A Patient with Sequential Diseases of Langerhans Cell Sarcoma, Langerhans Cell Histiocytosis, and Acute Lymphoblastic Leukemia / 罕见病研究

Langerhans cell histiocytosis(LCH)and Langerhans cell sarcoma(LCS)are characterized by clone proliferation of Langerhans-type cells, which may occur concurrently or sequentially with T-cell acute lymphoblastic leukemia (T-ALL) and other Lymphoid neoplasms. A 15-year old female patient diagnosed with T-ALL developed LCH involving multiple systems during maintenance chemotherapy of T-AL. After treated with chemotherapy with improved result, the patient showed progression of the illness and refractory to the second-line treatment. We found c.G35A (p.G12D)mutation in the KRAS gene and used the targeted drug Trametinib for treatment. The treatment proved effective, leading to partial remission within a week. Three months after Trametinib treatment, the patient developed new lymphadenopathy. Biopsy revealed the existence of LCS. The disease progressed quickly, and the patient died 7 days after diagnosis of LCS. The case of patients with T-ALL then developing LCH and LCS sequentially is extraordinarily rare. The causes of the case is unclear and may be related to cell transdifferentiation, clonal evolution, and chemotherapy. Targeted drugs can contain this disease for a short time.

Progress of targeted agents for childhood asthma / 国际儿科学杂志

Asthma is a heterogeneous respiratory disorder characterized by airway inflammation that is common in childhood, and some children cannot be controlled with conventional treatment.With the progress on the pathogenesis and endotypes of asthma, targeted agents for T2 asthma, such as omalizumab, mepolizumab, benralizumab and dupilumab have been approved prescripting in pediatric patients of some ages and have achieved good efficacy, becoming the new hope for children with severe and refractory asthma.However, there is a lack of effective targeted medicines for non-T2 asthma.This paper reviews the progress of targeted agents for childhood asthma in recent years for the better application of such drugs by clinical practitioners.

Precision therapeutic strategies for Hodgkin lymphoma / 白血病·淋巴瘤

Hodgkin lymphoma (HL) is a rare subtype of B-cell malignancies, and it often occurs in the youth. About 80 % patients can be cured with the advance of modern therapy. How to further improve the cure rate of HL and minimize adverse reactions are new tasks faced by the clinicians, meanwhile, short-term curative effect and long-term survival rate are worthy of attention. An accurate assessment of disease stage is crucial for the selection of the appropriate therapy. This review discusses the hot issues regarding HL treatments to further improve the precision therapeutics, and to provide more references for clinical treatment.

Re-differentiating therapy of radioiodine-refractory differentiated thyroid cancer / 中国癌症杂志

Clinical management of radioiodine-refractory differentiated thyroid cancer (RR-DTC) is extremely diffcult. Re-differentiation compounds, such as retinoids, peroxisome proliferator-activated receptor (PPAR) agonists, DNA methyltransferase inhibitors and histone deacetylase inhibitors, have been used in trials to increase iodine uptake in RR-DTC. However, data on these drugs failed to meet the initial high expectations. In recent years, targeted agents have been increasingly used in pre-clinical and clinical studies to induce re-differentiation and mediate131I therapy, and the outcomes are encouraging.

Population pharmacokinetic analysis to identify the possibility of interaction between anti‑cancer agents.

BACKGROUND: A number of molecularly targeted agents in oncology are tested in clinical studies in combination with conventional chemotherapy and/or radiotherapy. There is the possibility that the pharmacokinetics and dynamics of these targeted agents may be different when administered alone as against when administered in combination with other agents. AIM: The aim of this study is to understand the effects of addition of combination agents on the pharmacokinetics of a new, investigational, cyclin dependent kinase inhibitor anti‑cancer drug (Compound A) using population pharmacokinetic (pop‑PK) analysis. MATERIALS AND METHODS: Integrated pop‑PK analysis of data obtained from multiple phase I/II studies of Compound A, given alone or in combination with other agents. RESULTS: A two compartmental model was found suitable to explain the pharmacokinetics of Compound A. No statistically significant influence of patient covariates or combination agents on the pharmacokinetic parameters of the central compartment was detected up to a significance level of 0.01. Model evaluation showed that the parameter estimates are stable and that the variability in the data was well reproduced by the model. CONCLUSIONS: This study represents the first time that a pop‑PK analysis was performed in India for a targeted anti‑cancer agent being developed in India. Such an analysis is useful to not only understand the influence of patient covariates and combination agents on the pharmacokinetics of a new investigational agent, but would also be valuable in the simulation of later phase clinical trials for the agent under development.

Personalized cancer medicine: present status and future perspectives

Most cancers have oncogenes and tumor suppressor genes. First successful drug targeting a oncogene is imatinib. It was very effective for chronic myelogenous leukemia as well as gastrointestinal stromal tumors. Many other targeted agents showed good response: trastuzumab for breast cancer, epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer, etc. Tests for EGFR and ALK gene mutation are routinely recommended for adenocarcinoma of lung cancer for selection of anticancer treatment. In addition, large-scale genomic data generation (next generation sequencing) is feasible in a clinical setting and gives us high hope for personalized cancer medicine. However, there are many hurdles to overcome. Driver genes must be distinguished from the passenger genes that are present in tumor DNA. In case of targeted cancer therapy, emergence of drug resistance due to tumor cell heterogeneity and clonal evolution is difficult to manage. Genetic testing for cancer risk showed some success in preventing familial breast or ovarian cancers, but it cannot be generalized in other tumors. Application of genetic information in cancer medicine showed promise but evidence-based approach is needed in clinical practice.

Research progress on target therapeutic agents of HER-2 extracellular ligand-binding domain in breast cancer / 中国肿瘤临床

The target therapeutic agents of HER-2 extracellular ligand-binding domain have become the core of breast cancer research. A small peptide molecule and an anti-HER2 extracellular domain monoclonal antibody conjugated with protein toxins, radioisotopes, and chemotherapeutic drugs (immunoconjugate) can improve efficacy and reduce systemic toxicity. Vaccines based on HER-2 extracellular region should protect patients from HER-2-overexpressing breast cancer growth. In this review, studies on targeted-block therapies of the HER-2 extracellular ligand-binding domain in breast cancer were discussed to provide references for clinical applications.

Molecular targeted therapy for advanced gastric cancer

Although medical treatment has been shown to improve quality of life and prolong survival, no significant progress has been made in the treatment of advanced gastric cancer (AGC) within the last two decades. Thus, the optimum standard first-line chemotherapy regimen for AGC remains debatable, and most responses to chemotherapy are partial and of short duration; the median survival is approximately 7 to 11 months, and survival at 2 years is exceptionally > 10%. Recently, remarkable progress in tumor biology has led to the development of new agents that target critical aspects of oncogenic pathways. For AGC, many molecular targeting agents have been evaluated in international randomized studies, and trastuzumab, an anti-HER-2 monoclonal antibody, has shown antitumor activity against HER-2-positive AGC. However, this benefit is limited to only ~20% of patients with AGC (patients with HER-2-positive AGC). Therefore, there remains a critical need for both the development of more effective agents and the identification of molecular predictive and prognostic markers to select those patients who will benefit most from specific chemotherapeutic regimens and targeted therapies.

Novel therapeutic approaches to squamous cell carcinoma of the head and neck using biologically targeted agents.

Despite significant improvements in the treatment and outcomes of patients with squamous cell carcinoma of the head and neck (SCCHN) that have resulted from technological advances in radiation delivery and the use of cytotoxic chemotherapy, there is still a pressing need for novel therapies. In the last two decades, our understanding of the molecular biological basis of cancer has provided us with a new framework for developing specific targeted therapies. It is likely that the next wave of developments will include active small molecule inhibitors of epidermal growth factor receptor (EGFR) (and other members of the c-erbB family of receptors), antiangiogenic agents, and drugs that can increase proapoptotic signaling in cancer cells. As with cetuximab, it is most likely that these new agents will first find a niche in the context of combination regimens with standard anticancer therapeutics.

New drugs in hematological disorders / 대한내과학회지

Modern medical oncology has introduced various anti-cancer drugs since the World War I and II. Unlike for the solid tumors, hematological malignancies had been documented some limitations for curing it with chemotherapeutic agents only. In 1960, Dr. Nowell and Dr. Hungerford had discovered elongated chromosome (Philadelphia chromosome) which has documented as a product of translocation between 9th and 22nd chromosome in the patients with chronic myeloid leukemia. In 1970s, immunochemistry technique using monoclonal antibody has spread world widely and from 1990s, flow cytometry method has been available. In appreciation of these evolutions in basic science, the treatment strategy ofhematological malignancies has changed from the chemotherapeutic agents to targeted agents. Among the targeted agents, some drugs are newly developed and others are recreated as anti-cancer drugs after long-time of discard because of their toxicities or teratogenic effects. Nowadays, we are in the middle of flood of targeted agents, for example, tyrosinekinase inhibitors, epidermal growth factor receptor blockers, farnesyl transferase inhibitors, histone deacetylase inhibitors, and etc. In 21st century, the optimal treatment of hematological malignancies should follow a tailor- made strategy according to the patient and disease itself. In the present article, some representative agents will be introduced in accordance with target diseases.

Chemotherapy for Colorectal Cancer

Survival outcomes have been steadily improving for last 50 years in patients with colorectal cancer. The 5-fluorouracil (5-FU) is still one of the major chemotherapeutic agents. New cytotoxic agents, irinotecan and oxaliplatin, or targeted agents, bevacizumab and cetuximab, have been studied in the treatment of colon cancer. Adjuvant chemotherapy is indicated in patients with colon cancer at high-risk stage II and III, and after complete resection. Oxaliplatin-based regimens, FOLFOX, are considered as the standard adjuvant chemotherapy. If there are contraindications for oxaliplatin, the best alternatives are capecitabine or 5FU/LV. In rectal cancer, adjuvant chemotheradiotherapy is indicated in patients who had curative resection with stage II and III cancer. Adjuvant chemotherapy is necessary after neoadjuvant chemoradiotherapy in rectal cancer. The introduction of novel agents targeted to specific molecular features of cancer cells promises more options and marked improvements in efficacy for treatment of metastatic colon cancer. Bevacizumab has been shown to extend survival in colorectal cancer when used in combination with irinotecan and 5-fluorouracil-based chemotherapy, and the addition of cetuximab to irinotecan and 5-fluorouracil-based chemotherapy eliminates irinotecan resistance. Interestingly, there has been no clear association between the expression of epidermal growth factor receptor (EGFR) and response to the EGFR inhibitors. Instead, KRAS mutation has been accepted as a negative predictive factor for the treatment of cetuximab. In contrast, no valid biomarkers for bevacizimab were found so far. More studies are necessary to identify biomarkers of targeted agents. Recent advancement of chemotherapeutic agents extended survival in colorectal cancer.

Recent advances in the treatment of patients with colorectal liver metastases / 대한내과학회지

Colorectal cancer (CRC) is 2nd to 3rd common cancer and the annual incidence of CRC is increasing in Korea. The liver is the most frequent metastatic site of colorectal cancer and approximately one forth of patients presents with liver metastasis at initial diagnosis. Without treatment, patients with colorectal liver metastasis (CRLM) have a poor prognosis; however, long-term survival benefits and even cure have been reported in a portion of patients undergoing surgical resection of liver metastasis. In addition, advances in chemotherapeutic agents, imaging, and surgical techniques can increase the number of patients who are eligible for curative resection. In the past 10 years, combination chemotherapy with 5-fluorouracil (5-FU)/leucovorin (LV) and oxaliplatin or irinotecan was becoming the standard chemotherapy of treatment for metastatic CRC including CRLM. Furthermore, the combined use of targeted agents, such as cetuximab and bevacizumab, plus standard chemotherapeutics revealed more improvements in response rates and survival. Even in patients with resectable CRLM, perioperative chemotherapy with surgical resection could improve in progression free survival. However, the curable portion of patients with CRLM was still less than 20~30%, more detail management based on multidisciplinary team approaches should be needed.

Research progress of molecular-targeted agents in hepatocellular carcinoma / 中华消化外科杂志

Molecular-targeted therapy is a new method and tendency in the treatment of hepatocellular carcinoma (HCC). To date, sorafinib, a multi-targeted gent, is the only one proved to be effective in improving the survival of patients with advanced HCC. Sorafinib is also the first line systemic agent for advanced HCC. Other multi-targeted agents, such as sunitinib, are also proved to be effective. Erlotinib, gefitinib and eetuximab, which target epidermal growth factor receptor, show effectiveness but still need further investigation. Bevacizumab, which targets vascular endothelial growth factor and vascular endothelial growth factor receptor, shows excellent results and deserves more clinical trials. The effects of bortezomib, sirolimus and imatinib, which target other pathways, are still under investigation. The future studies of molecular-targeted therapy for HCC should be focused on the combination of different targeted medicine, and combination of molecular-targeted therapy and chemotherapy, as well as individualized therapy.

Target therapy in metastatic renal cell carcinoma / 国际肿瘤学杂志

The targeted agents of metastatic renal cell carcinoma include the inhibitor of the VHL- HIF-VEGF pathway(sunitinib、 sorafenib、 bevacizumab、 Axitinib) and the mTOR pathway (Temsirolimus, Everoli-mus). These targeted chugs suggest the onset of a new therapeutic era for patients with metastatic renal cell car-cinoma. It is necessary to pay more attention to the side effect. The therapeutic scheme choice of patients and the treatment effect of the non-clear cell carcinomal need further studies.

Chemotherapy for Colorectal Cancer / 대한소화기학회지

Recent advances in chemotherapy lead to improved survival outcomes in patients with colorectal cancer. The 5-fluorouracil (5-FU) is still one of the important chemotherapeutic agents since 1950s, but the introduction of newer cytotoxic agents, irinotecan and oxaliplatin, or targeted agents, bevacizumab and cetuximab, have changed treatment strategies for these patients. A deliberate choice should be made for adjuvant chemotherapy, because it has became complicated more than ever before. Oxaliplatin plus 5-FU seemed to be superior in terms of disease-free and overall survival than 5-FU alone after curative surgery for colon cancers. However not all of these patients seemed to receive benefit from this intensive adjuvant treatment, and some limitations are present according to the postoperative stage, tumor biology and clinical characteristics. For metastatic disease, there is no doubt that more complicated strategies are present because we have more abundant chemotherapeutic agents available for metastatic setting compared to adjuvant setting. Recently, targeted agents, such as bevacizumab or cetuximab, also took an important place in the treatment of metastatic colorectal cancer, and many efforts are also made to find the biomarkers for predicting treatment responses to these targeted agents. In this review, we intended to sort up the standard strategies of chemotherapy for patients with colorectal cancer according to the latest pivotal publications.

Targeted therapy and tailored chemotherapy for advanced non-small cell lung cancer / 대한내과학회지

The prognosis of advanced non-small cell lung cancer (NSCLC) is very poor and the median overall survival is 10 to 12 months, despite the use of chemotherapy and targeted therapy. Recently, many targeted agents for NSCLC have been developed and tested in clinical trials. Of these, chemotherapeutic agents targeting epidermal growth factor receptor (EGFR), such as gefitinib, erlotinib and cetuximab, have been very efficacious in the treatment of NSCLC. Many phase III trials have evaluated the efficacy of these agents in combination with cytotoxic chemotherapy. Based on the results of these trials, clinical and molecular predictors of the response to EGFR-targeted agents, such as EGFR mutations or gene amplification, have been elucidated. Recent advances in understanding the biologic basis of acquired resistance to these agents have potential to improve the clinical effectiveness of agents targeting EGFR. Another agent, bevacizumab, targets an angiogenesis inhibitor, and has improved the survival in advanced NSCLC when used in combination with chemotherapy. In addition, many agents targeting tyrosine kinase inhibitors are being used in clinical trials. This review summarizes the outcomes of clinical trials evaluating agents targeting EGFR, angiogenesis inhibitors, and other molecules used alone or in combination with chemotherapy for the treatment of advanced NSCLC. Also, the predictive role of NSCLC histology for chemotherapy response will be summarized from the results of phase III studies.

Targeted Therapy of Lung Cancer

Atherapeutic plateau has been reached with classical cytotoxic agents in the management of advanced non-small cell lung cancer (NSCLC) patients, even though there has been some modest improvement in overall survival by platinum-based combination chemotherapy with new agents, such as gemcitabine, taxanes, and vinorelbine during the last decades. Targets of pivotal importance for the molecular pathogenesis of the lung cancer have been identified and pharmaceutical compounds against these targets have been developed. At present, we have three targeted agents which have been approved for the management of advanced NSCLC patients; two EGFR-TKIs (epidermal growth factor receptor-tyrosine kinase inhibitors), gefitinib and erlotinib, and one agent targeting angiogenesis, bevacizumab. Erlotinib monotherapy in pretreated NSCLC patients has been shown to improve overall survival compared with the placebo in BR-21 trial, while gefitinib failed to demonstrate an improvement in survival compared with placebo in ISEL study. However, gefitinib has shown therapeutic efficacy in subgroup, such as female, nonsmoker, East-Asian ethnicity, and adenocarcinoma histology. These factors are known to be predictive markers for EFGR-TKI response. EGFR mutations, especially exon 19 deletion and exon 21 L858R point mutation, are highly predictable markers for the response to EGFR-TKI, but not prognostic markers for a survival with EGFR-TKI treatment. The anti-VEGF (vascular endothelial growth factor) antibody bevacizumab has improved efficacy in the front line setting with the combination of cytotoxic chemotherapy paclitaxel/carboplatin (ECOG 4599 trial). Even though there are some excluding factors, such as squamous histology, brain metastasis, and ongoing anti-coagulation, bevacizumab in combination with paclitaxel and carboplatin is likely to be a new standard for the advanced NSCLC patients who meet the eligibility criteria in the firstline regimen. Beside these three approved agents, a large number of new targeted agents have entered the stage of clinical development. Anti-EGFR antibody cetuximab is promising in combination with cytotoxic chemotherapy. Orally available anti-VEGF-TKIs and pan-HER inhibitors may be the next generation.

Developments in the chemotherapy treatment for advanced colorectal cancer / 中国癌症杂志

Metastatic colorectal cancer is a major cause of cancer-related mortality. Surgical resection of all known metastatic disease can be curative in selected patients. The majority of patients,however,require systemic chemotherapy as optimal palliative treatment for their disease. For years,effective treatment for advanced colorectal cancer was limited to fluorouracil. In the 1990s,two additional agents,irinotecan and oxaliplatin,were found to have activity against advanced colorectal cancer. Recently,new molecular targeted agents,bevacizumab and cetuximab,were for the first time demonstrated efficacy. Herein,we review recent developments in treatment for metastatic colorectal cancer and implication for optimal treatment in these patients.