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   Table of Contents - Current issue
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October-December 2019
Volume 6 | Issue 4
Page Nos. 155-207

Online since Friday, November 22, 2019

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REVIEW ARTICLES  

Future of 5-fluorouracil in cancer therapeutics, current pharmacokinetics issues and a way forward Highly accessed article p. 155
Sania Zafar Iqbal, Farhat Jubeen, Farooq Sher
DOI:10.4103/JCRP.JCRP_10_19  
Background: In addition to exhibiting antitumor potential, antitumor drugs exhibit toxicity due to a poor pharmacokinetic profile. An enormous amount of research has been carried out and is still ongoing to obtain more targeted, potent, and safe drugs to treat cancer, and pharmacokinetic evaluations of anticancer drugs are needed. Objectives: The present review examined different delivery systems and methodologies designed in recent years to investigate the pharmacokinetics of the anticancer drug, 5-fluorouracil (5-FU). These methodologies highlight how the issues of bioavailability, absorption, half-life, targeted neoplastic cell potential, and high therapeutic index of 5-FU are resolved. Results: A number of naturally occurring macromolecules such as modified starch, porphyran, peptides, and folic acids have been found to be successful in vitro to improve the permeability and retention effect of 5-FU against solid tumors. A promising approach for targeted 5-FU delivery to oncoproteins has resulted in a number of potentially sound anticancer nanocomposites. Chitosan nanoparticles loaded with 5-FU have been shown to exhibit cytotoxicity equivalent to 5-FU injections against gastric carcinoma. At the level of inter- and intra-molecular interactions, the co-crystal approach has been found to be successful against colorectal cancer proteins. Because of the 5-FU ligand-like nature and its metal-binding potential, researchers have shifted attention toward the synergistic co-administration of gold complexes with this drug. Conclusions: This study highlighted the techniques used to improve the pharmacokinetics of 5-FU and that "nanocarriers" are a promising approach in this field. The conclusion is supported by solid evidence.
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Thyroid hormone, PD-L1, and cancer p. 162
Yi-Ru Chen, Zi-Lin Li, Ya-Jung Shih, Paul J Davis, Jaqueline Whang-Peng, Hung-Yun Lin, Kuan Wang
DOI:10.4103/JCRP.JCRP_26_19  
Objective: Thyroid hormone plays a vital role in maintaining whole-body physiological activities. However, several different disorders can arise when thyroid hormone is abnormal. Even more, thyroid hormone has been shown to stimulate cancer cell proliferation at physiological concentration. By binding to cell surface integrin αvβ3, thyroid hormone, especially thyroxine activates ERK1/2 activation and sequentially stimulates cell proliferation. Different mechanisms have been demonstrated to be involved in thyroxine-induced cancer proliferation. Checkpoint, PD-1/PD-L1, has shown highly correlated to cancer proliferation and survival. Data Sources: We examined actions of thyroxine and Nano-diamino-tetrac (NDAT; Nanotetrac) on PD-L1 mRNA abundance (qPCR) and PD-L1 protein content in various cancer cells. Methodologies used are qPCR, Western blot analyses, confocal microscopy, and xenograft. Study Selection: We investigate mechanisms involved in thyroid hormone-induced PD-L1 expression and inhibitory effect of NDAT on thyroid hormone-induced PD-L1 expression. Either blocking thyroid hormone-binding on integrin αvβ3 or using NDAT can inhibit PD-L1 expression. Results: Our studies indicate that thyroid hormone induces PD-L1 expression via activating ERK1/2, PI3K, and STAT3 in different types of cancer cells. NDAT inhibits the cancer cell PI3-K and MAPK signal transduction pathways that are critical to PD-L1 gene expression. Other studies on PubMed also indicate thyroxine's actions are via integrin αvβ3. Conclusions: Thyroid hormone-induced PD-L1 expression not only facilitates cancer cell proliferation but also interferes with chemotherapy. In this current review, we will discuss mechanisms involved in thyroid hormone-induced PD-L1 expression. In addition, role of PD-L1 in thyroid hormone-induced cancer growth and metastasis will be addressed.
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ORIGINAL ARTICLES Top

Neutrophil lymphocyte ratio is an independent prognosticator in patients with locally advanced head and neck squamous cell carcinoma receiving induction chemotherapy with docetaxel, cisplatin, and fluorouracil p. 170
Hsiang-Lan Lai, Yeh Tang, Chih-Yen Chien, Fu-Min Fang, Tai-Lin Huang, Tai-Jan Chiu, Shau-Hsuan Li
DOI:10.4103/JCRP.JCRP_12_19  
Background: The aim of the present study was to evaluate the prognostic value of neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) receiving induction chemotherapy with docetaxel, cisplatin, and fluorouracil (TPF). Materials and Methods: We performed a single-center retrospective analysis of 126 patients with locally advanced HNSCC treated with TPF as induction chemotherapy at Kaohsiung Chang Gung Memorial Hospital. NLR and PLR were calculated from blood tests before induction chemotherapy and correlated with clinical parameters and treatment outcomes. Results: A NLR ≧3 was significantly associated with advanced clinical American Joint Committee on Cancer (AJCC) 7th stage, higher clinical T classification, oral cavity primary tumor site, and alcohol history. A PLR ≧120 was significantly correlated with advanced clinical AJCC 7th stage and oral cavity primary tumor site. The overall response rates of induction chemotherapy were 70% and 50% (P = 0.022) in patients with a NLR <3 and NLR ≧3 and 78% and 52% (P = 0.008) in patients with a PLR <120 and PLR ≧120, respectively. Univariate analysis showed 5-year progression-free survival (PFS) rates of 58% and 32% (P < 0.001) in the patients with a NLR <3 and NLR ≧3 and 59% and 38% (P = 0.022) in those with a PLR <120 and PLR ≧120, respectively. The 5-year overall survival (OS) rates were 51% and 24% (P < 0.001) in the patients with a NLR <3 and NLR ≧3 and 52% and 31% (P = 0.011) in those with a PLR <120 and PLR ≧120, respectively. In multivariate analysis, NLR ≧3 was significantly independently associated with worse PFS (P = 0.018, odds ratio [OR]: 2.11) and OS (P = 0.026, OR: 1.87). Conclusions: Our findings suggested that an elevated NLR was independently associated with the prognosis of patients with locally advanced HNSCC treated with induction chemotherapy with TPF, and that, it may be helpful in clinical practice.
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Association between serum folate level and invasive cervical cancer at a university teaching hospital in South-West Nigeria p. 179
Adebayo I Sekumade, Kehinde S Okunade, Gbenga Olorunfemi, Ebunoluwa O Daramola, Muisi A Adenekan, Adeyemi A Okunowo, Rose I Anorlu
DOI:10.4103/JCRP.JCRP_24_19  
Background: Cervical cancer is a common cause of cancer-related morbidity and mortality in developing countries. Serum folate may modify cancer risk through its role in DNA synthesis and methylation. Objective: To determine the association between serum folate levels and the occurrence of cervical cancer among women seen at a university teaching hospital in South-West Nigeria. Patients and Methods: This was an analytical cross-sectional study involving two groups of participants including 50 cases with invasive cervical cancer (ICC) and 50 controls with a normal cervix. Data analysis was performed between discrete baseline characteristics of the cases and controls using the Pearson's Chi-square test, whereas the mean serum folate levels of the cases and controls were compared using the independent sample t-test. P<0.05 was considered statistically significant. Results: There was no significant positive association between low serum folate and the occurrence of ICC (adjusted odds ratio: 2.99; P = 0.088). Conclusions: The findings of this study showed that low serum folate was not independently associated with an increased risk of ICC. However, a robust multicenter long-term longitudinal study will provide further evidence on the role of serum folate in the occurrence of ICC.
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CASE REPORTS Top

Identification of docetaxel, cisplatin, and 5-fluorouracil regimen hypersensitivity by In vitro T-cell activation assay p. 184
Hang Huong Ling, Chun-Bing Chen, Cheng-Hsu Wang, Yen-Min Huang
DOI:10.4103/JCRP.JCRP_11_19  
An in vitro T-cell activation assay measuring granulysin and granzyme B has been used to identify the drug hypersensitivity of common causative drugs, but not of chemotherapeutic drugs. Both granulysin and granzyme B are cytotoxic molecules involved in skin eruptions during drug hypersensitivity. Herein, we report the first clinical application of an in vitro T-cell activation assay to identify the causative agent in docetaxel, cisplatin, and 5-fluorouracil (5-FU)-related hypersensitivity in a patient with head-and-neck cancer. A significant increase in granulysin and granzyme B was observed for 5-FU rather than for docetaxel or cisplatin. Despite several limitations, we were still able to pinpoint 5-FU as the culprit drug in a chemotherapy combination without further drug rechallenge in our patient. In conclusion, an in vitro T-cell activation assay measuring granulysin and granzyme B can be a safe and alternative tool to determine the causative agent of hypersensitivity reactions in cancer patients who need combination chemotherapy.
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Osteosarcoma arising from preexisting Paget's disease of bone p. 188
Yi-Chen Li, Yu-Hsi Kao, Jen-Wei Tsai, Cheng-Yo Yen, Yuan-Kun Tu, Jih-Hsi Yeh
DOI:10.4103/JCRP.JCRP_14_19  
Paget's disease of bone (PDB) was first described by Sir James Paget in 1877 and is a relatively benign metabolic bone disease. It is believed to be a more common among European populations but is rare among Scandinavian and Asian populations. Malignant transformation is a rare, but fatal complications of PDB can occur, and most patients are elderly. Herein, we present a case of a tumor detected incidentally at the left proximal femur that was initially treated as metastatic bone disease, but the final pathology was proven to be secondary malignant transformation from preexisting PDB. Recent studies suggest that PDB may be under-represented in Asian populations. Thus, it is important that physicians pay more attention to PDB and its treatments. Early interventions and novel therapeutic agents can achieve better disease control and also prevent the complication of malignant transformation, which still has a poor prognosis.
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Allogeneic hematopoietic stem cell transplantation in a 76-year-old woman with relapsed acute myeloid leukemia p. 193
Kuan Yu Lee, Pei-Ying Hsieh
DOI:10.4103/JCRP.JCRP_15_19  
Acute myeloid leukemia (AML) is commonly diagnosed in the elderly. Treatment of AML frequently requires hematopoietic stem cell transplantation (HSCT), which is associated with significant treatment-related toxicity and is considered to be too intense for older patients. However, with the development of reduced intensity conditioning, patients of increasing age are now considered for HSCT. We present a case of relapsed AML in a 76-year-old woman who was successfully treated with allogeneic stem cell transplantation. She endured the process without significant complications and achieved a durable treatment response, demonstrating the feasibility of allogeneic HSCT in patients with very advanced age.
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A case of acute lymphoblastic leukemia with spontaneous tumor lysis syndrome after adenosine injection p. 197
Jeng-Shiun Du, Ya-Ting Cheng, Hui-Hua Hsiao
DOI:10.4103/JCRP.JCRP_18_19  
Tumor lysis syndrome (TLS) is a life-threatening oncological emergency that usually occurs after cytotoxic therapy in patients with a large tumor burden, for example, patients with high-grade lymphoma or acute lymphoblastic leukemia (ALL). We report a case of a patient with ALL who spontaneously developed TLS without having undergone cytotoxic therapy. The mechanisms of spontaneous TLS are unclear, and the relationship between adenosine and cell growth/cell death is controversial. Several literature reviews have revealed that adenosine plays a role in the survival signal pathway. Although rare, our case is an example of a patient developing spontaneous TLS after adenosine treatment.
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Liquefaction of metastatic radioactive iodine-refractory follicular thyroid carcinoma following radiotherapy and sorafenib p. 200
Jheng-Zong Tien, Chen-Yuan Lin
DOI:10.4103/JCRP.JCRP_19_19  
Sorafenib was approved for radioactive iodine (RAI)-refractory metastatic differentiated thyroid carcinoma in 2013. Herein, we describe the first case of metastatic RAI-refractory follicular thyroid carcinoma that markedly improved with liquefaction after radiotherapy and low-dose sorafenib use (200 mg twice daily).
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A 54-year-old man with primary mediastinum choriocarcinoma p. 203
Hsuan-Chih Kuo, Cheng-Hsu Wang
DOI:10.4103/JCRP.JCRP_22_19  
Primary mediastinum choriocarcinoma, an extragonadal germ cell tumor, is a rare malignant tumor that is more common in men. We present a case of primary mediastinum choriocarcinoma in a male patient who initially presented with gynecomastia and progressed to superior vena cava syndrome. Both surgical biopsy and pathologic diagnosis were challenging. After standard induction chemotherapy, the resected tumor underwent squamous cell transformation, which has rarely been reported in cases of choriocarcinoma. His critical condition was resolved using induction chemotherapy with a combination of bleomycin, etoposide, and cisplatin, followed by resection of the residual tumor. However, tumor recurrence occurred 9 months later, and he was treated with salvage radiotherapy and chemotherapy. This was a rare and challenging case from the aspects of initial approaches, pathologic differential diagnosis, and different treatment modalities.
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