display strong synergism. Scanning electron microscopy observations also demonstrated that the compound combination induced more severe and extensive alterations to the tegument and subtegument of S. japonicum than those with each compound alone. In vivo, compared with the single-compound-treated group, the group treated with the higher-dose combination demonstrated the best schistosomicidal efficacy, with significantly reduced worm burden, egg burden, and granuloma count and area, which was evident against schistosomula and adult worms. Conclusions Our study provides a potential novel chemotherapy for schistosomiasis caused by S. japonicum . It would improve the antischistosomal effect on schistosomula and adult worms of S. japonicum , and decrease individual dosages. Graphical Abstract

Background Rechallenge with platinum‐combination chemotherapy in patients with advanced non‐small cell lung cancer (NSCLC) after disease progression on platinum‐combination chemotherapy occasionally leads to a favorable response. The efficacy and safety of platinum‐combination chemotherapy with or without immune‐checkpoint inhibitor (ICI) for patients with recurrent NSCLC after surgery followed by adjuvant platinum‐doublet chemotherapy remains uncertain. Methods Patients who relapsed after surgery plus adjuvant platinum‐doublet chemotherapy and received platinum‐combination chemotherapy with or without ICI between April 2011 and March 2021 at four Nippon Medical School hospitals were retrospectively analyzed. Results Among 177 patients who received adjuvant platinum‐doublet chemotherapy after surgery, a total of 30 patients who received platinum‐combination rechemotherapy with or without ICI after relapse were included in this study. Seven patients received ICI‐combined chemotherapy. The median disease‐free survival (DFS) after surgery was 13.6 months. The objective response rate and disease‐control rate were 46.7% and 80.0%, respectively. The median progression‐free survival and overall survival were 10.2 and 37.5 months, respectively. Patients with longer DFS (≥12 months) had a better prognosis than others. The most common grade ≥3 toxicity associated with this treatment was neutropenia (33%). Grade ≥3 immune‐related adverse events were pneumonitis (14%) and colitis (14%). Treatment‐related deaths did not occur in this study. Conclusion Platinum‐combination chemotherapy with or without ICI for patients with postoperative recurrent NSCLC who previously received adjuvant platinum‐doublet chemotherapy was effective and safe. In particular, this therapy may be promising for patients with longer DFS. Platinum‐combination chemotherapy with or without immune‐checkpoint inhibitors for patients with postoperative recurrent non‐small cell lung cancer (NSCLC) who previously received adjuvant platinum‐doublet chemotherapy was effective and safe. The outcome was noninferior to that of first‐line treatment for stage IV NSCLC.

To date, there is no consensus regarding first-line chemotherapy for patients with HER2-negative, locally advanced/metastatic gastric cancer (a/m GC). In the present study we reported a retrospective case-series of patients treated with a weekly regimen containing timed-flat infusion of 5-fluorouracil (TFI/5-FU), docetaxel and oxaliplatin. From June 2007 to July 2017, 32 consecutive a/m GC patients were treated with first-line standard (st) or modulated (mod) 'FD/FOx' regimen: Weekly 12 h (from 10.00 p.m. to 10.00 a.m.) TFI/5-FU for two consecutive nights at 900 mg/m2/day, associated to weekly alternating docetaxel, 50 mg/m2 and oxaliplatin, 80 mg/m2. The median age of the patients was 60 years and their Eastern Cooperative Oncology Group-performance status (ECOG-PS) was as follows: i) ECOG-PS 0/1, (n=28, 87.5%); and ii) ECOG-PS 2 (n=4, 12.5%). Patient activity, efficacy and safety data were collected and subgroup analyses were conducted among patients treated with st and mod FD/FOx. In the intention-to-treat (ITT) analysis, the objective response rate (ORR) was 75% (95% CI, 53-90) and the disease control rate (DCR) was 87.5% (95% CI, 67.6-97.3). After a median follow-up of 16 months, median progression-free survival (PFS) and median overall survival (OS) were 14.0 and 19.0 months, respectively. The received dose-intensities were ~80% of the standard doses for each agent. The most relevant treatment-related grade 3 adverse events were: Neutropenia (40.6%), asthenia (18.7%) and diarrhea (18.7%). The only treatment-related grade 4 adverse event was neutropenia (9.3%). No febrile neutropenia was observed and none of the patients died as a result of adverse events. FD/FOx regimen appeared to be a feasible option as a first-line treatment of a/m GC patients, especially in case of high-tumor burden, with the need of rapid tumor shrinkage and disease-related symptoms palliation.

The platelet-activating factor receptor (PAFR) is a key molecule that participates in intracellular signaling pathways, including regulating the activation of kinases. It is involved in cancer progression, but the detailed mechanism of its chemosensitivity is unknown. The purpose of the current study was to elucidate the mechanism regulating cisplatin (CDDP) sensitivity through PAFR functions in oral squamous cell carcinoma (OSCC). We first analyzed the correlation between PAFR expression and CDDP sensitivity in seven OSCC-derived cell lines based upon cell viability assays. Among them, we isolated 2 CDDP-resistant cell lines (Ca9-22 and Ho-1-N-1). In addition to conducting PAFR-knockdown (siPAFR) experiments, we found that ginkgolide B (GB), a specific inhibitor of PAFR, enhanced both CDDP chemosusceptibility and apoptosis. We next evaluated the downstream signaling pathway of PAFR in siPAFR-treated cells and GB-treated cells after CDDP treatment. In both cases, we observed decreased phosphorylation of ERK and Akt and increased expression of cleaved caspase-3. These results suggest that PAFR is a therapeutic target for modulating CDDP sensitivity in OSCC cells. Thus, GB may be a novel drug that could enhance combination chemotherapy with CDDP for OSCC patients.

Background Both hormonal therapy (HT) and maintenance capecitabine monotherapy (MCT) have been shown to extend time to progression (TTP) in patients with metastatic breast cancer (MBC) after failure of taxanes and anthracycline‐containing regimens. However, no clinical trials have directly compared the efficacy of MCT and HT after response to first‐line capecitabine‐based combination chemotherapy (FCCT) in patients with hormone receptor (HR)‐positive and human epidermal growth factor receptor 2 (HER2)‐negative breast cancer. Methods We retrospectively analyzed the charts of 138 HR‐positive and HER2‐negative MBC patients who were in non‐progression status after FCCT and who were treated between 2003 and 2012 at the Cancer Institute and Hospital, Chinese Academy of Medical Sciences, in Beijing, China. The median number of first‐line chemotherapy cycles was 6 (range, 4–8); combined agents included taxanes, vinorelbine, or gemcitabine. Of these 138 patients, 79 received MCT, and 59 received HT. Single‐agent capecitabine was administered at a dose of 1250 mg/m2 twice daily for 14 days, followed by a 7‐day rest period, repeated every 3 weeks. Of the 59 patients who received HT, 37 received aromatase inhibitors (AIs), 8 received selective estrogen receptor modulators (SERMs), and 14 received goserelin plus either AIs or SERMs. We then compared the MCT group and HT group in terms of treatment efficacy. Results With a median follow‐up of 43 months, patients in the HT group had a much longer TTP than patients in the MCT group (13 vs. 8 months, P = 0.011). When TTP was adjusted for age, menopausal status, Karnofsky performance status score, disease‐free survival, site of metastasis, number of metastatic sites, and response status after FCCT, extended TTP was still observed for patients in the HT group (hazard ratio: 0.63; 95% confidence interval: 0.44–0.93; P = 0.020). We also observed a trend of overall survival advantage for patients in the HT group vs. patients in the MCT group, but the difference was not significant (43 vs. 37 months, P = 0.400). In addition, patients in the HT group generally tolerated the treatment well, whereas patients in the MCT group experienced grades 3–4 adverse events, the most frequent of which were hand‐foot syndrome (15.8%) and hematologic abnormalities (7.6%). Conclusion For HR‐positive and HER2‐negative MBC patients, HT might be considered a treatment after response to FCCT but prior to MCT as a long‐term administration.

Background The MORPHEUS platform comprises multiple open-label, randomized, phase Ib/II trials designed to identify early efficacy and safety signals of treatment combinations across cancers. Atezolizumab (anti-programmed cell death 1 ligand 1 [PD-L1]) was evaluated in combination with PEGylated recombinant human hyaluronidase (PEGPH20). Methods In 2 randomized MORPHEUS trials, eligible patients with advanced, previously treated pancreatic ductal adenocarcinoma (PDAC) or gastric cancer (GC) received atezolizumab plus PEGPH20, or control treatment (mFOLFOX6 or gemcitabine plus nab-paclitaxel [MORPHEUS-PDAC]; ramucirumab plus paclitaxel [MORPHEUS-GC]). Primary endpoints were objective response rates (ORR) per RECIST 1.1 and safety. Results In MORPHEUS-PDAC, ORRs with atezolizumab plus PEGPH20 (n = 66) were 6.1% (95% CI, 1.68%-14.80%) vs. 2.4% (95% CI, 0.06%-12.57%) with chemotherapy (n = 42). In the respective arms, 65.2% and 61.9% had grade 3/4 adverse events (AEs); 4.5% and 2.4% had grade 5 AEs. In MORPHEUS-GC, confirmed ORRs with atezolizumab plus PEGPH20 (n = 13) were 0% (95% CI, 0%-24.7%) vs. 16.7% (95% CI, 2.1%-48.4%) with control (n = 12). Grade 3/4 AEs occurred in 30.8% and 75.0% of patients, respectively; no grade 5 AEs occurred. Conclusion Atezolizumab plus PEGPH20 showed limited clinical activity in patients with PDAC and none in patients with GC. The safety of atezolizumab plus PEGPH20 was consistent with each agent’s known safety profile. (ClinicalTrials.gov Identifier: NCT03193190 and NCT03281369). In this clinical trial, atezolizumab was evaluated in combination with PEGPH20 to assess clinical activity in patients with pancreatic ductal adenocarcinoma or gastric cancer.

Cell cycle regulation is orchestrated by a complex network of interactions between proteins, enzymes, cytokines, and cell cycle signaling pathways, and is vital for cell proliferation, growth, and repair. The occurrence, development, and metastasis of tumors are closely related to the cell cycle. Cell cycle regulation can be synergistic with chemotherapy in two aspects: inhibition or promotion. The sensitivity of tumor cells to chemotherapeutic drugs can be improved with the cooperation of cell cycle regulation strategies. This review presented the mechanism of the commonly used chemotherapeutic drugs and the effect of the cell cycle on tumorigenesis and development, and the interaction between chemotherapy and cell cycle regulation in cancer treatment was briefly introduced. The current collaborative strategies of chemotherapy and cell cycle regulation are discussed in detail. Finally, we outline the challenges and perspectives about the improvement of combination strategies for cancer therapy.

Talacotuzumab, a humanized anti-CD123 monoclonal antibody, was evaluated in combination with decitabine in elderly patients with acute myeloid leukemia (AML) not eligible for intensive chemotherapy. A multicenter, phase 2/3 study was initiated to determine the recommended phase 2 dose (RP2D) of talacotuzumab (Part A) followed by an open-label, randomized comparison of talacotuzumab in combination with decitabine versus decitabine alone to assess achievement of complete response (CR) and overall survival (OS) in Part B. Ten patients were enrolled in Part A and 316 in Part B; the results presented here are based on a database lock on January 25, 2018. Part A confirmed the RP2D of talacotuzumab to be 9 mg/kg. In Part B, CR was achieved in 12/80 (15%) patients receiving combination therapy and in 9/82 (11%) patients receiving decitabine alone (odds ratio: 1.4; 95% confidence interval [CI]: 0.6–3.6; p  = 0.44). Median (95% CI) OS was 5.36 (4.27–7.95) months for combination therapy versus 7.26 (6.47–8.64) months for decitabine alone (hazard ratio: 1.04; 95% CI: 0.79–1.37; p  = 0.78). Combination therapy showed no improvement in efficacy versus decitabine alone, resulting in the Independent Data Monitoring Committee’s recommendation of early termination of enrollment and discontinuation of talacotuzumab treatment.