A review of ferric citrate clinical studies, and the rationale and design of the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) trial.

Pediatric chronic kidney disease (CKD) is characterized by many co-morbidities, including impaired growth and development, CKD-mineral and bone disorder, anemia, dysregulated iron metabolism, and cardiovascular disease. In pediatric CKD cohorts, higher circulating concentrations of fibroblast growth factor 23 (FGF23) are associated with some of these adverse clinical outcomes, including CKD progression and left ventricular hypertrophy. It is hypothesized that lowering FGF23 levels will reduce the risk of these events and improve clinical outcomes. Reducing FGF23 levels in CKD may be accomplished by targeting two key stimuli of FGF23 production-dietary phosphate absorption and iron deficiency. Ferric citrate is approved for use as an enteral phosphate binder and iron replacement product in adults with CKD. Clinical trials in adult CKD cohorts have also demonstrated that ferric citrate decreases circulating FGF23 concentrations. This review outlines the possible deleterious effects of excess FGF23 in CKD, summarizes data from the adult CKD clinical trials of ferric citrate, and presents the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) study, a randomized, placebo-controlled trial to evaluate the effects of ferric citrate on FGF23 in pediatric patients with CKD stages 3-4 (ClinicalTrials.gov Identifier NCT04741646).

Chronic kidney disease impacts health-related quality of life of children in Uganda, East Africa.

BACKGROUND: Limited data exist about causes of chronic kidney disease (CKD) and impact on health-related quality of life (HRQoL) in African children. We evaluated types of kidney disease in Ugandan children 0-18 years and compared HRQoL in children with CKD or with benign or resolving kidney disease (non-CKD) to assess predictors of HRQoL. METHODS: Demographic, socioeconomic, and clinical data were obtained for this cross-sectional study. Pediatric Quality of Life Core Scale™ (PedsQL) was used to survey 4 domains and overall HRQoL. CKD and non-CKD scores were compared using unpaired t test. HRQoL predictors were evaluated using linear and logistic regression analyses. RESULTS: One hundred forty-nine children (71 CKD, 78 non-CKD; median age 9 years; male 63%) had the following primary diseases: nephrotic syndrome (56%), congenital anomalies of the urinary tract (CAKUT) (19%), glomerulonephritis (17%), and other (8%). CAKUT was the predominant etiology (39%) for CKD; 63% had advanced stages 3b-5. Overall HRQoL scores were significantly lower for CKD (57 vs. 86 by child report, p < 0.001; 63 vs. 86 by parent proxy report, p < 0.001). Predictors of lower HRQoL were advanced CKD stages 3b-5, primary caregiver non-parent, vitamin D deficiency, and anemia. CONCLUSION: Like other parts of the world, CAKUT was the main cause of CKD. Most CKD children presented at late CKD stages 3b-5. Compared with non-CKD, HRQoL in CKD was much lower; only two-thirds attended school. Vitamin D deficiency and anemia were potentially modifiable predictors of low HRQoL. Interventions with vitamin D, iron, and erythropoietin-stimulating agents might lead to improved HRQoL.

Case report: a 5-year-old with new onset nephrotic syndrome in the setting of COVID-19 infection.

BACKGROUND: This is a case report of an asymptomatic SARS-CoV-2 infection associated with new-onset nephrotic syndrome in a pediatric patient. This is the third case of new-onset nephrotic syndrome in children associated with SARS-CoV-2 infection, but is the first case report describing a new-onset nephrotic syndrome presentation in a patient who had asymptomatic COVID-19 infection. CASE PRESENTATION: This is a case of a previously healthy 5 year old female who presented with new-onset nephrotic syndrome in the setting of an asymptomatic COVID-19 infection. She presented with progressive edema, and laboratory findings were significant for proteinuria and hypercholesterolemia. She was treated with albumin, diuretics, and corticosteroid therapy, and achieved clinical remission of her nephrotic syndrome within 3 weeks of treatment. Though she was at risk of hypercoagulability due to her COVID-19 infection and nephrotic syndrome, she was not treated with anticoagulation, and did not develop any thrombotic events. CONCLUSIONS: Our case report indicates that SARS-CoV-2 infection could be a trigger for nephrotic syndrome, even in the absence of overt COVID-19 symptoms.

Peritoneal dialysis catheter outcomes in infants initiating peritoneal dialysis for end-stage renal disease.

BACKGROUND: End-stage renal disease (ESRD) although rare among infants presents many management challenges. We sought to evaluate factors associated with PD catheter failure among infants initiated on chronic PD. METHODS: A retrospective chart review of all children under two years of age who had PD catheters placed for initiation of chronic PD from 2002 to 2015. Data was extracted for catheter related events occurring within 12 months of catheter placement. Cox and Poisson regression models were used to delineate factors associated catheter complications. RESULTS: Twenty-five infants with median age 18 days had PD catheters placed for chronic dialysis. Common complications included leakage around the exit site (31%), blockage (26%), migration or malposition (23%), catheter-related infections (18%), and other complications (2%). Predictors of initial PD catheter failure were age less than one month at catheter placement (hazard ratio (HR) 7.77, 95% CI, 1.70-35.39, p = 0.008), use of catheter within three days of placement (HR 5.67, 95% CI, 1.39-23.10, p = 0.015) and presence of a hernia (HR 8.64, 95% CI, 1.19-62.36, p = 0.033). In an adjusted Poisson regression model, PD catheter use within three days of placement was the only predictor of any catheter complication over the12 months of follow up. CONCLUSIONS: Use of PD catheters within three days of placement was associated with catheter failure. We recommend that when possible, catheters should be allowed to heal for at least three days prior to use to reduce risk of complications and improve catheter survival.

Acute kidney injury and its association with in-hospital mortality among children with acute infections.

BACKGROUND: We investigated prevalence of acute kidney injury (AKI) at hospitalization and its association with in-hospital mortality among Ugandan children hospitalized with common acute infections, and predictors of mortality among AKI children. METHODS: We enrolled 2,055 children hospitalized with primary diagnoses of acute gastroenteritis, malaria, or pneumonia. Serum creatinine, albumin, electrolytes, hemoglobin, and urine protein were obtained on admission. Participants were assessed for AKI based on serum creatinine levels. Demographic and clinical data were obtained using a primary care provider survey and medical chart review. Logistic regression was used to determine predictors of in-hospital mortality. RESULTS: A total of 278 (13.5%) of children had AKI on admission; for 76.2%, AKI was stage 2 (98/278) or stage 3 (114/278) defined as serum creatinine >2- or 3-fold above normal upper limit for age, respectively. AKI prevalence was particularly high in gastroenteritis (28.6%) and underweight children (20.7%). Twenty-five percent of children with AKI died during hospitalization, compared to 9.9% with no AKI (adjusted odds ratio (aOR) 3.5 (95% CI, 2.2-5.5)). In-hospital mortality risk did not differ by AKI stage. Predictors of in-hospital mortality among AKI children included primary diagnosis of pneumonia, aOR 4.5 (95% CI, 1.8-11.2); proteinuria, aOR = 2.1 (95% CI, 1.0-4.9) and positive human immunodeficiency virus (HIV) status, aOR 5.0 (95% CI, 2.0-12.9). CONCLUSIONS: Among children hospitalized with gastroenteritis, malaria, or pneumonia, AKI at admission was common and associated with high in-hospital mortality.

Human immunodeficiency virus infection and cerebral malaria in children in Uganda: a case-control study.

BACKGROUND: Human immunodeficiency virus (HIV)-1 infection increases the burden of malaria by increasing susceptibility to infection and decreasing the response to malarial treatment. HIV-1 has also been found to suppress the immune system and predispose to severe forms of malaria in adults. There is still a paucity of data on the association between HIV-1 infection and cerebral malaria in children. The aim of this study was to determine whether HIV-1 infection is a risk factor for cerebral malaria in children. METHOD: We conducted an unmatched case-control study, in which 100 children with cerebral malaria were compared with 132 with uncomplicated malaria and 120 with no malaria. In stratified analyses we estimated odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for age. RESULTS: HIV-1 infection was present in 9% of children with cerebral malaria compared to 2.3% in uncomplicated malaria (age-adjusted odds ratio (aOR) 5.94 (95% confidence interval (CI) 1.36-25.94, p = 0.012); and 2.5% in children with no malaria (aOR 3.85 (95% CI0.99-14.93, p = 0.037). The age-adjusted odds of being HIV-positive among children with cerebral malaria compared to the control groups (children with uncomplicated malaria and no malaria) was 4.98 (95% CI 1.54-16.07), p-value = 0.003. CONCLUSIONS: HIV-1 infection is associated with clinical presentation of cerebral malaria in children. Clinicians should ensure that children diagnosed with HIV infection are initiated on cotrimoxazole prophylaxis as soon as the diagnosis is made and caretakers counselled on the importance of adherence to the cotrimoxazole towards reducing the risk of acquiring P.falciparum malaria and associated complications such as cerebral malaria. Other malaria preventive measures such as use of insecticide-treated mosquito nets should also be emphasized during counselling sessions.

Toxicity and therapeutic efficacy of high-dose interleukin 2. In vivo infusion of antibody to NK-1.1 attenuates toxicity without compromising efficacy against murine leukemia.

In the current study we used the therapy of established murine leukemia to identify the lymphocyte subsets responsible for toxicity and for therapeutic efficacy of high-dose IL-2. Initial results confirmed that high-dose IL-2 induces marked proliferation of a variety of host cells, including NK cells, Lyt-2+ T cells, L3T4+ T cells, and B cells. Infusion of antibody to NK-1.1 depleted NK-1.1+ cells in vivo and greatly reduced the toxicity of IL-2, but did not decrease therapeutic efficacy. By marked contrast, depletion of host T cells, either Lyt-2+ or L3T4+, had no effect on toxicity but greatly reduced therapeutic efficacy. The requirement for host T cells for the curative effect of IL-2 gives credence to the possibility that substantial efficacy of high-dose IL-2 against established malignancy may require existent host antitumor immunity. Since the human tumors that have been shown to have the most substantial responses to IL-2 (i.e., malignant melanoma and renal cell carcinoma) are those long considered to be immunogenic in the autochthonous host, the current study predicts that for these, as well as other immunogenic human tumors, it should be possible to decrease the toxicity and thus increase the therapeutic index of IL-2 by selectively depleting NK cells in vivo.

Lysis of ras oncogene-transformed cells by specific cytotoxic T lymphocytes elicited by primary in vitro immunization with mutated ras peptide.

Ras protooncogenes are activated by characteristic point mutations in a wide variety of malignancies. The expressed p21ras proteins are oncogenic by virtue of single substituted amino acids, usually at position 12 or 61 of the 189-residue p21ras protein. In the current study, the ability of class I major histocompatibility complex (MHC)-restricted T cells to recognize the altered segment of a transforming p21ras protein and to lyse cells transformed by the corresponding ras oncogene was examined. Synthetic ras peptides encompassing the common activating substitution of leucine for glutamine at position 61 were constructed with an amino acid motif appropriate for binding to the H-2Kb murine class I MHC molecule. Cytotoxic T lymphocytes (CTL) specific for bound ras leucine 61 peptide were elicited by in vitro immunization of normal lymphocytes with synthetic peptides. The ras peptide-induced CTL specifically lysed syngeneic fibroblasts transformed by an activated ras gene encoding oncogenic p21ras protein containing the same single amino acid substitution. Thus, in some circumstances, mutated p21ras protein can serve as a tumor-specific antigen.

25-OH-vitamin D deficiency and cellular alloimmunity as measured by panel of reactive T cell testing in dialysis patients.

Primed antidonor alloreactive T cells are detrimental to transplant outcome, but factors that impact the strength of this immune response prior to transplantation are unknown. We tested peripheral blood mononuclear cells from dialysis patients, against panels of allogeneic, primary B-cell lines in a newly standardized IFNγ ELISPOT panel of reactive T cell (PRT) assay. Results were correlated with known alloantibody-sensitizing events and other clinical parameters. As 25-OH-vitamin D deficiency is associated with enhanced cellular immunity, is common in dialysis patients and is correctable, we assessed the relationship between serum 25-OH-vitamin D and the PRT. Using independent test and validation cohorts we found that low serum levels of 25-OH-vitamin D (<26 ng/mL) correlated with high-PRT values (in the upper 50th percentile, OR 0.02, p = 0.01) independent of age, sex, race, previous transplant, transfusion, pregnancy, time on dialysis, panel of reactive antibody, iPTH, and treatment with 1,25-OH-vitamin D. The data provide a potential mechanism for the possible relationship between vitamin D deficiency and poor posttransplant outcome, and support studies to test the impact of 25-OH-vitamin D repletion on alloimmunity and allograft injury in kidney transplant candidates.

Fludarabine/i.v. BU conditioning regimen: myeloablative, reduced intensity or both?

In this study, we utilized a conditioning regimen with fludarabine and myeloablative dose i.v. BU (12.8 mg/kg) (FluBU) in 36 adult patients (median age: 44 years, range: 18-61) with myeloid or lymphoid malignancies at standard risk (n=10) or high risk of relapse (n=26), who received an allogeneic hematopoietic SCT (HSCT) from HLA-matched related (n=16) or unrelated (n=20) donors. The source of hematopoietic stem cells was peripheral blood in 28 and marrow in 8 cases. Rabbit-antithymocyte globulin at 7 mg/kg was utilized in 21 patients. Acute GVHD grade II-IV was observed in 19% of the patients (grade III-IV in 14% of patients) and chronic GVHD in 11 of 30 evaluable patients (37%). At median follow-up of 737 days (range: 152-1,737) for alive patients, overall survival rates in standard- and high-risk patients were 80 and 35%, respectively, and event-free survival rates were 70 and 31%, respectively. TRM was 10% in standard-risk and 19% in high-risk patients. Post transplant relapse was observed in 20% standard-risk and in 46% high-risk patients. FluBU conditioning regimen is associated with a limited hematologic and extrahematologic toxicity and with an antitumor activity comparable to other standard myeloablative regimens.

Comparable kinetics of myeloablation between fludarabine/full-dose busulfan and fludarabine/melphalan conditioning regimens in allogeneic peripheral blood stem cell transplantation.

Fludarabine was utilized in the conditioning regimen of 30 adult patients undergoing an allogeneic hematopoietic stem cell transplant. In 18 patients it was combined with full-dose busulfan (FluBu) as a myeloablative regimen and in 12 cases with melphalan (FluMel) as a reduced intensity conditioning (RIC) regimen. Patients in the FluBu group were younger than in the FluMel group (P=0.03). Of 30 patients, 24 received peripheral blood stem cells (PBSC) whereas six patients in the FluBu group received bone marrow cells. The hematological toxicity of each regimen was evaluated by analyzing the kinetics of the neutropenia induced by preparative regimens and the time to recovery of the absolute neutrophils count (ANC) and platelets post transplantation. In PBSC transplants, the median day of severe neutropenia (<500 ANC/microl) occurred on day +6 after the FluBu regimen and on day +3 after FluMel (P=ns), whereas both groups had a duration of severe neutropenia of 9 days and a comparable time for ANC and platelet engraftment. Extra-hematological toxicities were also comparable in the two groups. These findings suggest that the hematological and extra-hematological toxicities induced by fludarabine/full-dose i.v. busulfan are similar to those induced by a standard RIC regimen such as fludarabine/melphalan.

Prolonged responses after autologous stem cell transplantation in African-American patients with multiple myeloma.

Multiple myeloma (MM) has a double incidence in African-American (AA) than in non-AA patients and previous studies have shown a higher mortality in the former patient population. Here, we retrospectively analyzed the results of autologous stem cell transplantation (ASCT) in 38 AA and 32 non-AA consecutive patients. The two groups were comparable at diagnosis for age, stage of the disease, cytogenetic abnormalities, beta(2) microglobulin and albumin blood levels, and plasma cell marrow infiltration. The rates of complete and partial response observed in AA and non-AA patients after induction chemotherapy (9 and 42 vs 13 and 33%) and at 2 months (31 and 25 vs 30 and 20%) following ASCT were similar. At 6 months after ASCT, a greater relapse rate was observed in non-AA patients (P=0.009). At a median follow-up of 26 months, AA patients had a greater event-free survival (P=0.02) than non-AA patients, whereas overall survival was comparable in the two groups. The initial finding that AA patients with MM, compared to non-AA patients, had more prolonged responses and comparable survival after ASCT suggests that intensified chemotherapy is equally effective in patients of various ethnicities.

Modulation of monocyte functions by muramyl tripeptide phosphatidylethanolamine in a phase II study in patients with metastatic melanoma.

BACKGROUND: Muramyl tripeptide phosphatidylethanolamine (MTP-PE) is a synthetic analogue of muramyl dipeptide (MDP), a component of bacterial cell walls that has potent in vitro monocyte-activating properties. We conducted a phase II clinical trial of MTP-PE in 30 patients with metastatic melanoma. PURPOSE: Our purpose was to define a clinical response rate for this agent in patients with advanced melanoma and to evaluate the agent's immunomodulatory properties. METHODS: Patients were randomly assigned to 1- or 4-mg dose levels of MTP-PE and received the drug intravenously once a week for 12-24 weeks. Immunological monitoring consisted of measurement of plasma tumor necrosis factor-alpha (TNF-alpha), neopterin, interleukin-1-beta, interleukin-6 (IL-6), and beta 2-microglobulin levels; phenotyping analysis of expression of human HLA-DR, CD-14 on mononuclear cells; and measurement of in vitro monocyte cytotoxicity against SKMel28 targets cells. RESULTS: MTP-PE was well tolerated; fever and chills were the major toxic effects. Plasma TNF-alpha levels increased 16-fold 2 hours after the first MTP-PE treatment. Increases in TNF-alpha levels after MTP-PE administration continued through week 12, but changes were of a lower magnitude after week 1. Plasma neopterin levels were significantly increased 24 hours after treatment at weeks 1, 6, and 12. A marked increase in IL-6 and a modest rise in beta 2-microglobulin levels were also seen at week 1. No significant changes from baseline IL-1 beta were observed. In the cytotoxicity assay, monocyte cytotoxic activity was significantly increased at weeks 4 and 6. Surface immuno-phenotyping revealed a consistent transient reduction in the number of circulating monocytes 2 hours after MTP-PE was administered. In addition, we observed a down-regulation (i.e., a decrease) in the expression of Leu M3 and HLA-DR on monocytes, 2 hours after MTP-PE treatment, followed by a recovery 24 hours after treatment. No objective clinical responses were seen in this advanced disease population. CONCLUSIONS: We conclude that MTP-PE has pleiotropic and potentially beneficial biologic effects and that further clinical investigations of MTP-PE are justified. IMPLICATIONS: In view of the clear immunomodulatory actions seen in our study and in earlier clinical trials, we believe that MTP-PE deserves further study in the adjuvant setting.

CD4+ T-cell immunity to mutated ras protein in pancreatic and colon cancer patients.

Mutated p21 ras proteins contain single substituted amino acid residues and represent cancer-specific proteins. The current study examined whether primed T cell immunity to mutant p21 ras proteins and/or peptides can be detected in patients with pancreatic or colon cancer. Studies focused on the aspartic acid substitution in amino acid position 12 (denoted D12) as the commonest mutation in gastrointestinal malignancy. Peripheral blood lymphocytes from patients or normal individuals were tested for the ability to proliferate in response to normal or mutated ras peptides or proteins. T-cell responses were defined as a stimulation index of > 2.0. Results showed that 7 of 16 (44%) pancreatic cancer patients responded to ras-D12 peptide. Responses to ras-D12 protein were studied in only the last four patients that responded to D12 peptides. Three of the 4 patients that responded to ras-D12 peptide showed a substantial response to p21 ras-D12 protein (stimulation indices of 12, 8, and 24). Specificity was validated by examining responses to normal and alternate ras peptides and proteins. T-cell responses to ras-D12 peptides were detected in only 2 of 25 (8%) colon cancer patients. None of 11 normal individuals tested had positive responses to normal or mutant ras p21 proteins and/or peptides. Thus, CD4+ T-cell immunity to the mutated segment of ras protein is present in some patients with gastrointestinal cancer.

Phase I evaluation of humanized OKT3: toxicity and immunomodulatory effects of hOKT3gamma4.

Murine anti-CD3 (OKT3, Muromonab-CD3) is a potent human T-lymphocyte mitogen. A previous clinical Phase I trial examined OKT3 as an immunomodulator for the treatment of cancer. However, the murine monoclonal antibody triggered a potent humoral response that neutralized the antibody activity during subsequent administration. Thus, a "humanized" form of OKT3 (hOKT3gamma4) was developed to minimize immunogenicity. The genetically engineered human anti-CD3 retained its binding activity and effectively activated T cells in vitro. Therefore, we evaluated the safety and activity of hOKT3gamma4 in a Phase I clinical trial. hOKT3gamma4 was administered as a 10-min i.v. infusion every 2 weeks for three injections (one course of therapy). Six dose levels ranging from 50 to 1600 microg/injection were evaluated. Headache and fever were common, transient toxicities but were not dose limiting. The dose-limiting toxicities were rigors and dyspnea at the 1600-microg dose level, which defined 800 microg as the maximally tolerated dose in this trial. A dose-dependent in vivo T-lymphocyte activation was produced by this treatment, and the most significant T-lymphocyte activation occurred in patients treated at the two highest dose levels (800 and 1600 microg). Persistent CD3 modulation occurred after administration of 1600 microg of hOKT3gamma4. Anti-idiotypic antibodies were detected in only 6 of 24 patients after multiple injections and were not associated with attenuation of T-lymphocyte activation. Malignant ascites resolved in three patients, one each with peritoneal mesothelioma, pancreatic adenocarcinoma, and ovarian adenocarcinoma. hOKT3gamma4 can induce T-lymphocyte activation in patients with cancer, and the immunogenicity of the "humanized" antibody is sufficiently reduced relative to its murine "parent" to permit immunostimulation by repetitive i.v. administration. The therapeutic potential of biweekly i.v. hOKT3gamma4 at a dose of 800 microg should be further evaluated.

Monoclonal antibody therapy of murine lymphoma: enhanced efficacy by concurrent administration of interleukin 2 or lymphokine-activated killer cells.

Lymphokine-activated killer (LAK) cells have recently been shown to be very efficient effector cells for antibody-dependent cellular cytotoxicity. Thus, we explored, in a murine lymphoma model, administration of LAK-inducing doses of interleukin 2 (IL-2) or adoptive transfer of LAK cells as a means of enhancing therapy with tumor-specific monoclonal antibody (mAb). AKR/Cum (Thy-1.2+) hosts were inoculated on day 1 s.c. with the SL-2 thymoma of AKR/J origin (Thy-1.1+) and developed palpable tumor on day 4. Tumor-specific anti-Thy-1.1 IgG2a mAb, 1A14, was given on days 4 and 8 with 50,000 units/day IL-2 i.p. divided in two doses on days 4-12. Therapy with IL-2 or mAb alone had minimal activity, prolonging control median survival of 22 days to 25 and 29 days, respectively, whereas therapy with IL-2 plus mAb significantly prolonged median survival to 40 days. However, combined therapy did not result in cures and long term survival. The efficacy of combined therapy did not result from alterations in the biodistribution of mAb by concurrent IL-2 infusions, as determined by studies with radiolabeled mAb. The combined effect of in vitro generated LAK (10(8) cells) adoptively transferred i.v. with 1A14 on days 4 and 8 following SL-2 inoculation was also evaluated. This regimen had no detectable toxicity, and treatment of mice with LAK and mAb resulted in 60% long term survival compared with 17% or 0% for mice treated with mAb or LAK alone. Thus, the therapeutic effects of tumor-specific mAb was enhanced by in vivo administration of IL-2 or by adoptively transferred LAK, which may represent means to provide the host with increased antibody-dependent cellular cytotoxicity effector cells. Adoptively transferred LAK has the additional benefit of augmenting mAb therapy of tumor without the toxicity associated with the induction of such cells in vivo with high dose IL-2.

High-dose chemotherapy with autologous transplantation for persistent/relapsed ovarian cancer: a multivariate analysis of survival for 100 consecutively treated patients.

PURPOSE: To examine the prognostic factors associated with prolonged progression-free survival (PFS) and overall survival (OS) in 100 consecutively treated women undergoing autologous stem-cell transplant for advanced ovarian cancer. PATIENTS AND METHODS: From October 1989 to February 1996, we transplanted 100 patients with ovarian cancer following chemotherapy with high-dose carboplatin, mitoxantrone, and cyclophosphamide with or without cyclosporine (n = 70); melphalan and mitoxantrone with or without paclitaxel (n = 25); or other regimens (n = 5). Their median age was 48 years (range, 23 to 65), 70% had papillary serous histology, 72% had grade III tumors, 66% were platinum-resistant, and 61% had > or = 1 cm bulk. The median number of prior regimens was two (range, one to six). Univariate and multivariate analyses were performed to examine age (< v > or = mean), stage, initial bulk, histology, grade, response to initial therapy, number of prior regimens, time from diagnosis to transplant, transplant regimen, platinum sensitivity, and bulk (< v > or = 1 cm) at transplant. RESULTS: The median PFS and OS times for the 100 patients were 7 and 13 months. A stepwise Cox proportional hazards model identified tumor bulk (P = .0001), and cisplatin sensitivity (P = .0249) as the best predictors of PFS. Age (P = .0017), bulk at transplant (P = .0175), and platinum sensitivity (P = .0330) provided the best prediction of OS. The median PFS and OS times for the 20 patients with platinum-sensitive, < or = 1-cm disease were 19 and 30 months. No differences in OS were seen when chemotherapy or surgery was used to achieve a minimal disease state. CONCLUSION: Before consideration of high-dose therapy for recurrent/persistent advanced ovarian cancer, patients should undergo debulking surgery or chemotherapy to achieve a minimal disease state. Patients with platinum-resistant, bulky disease should not be transplanted. The optimal patients for this therapy may be those with minimal disease responsive to initial chemotherapy.

Pilot trial of interleukin-2 with granulocyte colony-stimulating factor for the mobilization of progenitor cells in advanced breast cancer patients undergoing high-dose chemotherapy: expansion of immune effectors within the stem-cell graft and post-stem-cell infusion.

PURPOSE: To evaluate whether administration of interleukin-2 (IL-2) with granulocyte colony-stimulating factor (G-CSF) improves mobilization of immune effector cells into the stem-cell graft of patients undergoing high-dose chemotherapy and autografting. PATIENTS AND METHODS: We performed a trial of stem-cell mobilization with IL-2 and G-CSF in advanced breast cancer patients receiving high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin and stem cells followed by IL-2. The trial defined immune, hematologic, and clinical effects of IL-2 in this setting. RESULTS: Of 32 patients enrolled, nine received G-CSF alone for mobilization. Twenty-one of 23 patients mobilized with IL-2 plus G-CSF had stem cells collected with more mononuclear cells than those receiving G-CSF (19.3 v 10.4 x 10(8)/kg; P =.006), but fewer CD34(+) progenitor cells (6.9 v 22.0 x 10(6)/kg; P =.049). The IL-2 plus G-CSF-mobilized patients had greater numbers of activated T (CD3(+)/CD25(+)) cells (P =.009), natural killer (NK; CD56(+)) cells (P =.007), and activated NK (CD56 bright(+)) cells (P: =.039) than those patients mobilized with G-CSF. NK (P =.042) and lymphokine-activated killer (LAK) (P =.016) activity was increased in those mobilized with IL-2 + G-CSF, whereas G-CSF-mobilized patients had a decline in cytolytic activity. In the third week posttransplantation, immune reconstitution was superior in those mobilized with IL-2 plus G-CSF based on greater numbers of activated T cells (P =.003), activated NK cells (P =.04), and greater LAK activity (P =.003). The 16 of 21 IL-2 + G-CSF-mobilized patients with adequate numbers of stem cells (> 1.5 x 10(6) CD34(+) cells/kg) collected engrafted rapidly posttransplantation. CONCLUSION: The results demonstrate that G-CSF + IL-2 can enhance the number and function of antitumor effector cells in a mobilized autograft without impairing the hematologic engraftment, provided that CD34 cell counts are more than 1.5 x 10(6) cells/kg. Mobilization of CD34(+) stem cells does seem to be adversely affected. In those mobilized with IL-2 and G-CSF, post-stem-cell immune reconstitution of antitumor immune effector cells was enhanced.

High-dose chemotherapy combined with escalating doses of cyclosporin A and an autologous bone marrow transplant for the treatment of drug-resistant solid tumors: a phase I clinical trial.

High response rates are seen in patients undergoing dose-intensive chemotherapy and autologous marrow transplantation due to the ability of the therapy to overcome inherent or acquired drug resistance. However, relapse rates are also high because this drug resistance reversal is incomplete. Because both P-glycoprotein- and platinum-induced resistance appear to be clinically important and can be reversed in vitro with a short exposure of cyclosporin A (CSA) at 2000 and 5000 ng/ml, respectively, we undertook a trial of high-dose chemotherapy with carboplatin (1500mg/m2), mitoxantrone (75 mg/m2), and cyclophosphamide (120 mg/kg) over a 5-day period combined with escalating doses of CSA. Thirty-seven patients with primarily breast cancer (61% doxorubicin resistant) and ovarian cancer (85% platinum resistant) were treated with CSA given as a bolus 18 h prior to chemotherapy, followed by a 5-day infusion at doses of 5.0-28.2 mg/kg/day and the chemotherapy. The maximum tolerated dose of CSA was a bolus of 5.5 mg/kg and an infusion of 15. 9 mg/kg/day, which gave a mean serum CSA level of 1544 ng/ml. The dose-limiting toxicity was severe mucositis and enteritis, leading to infectious complications. Nephrotoxicity was seen in 42% and, while usually mild and reversible, was fatal in two patients with pretreatment creatinine clearances h80 ml/min. Grade III-IV isolated hyperbilirubinemia was seen in 39%, but appeared to be of no clinical significance. The overall response rate for the 26 patients with measurable/evaluable disease was 73% and 63% for those with doxorubicin- or platinum-resistant disease. The median overall survival and progression-free survival for the group were 18.1 and 8. 0 months. The overall survival for the nine patients with doxorubicin-resistant breast cancer was 19.3 months. Although we did not achieve CSA levels needed to reverse platinum resistance in vivo, levels approaching those needed to reverse P-glycoprotein resistance were reached at the maximum tolerated dose. The strategy of combining dose intensity with drug resistance reversal deserves further study, especially with the advent of potentially less toxic agents available to reverse P-glycoprotein-mediated resistance.

Depressed in vivo myocardial reactivity to dobutamine in streptozotocin diabetic rats: influence of exercise training.

To assess the effects of chronic diabetes on in vivo myocardial reactivity to beta 1 adrenergic receptor stimulation and to evaluate the therapeutic effect of exercise training in preventing the cardiac abnormalities induced by diabetes four groups of rats were studied: sedentary control, trained control, sedentary diabetic, and trained diabetic. Trained rats were adapted to treadmill running before the induction of diabetes with streptozotocin 55 mg.kg-1 iv. The duration, speed, and grade of exercise were then progressively increased during eight weeks of training until the rats could run for 90 min at 18 m/min, 5% grade. A training effect was confirmed by an increase in plantaris muscle cytochrome oxidase activity. In vivo cardiac contractile performance was assessed by intracardiac catheterisation. Heart rate, left intraventricular peak systolic pressure, and positive and negative dP/dt were measured under basal conditions and after the intravenous administration of dobutamine 10(-10) to 5 x 10(-7) mol.kg-1 body weight. Under basal conditions, there were no differences among the four groups in left intraventricular peak systolic pressure, positive dP/dt, and heart rate, but negative dP/dt was lower in both diabetic groups. The response to dobutamine of the sedentary diabetic group, as reflected in the measured cardiodynamic variables, was significantly attenuated compared with that of the sedentary control group. Exercise training tended to improve cardiac function towards the level detected in the sedentary controls; however, the differences between sedentary and trained diabetic groups were not statistically significant. Exercise training also did not significantly alter the response of the control group to dobutamine.(ABSTRACT TRUNCATED AT 250 WORDS)