- [Efficiency and adverse effects of the effective therapy applying etoposide + cisplatin and its subsequent maintenance therapy with different durations in patients with small cell lung cancer]. [English Abstract, Journal Article]
- Zhonghua Zhong Liu Za Zhi 2016 Jun 23; 38(6):454-9.
To explore the efficiency and adverse effects of the effective EP (etoposide + cisplatin) therapy and its subsequent maintenance therapy with different durations in patients with small cell lung cancer (SCLC).Clinical data of 104 SCLC patients diagnosed and treated at the Jilin Province Cancer Hospital between September 2010 and December 2013 were retrospectively analyzed.Among them, 35 patients were subsequently treated with a 4-week maintenance therapy following the original therapeutic regimen after the effective EP therapy (4-week maintenance therapy group), 35 patients were treated with a subsequent 6-week maintenance therapy (6-week maintenance therapy group), and 34 patients were treated without maintenance therapy (control group).52 patients were in limited stage, and 52 patients were in extensive stage. The progression-free survival (PFS), overall survival (OS) and adverse effects in the 4-week maintenance therapy group, 6-week maintenance therapy group and control group were analyzed.The median PFS in the control group, 4-week maintenance therapy group and 6-week maintenance therapy group was 4.0, 3.5, and 4.0 months, respectively, and the median OS was 9.0, 10.0 and 12.0 months, respectively, showing no significant difference among the groups (P>0.05 for all). The median PFS was prolonged by 2 months as compared with the control group after the 4-week maintenance therapy in the patients with complete remission in first-line chemotherapy (P=0.041), while the median OS was not improved (P=0.131). Neither the median PFS nor median OS showed statistically significant difference between each two groups in the patients with partial remission in first-line chemotherapy (P>0.05 for all). In the limited stage, the median PFS in the control group, 4-week maintenance therapy group, and 6-week maintenance therapy group was 5.0, 6.5, and 4.0 months, respectively, and median OS was 11.0, 13.5, and 13.0 months, respectively, the differences showed no statistical significance (P>0.05 for all). In the extensive stage, the median PFS in the control group, 4-week maintenance therapy group, and 6-week maintenance therapy group was 3.0, 3.0, and 3.5 months, respectively, showing significant differences (P=0.015); the median OS was 6.5, 8.0, and 8.0 months, respectively, presenting no statistically significant differences (P=0.096). In addition, the PFS in the 6-week maintenance therapy group was significantly improved as compared with that in the control group (P=0.016). Compared with the control group, the incidence rates of nausea (grade 3-4), vomiting, hypodynamia, leukopenia, neutropenia, and thrombocytopenia in the 4-week maintenance therapy group and 6-week maintenance therapy group were increased significantly (P<0.05 for all), however, the side effects were tolerable.Prolonging the treatment cycle of EP therapy can improve the PFS in SCLC patients in first-line CR chemotherapy and extensive stage.
- Hematopoietic Progenitor Cell Mobilization with ICE Chemotherapy Versus Plerixafor-Based Strategies in Patients with Hodgkin and Non-Hodgkin Lymphoma. [JOURNAL ARTICLE]
- Biol Blood Marrow Transplant 2016 Jun 21.
Studies comparing the efficacy and safety of chemo-mobilization with ifosfamide, carboplatin and etoposide (ICE) ± rituximab with plerixafor-based approaches in lymphoma patients have not been performed. We analyzed hematopoietic progenitor cell mobilization outcomes in lymphoma patients undergoing chemo-mobilization with ICE (n=35) compared with either routine plerixafor (n=30) or "just in time" (JIT) plerixafor (n=33) based mobilization. Chemo-mobilization provided a significantly higher total CD34+ cell yield (median collection 5.35x 10(6) cells /kg for ICE vs. 3.15 x 10(6) cells/kg for routine plerixafor and 3.6 x 10(6) cells/kg for JIT plerixafor, p <0.001). The median day 1 yield of CD34+ cells was not significantly different (median 2.2 x 10(6) cells/kg in ICE vs. 1.9 x 10(6) cells/kg in upfront plerixafor vs. 1.7 x 10(6) cells/kg in JIT plerixafor, p= 0.20). There was no significant difference in the three groups in terms of total number of apheresis sessions performed (median 2 in each group, p=0.78). There were no mobilization failures (unable to collect at least 2 x10(6) cells/kg) in chemo-mobilization group, while 5 patients (16.7%) in the routine plerixafor and 3 patients (9.1%) in JIT group had mobilization failure, (p=0.04). Mean time to neutrophil engraftment was faster in the chemo-mobilization group, 10.3 days (±1.2) compared to 12.1 days (±3.6) in the routine plerixafor group and 11.6 days (±3.0) in the JIT group (p<0.001) and mean time to platelet engraftment was 13.7 days (±0.7) in ICE vs. 20.3 days (±1.6) in routine plerixafor vs. 17.1 days (±0.9) in JIT group, (p<0.001). Red blood cell transfusions were significantly higher in the chemo-mobilization group (34.3% vs. 0 vs. 3.2% vs. 1, p<0.001) and so were the platelet transfusions (22.9% vs. 0 vs. 0, p<0.001). Excluding the cost of chemotherapy administration, chemo-mobilization was associated with significantly less mobilization cost (average cost $ 17,601.76 in ICE vs. $ 28,963.05 in routine and $ 25,679.81 in JIT, p<0.001). Our data suggests that chemo-mobilization with ICE provides a higher total CD34+ cell yield, lower rates of mobilization failure, faster engraftment and less cost as compared to plerixafor-based approaches with comparable toxicity profile between the groups except for higher transfusion requirements with chemo-mobilization.
- Scaffold-hopping of bioactive flavonoids: Discovery of aryl-pyridopyrimidinones as potent anticancer agents that inhibit catalytic role of topoisomerase IIα. [JOURNAL ARTICLE]
- Eur J Med Chem 2016 Jun 16.:43-54.
A strategy of scaffold-hopping of bioactive natural products, flavones and isoflavones, leading to target-based discovery of potent anticancer agents has been reported for the first time. Scaffold-hopped flavones, 2-aryl-4H-pyrido[1,2-a]pyrimidin-4-ones and the scaffold-hopped isoflavones, 3-aryl-pyrido[1,2-a]pyrimidin-4-ones were synthesized via Pd-catalyzed activation-arylation methods. Most of the compounds were found to exhibit pronounced human topoisomerase IIα (hTopoIIα) inhibitory activities and several compounds were found to be more potent than etoposide (a hTopoIIα-inhibiting anticancer drug). These classes of compounds were found to be hTopoIIα-selective catalytic inhibitors while not interfering with topoisomerase I and interacted with DNA plausibly in groove domain. Cytotoxicities against various cancer cells, low toxicity in normal cells, and apoptotic effects were observed. Interestingly, compared to parent flavones/isoflavones, their scaffold-hopped analogs bearing alike functionalities showed significant/enhanced hTopoIIα-inhibitory and cytotoxic properties, indicating the importance of a natural product-based scaffold-hopping strategy in the drug discovery.
- Daily Weight-Based Busulfan with Cyclophosphamide and Etoposide (Bu/Cy/E) Produces Comparable Outcomes to 4-Times-Daily Busulfan Dosing for Lymphoma Patients Undergoing Autologous Stem Cell Transplantation (ASCT). [JOURNAL ARTICLE]
- Biol Blood Marrow Transplant 2016 Jun 22.
High dose busulfan (Bu) is an integral component of commonly-used preparative regimens for both allogeneic and autologous transplantation. There is significant interest in comparing the efficacy and toxicity of administering Bu every 6 or every 24 hours (Bu6, daily Bu respectively). In order to facilitate a therapeutic dose-monitoring protocol, we transitioned from Bu6 to daily Bu dosing for patients with Hodgkin (HL) and Non-Hodgkin Lymphoma (NHL) undergoing autologous stem cell transplantation (ASCT). Here, we retrospectively review outcomes of 400 consecutive eligible lymphoma patients who underwent ASCT from 2007-2013 with high dose busulfan, cyclophosphamide and etoposide (Bu/Cy/E). Bu was given at a fixed dose of either 0.8 mg/kg every 6 hours for 14 doses for 307 patients or a fixed dose of 2.8 mg/kg every 24 hours for 4 doses (days -9 through -6) for 93 patients transplanted after the transition from Bu6 to daily Bu was made. Toxicity was assessed using pulmonary and liver function tests (PFTs and LFTs) at specified time-points before and after ASCT. Baseline patient and disease characteristics of patients dosed with Bu6 and daily Bu were similar. There was no significant difference in FEV1 or DLCO before and after transplant in the Bu6 vs. daily Bu cohorts. Changes in LFTs with daily Bu were not significantly different than with Bu6. There were no differences in relapse, non-relapse mortality, progression-free survival, or overall survival between Bu6 and Bu 24 administration schedules in univariable or multivariable analysis (P>0.34). For a subset of 23 patients who had first-dose Bu levels measured, we observed significant variation in an median estimated cumulative AUC of 17,568 µM-min (range 12,104 - 23,084 µM-min). In conclusion, daily Bu with Cy/E is more convenient than Bu6, has equivalent outcomes, and results in no increase in either hepatic or pulmonary toxicity. Consistent with previous reports, there is a significant range of Bu AUC levels, with a standard deviation of 13%. These data provide rationale for our prospective clinical trial of real-time therapeutic dose monitoring of Bu.
- Term pregnancy with choriocarcinoma presenting as severe fetal anemia and postpartum hemorrhage. [Journal Article]
- Taiwan J Obstet Gynecol 2016 Jun; 55(3):430-3.
Term pregnancy with choriocarcinoma is a rare condition that can be a serious health threat to both the mother and the fetus. We present a rare case of term pregnancy with choriocarcinoma presenting as severe fetal anemia and postpartum hemorrhage.A 34-year-old woman, gravida 3 para 2, was admitted for profuse vaginal bleeding 2 weeks after cesarean delivery of a full-term anemic baby. Transvaginal sonography revealed a 4.7-cm×10.6-cm heterogenous lesion in the endometrial cavity. Dilatation and curettage was done and a pathologic report revealed choriocarcinoma. Metastatic workup showed lung metastasis. The patient achieved remission after eight cycles of chemotherapy in the form of etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine. There was no evidence of recurrence in the subsequent 3 years of regular follow up.Although fetomaternal hemorrhage is a rare form of presentation of choriocarcinoma, its presence should alert the physician to investigate the cause further. This chemotherapy regimen was effective in our case and the patient needed to be followed up carefully.
- A siRNA screen reveals the prosurvival effect of protein kinase A activation in conditions of unresolved endoplasmic reticulum stress. [JOURNAL ARTICLE]
- Cell Death Differ 2016 Jun 24.
The endoplasmic reticulum (ER) has a crucial role in the proper folding of proteins that are synthesized in the secretory pathway. Physiological and pathological conditions can induce accumulation of mis- or unfolded proteins in the ER lumen and thereby generate a state of cellular stress known as ER stress. The unfolded protein response aims at restoring protein-folding homeostasis, but turns into a toxic signal when ER stress is too severe or prolonged. ER stress-induced cellular dysfunction and death is associated with several human diseases, but the molecular mechanisms regulating death under unresolved ER stress are still unclear. We performed a siRNA-based screen to identify new regulators of ER stress-induced death and found that repression of the Carney complex-associated protein PRKAR1A specifically protected the cells from ER stress-induced apoptosis, and not from apoptosis induced by etoposide or TNF. We demonstrate that the protection results from PKA activation and associate it, at least in part, with the phosphorylation-mediated inhibition of the PKA substrate Drp1 (dynamin-related protein 1). Our results therefore provide new information on the complex regulation of cellular death under ER stress conditions and bring new insights on the conditions that regulate the pro- versus anti-death functions of PKA.Cell Death and Differentiation advance online publication, 24 June 2016; doi:10.1038/cdd.2016.59.
- Paraneoplastic Dermatomyositis Associated with Metastatic Seminoma. [Journal Article]
- Case Rep Urol 2016.:7050981.
We report the first case in Japan of paraneoplastic dermatomyositis with pure seminoma, a tumor that extremely rarely accompanies dermatomyositis. The patient presented to the hospital with muscle weakness and erythema and was diagnosed with dermatomyositis from skin biopsy. Routine radiological screening revealed testicular tumor and massive lymph node metastases. We initially performed orchiectomy along with conventional immunotherapy. However, muscle weakness gradually worsened, and he eventually showed dysphagia and forced respiration and became bedridden. Although he seemed close to being too unstable to tolerate further treatment, we started carefully adjusted chemotherapy comprising 4 courses of etoposide plus cisplatin, which proved highly successful. Lymph node metastases completely disappeared and swallowing and respiration fully normalized after completing chemotherapy. We believe that this clinical success was due to our decision to initiate chemotherapy even in such a weak patient.
- Chemotherapy in non-small cell lung cancer: opportunities for advancement. [Journal Article]
- Chin J Cancer 2016; 35(1):56.
Locally advanced non-small cell lung cancer (NSCLC) continues to be a challenging disease to treat. With high rates of both local and distant failures, there is significant interest in finding more biologically active chemotherapy regimens that can contribute to reduce both failures. The phase III PROCLAIM trial, recently published in the Journal of Clinical Oncology entitled "PROCL
AIM:randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer", compared two different chemotherapy regimens given concurrently with radiotherapy in patients with stage III non-squamous lung cancer: pemetrexed plus cisplatin versus cisplatin plus etoposide. Both groups received consolidation chemotherapy. After enrolling 598 of planned 600 patients, the study was stopped early due to futility as no difference was seen in the primary end-point of overall survival. Since PROCLAIM was designed as a superiority trial, these results suggest that pemetrexed regimens do not offer a clinical advantage over standard cisplatin plus etoposide. There are some subpopulations who might still benefit from pemetrexed, especially if clinicians are concerned about myelosuppression-related adverse events. Future trials are needed to investigate novel biologic agents and irradiation techniques that can result in more durable local and distant disease control in locally advanced NSCLC.
- Neoadjuvant Intraarterial Chemotherapy for Treatment of Malignant Vaginal Tumors in Children: A Single-Center Experience. [Journal Article]
- J Vasc Interv Radiol 2016 Jul; 27(7):996-1000.
Six patients (aged 3-36 mo) with vaginal tumors (rhabdomyosarcoma and endodermal sinus tumor [EST]; n = 3 each) received intraarterial chemotherapy (IAC) and intravenous chemotherapy. Patients underwent internal iliac artery infusion with cisplatin, pirarubicin, and vindesine. Intravenous chemotherapy with vindesine, ifosfamide, and etoposide was administered after 3 weeks. Vaginal tumors disappeared in all patients after 2 or 3 cycles of alternating therapy. Two patients underwent resection of pelvic metastases. Intravenous consolidation chemotherapy was applied. Four patients were disease-free at a median follow-up of 5.8 years. One patient had pelvic recurrence treated with "salvage" therapy with IAC and surgery and was disease-free for 2.5 years.
- DNA Damage Reduces the Quality, but Not the Quantity of Human Papillomavirus 16 E1 and E2 DNA Replication. [Journal Article]
- Viruses 2016; 8(6)
Human papillomaviruses (HPVs) are causative agents in almost all cervical carcinomas. HPVs are also causative agents in head and neck cancer, the cases of which are increasing rapidly. Viral replication activates the DNA damage response (DDR) pathway; associated proteins are recruited to replication foci, and this pathway may serve to allow for viral genome amplification. Likewise, HPV genome double-strand breaks (DSBs) could be produced during replication and could lead to linearization and viral integration. Many studies have shown that viral integration into the host genome results in unregulated expression of the viral oncogenes, E6 and E7, promoting HPV-induced carcinogenesis. Previously, we have demonstrated that DNA-damaging agents, such as etoposide, or knocking down viral replication partner proteins, such as topoisomerase II β binding protein I (TopBP1), does not reduce the level of DNA replication. Here, we investigated whether these treatments alter the quality of DNA replication by HPV16 E1 and E2. We confirm that knockdown of TopBP1 or treatment with etoposide does not reduce total levels of E1/E2-mediated DNA replication; however, the quality of replication is significantly reduced. The results demonstrate that E1 and E2 continue to replicate under genomically-stressed conditions and that this replication is mutagenic. This mutagenesis would promote the formation of substrates for integration of the viral genome into that of the host, a hallmark of cervical cancer.