Fluctuation Relation for the Dissipative Flux: The Role of Dynamics, Correlations and Heat Baths.

The fluctuation relation stands as a fundamental result in nonequilibrium statistical physics. Its derivation, particularly in the stationary state, places stringent conditions on the physical systems of interest. On the other hand, numerical analyses usually do not directly reveal any specific connection with such physical properties. This study proposes an investigation of such a connection with the fundamental ingredients of the derivation of the fluctuation relation for the dissipation, which includes the decay of correlations, in the case of heat transport in one-dimensional systems. The role of the heat baths in connection with the system's inherent properties is then highlighted. A crucial discovery of our research is that different lattice models obeying the steady-state fluctuation relation may do so through fundamentally different mechanisms, characterizing their intrinsic nature. Systems with normal heat conduction, such as the lattice ϕ4 model, comply with the theorem after surpassing a certain observational time window, irrespective of lattice size. In contrast, systems characterized by anomalous heat conduction, such as Fermi-Pasta-Ulam-Tsingou-ß and harmonic oscillator chains, require extended observation periods for theoretical alignment, particularly as the lattice size increases. In these systems, the heat bath's fluctuations significantly influence the entire lattice, linking the system's fluctuations with those of the bath. Here, the current autocorrelation function allows us to discern the varying conditions under which different systems satisfy with the fluctuation relation. Our findings significantly expand the understanding of the stationary fluctuation relation and its broader implications in the field of nonequilibrium phenomena.

Switchable and spacing tunable dual-wavelength spatiotemporal mode-locked fiber laser.

We report a switchable and spacing tunable dual-wavelength spatiotemporal mode-locked (STML) laser based on the multimode interference filtering effect in an all-fiber linear cavity. The dual-wavelength STML operations combined with different pulse patterns are achieved. By adjusting the polarization controllers, the dual-wavelength STML pulses can be switched to single wavelength operation, which is tunable up to 35 nm under certain pump powers. Moreover, the dual-wavelength spacing can also be tuned from 8 nm to 22 nm. The obtained results contribute to understanding and exploring the spatiotemporal characteristics operating in the multi-wavelength regime of STML fiber lasers. All-fiber STML lasers with lasing wavelength tunability and flexibility may have applications in the fields of optical communications and optical measurements.

Antitumor Activity and Mechanism Study of Riluzole and Its Derivatives.

To explore novel antitumor agents with high efficiency and low toxicity, riluzole alkyl derivatives (4a-4i) were synthesized. Their anti-proliferative activities against HeLa, HepG2, SP2/0, and MCF-7 cancer cell lines were assessed by the CCK-8 assay and compared with human normal liver (LO2) cells. Most of them showed potent cytotoxic effects against four human tumor cell lines and low toxic to LO2 cells. In particular, 2-(N-ethylamine)-6-trifluoromethoxy- benzothiazole (4a) showed a IC50 value of 7.76 µmol/L in HeLa cells and was found to be nontoxic to LO2 cells up to 65 µmol/L. Furthermore, flow cytometry indicated that 4a could induce remarkable early apoptosis and G2/M cell cycle arrest in HeLa cells. It also impaired the migration ability of HeLa cells in wound healing assays. Western blot results demonstrated that 4a suppressed Bcl-2 protein expression but increased the level of Bax in HeLa cells, and elevated the Bax/Bcl-2 expression ratio. These new findings suggest that 4a exhibited beneficially anti-cervical cancer effect on HeLa cells by inducing HeLa cell apoptosis.

Combining a CD20 chimeric antigen receptor and an inducible caspase 9 suicide switch to improve the efficacy and safety of T cell adoptive immunotherapy for lymphoma.

Modification of T cells with chimeric antigen receptors (CAR) has emerged as a promising treatment modality for human malignancies. Integration of co-stimulatory domains into CARs can augment the activation and function of genetically targeted T cells against tumors. However, the potential for insertional mutagenesis and toxicities due to the infused cells have made development of safe methods for removing transferred cells an important consideration. We have genetically modified human T cells with a lentiviral vector to express a CD20-CAR containing both CD28 and CD137 co-stimulatory domains, a "suicide gene" relying on inducible activation of caspase 9 (iC9), and a truncated CD19 selectable marker. Rapid expansion (2000 fold) of the transduced T cells was achieved in 28 days after stimulation with artificial antigen presenting cells. Transduced T cells exhibited effective CD20-specific cytotoxic activity in vitro and in a mouse xenograft tumor model. Activation of the iC9 suicide switch resulted in efficient removal of transduced T cells both in vitro and in vivo. Our work demonstrates the feasibility and promise of this approach for treating CD20(+) malignancies in a safe and more efficient manner. A phase I clinical trial using this approach in patients with relapsed indolent B-NHL is planned.

Long-term outcomes of patients with newly diagnosed extranodal natural killer/T-cell lymphoma treated by etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin regimen: a single-institution experience.

One possible reason for the relapse and refractoriness of extranodal natural killer/T-cell (NK/T) lymphoma (ENKL) is resistance to a CHOP-like regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone). To evaluate the outcome of first-line EPOCH chemotherapy (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) for ENKL, 34 patients, including 30 with nasal ENKL (88.2%) and four with extranasal ENKL (11.8%), were studied. Involved-field radiation therapy (IFRT) was administered to patients with localized nasal focus after chemotherapy. Thirty-three cases were eligible for response evaluation. The response rate (RR) was 60.6% (20/33) with a complete remission (CR) rate of 45.5% (15/33). For patients with localized nasal ENKL, the CR rate was 57.7% (15/26). The 3-year progression-free survival and overall survival rates were 53.6% and 69.0%, respectively. After initial EPOCH chemotherapy followed by IFRT, the CR rate was 75.0% and the 3-year overall survival rate was 75.0%. However, patients with disseminated and extranasal disease responded poorly. These results indicate that EPOCH followed by IFRT yields promising outcomes for patients with localized nasal ENKL.

[Long-term results of rituximab-based salvage chemotherapy for relapsed or refractory diffuse large B-cell lymphoma].

OBJECTIVE: To investigate the efficacy and toxicity of rituximab-based salvage chemotherapy in the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL). METHODS: Sixty-nine patients with relapsed or refractory DLBCL were treated by rituximab-based salvage chemotherapy, including 40 male and 29 female patients with a median age of 51.5 years (range 17 to 82 years). All the patients had prior treatments including of EPOCH, ICE, DHAP, GEMOX, and GDP. Twenty-seven patients also received rituximab treatment as the first-line regimen. RESULTS: The objective response (OR) rate was 73.4% (47/64) in these patients with a complete response (CR) rate of 45.3%. The major adverse effects included bone marrow suppression, fatigue, and gastrointestinal toxicity. The side effects of rituximab were mild, including chill, fever and fatigue. The median follow-up was 40.6 (3.7-179.9) months. Twenty-eight patients died of tumor progression and two died from grade 4 myelosuppression accompanied by severe systemic infection. The median survival was 51.6 (3.7-179.9) months in this group. The 1, 3 and 5-year overall survival was 92%, 62% and 37%, respectively, and in patients without rituximab as the first line treatment, the overall survival at 1 and 3 years (97.4% and 73.5%) was much better than that in rituximab-treated patients (83.1% and 42.8%) (P=0.001). The patients of GCB subtype had better survival compared to the non-GCB subtype, with the 5-year overall survival of 42.3% and 21.4%, respectively (P=0.005). CONCLUSION: Rituximab-based salvage regimens are effective and well tolerable, but further clinical trial is warranted.

Lamivudine for the prevention of hepatitis B virus reactivation after high-dose chemotherapy and autologous hematopoietic stem cell transplantation for patients with advanced or relapsed non-Hodgkin's lymphoma single institution experience.

OBJECTIVE: Hepatitis B virus (HBV) reactivation is a well-known complication in cancer patients receiving cytotoxic chemotherapy, resulting in varying degrees of liver damage. The objective of this study was to investigate the efficacy of lamivudine for the prevention of HBV reactivation in non-Hodgkin's lymphoma (NHL) patients undergoing high-dose chemotherapy and autologous hematopoietic stem cell transplantation (AHSCT). RESEARCH DESIGN AND METHODS: Thirty-two patients with NHL who were HBV surface antigen (HBsAg)-positive were enrolled in this pilot study. They were divided into two groups: 20 patients received prophylactic oral lamivudine 100 mg/day before, and until at least 6 months after transplantation. The historical control group comprised 12 patients who received high-dose chemotherapy and AHSCT without lamivudine. The incidence and severity of hepatitis due to HBV reactivation, as well as other adverse clinical outcomes, were compared between the two groups. RESULTS: Most baseline clinical characteristics were similar in the two groups, except for HBV e-antigen (HBeAg)-positive status (85% in the lamivudine group vs 33.3% in the control group, p = 0.006) and the type of AHSCT. There was a lower incidence of hepatitis due to HBV reactivation in the lamivudine group than in the control group (10 vs 50%, p = 0.030), less severe hepatitis (0 vs 25%, p = 0.009), and lower mortality (0 vs 25%, p = 0.236). An HBV variant with tyrosine methionine aspartate aspartate (YMDD) mutation was detected in one patient in the lamivudine group (5%) after administration of lamivudine for 9 months. No significant adverse events were associated with the use of prophylactic lamivudine, and hematopoietic reconstitution was not affected by the intervention. CONCLUSIONS: Prophylactic lamivudine may reduce the incidence and severity of chemotherapy-related HBV reactivation and hepatitis-related mortality in HBsAg-positive NHL patients receiving high-dose chemotherapy and AHSCT. Additional randomized, multicenter trials are warranted.

[Prognostic value of serum CA19-9 in patients with advanced pancreatic cancer receiving gemcitabine based chemotherapy].

BACKGROUND AND OBJECTIVE: Gemcitabine is used as an effective drug for patients with advanced pancreatic cancer. Serum CA19-9 has been proven as the most sensitive and specific serum marker for pancreatic cancer. This study was to investigate the value of serum CA19-9 in evaluating treatment efficacy and predicting prognosis of patients with pancreatic cancer treated by gemcitabine-based chemotherapy. METHODS: Seventy-one patients with histologically confirmed, locally advanced or metastatic pancreatic adenocarcinoma, whose karnofsky's performance status (KPS) score was >or= 70 were treated with gemcitabine alone or with gemcitabine-based chemotherapy. CA19-9 was measured before and after chemotherapy. RESULTS: Ten out of 71 patients had normal baseline CA19-9 levels, and 61 patients had increased baseline CA19-9 levels. The overall survival of patients were similar between the two groups, which were 9.0 months and 7.9 months respectively (P=0.797). The median baseline CA19-9 level for patients who had increased CA19-9 was (682+/-558) U/mL before treatment. Patients whose pretreatment CA19-9 levels were <682 U/mL achieved better survival than those whose pretreatment CA19-9 levels were >or=682 U/mL (9.6 months vs. 5.1 months, p=0.001). In addition, patients with a pretreatment CA19-9 level of <682 U/mL also had a better tumor response (43.5% vs. 15.8%, p=0.051) and clinical benefit response (48.1% vs. 29.2%, P=0.125) than those whose pretreatment CA19-9 level was <682 U/mL, but the differences were not significant. Patients with a fall of >or=25% in the baseline CA19-9 level after chemotherapy achieved a longer median overall survival (10.2 months vs. 5.0 months, p<0.001), better tumor response (47.8% vs. 10.5%, p=0.002) and better clinical benefit response (69.2% vs. 8.0%, P=0.000) than those without a decrease of baseline CA19-9 or with a fall of <25%. Multivariate analysis revealed that the baseline CA19-9 level before chemotherapy, decreased percentage of the CA19-9 level after chemotherapy, and the differentiation degree of tumor cells were independent risk factors for patients whose baseline CA19-9 levels were increased. CONCLUSION: The level of pretreatment base-line CA19-9 and the decreased percentage of baseline CA19-9 level after chemotherapy are of predictive values for survival of patients with advanced pancreatic cancer undergoing gemcitabine-based chemotherapy and with an increased level of baseline CA19-9.

Efficacy and safety of transdermal fentanyl for treatment of oral mucositis pain caused by chemotherapy.

BACKGROUND/OBJECTIVE: We investigated the efficacy and safety of transdermal fentanyl for severe mucositis pain caused by chemotherapy. METHODS: Thirty-two patients who had moderate to severe pain using the Numeric Rating Scale (NRS) were enrolled in this study. The analgesic effect, quality of life and side effects were evaluated after the administration of transdermal fentanyl. RESULTS: The median NRS score was reduced from 6 (range 4 - 9) before treatment to 4 (range 0 - 9), 2.5 (range 0 - 8), 2 (range 0 - 8), 2 (range 0 - 6) and 0 (range 0 - 5) on days 3, 5, 7, 10 and 15, respectively, after treatment (p < 0.001). The patients' quality of life also improved significantly (p < 0.01). The side effects of treatment were mild, and disappeared within several days. CONCLUSIONS: Transdermal fentanyl is an effective, convenient and well-tolerated treatment for severe mucositis pain caused by chemotherapy that can improve patients' quality of life.

[Effects of infusion duration of high-dose methotrexate on cerebrospinal fluid drug levels in lymphoma patients].

BACKGROUND & OBJECTIVE: Methotrexate (MTX) Concentration of higher than minimal therapeutic level in cerebrospinal fluid (CSF) is essential for the therapeutic effects on central nervous system(CNS) lymphoma. The effect of infusion schedules on MTX penetrating into CSF is undear. This study was to evaluate the effect of duration of venous infusion of high-dose MTX (HD-MTX) on drug levels in CSF, and to define the optimal schedule of HD-MTX infusion with high efficiency and low toxicity in CNS lymphomas. METHODS: Thirty-four non-Hodgkin' lymphoma (NHL) patients received 6-hour or 24-hour continuous venous infusion of MTX (1-3 g/m2). CSF samples were obtained right after the end of HD-MTX infusion, and serum samples were obtained at 0 h, 24 h, and 48 h after the end of HD-MTX infusion. MTX concentration was measured by high-pressure liquid chromatography. RESULTS: The serum concentration of MTX at the end of infusion was higher in 6-hour group than in 24-hour group. The CSF concentration of MTX was significantly higher in 6-hour group than in 24-hour group (0.70 micromol/L vs. 0.49 micromol/L, P = 0.044). A weak positive correlation between CSF and serum levels of MTX was observed (r = 0.295, P = 0.002). CSF levels of MTX were much higher in the patients with CNS involvement than in those without CNS involvement. The occurrence rates of grade II-IV mucositis were 15.4% in 6-hour group and 37.8% in 24-hour group; those of grade III-IV myelosuppression were 46.2% in 6-hour group and 67.6% in 24-hour group. CONCLUSION: The shorter duration (6 h) of MTX administration is thought to be more beneficial on the aspects of reducing toxicity and enhancing CNS pharmacokinetics.

ApoG2 inhibits antiapoptotic Bcl-2 family proteins and induces mitochondria-dependent apoptosis in human lymphoma U937 cells.

Lymphoma is one of the most common types of hematological malignancies and proteins from the Bcl-2 family are highly expressed in human lymphomas. Apogossypolone (ApoG2), the most potent gossypol derivative, has been classified as a novel small-molecule inhibitor of antiapoptotic Bcl-2 family proteins. Here, we assessed the in-vitro cytotoxicity of ApoG2 on human U937 lymphoma cells, and explored the underlying intracellular molecular mechanisms of ApoG2. Using the WST-8 assay, we found that ApoG2 inhibited growth of U937 cells in a dose-dependent and time-dependent manner, and the IC50 values were 30.08, 14.81, and 9.26 mumol/l for 24, 48, and 72 h treatments, respectively. ApoG2 also induced apoptosis in U937 cells, as noted through changes in morphological characteristics, including cellular internucleosomal DNA fragmentation and the appearance of a sub-G1 apoptotic peak. Treatment with ApoG2 downregulated Bcl-xL and Mcl-1 protein expression and blocked the binding of Bcl-2 with Bax protein. Furthermore, ApoG2 led to an abundant release of cytochrome c from mitochondria and a five-fold increase in the activity of caspase-3 and caspase-9. Taken together, our results suggest that ApoG2 could effectively suppress the growth of human lymphoma cell line U937 through the inhibition of the antiapoptotic Bcl-2 family proteins and the induction of mitochondria-dependent apoptotic cell death.

[Preliminary result of multi-center clinical trial on the docetaxel, 5-Fu and DDP in the treatment of advanced, recurrent or metastatic nasopharyngeal carcinoma].

OBJECTIVE: This clinical study was designed to evaluate the efficacy and toxicity of the combined regimen of docetaxel, 5-Fu and DDP (TPF) in the treatment of advanced or relapsed nasopharyngeal carcinoma (NPC). METHODS: Fifty-six patients with newly diagnosed or recurrent/metastatic NPC following chemotherapy or radiotherapy were enrolled. Both docetaxel and DDP were administered intravenously for 6 hours at the dose of 70 mg/m2 on D1. 5-Fu was given at a dose of 400-500 mg/m2 for 6 hours from D1 to D5. Dexamethasone was routinely administered before injection of docetaxel. This combination was repeated every 3 to 4 weeks, and continued for 4-6 cycles or until PD for the responders. RESULTS: Fifty-one (91.1%) patients were evaluable for response assessment. The response rate for whole group was 72.5% (37/51) with a CR rate of 9.8% (5/51). The stable disease accounted for 17.6% (9/51). There were 17(30.4%) chemotherapy-naïve patients. The overall response rate in those was 82.4% with a CR rate of 29.4%. However, the response rate for previously treated patients was 64.7% without CR. Twelve patients had progressed disease, including 5 (8.9%) died of disease progression with a median follow-up of 11 month (ranged from 1 to 19 months). Totally, 196 courses of chemotherapy were administered. The major toxicity was myelosupression, nausea/vomiting. The incidence of leucopenia was 48% with 22.2% of these in NCI grade II or IV. But only 2 patients (3.6%) experienced leucopenia with a fever. Other mild toxicities including alopecia, asthenia, mucositis and diarrhea were also observed. CONCLUSION: Our preliminary outcome shows docetaxel, 5-Fu and DDP combination is effective and safe for the patients with advanced or relapsed nasopharyngeal carcinoma. But further clinical study is warranted.

[Efficacy and toxicity of trastuzumab combined with docetaxel for Her-2/neu overexpressing metastatic breast cancer].

BACKGROUND & OBJECTIVE: HER2 is overexpressed in approximately 20.0% to 30.0% of breast cancer patients. This alteration is associated with poor prognosis, and may affect response to hormonal therapy and chemotherapy. Chemotherapy combined with trastuzumab can significantly improve the treatment efficacy and survival of Her-2/neu overexpressing breast cancer patients. Docetaxel is an effective drug used for metastatic breast cancer recently. This study was to evaluate the efficacy and toxicity of trastuzumab combined with docetaxel in the treatment for metastatic breast cancer patients with overexpressed Her-2/neu. METHODS: Twenty-two metastatic breast cancer patients with overexpressed HER2/neu were entered into the study. Trastuzumab and docetaxel (75 mg/m(2)) were administrated on day 1 and repeated every 21 days. The initial dose of trastuzumab was 8 mg/kg and subsequent doses were 6 mg/kg. RESULTS: Overall 96 cycles were administrated to the 22 patients (medium three cycles per patient, range 2-6 cycles). All cases were evaluable. The overall response rate was 63.6% (14/22). Two patients achieved complete response (CR), 12 patients achieved partial response (PR), four patients achieved stable disease (SD), and four patients had progressive disease (PD). The median time to progression was 5.4 months. One year overall survival was 59.0%. The major toxicity was myelosuppression. A few patients had fever at first infusion of trastuzumab and minor heart failure. CONCLUSION: Trastuzumab combined with docetaxel is an effective and well-tolerated therapy for Her-2/neu overexpressing metastatic breast cancer.

[Clinical tolerance trial on recombinant human endostatin adenovirus].

BACKGROUND & OBJECTIVE: Recently, some phase I trials on endostatin has shown broad antitumor activity with low toxicity. This study was to determine the maximal tolerant dose (MTD) of recombinant human endostatin adenovirus Ad-Es for human. METHODS: For the sake of safety, 1 patient was treated with 1x10(10) VP Ad-Es single intratumoral injection in advance. A total of 14 patients with malignant tumors received weekly intratumoral injection of Ad-Es in a dose-escalation manner (1x10(11) VP, 5x10(11) VP, 1x10(12) VP) for 2 weeks. RESULTS: Toxicity profiles in all 15 cases were available. All patients tolerated well. No dose-limited toxicity (DLT) and serious adverse event were observed during treatment. Main adverse events were injection reaction (40.0%) and fever (53.3%). One patient with nasopharyngeal carcinoma had a minor response, 12 patients showed stable disease and 2 patients had progressive disease. CONCLUSION: Ad-Es is well tolerated up to 1x10(12) VP. The recommended dose for phase II trial is 1x10(12) VP intratumor injection for 4 consecutive weeks.

[Treatment outcomes and prognostic analyses of relapsed or refractory T-cell non-Hodgkin's lymphoma].

BACKGROUND & OBJECTIVE: The prognosis of relapsed or refractory T-cell non-Hodgkin's lymphoma (T-NHL) is poor. There is no definite prognostic factors and standard regimens for these patients. This study was to explore the prognostic factors and effective regimens for relapsed or refractory T-NHL. METHODS: Clinical records of 45 patients with relapsed or refractory T-NHL, treated in Cancer Center of Sun Yat-sen University from Jan. 1997 to Mar. 2003, were analyzed in terms of response, long-term survival and prognostic factors. RESULTS: By the end of Jul. 2006, 5 patients still alive; the median follow-up time was 30 (2-70) months. The median survival time after relapse was 22 (2-62) months. Of the 45 patients, 42 (93.3%) received salvage regimen, the response rate was 61.9% (26/42); for those received second-line chemotherapy, the response rate was 52.4% (22/42). The 1-, 3-, and 5-year overall survival rates were 75.6%, 17.8%, and 4.4% for the whole group, 82.1%, 25.0%, and 5.8% for low risk group and 64.7%, 6.5%, and 6.5% for high risk group, respectively (P=0.026). Multivariate analysis showed that serum lactate dehydrogenase (LDH) level (P=0.010), second-line Ann Arbor stage (P=0.009), second-line IPI score (P=0.015), autologous stem cell transplantation (P=0.026), performance status (P=0.002), and IMVP-16 regimen (P=0.026) were independent prognostic factors of relapsed or refractory T-NHL. CONCLUSIONS: Second-line IPI score, autologous stem cell transplantation, and so on, may be independent prognostic factors for relapsed or refractory T-NHL. The prognosis of this disease is poor and the addition of intensive treatments, such as stem cell transplantation, should be considered when alleviated after chemotherapy.

A phase I clinical trial of an adenovirus-mediated endostatin gene (E10A) in patients with solid tumors.

PURPOSE: The purpose of the current study were to assess the safety and feasibility of repetitive intratumoral administration of E10A, an adenoviral vector encoding the wild-type endostatin gene, to patients with solid tumors, and to evaluate its biologic effect and the pharmacokinetics of endostatin. METHODS: Patients were treated with escalating doses from 1 x 10(10) VP to 1 x 10(12) VP of E10A intratumorally on days 1 and 8. Patients were assessed for toxicity and viral shedding, and antitumor response was evaluated by imaging techniques and tumor biopsy. Circulating levels of endostatin were examined. RESULTS: Fifteen patients received 29 injections of E10A. No dose-limiting toxicity was developed, and the maximum tolerated dose had not yet been reached. Fever and local reaction of injection site were common, but rarely severe. Mild and transient hepatotoxicity was observed in one patient. Minor response of injected tumor was achieved and improvement of the control tumor was observed in one patient with nasopharyngeal carcinoma, and tumor necrosis was occurred in two patients. Sustained elevation of serum endostatin levels was detected. CONCLUSION: Weekly intratumoral injection of up to 1 x 10(12) VP of E10A to patients with solid tumor is a feasible and well-tolerated procedure that exerts mild antitumor effects. A small and sustained elevation of endogenous endostatin in blood possibly has antitumor activity.

[Transdermal fentanyl in treating severe painful mucositis caused by autologous hematopoietic stem cell transplantation].

BACKGROUND & OBJECTIVE: The incidence of mucositis caused by autologous hematopoietic stem cell transplantation (AHSCT) is relatively high. The severe painful mucositis can reduce the quality of life of patients obviously. Transdermal fentanyl is efficient in treating chronic pain of cancer, and also can relieve the severe pain of mucositis resulted from chemotherapy. This study was to investigate the efficacy and safety of transdermal fentanyl for the severe painful mucositis caused by AHSCT. METHODS: A total of 22 malignant tumor patients suffered from severe mucositis caused by high dose chemotherapy combined AHSCT. The analgesic degree before and after treatment was evaluated by the scores of Visual Analogue Scale (VAS) (range 0-10). The median VAS scores of all patients were above 4 (moderate to severe pain) before the administration of transdermal fentanyl. The quality of life before and after treatment was evaluated by the Standard of Quality of Life drew up in China in 1990. The adverse events after treatment were evaluated by Common Toxicity Criteria formulated by National Cancer Institute of the USA. RESULTS: The median VAS score has been decreased from baseline at 6 (4-9) to 3.5 (0-9) on Day 3, 2 (0-6) on Day 5, 0.5 (0-8) on Day 7, 0 (0-6) on Day 10, and 0 (0-5) on Day 15 after treatment (P<0.001). The overall response rate was 100%, while the complete response rate was 45.5%. The quality of life of the patients was improved significantly (P<0.01). The adverse events after treatment of transdermal fentanyl included dizziness, somnolence, dysuria, mild and transient nausea, vomiting, discomfort of stomach, and so on. All the adverse events disappeared within several days after proper managements. Neither severe adverse event nor drug addiction was found. CONCLUSIONS: Transdermal fentanyl has good analgesic effect on painful severe mucositis induced by AHSCT. It is convenient and well tolerated, and could improve quality of life significantly.

[Expression and clinical significance of Mcl-1 in T-cell non-Hodgkin's lymphoma].

BACKGROUND & OBJECTIVE: The prognosis of T-cell non-Hodgkin's lymphoma (T-NHL) is poor. Overexpression of myeloid cell leukemia-1 (Mcl-1) gene could inhibit irradiation-and drug-induced apoptosis in several lymphoma cell lines. This study was to detect the expression of Mcl-1 in T-NHL of various subtypes, and explore its correlation to clinicopathologic features and prognosis of T-NHL. METHODS: The expression of Mcl-1 protein in 72 specimens of T-NHL was detected by immunohistochemistry. The clinical features, treatments, and outcomes of the T-NHL patients were analyzed retrospectively. RESULTS: The weak positive rates of Mcl-1 were 44.4% in precursor T lymphoblastic lymphoma (T-LBL), 0% in anaplastic large T-cell lymphoma (ALCL), and 18.9% in other peripheral T-cell lymphoma (PTL); the positive rates were 0%, 100%, and 49.1%, respectively (P<0.001). Weak diffuse cytoplasmic staining of Mcl-1 was detected in T-LBL, and strong cytoplasmic staining with perinuclear accentuation was detected in ALCL. The overall survival time was significantly longer in the PTL patients with high Mcl-1 expression than in the PTL patients with weak/negative Mcl-1 expression (>32 months vs. 15 months, P=0.007), and longer in the T-LBL patients without Mcl-1 expression than in the T-LBL patients with weak Mcl-1 expression (21 months vs. 7 months, P=0.58). CONCLUSIONS: The intensities of Mcl-1 expression in T-NHL of various histological subtypes are different. It is specifically highly expressed in ALCL. High expression of Mcl-1 is correlated to better prognosis of PTL.

[Expression and clinical significance of nm23-H1 and MUC-1 in peripheral T-cell lymphoma].

BACKGROUND & OBJECTIVE: Peripheral T-cell lymphoma (PTCL) is a group of heterogeneous malignancy with poor prognosis. The role of international prognostic index (IPI) in PTCL remains to be determined. It is necessary to find new molecular markers for PTCL. This study was to evaluate the clinical significance of nm23-H1 and MUC-1 in predicting the prognosis of PTCL. METHODS: The expression of nm23-H1 and MUC-1 proteins in 96 specimens of PTCL was detected by SP immunohistochemistry. The correlations of nm23-H1 and MUC-1 expression to clinical features, objective response, and overall survival of PTCL patients were analyzed. RESULTS: Of the 96 patients, 78 (81.2%) were nm23-H1-positive, 56 (58.3%) were MUC-1-positive. Neither of the expression of nm23-H1 and MUC-1 was correlated to the pathologic subtype of PTCL (P>0.05). The high expression of nm23-H1 was associated with some poor prognostic factors such as stage III-IV, performance status (PS)> or =2, extranodal involvement, and more than one site of extranodal involvement (P<0.05). The high expression of MUC-1 was only associated with stage III-IV and more than one site of extranodal involvement (P<0.05). Of the 89 patients with evaluable disease, the overall response rate was 87.8% with a complete remission (CR) rate of 56.7%. The CR rate was significantly higher in nm23-H1-negative patients than in nm23-H1-positive patients (66.7% vs. 55.4%, P<0.05), and significantly higher in the patients with low nm23-H1 expression than in those with high nm23-H1 expression (79.9% vs. 44.0%, P<0.05); the CR rate was higher in MUC-1-negative patients than in MUC-1-positive patients, and higher in the patients with low MUC-1 expression than in those with high MUC-1 expression, but the differences were not significant. The median follow-up of the whole group was 30 months (range, 2-98 months), and the median survival time was 32 months [95% confidence interval (CI)= 26-34 months]. The overall 5-year survival rate of the whole group was 35.1%. The overall 5-year survival rate was significantly higher in nm23-H1-negative patients than in nm23-H1-positive patients (86.7% vs. 24.9%, P=0.001), and significantly higher in the patients with low nm23-H1 expression than in those with high nm23-H1 expression (52.3% vs. 21.7%, P<0.001). The overall 5-year survival rate was slightly higher in MUC-1-negative patients than in MUC-1-positive patients (47.9% vs. 28.5%, P>0.05), and slightly higher in the patients with low MUC-1 expression than in those with high MUC-1 expression (46.2% vs. 22.2%, P>0.05). Multivariant analysis showed that IPI score and nm23-H1 expression were independent prognostic factors of PTCL. CONCLUSIONS: Overexpression of nm23-H1 is related to poor prognosis of PTCL; it may be a potential prognostic index of PTCL. Overexpression of MUC-1 is not related to.

[Preliminary assessment of immune reconstitution after autologous peripheral hematopoietic stem cell transplantation (AHSCT)].

BACKGROUND & OBJECTIVES: Though high dose chemo-therapy combined with autologous hematopoietic stem cell transplantation (AHSCT) has made great progress on the treatment of chemo-sensitive malignant tumors, the relapse rate remains high. Successful immune reconstitution after AHSCT may reduce recurrence; therefore this study was to explore the characteristics of immune reconstitution after AHSCT and assess its feasibility in clinical use. METHODS: Twenty four cases after AHSCT were enrolled in our study. There were 19 Non-hodgkin Lymphoma (NHL), 3 Hodgkin Lymphoma (HD) and 2 rhabdomyosarcoma. Nineteen cases had achieved complete remission (CR) while 5 partial remission (PR) before AHSCT. All cases were administered Interleukin (IL)-2 and Interferon (IFN)-alpha after AHSCT. Some patients were given thymus factor and/or CIK infusion. Phenotypes of peripheral blood T, B, NK subsets and immunological profile of TH1/TH2 by intracellular staining of cytokines after PMA/ionomycin stimulation were evaluated. RESULTS: 75% of the cases achieved CR while 4.17% were progression of disease (PD) and 16.67% were relapsed during the median follow-up time of 12 (2-60) months. The changes of immune parameters after AHSCT were as followed: (1) CD4+T cells (normal control 33.5+/-6.9%) started to decrease dramatically one month after AHSCT, which was 2.5-13% (median rate 5.6%)in the 2nd month; and then slowly increased to 10-20% in the 7th month, but did not return back to normal even after one year in all patients. In addition, reversed ratio of CD4/CD8 lasted for a long period of time. B cells also began to decrease 1 month after AHSCT, and recovered to normal in the 4th month. But B cells remained 0% in the 6th month and 1% in 12th month in patients treated by rituximab before receiving AHSCT. The ratio of NK cells was 10-20% (higher than normal controls) in the 2nd month, then returned to normal thereafter. (2) The cytokine secretion by T cell: there were 48.79% patients whose TH1 was lower than normal controls or at the lower limit of normal range. All the patients with normal TH1 were treated by IFN-alpha or CIK cell infusion. TH2 was much higher than normal level among 68.29% cases and this abnormality lasted at least for 1 year in some cases. TH2 at normal range was only observed in cases receiving IFN-alpha treatment. Furthermore, IFN-alpha could significantly decrease TH2 level. (3) Increasing tendency of CD4+CD25+/CD4+, CD4+CD69+/CD4+ ratio was observed in patients received additional thymus factor treatment compared to those did not. CONCLUSIONS: Administration of CIK cells, thymus factor, IL-2 and IFN-alpha after AHSCT could improve the immunologic function of patients, and TH1/TH2 ratio may virtually reflect the immune status of patients. However more information is required to make prognostic assessments of immune reconstruction and the long-term survival rate.