Biomedical subjects

James Garvin

Publications and source records attributed to James Garvin.

6 recordsLinked to original sources

PubMed2006

Androgen and c-Kit receptors in desmoplastic small round cell tumors resistant to chemotherapy: novel targets for therapy.

PURPOSE: Desmoplastic small round cell tumor (DSRCT) is a highly fatal, mainly peritoneal cell origin cancer which predominantly affects young adult males. This predilection in young males led us to examine the role of androgen receptors (AR), testosterone, and growth factors in the biology of DSRCT. METHODS: Slides were prepared from 27 multi-institutional patients all with end-stage DSRCT. Slides were stained for AR, c-Kit, various growth factors, and drug resistance-associated proteins. Immunohistochemical (IHC) expression was scored semi-quantitatively. Western blot and MTT studies were performed to validate the IHC findings of over-expression of the AR and its functional status by stimulation of growth by dihydrotestosterone, respectively. Six patients with positive AR status were treated solely with combined androgen blockade (CAB) as used for prostate cancer. RESULTS: Twenty-two patients were male (81%) and five were female (19%) with a median age at diagnosis of 23. All patients had failed at least two prior multi-agent chemotherapy regimens and 44% had progressed after autologous stem cell transplant. DSRCT samples from 10 of 27 patients were >or=2+ IHC positive for AR (37%,P=0.0045) and 7 of 20 patients were >or=2+ IHC positive for c-Kit (35%, P=0.018). We found elevated IHC expression of GST-pi, MRP and thymidylate synthase in smaller subsets of patients. In vitro studies for AR by Western blot and stimulation of growth by dihydrotestosterone in MTT assays suggest that the AR in DSRCT cells is functional. Six patients with positive AR status were treated with CAB alone and three of six attained clinical benefit (1-PR, 1-MR, 1-SD) in a range of 3-4 months. The three patients who responded to CAB had normal testosterone levels before CAB, while the three who did not respond to CAB had baseline castrate levels of testosterone. CONCLUSIONS: DSRCT has significant IHC expression of AR and c-Kit in heavily pre-treated patients. The presence of significant AR expression in 37% suggests that these patients could possibly respond to CAB. The significance of c-Kit expression in 35% of DSRCT patients is unknown and warrants further investigation.

Adolescent↗

PubMed2006

A low incidence of nontuberculous mycobacterial infections in pediatric hematopoietic stem cell transplantation recipients.

Hematopoietic stem cell transplantation (HSCT) is being used to treat a wide spectrum of clinical disorders but opportunistic infection remains an important factor determining outcomes for these patients. Nontuberculous mycobacterial (NTM) infections are being reported more frequently in HSCT recipients and the incidence of NTM infections in adult recipients is reported to be 0.4%-4.9%. However, the incidence and severity of NTM infections are less well described in pediatric HSCT recipients. Centers for Disease Control and Prevention guidelines were used to define definite and probable NTM infection among 132 children undergoing 169 HSCT between January 2000 and December 2004 at our institution. NTM infection was diagnosed in 5 of 132 pediatric recipients (3.8%). There were no NTM infections diagnosed in the autologous HSCT recipients and the incidence of NTM in allogeneic HSCT recipients was 6.4% (95% confidence interval, 0.8-11.9). The mean age of the HSCT recipients who developed NTM infections was 8 years (range, 2-19 years); 3 were male and 2 were female. Four conditioning regimens included alemtuzumab and 3 had antithymocyte globulin. Of the 5 patients with NTM infections, 2 met the criteria for definite infection and 3 for probable infection. Of the 2 patients with definite NTM infection, 1 had disseminated disease with Mycobacterium avium complex and the other had Mycobacterium chelonae catheter-related bloodstream infection. The probable NTM infections were 1 skin infection with Mycobacterium kansasii and 2 lower respiratory tract infections with M avium complex. Median time to NTM infection was 115 days (range, 14-269 days) after HSCT. Two patients had graft-versus-host disease at the time of NTM infection. All 5 patients received 3-4 antimycobacterial drugs and all NTM infections resolved. In summary, the incidence of NTM infection in pediatric HSCT recipients appears similar to that described in adult HSCT recipients and the outcome appears to be excellent with the proper antibiotic therapy. The increased use of anti-T cell antibodies appears to be associated with an increased risk of NTM infections in pediatric HSCT recipients. Multicenter studies are needed to identify the risk factors, early diagnostic criteria, and optimal therapy.

Adolescent↗

PubMed2005

Preliminary results of the safety of immunotherapy with gemtuzumab ozogamicin following reduced intensity allogeneic stem cell transplant in children with CD33+ acute myeloid leukemia.

PURPOSE: Myeloablative allogeneic stem cell transplantation (SCT) has been successful in the treatment of childhood acute myeloid leukemia (AML), but may be associated with significant toxicity and recurrent disease. Reduced-intensity allogeneic SCT may offer a less toxic approach to patients with AML. Targeted immunotherapy with gemtuzumab ozogamicin has been shown to be safe, well tolerated in children, and, as a single agent, gemtuzumab ozogamicin has induced responses in 30% of patients with recurrent CD33+ AML. There are no safety data with gemtuzumab ozogamicin post allogeneic SCT in children. Therefore, we explored the feasibility and toxicity of targeted immunotherapy following reduced-intensity allogeneic SCT in children with CD33+ AML. EXPERIMENTAL DESIGN: Eight patients with CD33+ AML received a reduced-intensity allogeneic SCT following fludarabine 30 mg/m2 for 6 days and busulfan 3.2 mg/kg (<4 years, 4 mg/kg/d) for 2 days. Donor sources included six 6/6 HLA-matched related peripheral blood stem cells, one 6/6 sibling cord blood, and one 4/6 unrelated cord blood. RESULTS: Day 30 and day 60 donor chimerisms in seven of eight evaluable patients were 96 +/- 2% (n = 7) and 94 +/- 3% (n = 6), respectively. Five of six patients (too early for one patient) received two doses of gemtuzumab ozogamicin and one patient received only one dose. After each dose, all patients developed grade 4 neutropenia, with recovery on median days 16 and 13, respectively, after dose 1 and dose 2. Grade 4 thrombocytopenia was only observed in 2 of 11 gemtuzumab ozogamicin courses. No patients have developed dose-limiting toxicity secondary to gemtuzumab ozogamicin. CONCLUSIONS: The administration of gemtuzumab ozogamicin post reduced-intensity allogeneic SCT in children with average risk AML is feasible and well tolerated with minimal toxicity. The maximal tolerated dose has yet to be determined for gemtuzumab ozogamicin post reduced-intensity allogeneic SCT in children with CD33+ AML. Additional studies in a larger group of patients will be required to adequately assess the safety of this approach.

Adolescent↗

PubMed2005

Recurrent central nervous system medulloepithelioma: response and outcome following marrow-ablative chemotherapy with stem cell rescue.

Medulloepithelioma is a rare primitive neuroectodermal tumor of the central nervous system usually developing in childhood, displaying highly malignant behavior, with early progression or recurrence. Once a recurrence develops, death reportedly follows with invariable rapidity. The purpose of this study was to evaluate the efficacy of high-dose, marrow-ablative chemotherapy with autologous hemopoietic stem cell rescue in the treatment of recurrent central nervous system medulloepithelioma. Three young children with recurrent central nervous system medulloepithelioma received high-dose marrow-ablative chemotherapy with thiotepa and etoposide either alone (one patient) or with the addition of carboplatin (two patients). This was followed by irradiation only in one patient. One child with residual radiographic tumor at the time of treatment could be evaluated for response and showed complete resolution of leptomeningeal disease after receiving marrow-ablative chemotherapy. Two children developed tumor recurrence at 2.0 and 5.5 months after receiving marrow-ablative chemotherapy. The third child continues free of tumor beyond 12 years from treatment. The authors' experience with marrow-ablative chemotherapy and autologous hemopoietic stem cell rescue suggests that this treatment strategy might be beneficially incorporated into the initial treatment approach for young children with medulloepithelioma.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2004

A pilot study of tacrolimus and mycophenolate mofetil graft-versus-host disease prophylaxis in childhood and adolescent allogeneic stem cell transplant recipients.

Tacrolimus (FK506)/mycophenolate mofetil (MMF) has been demonstrated to be an effective salvage therapy for steroid-resistant chronic graft-versus-host disease (GVHD), but its effectiveness as prophylaxis for acute GVHD (aGVHD) is unknown. We investigated the safety and efficacy of FK506/MMF in preventing aGVHD and sparing the use of methotrexate and methylprednisolone in childhood and adolescent allogeneic stem cell transplant (AlloSCT) recipients. Thirty-four childhood and adolescent patients (median age, 7 years; range, 0.5-21 years; 24 males and 10 females) undergoing 37 AlloSCTs for malignant (n = 22) and nonmalignant (n = 12) disorders received FK506 (0.03 mg/kg/d by continuous intravenous infusion) and MMF (15 mg/kg per dose orally or intravenously twice daily). Stem cell sources included 22 umbilical cord blood donors (21 unrelated and 1 related), 6 related bone marrow donors, and 9 related peripheral blood donors. Malignant diagnoses included 7 acute lymphoblastic leukemias, 3 acute myeloid leukemias, 1 acute promyelocytic leukemia, 2 non-Hodgkin lymphomas, 4 Hodgkin diseases, 3 chronic myeloid leukemias, and 2 neuroblastomas; nonmalignant diagnoses included 2 beta-thalassemias, 1 sickle cell disease, 4 aplastic anemias, 1 Wiskott-Aldrich syndrome, 1 Hurler syndrome, 2 hemophagocytic lymphohistiocytoses, and 1 myelodysplastic syndrome. The probability of developing grade > or =II aGVHD was 45.4% +/- 9.7% (7 related bone marrow/related peripheral blood; 5 umbilical cord blood), and for chronic GVHD it was 38.1% +/- 19.7%. FK506/MMF was well tolerated. Three patients had grade III to IV neurotoxicity (disorientation and leukoencephalopathy); 4 patients developed grade III to IV nephrotoxicity (all received concomitant nephrotoxins). Patients who achieved target mycophenolic acid levels (1.0-3.5 microg/mL) before day +30 had a significantly reduced incidence of developing grade >/=II aGVHD (16.7% +/- 15.2% versus 100%; P <.02). These results suggest that FK506/MMF is well tolerated and may be a safe and effective methotrexate- and methylprednisolone-sparing alternative GVHD prophylaxis regimen after AlloSCT. Further pharmacokinetic and pharmacodynamic studies are ongoing in pediatric and adolescent AlloSCT recipients to define optimal MMF dosing.

Adolescent↗

PubMed2003

Foamy podocytes.

Explore the source record for details and available documents.

Diagnosis, Differential↗