Effective Combination Chemotherapy Research Articles

Emergency IVF versus ovarian tissue cryopreservation: decision making in fertility preservation for female cancer patients

Hundreds of thousands of women in their reproductive years are diagnosed with cancer each year. As the number of female patients who survive cancer increases, the demand for effective and individualized fertility preservation options grows. Currently there are limited clinical options for fertility preservation, and the paucity of publications describing clinical experience and outcomes data has limited accessibility to these options. Decision making for patients diagnosed with cancer requires up-to-date knowledge of the efficacy and safety of available techniques. This article describes a step-by-step approach to evaluation of the cancer patient and presents an accumulation of clinical experience with challenges unique to patients with breast cancer and leukemia. Current data on reproductive outcomes of fertility preservation techniques are examined, demonstrating increasing evidence that these techniques are becoming effective enough to offer routinely to patients facing gonadotoxic cancer therapies, including those still considered to be "experimental."

Quality of life of older adult patients receiving docetaxel-based chemotherapy triplets for esophagogastric adenocarcinoma: a randomized study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)

Treatment of patients with advanced or metastatic esophagogastric adenocarcinoma should not only prolong life but also provide relief of symptoms and improve quality of life (QOL). Esophagogastric adenocarcinoma mainly occurs in elderly patients, but they are underrepresented in most clinical trials and often do not receive effective combination chemotherapy, most probably for fear of intolerance. Using validated instruments, we prospectively assessed QOL within the randomized FLOT65+ phase II trial. Within the FLOT65+ trial, a total of 143 patients aged ≥65 years were randomly allocated to receive biweekly oxaliplatin plus 5-fluorouracil (5-FU) continuous infusion and folinic acid (FLO) or the same regimen in combination with docetaxel 50 mg/m(2) (FLOT). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and the gastric module STO22 were administered every 8 weeks until progression. Time to definitive deterioration of QOL parameters was analyzed and compared within the treatment arms. The median age of patients was 70 years. Patients receiving FLOT exhibited higher response rates and had improved disease-free and progression-free survival (PFS). The proportions of patients with evaluable baseline EORTC QLQ-C30 and STO22 questionnaires were balanced (83 % in FLOT and 89 % in FLO). Considering evaluable patients with assessable questionnaires (n = 123), neither functioning nor symptom parameters differed significantly in favor of one of the two treatment groups. Particularly, there was no significant difference regarding time to definitive deterioration of global health status/quality of life from baseline (primary endpoint). Notably, patients receiving FLO or FLOT as palliative treatment (n = 98) achieved comparable QOL results. Although toxicity was higher in patients receiving FLOT, no negative impact of the addition of docetaxel on QOL parameters could be demonstrated. Thus, elderly patients in need of intensified chemotherapy may receive FLOT without compromising patient-reported outcome parameters.

Regorafenib Improves Survival in Refractory Colorectal Cancer

Survival in metastatic colorectal cancer (CRC) has improved during the past two decades thanks to the advent of more effective combination chemotherapy

Water‐Dispersible Fullerene Aggregates as a Targeted Anticancer Prodrug with both Chemo‐ and Photodynamic Therapeutic Actions

Prodrug therapy is one strategy to deliver anticancer drugs in a less reactive manner to reduce nonspecific cytotoxicity. A new multifunctional anticancer prodrug system based on water-dispersible fullerene (C60) aggregates is introduced; this prodrug system demonstrates active targeting, pH-responsive chemotherapy, and photodynamic therapeutic (PDT) properties. Incorporating (via a cleavable bond) an anticancer drug, which is doxorubicin (DOX) in this study, and a targeting ligand (folic acid) onto fullerene while maintaining an overall size of approximately 135 nm produces a more specific anticancer prodrug. This prodrug can enter folate receptor (FR)-positive cancer cells and kill the cells via intracellular release of the active drug form. Moreover, the fullerene aggregate carrier exhibits PDT action; the cytotoxicity of the system towards FR-positive cancer cells is increased in response to light irradiation. As the DOX drug molecules are conjugated onto fullerene, the DOX fluorescence is significantly quenched by the strong electron-accepting capability of fullerene. The fluorescence restores upon release from fullerene, so this fluorescence quenching-restoring feature can be used to track intracellular DOX release. The combined effect of chemotherapy and PDT increases the therapeutic efficacy of the DOX-fullerene aggregate prodrug. This study provides useful insights into designing and improving the applicability of fullerene for other targeted cancer prodrug systems.

TS-1 and docetaxel followed by 5-FU/epirubicin/cyclophosphamide (FEC) as preoperative treatment in women with stage II/III breast cancer: A phase II study.

124 Background: The sequential combination of anthracycline and docetaxel (TXT) is one of the standard regimen in the preoperative setting, however, the adverse events of TXT such as febrile neutropenia, fatigue, edema is not low at all. Several reports showed a synergistic effect of combination chemotherapy with 5-FU and TXT through down-regulation of dihydropyrimidine dehydrogenase (DPD) and thymidine synthetase (TS). (Suto et al., Oncol Rep 2006) Okazaki et al. reported the trial of pre-operative combination chemotherapy of TS-1 (80mg/m2) and TXT (40mg/m2) with 13% of pCR rates (HER2-negative), and less adverse events. This study's purpose was to determine the efficacy of TS-1 and TXT followed by FEC in preoperative setting. Methods: This was a single-arm, clinical study evaluating the patients with stage II/III and HER2 negative breast cancer received 4 cycles of TS-1 (TS-1 80 mg/m2 on days 1-14 and docetaxel 40 mg/m2 on day 1 every 3 weeks), followed by 4 cycles of FEC (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2on day 1 every 3 weeks). The primary end point was the pCR rate. The secondary end points were the clinical response rate, adverse drug reactions. The sample size of this study (55 patients) was calculated based on pCR rate obtained in previous studies of the sequential combination of anthracycline and TXT in preoperative setting (HER2-negative). Results: From November 2009 to April 2010, 55 patients were enrolled and 50 patients were assessable for clinical and pathologic responses. The overall response rate (caliper) was 82.0%. The pCR rate was 12.0% (6/50). The breast-conserving rate in patients whose tumor size was larger than 3 cm was 53.3%. PgR status was significantly correlated with pCR. (p=0.024) Grade 4 neutropenia was observed in one patient (2.0%) at the first cycle. The most common grade 3/4 non-hematologic adverse event was hand-foot syndrome, observed in 12 patients (24.5%). One patient (2.0%) showed grade 4 diarrhea. Conclusions: These results indicate that the sequential combination of TS-1 and docetaxel followed by FEC is a well-tolerated, effective neoadjuvant treatment for stage II/III breast cancer.

Cervical non-squamous carcinoma: an effective combination chemotherapy of taxane, anthracycline and platinum for advanced or recurrent cases

An effective salvage chemotherapy for advanced and recurrent non-squamous carcinoma of the uterine cervix has not yet been established. The aim of the present study was to analyze the safety and efficacy of a combination chemotherapy for this disease using taxane, anthracycline, and platinum. This was a retrospective analysis of advanced and recurrent non-squamous cervical cancers treated at the Osaka University Hospital and the Osaka Medical Center for Cancer and Cardiovascular Diseases during a 10 year study period from 2000 to 2009. Single agent chemotherapies and combination chemotherapies for advanced and recurrent cervical cancer cases of non-squamous histology which were reported in the English literature were also reviewed. Salvage chemotherapy, using taxane, anthracycline and platinum, was performed for 5 advanced and 14 recurrent cases. Prior to the salvage chemotherapy, 15 (79%) of the 19 patients had already received either radiation or chemotherapy. A complete or partial tumor response was achieved in 8 (42%) of the 19 cases. The response rate for recurrent disease in a previously irradiated field was 40%. The median progression-free survival (PFS) and overall survival (OS) were 8 months (1-108) and 13 months (5-108), respectively. Grade 4 and febrile grade 3 neutropenia was observed in 6 cases (32%), but there was no case in which salvage chemotherapy had to be cancelled due to toxicity. According to previous reports, the cumulative response rate of combination chemotherapy (35%) was significantly higher than that of single agent chemotherapy (17%) (p<0.001). OS tended to be longer in the combination chemotherapy cases (8.7 months to 18 months) than that of single agent chemotherapy cases (7.3+ months to 9.1+ months). Combination chemotherapy of taxane, anthracycline, and platinum was found to have a survival benefit for advanced and recurrent cervical cancer patients of non-squamous carcinoma histology, with a tolerable toxicity.

In vitro survival of MCF-7 breast cancer cells following combined treatment with ionizing radiation and mitoxantrone-mediated photodynamic therapy

This study evaluated the effects of mitoxantrone (MX) as a sensitizer following combined treatment with ionizing radiation and photodynamic therapy in the MCF-7 human breast cancer cell line. Cells were incubated with MX at different concentrations for 90min and exposed to different fluence rates of non-coherent light and different dose rates of ionizing X-ray radiation in independent treatment groups. Additionally, the combined effects of chemotherapy, phototherapy, and radiotherapy were evaluated. The percent cell survival was investigated using the MTT assay. MX acted as both a photosensitizer and radiosensitizer. Furthermore, the use of 1μM MX in combination with PDT at 10J/Cm(2) and 4Gy of X-ray radiation strongly resulted in the death of cancer cells and reduced the percentage of viable cancer cells to 2.4±1.15. Our data demonstrated that the adverse effects of MX in combination with radiotherapy were partially abated, without a reduction in the efficacy of treatment. This new therapeutic avenue for breast cancer therapy merits further investigation using in vivo models for application in humans.

Fatal hepatic sinusoidal obstruction syndrome in a child with primary CNS lymphoma during induction therapy

Hepatic sinusoidal obstructive syndrome (HSOS) is a lifethreatening syndrome characterized by painful liver enlargement, weight gain, and jaundice, and generally occurs as a complication of hematopoietic stem cell transplantation (HSCT) [1] and chemotherapy in Wilm’s tumor [2]. HSOS after conventional chemotherapy for malignant disease other than Wilm’s tumor is unusual. Here, we report the first case to our knowledge of a 9-yearold boy with PCNSL who developed fatal HSOS during induction therapy. A 9-year-old boy presented with a 4-month history of hyperphagia. He was admitted to our department because of headache. The patient’s body weight was 40 kg (28 % obesity compared to ideal body weight). He had gained 15 kg in body weight over the previous 4 months. A physical examination revealed left-sided hemiparesis with a decreased mental status. The Eastern Cooperative Oncology Group performance status (ECOG-PS) was 3. Laboratory and coagulation tests showed the following: AST, 20 U/L; ALT, 21 U/L; LDH, 384 IU/L; total bilirubin, 0.3 mg/dl; activated partial thromboplastin time (aPTT), 33.2 s (normal 26–36 s); prothrombin time (PT), 10.8 s (normal 10–15 s), prothrombin time in international normalized ratio (PT-INR), 1.05 (normal 0.9–1.1); AT III activity level, 115 % (normal 80–120 %). Magnetic resonance imaging of the brain showed a mass with a homogeneous enhancement located in the right frontal lobe, and this lesion reached the hypothalamus (Fig. 1a). As the leftsided hemiparesis progressed rapidly, a sub-total excision of the tumor was performed. A pathological examination of the surgical specimen revealed a monotonous population of small-sized mononuclear lymphoblastic cells (Fig. 1b). Flow cytometry analysis revealed that lymphoblasts expressed TdT, cytoplasmic CD79a, CD10, and HLA-DR, leading to the diagnosis of precursor B-cell lymphoblastic lymphoma of the right cerebral hemisphere. A bone marrow examination revealed 6 % lymphoblasts. Cerebrospinal fluid (CSF) revealed 81 cells/mm leukocytes, with 82 % lymphoblasts. He showed no evidence of immunodeficiency, and a serological test for HIV was negative. Although optimal treatment of PCNSL in children has not yet been established, the effectiveness of combination chemotherapy for lymphoblastic lymphoma has been studied [3, 4]. We decided to treat the patient according to the protocol of pediatric advanced lymphoblastic lymphoma (ALBNHL03). An induction therapy regimen based on prednisone (60 mg/m daily for 5 weeks), vincristine (VCR) (1.5 mg/m on days 8, 15, 22, and 29), cyclophosphamide (1.0 g/m on day 8), daunorubicin (40 mg/m on days 8, 15, and 22), L-asparaginase (6,000 U/m on days 9, 11, 13, 16, 18, 20, 23, 25, and 27), and triple intrathecal therapy (methotrexate, cytarabine, and hydrocortisone, 12.5, 25, and 25 mg, respectively, on days 1, 15, and 29) (Fig. 2). Although he had shown rapid-onset obesity, no dose modification was made. His left-sided hemiparesis did not change; however, his mental status improved, and CSF tumor cells became negative on day 15. On day 27 of induction therapy, he developed peripheral neuropathy with pain. We stopped the induction therapy other than prednisone thereafter. However, the total bilirubin level was elevated to 2.1 mg/dl, with massive abdominal effusion and pain in the right upper quadrant on day 29. S. Yamamoto (&) K. Akiyama N. Oyama M. Hayashi Y. Fujimoto H. Ikeda K. Isoyama Division of Pediatrics, Department of Showa University Fujigaoka Hospital, 1-30 Fujigaoka Aoba-ku, Yokohama 227-8501, Japan e-mail: shohei-y@med.showa-u.ac.jp

Combination Chemotherapy for Solid Tumors in Head and Neck

Purpose: The basic idea of combination chemotherapy is to eradicate tumor cells through potent therapy before the appearance of resistant cells or an elevation in the number of the resistant cells. This article explores the use of combination chemotherapy in the treatment of solid tumors in head and neck. Method: The efficacy of chemotherapy for head and neck tumors is specifically reviewed. Results: Several hypotheses are generally well known and accepted as basic theories in cancer chemotherapy, and researchers have developed effective combination chemotherapy regimens based on these theories. Chemoradiotherapy was initially developed to regulate the local tumor through radiation and control distant metastases through chemotherapy. The purpose of adjuvant chemotherapy is to treat latent tumor cells that cannot be seen macroscopically after completion of first-line therapy. Continuous administration of a small dosage is a new concept that has recently been proposed to replace the conventional concept of total cell-killing. Conclusion: This article examines the use of combination chemotherapy in the treatment of solid tumors and reviews the efficacy of chemotherapy, which should be understood by head and neck surgeons.

P3-14-24: A Phase II Trial of TS-1 and Docetaxel Followed by 5-FU/Epirubicin/Cyclophosphamide (FEC) as Preoperative Treatment in Women with Stage II/III Breast Cancer.

Abstract Background: TS-1 is an oral anticancer drug, composed of tegafur, gimestat and otastat potassium in a molar ratio of 1:0.4:1, based on the biochemical modulation of 5-Fuorouracil. In vivo xenograft model showed a synergistic effect of combination chemotherapy with TS-1 and docetaxel through down-regulation of dihydropyrimidine dehydrogenase (DPD). (Suto et al, Oncology Reports 2006) The sequential combination of anthracycline and taxane is a standard of care in the preoperative setting, as well as the adjuvant setting. This study's purpose was to determine the efficacy of TS-1 and docetaxel followed by fluorouracil/epirubicin/cyclophosphamide (FEC) in the preoperative setting. Patients and Methods: Patients with stage II/III breast cancer received 4 cycles of TS-1 (TS-1 80 mg/m2 on days 1–14 and docetaxel 40 mg/m2 on day 1 every 3 weeks), followed by 4 cycles of FEC (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2 on day 1 every 3 weeks). The tumor objective response was assessed by both caliper and ultrasound. Primary endpoint was the pathological complete response (pCR) rate. Secondary endpoints were the clinical response rate, adverse drug reactions, and the breast conservation rate. Results: From November 2009 to December 2010, 39 patients were enrolled and 38 patients were assessable for clinical and pathologic responses. The overall response rate (caliper) was 81.5% and ultrasound response rate was 76.3%. The pCR rate was 13.2% (5/38). The breast-conserving rate in patients whose tumor size was 3 cm or smaller was 92.9%, and 54.5% of patients whose tumor size was larger than 3 cm underwent breast-conserving surgery. The ratio of Ki-67 positive cell and progesterone receptor (PgR) status were significantly correlated with pCR. Grade 4 neutropenia was observed in a patient (2.6%) at the first cycle. The most common grade 3/4 non-hematologic adverse event was hand-foot syndrome, observed in 3 patients (7.9%). One patient (2.6%) showed grade 3 diarrhea. Conclusions: These results indicate that the sequential combination of TS-1 and docetaxel followed by FEC is a well-tolerated, effective neoadjuvant treatment for stage II/III breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-24.

Therapy-Related Myelodysplasia/Acute Myeloid Leukemia (t-MDS/AML) After Conventionally-Treated Breast Cancer: Impact of Cytogenetics on Outcome After Allogeneic Hematopoietic Cell Transplantation (HCT),

Abstract 4149 Background: The outcome of early stage breast cancer has improved in recent years with use of effective combination chemotherapy, including cyclophosphamide, anthracyclines or taxanes. Patients who undergo lumpectomy also receive radiation therapy for locoregional control. t-MDS/AML are rare but serious consequences of these therapeutic exposures; historically with an overall poor prognosis. Translocations involving the mixed-lineage leukemia (MLL) gene on chromosome band 11q23, and core binding factor genes on 21q22 and 16q22, are hallmarks of t-MDS/AML resulting from treatment with topoisomerase II inhibitors (anthracyclines). Loss of part or whole of chromosomes 5 and/or 7 (5-/7- abnormality) are associated with t-MDS/AML after treatment with alkylating agents and radiation. Allogeneic HCT (sibling-related, unrelated or double-cord) offers the only curative option for some of these patients. However, the long-term outcome of post-breast cancer t-MDS/AML after allogeneic HCT has not been described, and subgroups with better or worse prognosis not identified. Methods: From 1997 to 2011, 28 patients with t-MDS/AML after treatment of breast cancer with conventional chemotherapy and/or radiation underwent allogeneic HCT at City of Hope. Overall survival defined from the time of allogeneic HCT to the last date of follow up or date of death, was estimated using Kaplan-Meier method. Cox regression techniques were utilized to understand predictors of overall survival. Results: Of the 28 patients, 16 had been treated for early-stage breast cancer (I/IIA), 11 had received treatment for locally advanced disease (IIB/ III) and 1 patient had metastatic disease. Twenty-five patients received combination chemotherapy as adjuvant therapy or for metastatic disease; this included cyclophosphamide (100%), doxorubicin (88%) and taxanes (52%). Details of chemotherapy are unknown for one patient. Twenty-one patients (75%) also received radiation (2 received radiation alone). Median age at time of diagnosis of t-MDS/AML was 56 years (range: 34–79); median time from diagnosis of breast cancer to diagnosis of t-MDS/AML was 2.4 years (range 1–12.3); median time from t-MDS/AML to allogeneic HCT was 0.55 year (range: 0.15–4.1). Ten patients presented with MDS and 18 with AML. Cytogenetic abnormalities included MLL - 11q23 abnormality (n=12), 5-/7- and/or complex abnormalities (n=9), t(15;17)(q22;q21.1) (n=1), t(8;21) (n=1), inv(16)(p13.1;q22) (n=2). Of the 28 patients, 27 were treated with induction therapy and 74% were in complete remission (CR) at the time of HCT. Fourteen patients (50%) received sibling-related HCT, 13 received matched unrelated donor (MUD) transplant and 1 received a double cord transplant. Two patients received second allogeneic HCT and one patient received donor lymphocyte infusion (DLI) for relapsed t-MDS/AML. Sixty-one percent received reduced-intensity conditioning with fludarabine/melphalan and others received full-intensity conditioning. Sixteen patients developed cGvHD after transplant. After a median follow up of 2.2 years, 8 patients had died (cause of death: t-MDS/AML [n=5], sepsis [n=1], GvHD [n=1], breast cancer [n=1]), with an overall survival of 78.2% at two years post-HCT for the entire cohort. The 2-year overall survival was 71.4% for sibling-related HCT and 84.4% for MUD (log-rank p=0.14). There was a difference in overall survival by the type of cytogenetic abnormalities. Thus, the 2-year survival rate for patients with 11q23 abnormality was 90.9% while that for patients with chromosome 5-/7- abnormalities or complex abnormalities was 62.5% (log rank p=0.27). Patients with cGvHD had better outcome compared with those without cGvHD (2 year survival 87.5% vs. 64.3%, log-rank p value=0.03). These findings were confirmed on multivariate regression analysis, which revealed chromosome 5-/7- or complex abnormalities to be associated with a significantly worse outcome (HR=6.9, p=0.035), while cGvHD was associated with a better outcome (HR=0.14, p=0.02) after adjustment for age at HCT. Conclusions: Although t-MDS/AML after conventional treatment of breast cancer has historically been shown to have a poor prognosis, allogeneic HCT in patients with available donors provides a chance of cure. Among patients undergoing allogeneic HCT, a superior outcome was observed in patients with 11q23 abnormalities and among those with cGvHD. Disclosures: No relevant conflicts of interest to declare.

Cognitive Effects of Chemotherapy-Induced Menopause in Breast Cancer

This study examined whether chemotherapy-induced menopause affects cognitive functioning in women with early breast cancer. The neuropsychological performance of 121 breast cancer patients (age M = 49.62, SD = 8.11, range = 25.25–67.92) treated with chemotherapy was assessed pre-chemotherapy, as well as 1, 6, and 18 months post-chemotherapy completion. Linear mixed modeling was used to evaluate the data. Type of menopause (pre, chemotherapy-induced, and post menopause) was found to significantly interact with cognitive performance on two cognitive variables. Specifically, chemotherapy-induced menopausal women did not show any significant changes in performance on an abstract reasoning task, while the pre-menopausal and post-menopausal groups significantly improved over time. A significant interaction on a test of finger dexterity and coordination was also found, although inspection of the results indicated that this was due to a significant improvement in the pre-menopausal groups at 6 months post chemotherapy. After chemotherapy most cognitive variables showed improvements over time, although two indicators of verbal memory showed significant declines immediately after chemotherapy, with improvement by 18 months post completion. The current study found little evidence to suggest that chemotherapy-induced menopause broadly affects cognitive functioning after treatment administration. However, longer follow-up assessments are warranted to assess the long-term effects of combined chemotherapy and endocrine treatment.

Regulation of β‐tubulin isotypes by micro‐RNA 100 in MCF7 breast cancer cells

Antimitotic drugs are key components of combination chemotherapy protocols for hematological and solid tumors. The taxanes (e.g., paclitaxel) bind to the β subunit of the tubulin heterodimer and reduce microtubule dynamics, leading to cell cycle arrest in G2/M. The effectiveness of combination chemotherapy is limited by tumor resistance to drugs initially or as a cumulative effect after several cycles of treatment. Because changes in the drug receptor may be linked to drug resistance, we investigated changes in β-tubulin isotypes in response to paclitaxel treatment in MCF7 breast cancer cells. We found that paclitaxel induced a 2-3 fold increase in mRNA for β-tubulin IIA and III genes, TUBB2A, and TUBB3. β-Tubulin class III protein increased; however, β-tubulin class II protein was not detected in these cells. Paclitaxel treatment following pretreatment with actinomycin D showed that the change in β-tubulin class III was due to increased transcription and linked to G2/M arrest. The increase in β-tubulin IIA mRNA was due to both enhanced stability and increased transcription, unassociated with G2/M arrest. We used micro-RNA superarrays to look for changes in families of micro-RNAs that might be linked to drug-induced changes in β-tubulin isotype mRNA and/or protein. We found a significant decrease in the tumor suppressor, miR-100, in MCF7 cells in response to paclitaxel treatment. Transfection of MCF7 cells with miR-100 significantly reduced β-tubulin I, IIA, IIB and V mRNA and prevented paclitaxel-induced increases in β-tubulin isotypes. This is the first report of a micro-RNA that regulates these specific β-tubulin isotype mRNAs.

Effect of combined chemotherapy following the guidelines on treatment for Mycobacterium avium complex pulmonary disease

We retrospectively investigated the clinical appropriateness of combined chemotherapy following the Japanese Society for Tuberculosis guidelines corresponding with those of the American Thoracic Society guideline for MAC pulmonary disease including a comparison with the past treatment for MAC pulmonary disease. The subjects of this study were 159 patients at several hospitals surveyed by the Chugoku-Shikoku Research Committee on Mycobacterium who were diagnosed as having MAC pulmonary disease between April 1995 and March 2001. Among them, 102 patients were treated using a regimen of antituberculous drugs with CAM, 33 patients received antituberculous drugs without CAM, and 24 patients were treated using other regimens. With a regimen of antituberculous drugs plus CAM, the sputum conversion rate was 45.1%, the relapse rate was 39.1% and clinical improvement was obtained in only 29.4%. On a regimen of only antituberculous drugs, the sputum conversion rate was 30.3%, the relapse rate was 70.0% and clinical improvement was obtained in 12.1%. Among the 102 patients receiving the regimen of antituberculous drugs plus CAM, 41 patients were treated with RFP, EB, SM and CAM following exactly the guidelines. The sputum conversion rate was 58.5%, the relapse rate was 37.5% and clinical improvement was obtained in 36.6%. Among 61 patients treated with other antituberculous drugs plus CAM, the sputum conversion rate was 36.1%, the relapse rate was 40.9% and clinical improvement was obtained in 24.6%. The clinical effect of the combined chemotherapy (RFP, EB, SM and CAM) was better than that of the other regimens throughout this study. However, the efficacy of this combined chemotherapy was unsatisfactory compared with the clinical effect for pulmonary tuberculosis. Therefore, the development of new companion drugs for the disease with mycobacteria other than M. tuberculosis is needed.

Combination chemotherapy of gemcitabine and cisplatin by double way plus implantation of radioactive seed 125I in treating stage III non-small cell lung cancer

Objective To assess the therapeutic effect of combination chemotherapy of gemcitabine and cisplatin by double way plus implantation of radioactive seed 125I implantation in treating stage Ⅲ non-small cell lung cancer. Methods Sixty cases with stage Ⅲ non-small cell lung cancer were randomly divided into two groups with random number table. In group A (in interventional treatment group, n = 30),the gemcitabine 1000 mg/m2 and one third of the cisplatin 100 mg/m2 was given using seldinger technique for transcatheter bronchial arterial infusion chemotherapy on day 1. Two-thirds of the cisplatin 100 mg/m2 was infused in veins on day 2 and 3. The gemcitabine 1000 mg/m2 was infused in veins on day 8, 21 days for a period. In group B (interventional - 125I groups), the method of combination chemotherapy of gemcitabine and cisplatin was the same as in Group A. After ten days of arterial perfusion, 125I seeds were implantated, 21 days for a period. All patients received at least 2 cycles. The imaging evaluation of patients after treatment standards included complete remission (CR), partial remission (PR), stable (SD),progressive disease (PD), effective rate (CR + PR)/30 and clinical benefit rate (CR + PR + SD)/30.Non-parametric rank sum test was used to compare short-term effect of the two groups treatment of two cycles.x2 test was used to compare year survival, Kaplan-Meier method was used to calculate median survival,log-rank test method was used to difference between the groups. Results In group A, there were 17 PR,9SD and 4 PD. The overall response rate was 56. 7% (17/30) and clinical beneficial rate was 86. 7% (26/30). In Group B, there were 2 CR, 21 PR, 7 SD. The overall response rate was 76.7% (23/30) and clinical beneficial rate was 100% (30/30). There was significant difference between the two groups (P =0. 036). In group A, the 1 year survival rate was 46. 7% (14/30) and the 2 year survival rate was 36. 7%(11/30), median survival time (MST) was 10 months . In group B, the 1 year survival rate was 76. 7%(23/30) and the 2 year survival rate was 63. 3% (19/30) , median survival time (MST) was 27 months.There was a significant difference between two group in 1 year survival rate (P = 0. 017), 2 year survival rate (P = 0. 039) and median survival time (P = 0. 006). Conclusion The treatment effects of Ⅲ stage non-small cell lung cancer by gemcitabine and cisplatin combination chemotherapy with double way plus radioactive seed 125I implantation was better than gemcitabine and cisplatin combination chemotherapy with double way. Key words: Carcinoma,non-small-cell lung; Radiology,interventional; Iodine isotopes

Clinicopathologic characteristics of extramammary Paget’s disease of the scrotum associated with sweat gland adenocarcinoma—a clinical retrospective study

Extramammary Paget’s disease of the scrotum with sweat gland adenocarcinoma is a rare malignant tumor. This study aims to summarize the clinicopathologic characteristics related to the prognosis of scrotal Paget’s disease with underlying sweat gland adenocarcinoma. Clinical datum of four patients with scrotal Paget’s disease with sweat gland carcinoma, treated in Beijing Chao-Yang Hospital from 2002 to 2009 was analyzed, and a literature review was conducted. The typical manifestation of scrotal Paget’s disease with sweat gland carcinoma was eczematoid-like skin lesions. All patients underwent primary lesion resection plus inguinal lymphadenectomy. Three patients had inguinal lymph metastasis. One of them developed distant metastases in bone and bone marrow and died of metastatic carcinoma. The dead patient had higher serum carcinoma embryonic antigen (CEA) level, Her-2 overexpression and shorter disease course than the other patients. The other patients were observed for at least 3 years, and lived without tumor. Scrotal Paget’s disease with sweat gland adenocarcinoma may be prone to inguinal lymph node and bone metastasis. Serum CEA level, Her-2 overexpression, dermis and lymphovascular invasion may be associated with the prognosis of scrotal Paget’s disease with sweat gland adenocarcinoma. The primary lesion resection plus inguinal lymphadenectomy is the major treatment for scrotal Paget’s disease with sweat gland adenocarcinoma. The effect of combination chemotherapy in the treatment of metastatic extramammary Paget’s disease remains to be proven by prolonged follow-up and wide experience.

Effects of temperature on diffusion from PNIPA-based gels in a BioMEMS device for localized chemotherapy and hyperthermia

This paper presents the results of an experimental study of the effects of temperature on the diffusion from poly(N-isopropylacrylamide) (PNIPA)-based gels with hydrophilic (acrylamide) or hydrophobic (butyl methacrylate) co-monomers. The elutions of rhodamine dye and cancer drug, paclitaxel™ are studied over a range of temperatures in which localized chemotherapy can be combined with hyperthermia (37–45°C). Dye and drug release from the gels is shown to be well described by monolithic and membrane diffusion models. The current work introduces a multi-modal device that can potentially kill cancer cells by chemotherapy and hyperthermia. A clear advantage over prior devices is the ability to combine these two therapeutic interventions in one device. The implications of the results are discussed for the development of thermosensitive drug eluting Bio-Micro-Electro-Mechanical Systems (BioMEMS) devices that can treat cancer locally via the combined effects of chemotherapy and hyperthermia.

CADM1 Interacts with Tiam1 and Promotes Invasive Phenotype of Human T-cell Leukemia Virus Type I-transformed Cells and Adult T-cell Leukemia Cells

CADM1 encodes a multifunctional immunoglobulin-like cell adhesion molecule whose cytoplasmic domain contains a type II PSD95/Dlg/ZO-1 (PDZ)-binding motif (BM) for associating with other intracellular proteins. Although CADM1 lacks expression in T lymphocytes of healthy individuals, it is overexpressed in adult T-cell leukemia-lymphoma (ATL) cells. It has been suggested that the expression of CADM1 protein promotes infiltration of leukemic cells into various organs and tissues, which is one of the frequent clinical manifestations of ATL. Amino acid sequence alignment revealed that Tiam1 (T-lymphoma invasion and metastasis 1), a Rac-specific guanine nucleotide exchange factor, has a type II PDZ domain similar to those of membrane-associated guanylate kinase homologs (MAGUKs) that are known to bind to the PDZ-BM of CADM1. In this study, we demonstrated that the cytoplasmic domain of CADM1 directly interacted with the PDZ domain of Tiam1 and induced formation of lamellipodia through Rac activation in HTLV-I-transformed cell lines as well as ATL cell lines. Our results indicate that Tiam1 integrates signals from CADM1 to regulate the actin cytoskeleton through Rac activation, which may lead to tissue infiltration of leukemic cells in ATL patients.

Flow cytometric analysis for the mechanism of the new antineoplastic agent temozolomide in glioma cells

Temozolomide (TMZ) has been accepted as a standard antitumor drug for glioma worldwide. Regarding its mechanism of action, there are quite a few analyses. In the present study, we investigated the cell-killing effect and mechanism of action of TMZ with flow cytometry using glioblastoma cell lines. Each cell line was divided into three groups: a control group, a low-dose TMZ group, and a high-dose TMZ group. On day 1, TMZ was added to each cell line. Then, we counted the numbers of cells on days 2, 3, 4, and 5; in U87MG, we counted the number of cells on days 8 and 9. Simultaneously, we performed flow cytometric analysis with single- and double-staining methods. Although results varied slightly depending on the cell line, with flow cytometric analysis we identified the G(0)G(1)-, S-phase block on days 2 through 4, at the beginning of TMZ administration. After that we identified the deviation of the G(2)M block over days 3 to 5. Dominant morphological changes observed in U87MG were confined to the nuclei, with positive TUNEL staining. Early S-phase block and then a G(2)M block were observed; consecutively, we could analyze these blocks with a double-staining method more clearly. The flow cytometric method is very effective in the analysis of the antitumor mechanism of each agent. On the basis of our analysis, more effective combined chemotherapy may be expected.

Combination of chemotherapy and mild hyperthermia enhances the anti-tumor effects of cisplatin and adriamycin in human bladder cancer T24 cells in vitro

Although the combined effects of hyperthermia and chemotherapy for cancer therapy have been theoretically established, combination therapy with hyperthermia is not widely used clinically, since the application of hyperthermia is complex and maintaining a tumor temperature of 43°C or above is very difficult. Thus, in the present study, the combined effects of chemotherapy and mild hyperthermia, which is easier to apply than hyperthermia, were examined using a human bladder cancer cell line, T24. T24 cells were incubated at 37-47°C for 0-5 h, and the survival rate of cells was measured using the MTT method. Cisplatin and adriamycin, which are indicated for human bladder cancer, were used as anti-tumor drugs. In the combination experiment, T24 cells were treated with cisplatin (20 and 200 µg/ml) or adriamycin (4 and 40 µg/ml) at 41°C for 0-5 h and at 37°C for 7-12 h. After a total incubation of 12 h, cell survival was measured by the MTT method. i) T24 cells, like cells in general, survived mild hyperthermia at 41°C, but were killed at over 43°C. ii) Although a low concentration (20 µg/ml) of cisplatin or of mild hyperthermia at 41°C did not affect the survival rate of T24 cells, this combination therapy decreased the survival rate of T24 cells with increasing incubation times at 41°C. The anti-tumor effect of the combination of 20 µg/ml cisplatin and 41°C for 5 h was the same as that of 10 times the concentration (200 µg/ml) of cisplatin. iii) Adriamycin showed the same effects as cisplatin. The anti-tumor effect of the combination of 4 µg/ml adriamycin and 41°C for 5 h was identical to the anti-tumor effect of a 10-fold higher concentration (40 µg/ml) of adriamycin. Based on these results, combination with mild hyperthermia may enable a reduction in the dose of anti-tumor drugs. It was suggested that the side effects of chemotherapy could be reduced clinically by combining the drugs with mild hyperthermia. Mild hyperthermia might be a useful and practical heating method which could lead to the increased clinical applications of hyperthermia. We previously reported the preliminary results of M-VAC chemotherapy (methotrexate, vinblastine, doxorubicin and cisplatin) combined with mild hyperthermia, a new therapeutic strategy for advanced or metastatic transitional cell carcinoma of the urothelium. This basic research strongly supports the clinical beneficial results of chemotherapy combined with mild hyperthermia.