Ambulatory administration of 5-day infusion ifosfamide + mesna: a pilot study in sarcoma patients

Purpose

Ifosfamide is a cornerstone of chemotherapy in bone and soft-tissue sarcoma. Results of pharmacokinetic studies indicate that the optimal schedule of ifosfamide should be repeated doses over several days. With the development of 5-day infusion devices, we developed and evaluated a 5-day infusion regimen of ifosfamide in sarcoma patients in the outpatient setting.

Methods

Sarcoma patients requiring chemotherapy after at least one doxorubicin-based line were enrolled in this study. Ifosfamide + mesna was administered as 1:1 concentration for a total of 6 g/m² of each over 5 days (i.e. 1.2 g/m² per day as continuous infusion) every 3 weeks. Patients were treated until progression or limiting toxicity, and salvage surgery was attempted when possible. An economic study was run comparing ifosfamide plus mesna as a 5-day infusion regimen and conventional Ifosfamide regimen.

Results

Thirteen sarcoma patients were evaluable. The median number of cycles per patient was 6 (range, 1–8), for a total of 69 cycles. No acute encephalopathy or aggravation of renal function was noted. Acute grade 3 and 4 haematological toxicities were observed in 11.6 and 1.4% of patients, respectively without febrile neutropenia. Median time to progression survival and overall survival were 8.7 and 21.5 months, respectively. Total cost per cycle for a 2-m² patient body surface area was ambulatory infusion = 1,891 € and conventional ifosfamide = 6,256 €.

Conclusion

The combination of ifosfamide and mesna as a continuous infusion over 5 days is feasible and well tolerated in the outpatient setting using infusion device. Its very favourable cost-effectiveness invites to further develop this approach.     

A feasibility study of outpatient chemotherapy with S-1 + cisplatin in patients with advanced gastric cancer

Background

Regimens of standard-dose cisplatin have usually been administered as inpatient chemotherapy in Japan. This prospective study evaluated the feasibility of outpatient chemotherapy with standard-dose cisplatin in Japanese patients with advanced gastric cancer.

Methods

Advanced gastric cancer patients received an S-1 + cisplatin regimen (S-1: 80–120 mg days 1–21; cisplatin: 60 mg/m² day 8, every 4–5 weeks), either as outpatient chemotherapy with oral hydration on days 9–10, or as inpatient chemotherapy with intravenous hydration on days 9–10, based on the results of an oral hydration test during days 1–7 of the first cycle. The primary endpoint was the completion rate of two cycles in the outpatient group.

Results

A total of 36 patients were enrolled: 32 were allocated to the outpatient group and 4 to the inpatient group. The completion rate of two cycles in the outpatient group was 78% [90% confidence interval (CI): 63–89]. The median of the total number of treatment cycles of S-1 + cisplatin and the median progression-free survival in the outpatient group were 5 (range 1–11) and 10.6 months (95% CI 4.2–16.9), respectively. Although seven patients in the outpatient group discontinued treatment, mainly owing to gastrointestinal toxicity, most of them could continue S-1 + cisplatin by switching to inpatient chemotherapy from the next cycle.

Conclusion

Outpatient chemotherapy with S-1 + cisplatin in advanced gastric cancer patients can be safely and effectively administered in Japan with appropriate patient selection and supportive treatment.     

Toxic death-case after capecitabine + oxaliplatin (XELOX) administration: probable implication of dihydropyrimidine deshydrogenase deficiency

This report here is the case of a 52-year-old male patient who suffered from extremely severe haematological toxicities (G4 neutropenia, G4 thrombocytopenia) while undergoing Xelox (Xeloda + Oxaliplatin) treatment for his multifocal hepatocarcinoma. Despite appropriate supportive treatment, his condition quickly deteriorated and led to death. It was hypothesized that dihydropyrimidine deshydrogenase (DPD) gene polymorphism could be, at least in part, responsible for this fatal outcome. To test this hypothesis, both phenotypic and genotypic studies were undertaken, and fully confirmed the DPD-deficient status of this patient. Uracil to dihydrouracil ratio in plasma was evaluated as a surrogate marker for DPD deficiency, and showed values out of the range previously recorded from a reference, non-toxic population. Interestingly, the canonical IVS14+1G>A single nucleotide polymorphism, usually associated with the most severe toxicities reported with 5-fluorouracil (5-FU), was not found in this patient, but further investigations showed instead a heterozygosity for the 1896C>T mutation located in the exon 14 of the DPYD gene. Taken together, the data strongly suggest for the first time that a toxic-death case after capecitabine-containing protocol could be, at least in part, linked with a DPD-deficiency syndrome. The case reported here warrants therefore systematic detection of patients at risk, including when oral capecitabine is scheduled.     

Expression of CD44s mRNA in Gastric Carcinoma

Objective： To study the expression of CD44s mRNA in the occurrence, development and invasion of gastric carcinoma （GC）. Methods： The expressions of CD44s mRNA in 66 cases of GC, 25 cases of superficial gastritis and 25 cases of atypical hyperplasia were examined by in situ hybridization （ISH）. Results： There was no expression of CD44s mRNA in the group of superficial gastritis; the positive rate was 20%（5/25） in the group of atypical hyperplasia and 62.12%（41/66） in the group of gastric carcinoma. The positive rate in poor differentiation group was significantly higher than that in well differentiation group （P〈0.05）, and the positive rate of lymph node metastasis group was significantly higher than that in negative lymph node metastasis group（P〈0.05）. Conclusion： The expression of CD44s mRNA was related to cell differentiation degree and lymph node metastasis, the activation of CD44s gene was related to strong invasion of cancer cells and poor prognosis.     

CD8+CD28− cells and CD4+CD25+ regulatory T cells in the peripheral blood of advanced stage lung cancer patients

Aim To evaluate the CD8+CD28? and CD4+CD25+ regulatory T (Treg) cells in addition to other some lymphocyte subgroups in peripheral blood of advanced stage lung cancer patients. Methods The study group (n = 28) comprised chemotherapy and radiotherapy naïve patients with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). The control group (n = 22) consisted of age- and sex-matched healthy volunteers. Flow cytometry was used to count T cells, natural killer (NK) cells and CD4+CD25 Treg cells, and for CD8+ T cell subgroup analysis. Flow cytometry was performed and annexin V binding was used for apoptotic cell evaluation. Results In patient group, the percentage of CD8+CD28? cells among lymphocytes was elevated, and there was also an increase in the CD28?/CD28+ cell ratio among CD8 lymphocyte population. The distribution of CD8 cells was different in lung cancer patients when compared with the control group. The absolute count of CD4+CD25^bright cells and the percentages of these cells among total lymphocytes were higher in the patient group. The Annexin V(+) cell percentages among CD8+CD28? and CD8+CD28+ lymphocytes were higher in the patient group than in the control group. No differences were found between the NSCLC and SCLC patients with respect to the hematological parameters and the distribution of lymphocyte subgroups. In NSCLC patients, the percentage of CD8+CD28? cells among the lymphocyte population was higher in patients with stage IV than those with stage III. Conclusion These findings may reflect the possibility of tumor-induced immunosuppression and they should be complemented with further studies.     

A case of CD4+/CD8− adult T-cell leukemia with good response to interferon-beta terminating as a CD4+/CD8+ adult T-cell lymphoma

The leukemic cells of adult T-cell leukemia (ATL) usually express the helper/inducer associated antigen reactive with anti-CD4 antibodies but not with anti-CD8. We present a 63-yr-old woman with ATL characterized by circulating leukemic cells with CD4+/CD8− phenotype, hepatosplenomegaly with no lymphadenopathy, and the presence of proviral DNA of human T-cell leukemia virus I in the leukemic cells. She was successfully treated with interferon beta and the remission lasted for 12 months. She then relapsed in the lymph nodes with minimal peripheral blood involvement. The neoplastic cells of the lymph node now co-expressed CD4 and CD8 antigens indicating that the change in clinical manifestation was accompanied by a phenotypic change of the leukemic cells.     

Dendritic cell internalization of α-galactosylceramide from CD8 T cells induces potent antitumor CD8 T-cell responses

Dendritic cells (DC) present α-galactosylceramide (αGalCer) to invariant T-cell receptor-expressing natural killer T cells (iNKT) activating these cells to secrete a variety of cytokines, which in turn results in DC maturation and activation of other cell types, including NK cells, B cells, and conventional T cells. In this study, we showed that αGalCer-pulsing of antigen-activated CD8 T cells before adoptive transfer to tumor-bearing mice caused a marked increase in donor T-cell proliferation, precursor frequency, and cytotoxic lymphocyte activity. This effect was interleukin (IL)-2 dependent and involved both natural killer T cells (NKT) and DCs, as mice lacking IL-2, NKTs, and DCs lacked any enhanced response to adoptively transferred αGalCer-loaded CD8 T cells. iNKT activation was mediated by transfer of αGalCer from the cell membrane of the donor CD8 T cells onto the αGalCer receptor CD1d which is present on host DCs. αGalCer transfer was increased by prior activation of the donor CD8 T cells and required AP-2-mediated endocytosis by host DCs. In addition, host iNKT cell activation led to strong IL-2 synthesis, thereby increasing expansion and differentiation of donor CD8 T cells. Transfer of these cells led to improved therapeutic efficacy against established solid tumors in mice. Thus, our findings illustrate how αGalCer loading of CD8 T cells after antigen activation in vitro may leverage the therapeutic potential of adoptive T-cell therapies.     

A randomized phase II study of lapatinib + pazopanib versus lapatinib in patients with HER2+ inflammatory breast cancer

This multi-center Phase II study evaluated lapatinib, pazopanib, and the combination in patients with relapsed HER2+ inflammatory breast cancer. In Cohort 1, 76 patients were randomized 1:1 to receive lapatinib 1,500 mg + placebo or lapatinib 1,500 mg + pazopanib 800 mg (double-blind) once daily until disease progression, unacceptable toxicity, or death. Due to high-grade diarrhea observed with this dose combination in another study (VEG20007), Cohort 1 was closed. The protocol was amended such that an additional 88 patients (Cohort 2) were randomized in a 5:5:2 ratio to receive daily monotherapy lapatinib 1,500 mg, lapatinib 1,000 mg + pazopanib 400 mg, or monotherapy pazopanib 800 mg, respectively. The primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival, and safety. In Cohort 1, ORR for the lapatinib (n = 38) and combination (n = 38) arms was 29 and 45 %, respectively; median PFS was 16.1 and 14.3 weeks, respectively. Grade ≥3 adverse events (AEs) were more frequent in the combination arm (71 %) than in the lapatinib arm (24 %). Dose reductions and interruptions due to AEs were also more frequent in the combination arm (45 and 53 %, respectively) than in the lapatinib monotherapy arm (0 and 11 %, respectively). In Cohort 2, ORR for patients treated with lapatinib (n = 36), lapatinib + pazopanib (n = 38), and pazopanib (n = 13) was 47, 58, and 31 %, respectively; median PFS was 16.0, 16.0, and 11.4 weeks, respectively. In the lapatinib, combination, and pazopanib therapy arms, grade ≥3 AEs were reported for 17, 50, and 46 % of patients, respectively, and the incidence of discontinuations due to AEs was 0, 24, and 23 %, respectively. The lapatinib–pazopanib combination was associated with a numerically higher ORR but no increase in PFS compared to lapatinib alone. The combination also had increased toxicity resulting in more dose reductions, modifications, and treatment delays. Activity with single-agent lapatinib was confirmed in this population.     

Overactivation of Ras signaling pathway in CD133+?MPNST cells

Cancer stem cells (CSCs) are believed to be the regenerative pool of cells responsible for repopulating tumors. Gaining knowledge about the signaling characteristics of CSCs is important for understanding the biology of tumors and developing novel anti-cancer therapies. We have identified a subpopulation of cells positive for CD133 (a CSC marker) from human primary malignant peripheral nerve sheath tumor (MPNST) cells which were absent in non-malignant Schwann cells. CD133 was also found to be expressed in human tissue samples and mouse MPNST cells. CD133+?cells were capable of forming spheres in non-adherent/serum-free conditions. The activation levels of Ras and its downstream effectors such as ERK, JNK, PI3K, p38K, and RalA were significantly increased in this population. Moreover, the CD133+?cells showed enhanced invasiveness which was linked to the increased expression of β-Catenin and Snail, two important proteins involved in the epithelial to mesenchymal transition, and Paxilin, a focal adhesion protein. Among other important characteristics of the CD133+?population, endoplasmic reticulum stress marker IRE1α was decreased, implying the potential sensitivity of CD133+?to the accumulation of unfolded proteins. Apoptotic indicators seemed to be unchanged in CD133+?cells when compared to the wild (unsorted) cells. Finally, in order to test the possibility of targeting CD133+?MPNST cells with Ras pathway pharmacological inhibitors, we exposed these cells to an ERK inhibitor. The wild population was more sensitive to inhibition of proliferation by this inhibitor as compared with the CD133+?cells supporting previous studies observing enhanced chemoresistance of these cells.     

Role for CD40L in the Therapy of Human Cancer

CD40L-CD40 interaction is central to the control of thymusdependent humoral immunity and cell mediated immune responses. CD40, a member of the tumor necrosis factor receptor （TNF- R） family, has been found on the surface of B lymphocytes, monocytes, hematopoietic progenitors, dendritic cells （DCs）, endothelial cells, epithelial cells and so on. Its natural ligand （CD40 ligand, CD40L）, CD154, a member of the tumor necrosis factor （TNF） family, is mainly expressed on activated CD4^＋ T lymphocytes. A direct growth-inhibitory effect can be found when ligated CD40 is on human breast, ovarian, cervical, bladder, non-small cell lung, and squamous epithelial carcinoma cells. This effect is related to the induction of cell cycle blockage and/or apoptosis. CD40L induces phenotypic and functional maturation of DCs, and can increase tumor immunogenicity through up-regulation of costimulatory molecular expression and cytokine production by epithelial cancer cells. As a result, CD40L can enhance tumor rejection immune responses. Furthermore, by means of a “bystander effect”, even CD40-negative tumor subsets can be eliminated by activated tumor-reactive cytotoxic T lymphocytes（CTL）. This review summarizes recent findings on CD40L recombinant protein and gene therapy-based tumor treatment approaches.     

Effect of Homoharringtonine on Bone Morrow CD34^＋CD7^＋ Cells in Chronic Granulocytic Leukemia

Objective： To explore the effect of homoharringtonine （HHT） on bone morrow CD34^＋CD7^＋ cells in chronic granulocytic leukemia （CGL）. Methods： The changes of bone morrow CD34^＋CD7^＋ cells were observed after the treatment of HHT in 23 cases with CGL. The proliferation and apoptosis of CD34^＋CD7^＋ cells treated with HHT in vitro were studied. Results： The proportion of CD34^＋CD7^＋ cells in CGL （0.145±0.021） was higher than that of normal control （0.052±0.013）. The proportion of CD34^＋CD7^＋ cells in patients who got cytogenetic responses to HHT （0.072±0.020） decreased remarkably, but not in those patients who did not got cytogenetic responses to HHT, （0.137±0.023）. the proliferation of CD34^＋ cells was inhibited and the proportion of CD34^＋CD7^＋ cells decreased after cultured with HHT （0.134 in 24 h, 0.126 in 48 h and 0.102 in 72）. The apoptosis rate of CD34^＋CD7^＋ cells was higher than that in CD34^＋CDT cells （35.39%±4.39% versus 24.57%±4.01%, P〈0.05） 72 h after culture with HHT. Conclusion： The proportion of CD34^＋CD7^＋ cells in CGL was higher than that of normal control and HHT may inhibit the proliferation and induce apoptosis of bone marrow CD34^＋CD7^＋ cells.     

Elevated frequencies of CD4⁺ CD25⁺ CD127lo regulatory T cells is associated to poor prognosis in patients with acute myeloid leukemia

Regulatory T cells (Treg) mediate amelioration of disease and immune homeostasis by inhibiting immune activation and maintaining peripheral immune tolerance. The suppressive mechanisms and clinical significance of Treg have not been completely elucidated in patients with acute myeloid leukemia (AML). Here, we demonstrated that CD127 in combination with CD4 and CD25 can identify FoxP3(+) Treg in peripheral blood (PB) and bone marrow (BM) using multicolor flow cytometry. We showed that the CD4(+) CD25(+) CD127(lo) Treg frequencies were significantly increased and their phenotypes were different in PB from newly diagnosed AML patients compared to those from healthy volunteers (HVs). Moreover, the Treg frequencies were significantly higher in BM than those from PB in the same patients. The Treg frequencies were reduced when patients achieved complete remission (CR) and were increased when patients relapsed. The Treg frequencies at diagnosis in PB and BM of patients who had achieved CR were lower than those of patients who had persistent leukemia or died, respectively. CD4(+) CD25(+) Treg were isolated by magnetic-activated cell sorting and tested for suppressive functions in coculture with allogeneic carboxyfluorescein diacetate succinimidylester-labeled CD4(+) CD25(-) responder cells. Suppression mediated by Treg was higher in AML patients compared to HVs. No significant differences were observed in the cytokines production of Treg, including interferon-gamma (IFN-γ), interleukin (IL)-4,IL-2 and IL-10, between patients with AML and HVs. Our study suggests that Treg may play a role in the pathogenesis of AML, and sequential measurements of Treg frequency may have clinical value in the evaluation of therapeutic effects and clinical outcome.     

Invasive ductal carcinoma and invasive lobular carcinoma of breast differ in response following neoadjuvant therapy with epidoxorubicin and docetaxel + G-CSF

Purpose Preoperative chemotherapy in patients with primary breast cancer treated with anthracyclines and taxanes results in high response rates, allowing breast conserving surgery (BCS) in patients primarily not suitable for this procedure. Pathological responses are important prognostic parameters for progression free and overall survival. We questioned the impact of histologic type invasive ductal carcinoma (IDC) versus invasive lobular carcinoma (ILC) on response to primary chemotherapy. Patients and Methods 161 patients with breast cancer received preoperative chemotherapy consisted of epidoxorubicin 75 mg/m² and docetaxel 75 mg/m² administered in combination with granulocyte-colony stimulating factor (G-CSF) on days 3–10 (ED + G). Pathological complete response (pCR), biological markers and type of surgery as well as progression free and overall survival were compared between IDC and ILC. Results Out of 161 patients, 124 patients presented with IDC and 37 with ILC. Patients with ILC were less likely to have a pCR (3% vs. 20%, P < 0.009) and breast conserving surgeries (51% vs. 79%, P < 0.001). Patients with ILC tended to have oestrogen receptor positive tumors (86% vs. 52%, P < 0.0001), HER 2 negative tumors (69% vs. 84%), and lower nuclear grade (nuclear grade 3, 16% vs. 46%, P < 0.001). Patients with ILC tended to have longer time to progression (TTP) (42 months vs. 26 months) and overall survival (69 months vs. 65 months). Conclusions Our results indicate that patients with ILC achieved a lower pCR rate and ineligibility for BCS to preoperative chemotherapy, but this did not result in a survival disadvantage. Because of these results new strategies to achieve a pCR are warranted.     

T cell activation independent of CD28 co-stimulation by depletion of E3 ubiquitin ligase Cblb

It has been well established that eytotoxic T lymphocytes(CTLs)are responsible for the mediation of host immune response against immunogenic tumors.However,their effective use in cancer immunotherapy is hampered because T cell activation requires co-stimulatory signals,such as ligands for CD28 besides T-cell receptor(TCR) occupancy.Unfortunately,many malignant tumors of epithelial origin do not express ligands for CD28.Two groups     

TNF-α enhancement of CD62E mediates adhesion of non–small cell lung cancer cells to brain endothelium via CD15 in lung-brain metastasis

BackgroundCD15, which is overexpressed on various cancers, has been reported as a cell adhesion molecule that plays a key role in non-CNS metastasis. However, the role of CD15 in brain metastasis is largely unexplored. This study provides a better understanding of CD15/CD62E interaction, enhanced by tumor necrosis factor-α (TNF-α), and its correlation with brain metastasis in non–small cell lung cancer (NSCLC).MethodsCD15 and E-selectin (CD62E) expression was demonstrated in both human primary and metastatic NSCLC cells using flow cytometry, immunofluorescence, and Western blotting. The role of CD15 was investigated using an adhesion assay under static and physiological flow live-cell conditions. Human tissue sections were examined using immunohistochemistry.ResultsCD15, which was weakly expressed on hCMEC/D3 human brain endothelial cells, was expressed at high levels on metastatic NSCLC cells (NCI-H1299, SEBTA-001, and SEBTA-005) and at lower levels on primary NSCLC (COR-L105 and A549) cells (P < .001). The highest expression of CD62E was observed on hCMEC/D3 cells activated with TNF-α, with lower levels on metastatic NSCLC cells followed by primary NSCLC cells. Metastatic NSCLC cells adhered most strongly to hCMEC/D3 compared with primary NSCLC cells. CD15 immunoblocking decreased cancer cell adhesion to brain endothelium under static and shear stress conditions (P < .0001), confirming a correlation between CD15 and cerebral metastasis. Both CD15 and CD62E expression were detected in lung metastatic brain biopsies.ConclusionThis study enhances the understanding of cancer cell-brain endothelial adhesion and confirms that CD15 plays a crucial role in adhesion in concert with TNF-α activation of its binding partner, CD62E.     

CD46 CD55 CD59在结肠癌组织中的表达及意义

目的:检测CD46、CD55、CD59在结肠癌组织中的表达情况,分析其与结肠癌临床病理参数间的相关性及意义。方法:选取有详细性别、年龄、组织分化、病理分期、肿瘤部位、组织类型资料的组织芯片标本,包括121 例结肠癌和121 例癌旁结肠组织,均为2004年10月至2006年6 月第四军医大学西京消化病医院胃肠外科手术切除标本。应用免疫组织化学改良二步法分别检测CD46、CD55、CD59的表达情况。结果:CD46、CD55及CD59在结肠癌组织中的阳性表达率均显著高于对应的癌旁组织（P < 0.001）。 CD46表达水平与性别、年龄、组织分化、TNM 病理分期、肿瘤位置、病理组织类型均无关（P > 0.05）。 CD55、CD59的表达水平与性别、年龄、肿瘤位置、病理类型无关（P > 0.05）,而与组织分化、TNM 病理分期有关（P < 0.05）。 其表达强度阳性率中低分化组明显高于高分化组（P < 0.05）。 TNM 分期中Ⅲ、Ⅳ期患者肿瘤病理组织强阳性表达率高于Ⅰ、Ⅱ期阳性表达率,两者比较有统计学意义（P < 0.05）。 结论:CD46、CD55及CD59在结肠癌组织中高表达,特别是CD55、CD59的表达与肿瘤分化、病理分期相关,提示三者表达水平与结肠癌生物学行为密切相关。