Using the Child Perceptions Questionnaire with young adults.

OBJECTIVES: That no study has investigated oral health-related quality of life (OHRQoL) through the transition from adolescence to young adulthood is partly due to no OHRQoL index having been validated in both adult and child populations. Having separate measures for adolescence and young adulthood has meant that the different measures cannot be compared directly. Accordingly, the study objectives were: to determine whether the CPQ11-14 is a valid and reliable OHRQoL measure in young adults and to compare its performance with the OHIP-14 in young adults. METHODS: A cross-sectional study was undertaken of a convenience sample of 968 young New Zealand adults aged 18-30 years (83.1% female) using RedCap. Two separate measures of OHRQoL were used (the CPQ11-14 and OHIP-14), along with Locker's global oral health item. RESULTS: Internal consistency reliability was high for the CPQ11-14 and the OHIP-14, with Cronbach's alpha scores of .87 and .92, respectively. Mean scale scores were 15.8 (SD = 9.7) for the CPQ11-14 and 24.1 (SD = 10.1) for the OHIP-14. The scale scores were strongly and positively correlated (Pearson's r = .8). Both demonstrated acceptable construct validity, represented by ascending gradients in mean scores across the ordinal response categories of Locker's global oral health item. Ordinal logistic regression modelling of Locker's item showed the CPQ11-14 to have a slightly better fit and explain more variance than the OHIP-14. CONCLUSION: The CPQ11-14 was valid and reliable in this young adult population. Further epidemiological validation studies should confirm the findings in representative samples.

Decreasing cost of flexible ureterorenoscopy: single-use laser fiber cost analysis.

OBJECTIVE: To demonstrate a cost benefit while using disposable laser fibers as compared with reusable laser fibers. Flexible ureteroscopy (FURS) is a central component of endourology. It is vital that for service provision and training purposes, costs are kept down while delivering this service. Laser fibers are known to damage scopes causing high repair and/or replacement costs. MATERIALS AND METHODS: Data for consecutive FURS procedures during 2 periods in a single center were compared. First, with the use of reusable fibers and second, with single-use fibers. Cost of laser fibers and repairs was recorded. The study excludes the cost of the initial purchase of the ureterorenoscopes or the holmium laser equipment and costs associated with staffing and hospital stay. RESULTS: The total number of FURS carried out in period 1 and period 2 was 260 and 265, respectively. A total of 13 reusable (185 procedures) and 168 disposable laser fibers were used in these 2 periods, respectively. There was a reduction in laser damaged ureteroscopes from 9 to 3 in the second period. This resulted in a £ 16,800 reduction in repair cost. This more than offsets the increased costs of single-use fibers. CONCLUSION: On the basis of our data, it is more cost-effective to use a disposable laser fiber, as it prevents scope damage, which can happen because of microfractures with repeated laser use. Moreover, this will also save time and/or resource required with sterilization.

Immunomodulatory activity of resveratrol: suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production.

trans-Resveratrol, a phytoalexin found in grapes, wine, and other plant products, has been shown to have anti-inflammatory, antioxidant, and antitumor activities. Many of these beneficial effects of resveratrol require participation of the cells of the immune system; however, the effect of resveratrol on the development of immunological responses remains unknown. We have investigated the effect of resveratrol on mitogen/antigen-induced proliferation of splenic lymphocytes, induction of cytotoxic T lymphocytes (CTLs) and lymphokine activated killer (LAK) cells, and the production of the cytokines interferon (IFN)-gamma, interleukin (IL)-2, tumor necrosis factor (TNF)-alpha, and IL-12. We found that mitogen-, IL-2-, or alloantigen-induced proliferation of splenic lymphocytes and the development of antigen-specific CTLs were suppressed significantly at 25-50 microM resveratrol. The generation of LAK cells at similar concentrations was less sensitive to the suppressive effect of resveratrol. The suppression of cell proliferation and CTL generation by resveratrol was not only reversible, but in some cases the response (mitogen/IL-2-induced proliferation and CTL generation) was actually enhanced following pretreatment of cells with resveratrol. Resveratrol also inhibited the production of IFN-gamma and IL-2 by splenic lymphocytes, and the production of TNF-alpha and IL-12 by peritoneal macrophages. The inhibition of cytokine production by resveratrol was irreversible. Further, resveratrol blocked the activation of the transcription factor NF-kappaB without affecting basal NF-kappaB activity. The latter result suggests that resveratrol inhibits cell proliferation, cell-mediated cytotoxicity, and cytokine production, at least in part through the inhibition of NF-kappaB activation.

IL-12 gene therapy of leukemia with hematopoietic progenitor cells without the toxicity of systemic IL-12 treatment.

We have previously shown that the myeloid progenitor cell line 32Dc13 transduced with mIL-12 cDNAs (32DIL-12 cells) induces IFN-gamma and NK-cell-mediated cytotoxicity in vivo. Since systemic therapy with recombinant IL-12 protein has been shown to produce moderate to severe toxic side effects we examined whether IL-12 gene therapy with hematopoietic progenitor cells also induces systemic toxicities that are commonly associated with the administration of rIL-12 protein. Injection of large doses of IL-12 secreting 32DIL-12 cells (5 to 6 x 10(7) cells) significantly reduced mortality in mice injected with a lethal dose of 32Dp210 myeloid leukemia cells. More importantly, injection of similar doses of transduced cells failed to reduce body weight significantly or produce other visible signs of toxicity, i.e., fur ruffling or lethargy. There was no evidence of hematologic or hematopoietic toxicity resulting from the injection of transduced cells. In addition, microscopic examination of liver, kidney, lung, and intestine of mice injected with transduced cells revealed the absence of tissue necrosis or inflammatory response in any of these organs. Finally, 32DIL-12 cells were not found to interfere with the engraftment of syngeneic bone marrow transplant or the hematopoietic reconstitution of irradiated mice. These results demonstrate that IL-12 gene therapy with hematopoietic progenitor cells is nontoxic and provide a rationale for exploring the feasibility of treating minimal residual leukemia with IL-12 gene therapy.

Interleukin-12 (IL-12) gene therapy of leukemia: immune and anti-leukemic effects of IL-12-transduced hematopoietic progenitor cells.

Recombinant interleukin-12 (rlL-12) is a potent immunomodulatory cytokine that has been shown to exert strong antitumoral and antimetastatic activity against several mouse tumors grown as solid lesions. The therapeutic efficacy of rIL-12 against hematological tumors and the transfer of IL-12 genes into hematopoietic progenitor cells to deliver IL-12 to the bone marrow (BM) to treat residual leukemia has not been studied adequately. We have investigated the retroviral-mediated transduction of hematopoietic progenitor cells with IL-12 genes and the in vivo anti-leukemic activity of transduced cells against the murine myeloid leukemia cell line 32Dp210. We were able to efficiently transduce the IL-3-dependent 32Dc13 myeloid progenitor cell line and primary hematopoietic progenitor cells using an MFG-based polycistronic retroviral vector containing the cDNAs of p35 and p40 murine IL-12 genes. 32Dc13 myeloid progenitor cells expressing IL-12 genes (32DIL-12 cells) have stably secreted biologically active murine IL-12 for >9 months. Mice transplanted with 32DIL-12 cells transiently express the transgene in the BM and spleen, which is associated with a rapid elevation of interferon-gamma (IFN-gamma) in the circulation and with secretion of IFN-gamma by spleen cells in vitro. In addition, spleen and BM cells of mice injected with 32DIL-12 cells readily acquire the capacity to lyse natural killer cell-sensitive YAC-1 target cells and 32Dp210 myeloid leukemia cells. Furthermore, whereas mice challenged with leukemia cells suffered 100% mortality within 14 days, approximately 40% of mice coinjected with 32Dp210 leukemia cells and 32DIL-12 progenitor cells exhibited long-term, leukemia-free survival (>60 days). This study demonstrates that IL-12 can be stably expressed in hematopoietic cells; in addition, when transplanted, transduced cells induce IFN-gamma production and activation of natural killer cells, both of which may be involved in inhibiting the progression of leukemia in vivo.

A phase II trial of etoposide, leucovorin, 5-FU, and interferon alpha 2b (ELFI) + G-CSF for patients with pancreatic adenocarcinoma: a Southwest Oncology Group study (SWOG 9413).

BACKGROUND: Chemotherapeutic treatments using combinations of etoposide, leucovorin and 5-FU (ELF) have shown activity in the treatment of gastrointestinal malignancies. Interferon alpha 2b is known to have antiproliferative effects on several cell lines and has well documented in vitro evidence of synergism with 5-FU. It was postulated that the combination of ELF and interferon alpha 2b would improve response rates and survival in patients with pancreas cancer. METHODS: Fifty-five eligible patients with locally-advanced or metastatic pancreatic adenocarcinoma received a regimen consisting of: i.v. leucovorin at 300 mg/m2/day on Days 1-3 (of 28-day cycle), i.v. etoposide at 80 mg/m2/day on Days 1-3, i.v. 5-FU at 500 mg/m2/day on Days 1-3, subcutaneous interferon alpha 2b at 3 million units TIW, and subcutaneous G-CSF at 5 microg/kg/day on Days 4-14 (or until WBC exceeds 10,000/microl). Patients with no evidence of disease progression continued on treatment for a total of 6 cycles. RESULTS: Complete response was demonstrated in 1 patient, partial response in 5 patients (11% confirmed response rate). The median survival was 5 months, and the six-month survival rate was 40%. Ten patients completed all 6 cycles of treatment. Toxicity-related dose delays and reductions were necessary for most patients. CONCLUSIONS: Although the combination of ELF and interferon alpha 2b (ELFI) has modest activity in pancreatic cancer, it is a toxic and complex regimen that is not superior to other currently available approaches for the chemotherapeutic management of pancreatic cancer. ELFI cannot be recommended as a standard therapy.

Resveratrol selectively inhibits leukemia cells: a prospective agent for ex vivo bone marrow purging.

Ex vivo purging of contaminating tumor cells may reduce the incidence of relapse in patients undergoing bone marrow transplantation. In this study we demonstrate that resveratrol, a phytoalexin with anti-oxidant and chemopreventive activity, exhibits anti-leukemic activity against mouse (32Dp210, L1210) and human (U937, HL-60) leukemic cell lines by inhibiting cell proliferation. Long-term exposure to resveratrol also inhibits the clonal growth of normal hematopoietic progenitor cells but at a higher IC50 of resveratrol than that for most of the leukemia cell lines tested. The inhibitory effect of resveratrol on hematopoietic progenitors is partially reversible, whereas the effect on leukemia cells is largely irreversible. The inhibition of leukemia cells by resveratrol involves nucleosomal DNA fragmentation (apoptosis). On the other hand, resveratrol does not induce or enhance spontaneously occurring apoptotic death in normal hematopoietic progenitor cells. In vivo experiments performed with untreated and resveratrol-treated bone marrow showed comparable hematopoietic reconstitution in lethally irradiated mice (10 Gy) as determined by survival, hematologic recovery, and the number of hematopoietic progenitor cells present in the marrow of reconstituted animals. Taken together, these results indicate the potential use of resveratrol for ex vivo pharmacological purging of leukemia cells from bone marrow autografts without significant loss in the hematopoietic activity of progenitor cells.

Extracorporeal resuscitation of cardiac arrest.

OBJECTIVE: Extracorporeal support of heart and lung function (venoarterial perfusion) during cardiac arrest (ECPR) has been advocated as a means of improving survival following cardiac arrest. The authors retrospectively reviewed their institution's seven-year experience with this intervention. METHODS: Emergency department patients and inpatients in cardiac arrest or immediately postarrest were considered candidates. ECPR was instituted using venoarterial bypass and was continued until patients regained sufficient cardiopulmonary function to allow weaning from the device or until their condition was deemed irrecoverable. RESULTS: ECPR was attempted in 25 patients and successfully instituted in 21. Four patients (16%) were converted from ECPR to ventricular assist devices, two of whom survived and await transplantation. Seven additional patients were discharged from the hospital, resulting in an overall survival of 36%. Because none of the children treated survived, there was a trend toward higher age among survivors (survivors 40 +/- 14 yr, nonsurvivors 33 +/- 15 yr, p = 0.29). The duration of conventional CPR was shorter among survivors (survivors 21 +/- 16 min, nonsurvivors 43 +/- 32 min, p = 0.04), as was the duration of extracorporeal support (survivors 44 +/- 21 hr, nonsurvivors 87 +/- 96 hr, p = 0.18). Survival was seen only in patients whose conditions were amenable to a definitive therapeutic intervention, particularly cardiac arrest due to respiratory or pulmonary embolic disease. While four of the five patients treated in the ED were successfully supported, none survived to discharge. CONCLUSION: In select patients with reversible disease, extracorporeal CPR can be used to successfully treat cardiac arrest. Further investigation into its most appropriate application is warranted.

TNF-alpha gene therapy with myeloid progenitor cells lacks the toxicities of systemic TNF-alpha therapy.

We examined the antileukemic activity and the toxicity of HPC transduced with human tumor necrosis factor (TNF) cDNA. Both clonal (32Dcl3) and BM-derived primary hematopoietic progenitors (BM-Prog) expressing hTNF-alpha gene (32DTNF-alpha and BMTNF-alpha cells, respectively) inhibited the development of leukemia in mice with a small dose of 32Dp210 cells, a myeloid leukemia cell line. Whether the trans-gene expressing 32DTNF-alpha cells produce toxicities commonly associated with systemic TNF-alpha therapy was determined by examining the effect of TNF-alpha-secreting progenitor cells on body weight, tissue histology, growth of HPC, and engraftment of BMT. Administration of a low or high dose of TNF-alpha-secreting 32DTNF-alpha cells to mice failed to produce loss in body weight, a measure of TNF-alpha-related cachexia. There was also no evidence of tissue necrosis or mononuclear cell (MNC) infiltration in lung, liver, kidney, or intestine of mice injected with transduced progenitor cells. Furthermore, 32DTNF-alpha cells showed no effect on the clonal growth of HPC in colony-forming assays or loss of cellularity in BM, spleen, or blood. Finally, TNF-alpha-secreting cells were found not to interfere with the engraftment of BM transplant and hematopoietic reconstitution thereafter. We conclude from these findings that unlike systemic administration of TNF-alpha, TNF-alpha gene therapy with transduced HPC is nontoxic and may have a role in eradicating residual leukemia after BMT.

Effect of phosphorylation on L-type calcium current in ventricular myocytes dialysed with proteolytic enzymes.

1. L-Type Ca2+ channels play important roles in cardiac excitation and conduction. The present study used the whole-cell patch-clamp technique to investigate properties of Ca2+ channels in guinea-pig isolated ventricular myocytes. The effects of internal application of the proteolytic enzymes trypsin and carboxypeptidase (CBP) on the whole-cell L-type Ca2+ current (ICa) were determined. When the effects of the enzymes on ICa had reached steady state, the effects of isoprenaline (ISP) or 2,3-butane-dione monoxime (BDM), which increase and decrease channel phosphorylation, respectively, were examined. The effects of these agents were compared with those observed in the absence of enzyme pretreatment. 2. The amplitude and inactivation characteristics of ICa during depolarizing voltage-clamp commands to +10 mV (0.1 Hz) were determined at 37 degrees C. 3. Trypsin and CBP (both at concentrations of 1 mg/mL in the pipette solution) increased the amplitude of ICa 4.2- and 2.8-fold, respectively, and each enzyme increased the time constant of the slowly inactivating current by 50%. 4. Trypsin decreased the potential at which ICa was half maximally activated from (mean +/- SD) -1.4 +/- 2.2 mV (n = 9) to -11.3 +/- 2.5 mV (n = 7). Although CBP increased ICa amplitude, it did not shift the half-maximal activation voltage. Maximum conductance was increased 5.3-fold by trypsin and 2.2-fold by CBP. 5. Isoprenaline (1 mumol/L) had no effects in myocytes dialysed with trypsin, but significantly increased the current in myocytes dialysed with CBP by 8%. 6. At 12 mmol/L, BDM had no effect on current amplitude in the presence of trypsin, but decreased the time constant of slow inactivation to control values. After dialysis with CBP, BDM significantly decreased the maximum current by 11% and also decreased the rate of slow inactivation towards control values. 7. These data suggest that trypsin and CBP may have digested a part of the calcium channel that normally restricts current flow, but to different extents. The enzymes interacted with BDM and ISP in a fashion suggesting that two sites may influence the amplitude of the current and at least two other sites may influence the time course of the slowly inactivating current.

Growth Factors: Production of Monocyte Chemotactic Protein-1 (MCP-1/JE) by Bone Marrow Stromal Cells: Effect on the Migration and Proliferation of Hematopoietic Progenitor Cells.

Recombinant chemotactic cytokines (chemokines) have been shown to modulate in vitro proliferation of hematopoietic progenitor cells. Whether bone marrow stromal cells produce chemokines and the physiological role they may have in the regulation of hematopoiesis has largely remained unexamined. We have examined the expression of monocyte chemoattractant protein-1 (MCP-1/JE) in bone marrow stromal cells and its effect on the migration and proliferation of murine hematopoietic progenitor cells. Freshly derived murine bone marrow stromal cells were found to secrete abundant amounts of MCP-1/JE, which was further increased upon stimulation of stromal cells with pro-inflammatory agents LPS, IL1-alpha, IFN-gamma, or TNF-alpha. Although culture supernatant conditioned by stromal cells exhibited chemotactic activity toward hematopoietic progenitor cells, the chemotactic activity was not due to MCP-1/JE. Furthermore, rMCP-1/JE also failed to induce migration of progenitor cells. MCP-1/JE, however, caused 20 to 30% increase in the clonal expansion of progenitor cells. Thus, although MCP-1/JE does not chemoattract hematopoietic progenitor cells it may have a role in their proliferation and clonal expansion.

On the mechanism of the failure of mitochondrial function in isolated guinea-pig myocytes subjected to a Ca2+ overload.

OBJECTIVE: The influence of agents that inhibit the movement of Ca2+ across the mitochondrial membrane or Ca2+ dependent changes to this membrane upon the response of isolated ventricular myocytes to a Ca2+ overload has been investigated. METHODS: The changes of intracellular Ca2+ and Mg2+ ([Ca2+]i, [Mg2+]i) (as reflected by cellular ATP), mitochondrial membrane potential (psi m) and NADH was measured upon the response of isolated ventricular myocytes to a Ca2+ overload. RESULTS: A slow depolarization of psi m during Ca2+ depletion and its prompt recovery on Ca2+ repletion were unaffected by ruthenium red, clonazepam, CGP-37157 which is a high potent inhibitor of the mitochondrial Na+/Ca2+ antiport or cyclosporin A but a large delayed sustained depolarization was inhibited. The slow small fall in [Mg2+]i on Ca2+ depletion and a rapid recovery on Ca2+ repletion were unaffected by ruthenium red, clonazepam, CGP-37157 or cyclosporin A. A delayed sustained larger rise in [Mg2+]i was inhibited. The marked sustained fall in NADH autofluorescence that occurs on Ca2+ overload was attenuated and transient in the presence of ruthenium red, CGP-37157 and cyclosporin A. CONCLUSION: These results are consistent with an increase in Ca2+ cycling across the mitochondrial membrane provoked by the combined Na+ and Ca2+ overload of cardiac myocytes, causing a depolarization sufficient to uncouple respiration and lead to the depletion of cellular ATP.

[Dependence of the protective effect of the elevated sodium level on the type of oxidative substrate in the isolated heart during "calcium paradox"]. / Zavisimost' zashchitnogo deistviia gipernatrievoi sredy ot vida substrata okisleniia v tselom serdtse pri kal'tsievom paradokse.

Isolated guinea pig heart were perfused with the Tyrode solution followed in 15 min. by a 10-min. Ca(2+)-free solution with subsequent return to the normal Ca(2+)-containing Tyrode solution. Sarcolemma damage was measured by myoglobin release. The perfusion resulted in damage of the myocardium cells. The data obtained show that elevation of the extracellular pressure during reperfusion with the Ca(2+)-containing medium is more important than the absolute value of the osmotic pressure.

Nonselective inhibition of proliferation of transformed and nontransformed cells by the anticancer agent curcumin (diferuloylmethane).

We have investigated the antiproliferative effect of curcumin, an antitumor agent with antioxidant and anti-inflammatory properties, against a variety of transformed and nontransformed cell types. At equimolar concentrations ranging from 6.25 to 50 microM, curcumin inhibited DNA synthesis, as revealed by 3H-incorporation, in five leukemia lines, three nontransformed hematopoietic progenitor cell populations, and four nontransformed fibroblastic cell lines in a concentration-dependent manner. Curcumin also inhibited the cellular growth of both transformed and nontransformed cells in clonogenic assays. Without discriminating between transformed or nontransformed cells, the inhibition of cell proliferation by curcumin was not always associated with programmed cell death. These findings have implications for developing curcumin-based anticancer and anti-inflammation therapies.

Antileukemic activity of TNF-alpha gene therapy with myeloid progenitor cells against minimal leukemia.

Tumor necrosis factor-alpha (TNF-alpha) has exhibited antitumor activity against a variety of tumors in rodents and human tumor xenografts in nude mice, but it has been only marginally effective in cancer patients because of dose-limiting toxicity associated with systemic TNF-alpha therapy. To circumvent toxicity and to test the antileukemic activity against quantitated minimal leukemia, we have cloned human TNF-alpha (HuTNF-alpha) gene in an advanced myeloid progenitor cell line. 32Dcl3 myeloid progenitor cells transfected with HuTNF-alpha cDNA by the retroviral supernatant infection method stably express HuTNF-alpha gene and secrete substantial amounts of HuTNF-alpha. When injected i.v. into irradiated mice, transduced cells could be detected in the marrow but not in spleen or liver 10-12 days later. Injection of 5 x 10(6) transduced cells produced no obvious symptoms of TNF-alpha toxicity (i.e., weight loss, cachexia, or fever) suggesting that TNF-alpha producing cells are well tolerated by the recipient mice. Coinjection of 5 x 10(6) transduced cells and 10(2) or 10(3) 32Dp210 leukemia (BCR/ABL+) cells resulted in inhibition of leukemia development by 10(2) but not 10(3) 32Dp210 cells. An equal dose of nontransduced 32Dcl3 cells was ineffective in inhibiting leukemia progression by 10(2) 32Dp210 cells. Mice that rejected leukemia were BCR/ABL oncogene negative 8 weeks after leukemia cell injection. These data demonstrate the potential for TNF-alpha gene therapy for destroying residual leukemia, without the toxicity of systemic TNF-alpha therapy, following cytoreductive therapy and bone marrow transplant.

The Henry Ford Health System.

The Henry Ford Health System is a large, vertically integrated health care delivery system, with its core service delivery team comprised of a 1000-person salaried medical group. Oncology services are coordinated through its Cancer Center, which organizes regional distribution of oncology services for residents of southeast Michigan. Oncology services are delivered through five regionally distributed sites, affording a vast majority of cancer services to be provided for patients a short distance from their homes. The System owns the largest health maintenance organization in Michigan (Health Alliance Plan) and its organizational structure affords the opportunity of offering purchasers specific oncology service contracting opportunities. Advantages of providing comprehensive oncology services through an integrated health system include: 1) standardized cancer care guidelines, 2) medical information exchange through an electronic medical record, 3) interdisciplinary cancer care provided by salaried physicians, minimizing potentially conflicting financial issues in treatment decisions, 4) state-of-the-art care afforded through availability of involvement in a large number of National Institutes of Health-sponsored clinical trials, 5) high standards of credentialing for oncology physicians, and 6) integrative managed care perspectives and continuous attention to cost and quality of care issues.

Phase II trial of paclitaxel by 24-hour continuous infusion for relapsed non-Hodgkin's lymphomas: Southwest Oncology Group trial 9246.

PURPOSE: The Southwest Oncology Group (SWOG) recently conducted a multiinstitutional phase II trial to determine the complete response (CR) and partial response (PR) rates, toxicities, and progression-free and overall survivals of patients with relapsed non-Hodgkin's lymphomas (NHLs) treated with a 24-hour continuous infusion of paclitaxel at a dose of 175 mg/m2. PATIENTS AND METHODS: Sixty-six patients with relapsed NHL who had received minimal prior therapy (one prior chemotherapy regimen for intermediate- to high-grade NHL [44 patients] or one or two prior regimens for low-grade NHL [22 patients]) were premedicated with dexamethasone, diphenhydramine, and cimetidine and then treated with continuous intravenous infusion paclitaxel over 24 hours every 21 days. RESULTS: Eleven of 66 patients (17%) achieved rigorously documented objective remissions, including two CRs (3%) and nine PRs (14%). In addition, another five patients (8%) achieved apparent PRs on a single computed tomographic (CT) scan. Responses were brief, lasting a median of 3 months (5 months for indolent lymphomas and 3 months for intermediate- to high-grade lymphomas). Grade 4 or 5 granulocytopenia was the only common serious toxicity, and occurred in 42 of 66 patients (64%). CONCLUSION: Paclitaxel is generally well tolerated when given as a continuous infusion of 175 mg/m2 over 24 hours, despite predictable granulocytopenia. However, single-agent paclitaxel has modest clinical efficacy compared with other available treatments for relapsed NHL.

IL1α and TNFα Induction of Monocyte Chemoattractant Protein-1 (MCP-1/JE) in Bone Marrow Stromal Cells: The Role of Protein Kinase C (PKC) and Protein Tyrosine Kinase (PTK) Activity.

Chemotactic cytokines (chemokines) have been shown to influence myelopoiesis. Bone marrow stromal cell line +/+-1. LDA11 expresses MCP-1/JE chemokine upon stimulation with ILlα and TNFα. We have examined the role of PKC and PTK dependent protein phosphorylation in induction of MCP-1/JE by using PKC and PTK specific inhibitors. PKC inhibitors staurosporine and H-7, as well as PTK inhibitors herbimycin A and genistein suppressed MCP-1/JE expression (mRNA and protein) in a dose dependent manner. The suppression of MCP-1/JE by both classes of inhibitors was partially to completely reversible. While PKC only regulated gene expression posttranscriptionally (mRNA stability), transcription of MCP-l/JE gene by ILlα and TNFα depends both upon PKC and PTK activity, as demonstrated by nuclear run-on analyses. Furthermore, treatment of cells with IL1a and TNFα involved NF-kB mobilization. There was no effect of PKC inhibitors on NF-kB mobilization by either ILlα or TNFα. In contrast, mobilization of NF-kB was negatively affected by PTK inhibitors in a stimulus selective manner (e.g., herbimycin A and genistein inhibited IL1α and TNFα induced NF-kB mobilization, respectively). We conclude from these findings that while both PKC and PTK inhibitors suppress MCP-1/JE gene transcription, only PTK inhibitors do so by suppressing NF-kB activation.

Curcumin, a compound with anti-inflammatory and anti-oxidant properties, down-regulates chemokine expression in bone marrow stromal cells.

Chemotactic cytokines or chemokines play an important role in the regulation of myelopoiesis. Since the production of chemokines and colony stimulating factors (CSFs) by bone marrow stromal cells requires inflammatory conditions, we investigated the effect of curcumin, an agent with anti-inflammatory and anti-oxidant activities, on the expression of monocyte chemoattractant protein-1 (MCP-1 or MCP-1/JE) and interferon inducible protein-10kD (IP-10) in mouse bone marrow stromal cell line +/+-1.LDA11. Both chemokines are readily expressed in stromal cells after stimulation with pro-inflammatory interleukin-1alpha (IL-1alpha), interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and endotoxin lipopolysaccharide (LPS). Curcumin attenuates the levels of MCP-1/JE and IP-10 mRNA expression by all of these stimulatory agents. A detailed analysis of the regulatory effects of curcumin on chemokine expression by IL-1alpha was performed. Curcumin inhibits both chemokine mRNAs in a dose- and time-dependent manner. The suppressive effect of curcumin on both mRNAs is reversible with complete recovery from suppression within 24 hours after removal of curcumin. The suppression of mRNA by curcumin is dependent on de novo synthesis of an intermediary protein(s), since suppression is abrogated by concomitant treatment with cycloheximide (CHX). Destabilization of mRNA transcripts is not the mechanism by which curcumin lowers the levels of mRNA; however, transcripts formed in the presence of curcumin are more stable, as indicated by their slower degradation kinetics. Run-on transcriptional assays demonstrate that curcumin inhibits the transcriptional activity of both genes. Finally, the attenuation of chemokine gene expression is associated with decreased production of chemotactic activity. Together, these findings indicate that while curcumin may post-transcriptionally stabilize mRNA transcripts formed in its presence, the overall reduction in mRNA levels by curcumin is mediated by inhibition of the transcription of chemokine genes.

A study of reproductive function in patients with seminoma treated with radiotherapy and orchidectomy: (SWOG-8711). Southwest Oncology Group.

PURPOSE: The results of Southwest Oncology Group Study 8711 (Group 2B) are presented. The objective was to evaluate the natural history of sperm concentration and selected hormonal parameters in patients with testicular cancer treated with orchiectomy and radiotherapy. METHODS AND MATERIALS: Of a total of 207 patients enrolled on SWOG 8711, 53 pure seminoma patients were identified who were treated with orchiectomy and radiotherapy only. Sperm concentration, follicle-stimulating hormone (FSH) levels, and sexual satisfaction scores were the main parameters followed. RESULTS: A fraction of the patients were infertile prior to receiving radiotherapy. Our analysis indicates that incidental radiation dose to the remaining testicle affects time to recovery of fertility, and at an aggregate level, changes in FSH mirror changes in sperm concentration over time. This phenomenon is the same as that described in patients free from testicular cancer. These men evaluated their sexual activity as good after orchidectomy. CONCLUSION: Our data support the use of clamshell-type testicular shields as a means of providing maximum protection to the remaining testicle.