Phase II study of everolimus-erlotinib in previously treated patients with advanced non-small-cell lung cancer.

BACKGROUND: Preclinical data suggest combining a mammalian target of rapamycin inhibitor with erlotinib could provide synergistic antitumor effects in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: In this multicenter, open-label, phase II study, patients with advanced NSCLC that progressed after one to two previous chemotherapy regimens were randomized 1:1 to erlotinib 150 mg/day±everolimus 5 mg/day. Primary end point was the disease control rate (DCR) at 3 months; secondary end points included progression-free survival (PFS) and safety. RESULTS: One hundred thirty-three patients received everolimus-erlotinib (n=66) or erlotinib alone (n=67). The DCR at 3 months was 39.4% and 28.4%, respectively. The probability for the difference in disease control at 3 months to be ≥15% was estimated to be 29.8%, which was below the prespecified probability threshold of ≥40%. Median PFS was 2.9 and 2.0 months, respectively. Grade 3/4 adverse events occurred in 72.7% and 32.3% of patients, respectively. Grade 3/4 stomatitis was observed in 31.8% of combination therapy recipients. CONCLUSIONS: Everolimus 5 mg/day plus erlotinib 150 mg/day was not considered sufficiently efficacious per the predefined study criteria. The combination does not warrant further investigation based on increased toxicity and the lack of substantial improvement in disease stabilization.

A retrospective cohort study of the anesthetic management of postpartum tubal ligation.

BACKGROUND: Neuraxial anesthesia with reactivation of a labor epidural catheter is commonly utilized for postpartum tubal ligations (PPTL), although the optimal anesthetic approach is unknown. We assessed institutional anesthesia practices for PPTL, and evaluated the failure rates of reactivation of labor epidural catheters, de novo spinal anesthesia, and spinal anesthesia after failed blocks. METHODS: We conducted a single-center retrospective cohort analysis of 300 consecutive patients who underwent a PPTL and 100 having spinal anesthesia for cesarean delivery. Anesthetic management data (existing labor epidural catheter reactivation, de novo spinal anesthesia or general anesthesia) were collected from electronic medical records. Anesthetic block failure rates were determined for each anesthetic technique. RESULTS: The failure rate was 15% for de novo spinal anesthesia and 23% after failed reactivation of a labor epidural catheter or spinal anesthesia. The epidural catheter reactivation failure rate was 35%. The failure rate of spinal anesthesia for cesarean delivery was 4%. Drug dosage, epidural catheter use in labor, time since epidural catheter placement or delivery, labor neuraxial technique (combined spinal-epidural, epidural), supplemental top-up doses during labor, and anesthesiologist experience did not predict neuraxial anesthesia failures. CONCLUSIONS: Our analysis revealed an unexpectedly high neuraxial anesthesia failure rate even when de novo spinal anesthesia was used for PPTL. The results are consistent with other institutions' recent findings, and are higher than spinal anesthesia failure rates associated with cesarean delivery. Further studies are required to determine optimal anesthesia dosing strategies, and to understand the mechanisms behind high neuraxial anesthesia failures for PPTL.

An analysis of emerging food safety and fraud risks of novel insect proteins within complex supply chains.

Food consumption play a crucial role in human life, yet conventional food production and consumption patterns can be detrimental to the environment. Thus, research and development has been directed towards alternative proteins, with edible insects being promising sources. Edible insects have been recognised for their sustainable benefits providing protein, with less emission of greenhouse gas, land and water usage compared to sources, such as beef, chicken, and dairy products. Among the over 2000 known edible insect species, only four, namely yellow mealworm (Tenebrio molitor), migratory locust/grasshopper (Locusta migratoria), grain mould beetle, also known as lesser mealworm which is a larval form of Alphitobius diaperinus (from the family of Tenebrionidae of darkling beetles) and house cricket (Acheta domesticus), are currently authorised in specific products through specific producers in the EU. The expansion of such foods into Western diets face challenges such as consumer barriers, gaps in microbiological and chemical safety hazard data during production and processing, and the potential for fraudulent supply chain activity. The main aim of this study was to map the supply chain, through interviews with personnel along the supply chain, coupled with searches for relevant publications and governmental documents. Thus, the main potential points of food safety and fraud along the edible insect supply chain were identified. Feed substrate was identified as the main area of concern regarding microbiological and chemical food safety and novel processing techniques were forecast to be of most concern for future fraudulent activity. Despite the on-going authorisation of insect species in many countries there are substantial food safety and authenticity information gaps in this industry that need to be addressed before edible insects can be viewed as a safe and sustainable protein sources by Western consumers.

A survey of United States obstetric anesthesiologists' perceived value of obstetric anesthesiology fellowship.

INTRODUCTION: Subspecialty training in obstetric anesthesiology is associated with improved patient outcomes and reduced anesthesia-related morbidity and mortality. Despite this, the demand for fellowship-trained obstetric anesthesiologists far exceeds the supply. This survey study aimed to evaluate the perceived value of obstetric anesthesiology subspecialty training on career trajectory, job satisfaction, quality of life, and job autonomy. METHODS: After Institutional Review Board approval, we conducted a cross-sectional study of fellowship-trained obstetric anesthesiologists in the United States of America. In March and April 2022, program directors of obstetric anesthesiology fellowships distributed an electronic survey link containing 29 multiple-choice questions to their program alumni. Survey content included respondent demographic characteristics, practice models, career information, and perceived value of an obstetric anesthesiology fellowship. RESULTS: We surveyed 217/502 (43%) fellowship-trained obstetric anesthesiologists with a response rate of 158/217 (73%). Most worked in urban, academic, and level IV perinatal health centers. The majority believed an obstetric anesthesiology fellowship was "extremely beneficial" (77%), enhanced quality of life (84%), improved the quality of patient care (99%), and was influential in helping obtain their first post-training job (86%). The perceived value of the fellowship included an enhanced career trajectory, a sense of purpose, improved job satisfaction, a sense of work community, lower burnout, involvement in maternal health initiatives, increased mentorship, and departmental leadership. CONCLUSION: In this survey study, fellowship-trained obstetric anesthesiologists perceived a positive impact of fellowship training on career trajectory, job protection and autonomy, quality of life, and job satisfaction. This information may be meaningful to trainees considering pursuing a fellowship and a career in obstetric anesthesiology.

A phase I, open-label dose-escalation study of continuous treatment with BIBF 1120 in combination with paclitaxel and carboplatin as first-line treatment in patients with advanced non-small-cell lung cancer.

BACKGROUND: BIBF 1120 is an oral potent inhibitor of vascular endothelial growth factor receptor, fibroblast growth factor receptor and platelet-derived growth factor receptor, the three key receptor families involved in angiogenesis. This phase I, open-label dose-escalation study investigated BIBF 1120 combined with paclitaxel (Taxol) and carboplatin in first-line patients with advanced (IIIB/IV) non-small-cell lung cancer. PATIENTS AND METHODS: Patients received BIBF 1120 (starting dose 50 mg b.i.d.) on days 2-21 and paclitaxel (200 mg/m2) and carboplatin [area under curve (AUC)=6 mg/ml/min] on day 1 of each 21-day cycle. Primary end points were safety and BIBF 1120 maximum tolerated dose (MTD) in this combination. Pharmacokinetics (PK) profiles were evaluated. RESULTS: Twenty-six patients were treated (BIBF 1120 50-250 mg b.i.d.). BIBF 1120 MTD was 200 mg b.i.d. in combination with paclitaxel and carboplatin. Six dose-limiting toxicity events occurred during treatment cycle 1 (liver enzyme elevations, thrombocytopenia, abdominal pain, and rash). Best responses included 7 confirmed partial responses (26.9%); 10 patients had stable disease. BIBF 1120 200 mg b.i.d. had no clinically relevant influence on the PK of paclitaxel 200 mg/m2 and carboplatin AUC 6 mg/ml/min and vice versa. CONCLUSIONS: BIBF 1120 MTD was 200 mg b.i.d when given with paclitaxel and carboplatin; this combination demonstrated an acceptable safety profile. No relevant changes in PK parameters of the backbone chemotherapeutic agents or BIBF 1120 were observed.

Dose escalated, hypofractionated radiotherapy using helical tomotherapy for inoperable non-small cell lung cancer: preliminary results of a risk-stratified phase I dose escalation study.

To improve local control for inoperable non-small cell lung cancer (NSCLC), a phase I dose escalation study for locally advanced and medically inoperable patients was devised to escalate tumor dose while limiting the dose to organs at risk including the esophagus, spinal cord, and residual lung. Helical tomotherapy provided image-guided IMRT, delivered in a 5-week hypofractionated schedule to minimize the effect of accelerated repopulation. Forty-six patients judged not to be surgical candidates with Stage I-IV NSCLC were treated. Concurrent chemotherapy was not allowed. Radiotherapy was delivered via helical tomotherapy and limited to the primary site and clinically proven or suspicious nodal regions without elective nodal irradiation. Patients were placed in 1 of 5 dose bins, all treated for 25 fractions, with dose per fraction ranging from 2.28 to 3.22 Gy. The bin doses of 57 to 80.5 Gy result in 2 Gy/fraction normalized tissue dose (NTD) equivalents of 60 to 100 Gy. In each bin, the starting dose was determined by the relative normalized tissue mean dose modeled to cause < 20% Grade 2 pneumonitis. Dose constraints included spinal cord maximum NTD of 50 Gy, esophageal maximum NTD < 64 Gy to < or = 0.5 cc volume, and esophageal effective volume of 30%. No grade 3 RTOG acute pneumonitis (NCI-CTC v.3) or esophageal toxicities (CTCAE v.3.0 and RTOG) were observed at median follow-up of 8.1 months. Pneumonitis rates were 70% grade 1 and 13% grade 2. Multivariate analysis identified lung NTD(mean) (p=0.012) and administration of adjuvant chemotherapy following radiotherapy (p=0.015) to be independent risk factors for grade 2 pneumonitis. Only seven patients (15%) required narcotic analgesics (RTOG grade 2 toxicity) for esophagitis, with only 2.3% average weight loss during treatment. Best in-field gross response rates were 17% complete response, 43% partial response, 26% stable disease, and 6.5% in-field thoracic progression. The out-of-field thoracic failure rate was 13%, and distal failure rate was 28%. The median survival was 18 months with 2-year overall survival of 46.8% +/- 9.7% for this cohort, 50% of whom were stage IIIB and 30% stage IIIA. Dose escalation can be safely achieved in NSCLC with lower than expected rates of pneumonitis and esophagitis using hypofractionated image-guided IMRT. The maximum tolerated dose has yet to be reached.

Autologous hematopoietic stem cell transplantation in systemic lupus erythematosus patients with cardiac dysfunction: feasibility and reversibility of ventricular and valvular dysfunction with transplant-induced remission.

Patients with cardiac dysfunction may be at increased risk of cardiac toxicity when undergoing hematopoietic stem cell transplantation (HSCT), which may preclude them from receiving this therapy. Cardiac dysfunction is, however, common in systemic lupus erythematosus (SLE) patients. While autologous HSCT (auto-HSCT) has been performed increasingly for SLE, its impact on cardiac function has not previously been evaluated. We, therefore, performed a retrospective analysis of SLE patients who had undergone auto-HSCT in our center to determine the prevalence of significant cardiac involvement, and the impact of transplantation on this. The records of 55 patients were reviewed, of which 13 were found to have abnormal cardiac findings on pre-transplant two-dimensional echocardiography or multi-gated acquisition scan: impaired left ventricular ejection fraction (LVEF) (n = 6), pulmonary hypertension (n = 5), mitral valve dysfunction (n = 3) and large pericardial effusion (n = 1). At a median follow-up of 24 months (8-105 months), there were no transplant-related or cardiac deaths. With transplant-induced disease remission, all patients with impaired LVEF remained stable or improved; while three with symptomatic mitral valve disease similarly improved. Elevated pulmonary pressures paralleled activity of underlying lupus. These data suggest that auto-HSCT is feasible in selected patients with lupus-related cardiac dysfunction, and with control of disease activity, may improve.

Mobilization, harvesting and selection of peripheral blood stem cells in patients with autoimmune diseases undergoing autologous hematopoietic stem cell transplantation.

Peripheral blood stem cells (PBSC) were mobilized in 130 patients with autoimmune diseases undergoing autologous hematopoietic stem cell transplantation using cyclophosphamide 2 g/m(2) and either granulocyte colony-stimulating factor (G-CSF) 5 mcg/kg/day (for systemic lupus erythematosus (SLE) and secondary progressive multiple sclerosis, SPMS) or G-CSF 10 mcg/kg/day (for relapsing remitting multiple sclerosis (RRMS), Crohn's disease (CD), systemic sclerosis (SSc), and other immune-mediated disorders). Mobilization-related mortality was 0.8% (one of 130) secondary to infection. Circulating peripheral blood (PB) CD34(+) cells/microl differed significantly by disease. Collected CD34(+) cells/kg/apheresis and overall collection efficiency was significantly better using Spectra apheresis device compared to the Fenwall CS3000 instrument. Patients with SLE and RRMS achieved the lowest and the highest CD34(+) cell yields, respectively. Ex vivo CD34(+) cell selection employing Isolex 300iv2.5 apparatus was significantly more efficient compared to CEPRATE CS device. Circulating PB CD34(+) cells/microl correlated positively with initial CD34(+) cells/kg/apheresis and enriched product CD34(+) cells/kg. Mean WBC and platelet engraftment (ANC>0.5 x 10(9)/l and platelet count >20 x 10(9)/l) occurred on days 9 and 11, respectively. Infused CD34(+) cell/kg dose showed significant direct correlation with faster white blood cell (WBC) and platelet engraftment. When adjusted for CD34(+) cell/kg dose, patients treated with a myeloablative regimen had significantly slower WBC and platelet recovery compared to non-myeloablative regimens.

Cyclic adenosine-3',5'-monophosphate-mediated cytotoxicity in steroid sensitive and resistant myeloma.

Multiple myeloma is a neoplastic proliferation of plasma cells. Glucocorticoids are among the most effective agents against multiple myeloma, acting through the glucocorticoid receptor to induce programmed cell death. However, some patients do not respond to glucocorticoids, and those that do respond eventually develop resistance to this therapy. Alternative strategies using drugs that mediate cytotoxicity through complementary pathways have theoretical appeal. Cyclic adenosine-3',5'-monophosphate (cAMP) derivatives are cytotoxic to a number of cell lines of lymphocytic origin. cAMP analogues activate protein kinase A, affecting cell growth and differentiation. The cascade of events initiated by cAMP derivatives and glucocorticoid, although distinct, may share some distal molecular targets. We have found that pharmacological concentrations of 8-chloro-cAMP, dibutyryl-cAMP, and 8-bromo-cAMP are cytotoxic to multiple myeloma cells, enhance glucocorticoid effects, and can kill glucocorticoid-resistant clones. cAMP analogues induce apoptosis as demonstrated by the fragmentation of myeloma DNA chromatin in a distinctive ladder pattern. In contrast to glucocorticoids, cAMP growth inhibition cannot be reversed by exogenous interleukin 6. cAMP derivatives have activity against multiple myeloma and are appropriate candidates for clinical trials.

The kinetics of secretion from permeabilized human neutrophils: release of elastase and correlations with other granule constituents and right angle light scatter.

We have previously reported that human neutrophils can be permeabilized with the cholesterol-complexing agent digitonin. These permeabilized cells can be induced to secrete lysosomal constituents when exposed to micromolar levels of free Ca2+, a process that is enhanced by certain guanine nucleotides. We examined the kinetics in this system by employing both direct and indirect measures of secretion. A continuous, fluorescent assay of elastase permits real-time monitoring of secretion from azurophil granules. The kinetics of elastase release proved to be rapid, beginning within 3-10 sec and reaching a maximum at 1-2 min. Changes in the Ca2+ concentration did not affect the "lag period" for release. A comparison of the Ca2+ dose-response curves for release of the various granule constituents indicated that elastase was being secreted along with other contents of the azurophil granules. Changes in right angle light scatter (RLS), which have been shown to correlate closely with secretion, also commenced rapidly after the addition of Ca2+; when measured simultaneously, both the Ca2+ dose-response characteristics for changes in RLS and elastase release were very similar. Changes in RLS could be halted within 5 sec by excess EGTA and restarted promptly by repletion with secretory concentrations of Ca2+. In addition, neomycin, a phospholipase C inhibitor, profoundly diminished degranulation as monitored by RLS and end-point techniques. A continuous assay employing 9-aminoacridine self-quenching as a measure of secretion proved far less satisfactory, but, nonetheless, produced similar kinetics and dose-response characteristics.(ABSTRACT TRUNCATED AT 250 WORDS)

Transient catecholamine modulation of neutrophil activation: kinetic and intracellular aspects of isoproterenol action.

Modulation of neutrophil activation by catecholamines may reflect regulatory mechanisms that couple beta-adrenergic and N-formyl peptide receptors to antagonistic biochemical pathways. We examined kinetic and mechanistic aspects of the inhibition by catecholamines of neutrophil activation by formyl peptides. Inhibition of oxidant production by isoproterenol (ISO) was detected as low as 3 nM, had an ID50 of 10(-7) M, and could be blocked and reversed by propranolol. Recovery of cell function occurred over a period of minutes when the concentration of ISO was less than 10(-6) M. These observations are discussed in terms of the interaction of ISO with the adrenergic receptors. The site of catecholamine action is addressed. ISO neither influences formyl peptide-receptor interaction nor does it inhibit oxidant production by phorbol ester. These results suggest an impairment of intracellular signalling processes that couple the formyl peptide-receptor binding to cell activation. We observed inhibition of intracellular Ca++ elevation by ISO only at low formyl peptide concentrations. This inhibition is consistent with a partial inhibition of phosphoinositide metabolism, which was observed. Several other cell responses, including actin polymerization and right angle light scatter, are minimally inhibited by 10(-6) M ISO indicating that the cell activation process is not entirely obliterated. The presence of catecholamine and formyl peptide results in a synergistic elevation of cAMP. The intracellular targets of ISO action may be regulated by cAMP dependent kinases and could follow a branchpoint in the activation sequence that leads distinctly to oxidase activation and cytoskeletal activation.

Adoptive immunotherapy for leukemia: donor lymphocytes transduced with the herpes simplex thymidine kinase gene for remission induction. HGTRI 0103.

This study will evaluate the safety and efficacy of allogenic donor lymphocyte infusions in patients who have relapsed hematologic malignancies after allogeneic bone marrow transplantation (BMT). Donor lymphocyte transfusions have resulted in the cure of some patients with relapsed leukemia or lymphoproliferative disorder after allogeneic BMT, but has been complicated by the development of graft versus host disease (GvHD). We hypothesize that a retroviral vector containing the Herpes simplex thymidine kinase (HStk) gene will allow for retention of the anti-leukemia response of transfused donor lymphocytes while allowing for the adverse effects of GVHD to be mitigated. Patients with relapsed hematologic malignancies after allogeneic BMT will be infused with ex vivo gene modified donor lymphocytes. The Herpes Simplex thymidine kinase (HStk) gene will be transduced into the cells ex vivo using LTKOSN. 1 vector supernate. Insertion of the HStk gene into lymphocytes confers a sensitivity to the anti-herpes drug ganciclovir (GCV). This selective destruction of donor lymphocytes in situ will be used to abrogate the effect of graft versus host disease, if it develops.

Management of multiple myeloma today.

Multiple myeloma is almost invariably fatal despite a wide variety of chemotherapeutic and supportive treatment options. There are several unresolved problems with existing approaches, including the specific indications for treatment; the optimal combination of agents and doses; and the type, frequency, and timing of high-dose therapy and stem-cell transplantation. High-dose chemotherapy followed by stem-cell transplantation produces higher remission rates, but patients rarely, if ever, are cured by a single regimen. Allogeneic hematopoietic stem-cell transplantations offer a potential graft-versus-myeloma (GVM) effect. Researchers are focusing efforts on improving the safety of transplant procedures, increasing response rates to ablative therapy, and testing novel posttransplant options to improve outcomes. The newly devised National Comprehensive Cancer Network (NCCN) guidelines for treating multiple myeloma are also discussed.

DNA vaccination against multiple myeloma.

A variety of approaches to antitumor therapy are currently being explored that use both antigen-encoding DNA and noncoding nucleotides as a component of gene vaccination. Among the specific strategies reviewed are a construct that fuses a single-chain variable fragment (scFv) that incorporates both the variable-region genes necessary to encode the idiotypic determinants with fragment C (FrC) of tetanus toxin; a novel vector system using herpes simplex virus 1 (HSV-1) for in vivo gene delivery; the possibility of eliciting hyperacute xenograft response to treat human cancer; and the use of gene gun-mediated granulocyte-macrophage colony-stimulating factor (GM-CSF) cDNA-based tumor cell vaccines. The protection provided by DNA vaccination against viral diseases such as influenza suggested a role for such vaccines against cancer. However, unlike vaccines against infectious diseases, cancer vaccines are therapeutic, rather than prophylactic. With multiple myeloma, for example, it is possible that the optimal timing of administration of such a vaccine is during a remission that has been induced by traditional therapies, to eliminate residual disease. DNA cancer vaccines are designed to activate immune responses to tumor antigens to which the immune system has already been exposed. To do so, the vaccines must first overcome immune tolerance that may have already developed to the tumor. There is increasing evidence that tumor antigens, unlike viral or bacterial antigens, do not consistently activate an immune response. One major factor in determining whether a reaction occurs appears to be whether antigen presentation is accompanied by danger signals. With viral or bacterial infection, the accompanying tissue destruction and inflammation produce costimulatory signals that promote T-cell activation. However, inflammatory and tissue-destructive processes are absent during initial tumor transformation. The typical outcome may be immunologic tolerance.

Inhibition of UDP-N-acetylglucosamine import into Golgi membranes by nucleoside monophosphates.

The specificity of the UDP-N-acetylglucosamine (UDP-GlcNAc) translocator for the binding of nucleoside monophosphates (NMPs) and nucleotide-sugars was examined in order to develop a quantitative understanding of how this enzyme recognizes its substrates and to provide a framework for development of novel drugs that target glycosylation. Competition studies reveal that tight binding requires a complete ribose ring and a 5'-phosphate. The enzyme is extremely tolerant to changes at the 3'-position, and the presence of 3'-F actually increases binding of the NMP to the enzyme. At the 2'-position, substitutions in the ribo configuration are well tolerated, although these same substitutions greatly diminish binding when present in the ara configuration. For the base, size appears to be the key feature for discrimination. The enzyme tolerates changing the C-4 oxygen of uridine to an amino group as well as substituting groups containing one or two carbons at C-5. However, substitution of groups containing three carbons at C-5, or exchange of the pyrimidine for a purine, greatly weakens binding to the translocator. Comparison of various UDP-sugars reveals that the UDP-GlcNAc translocator has lower affinity for UDP-N-acetylgalactosamine and UDP-glucose than for its cognate substrate and therefore indicates that this translocator requires both proper stereochemistry at C-4 and an aminoacetyl group at C-2. The impact of these observations on the design of more powerful nucleoside-based inhibitors of nucleotide-sugar import is discussed.

Ifosfamide, carboplatin and etoposide combined with 41.8 degrees C whole body hyperthermia for malignant pleural mesothelioma.

We performed a phase II study combining 41.8 degrees C whole body hyperthermia with ICE chemotherapy, i.e. ifosfamide (5 g/m(2)), carboplatin (300 mg/m(2)) and etoposide (150 mg/m(2) on days 2 and 3), administered every 4 weeks, for patients with malignant pleural mesothelioma. Of 27 chemonäive, non-metastatic patients enrolled, 25 patients were evaluable for response. Overall response rate was 20% (five partial remissions; 95% CI 8.9-39.1%). Median survival time from the start of treatment for all patients was 76.6 weeks (95% CI 65.4-87.8 weeks). Progression free survival for all patients measured 29.6 weeks (95% CI 24.4-34.7 weeks). One year overall survival was 68% and 2 year overall survival was 20%. Major treatment toxicities included grade 3/4 neutropenia and thrombocytopenia in 74 and 33% of treatment cycles, respectively. One patient died due to sepsis. These promising results are consistent with continued clinical investigation; a phase III clinical trial with whole body hyperthermia as the independent variable has been initiated.

The promise of hematopoietic stem cell transplantation for autoimmune diseases.

Hematopoietic stem cell transplantation (HSCT) is being increasingly utilized for the treatment of a whole spectrum of severe autoimmune diseases refractory to conventional therapy. Although allogeneic HSCT has been followed by durable complete remission in a restricted number of patients with coincidental disease, the autologous procedure is generally preferred because of its lesser toxicity. Most autoimmune diseases are the consequence of a multistep process, mainly originating from the interplay of genetic, environmental, and hormonal factors. It has been postulated that if immunosuppressive regimens can eliminate or effectively reduce the level of autoreactive T and B cells, then regeneration of de novo immunity even in the autologous setting may bypass the initial breakdown of self-tolerance and ensure prolonged disease remission. As mentioned in a recent review of this field, protocol design including conditioning regimen, patient selection, stem cell source and final outcome are likely to be disease-specific. The following is a summary of the 2002 International Bone Marrow Transplantation Registry/American Society of Blood and Bone Marrow Transplantation (IBMTR/ASBMT) satellite symposium in Orlando, Florida on 24 February 2002 on 'Expanding the Promise of Hematopoietic Stem Cell Transplantation in Autoimmune Diseases'.

Hematopoietic stem cell transplantation for severe Crohn's disease.

It is clear that some patients with severe Crohn's disease (CD) fail to respond favorably to the standard treatment, including antibody to Tumor Necrosis Factor alpha (TNFalpha), We have embarked on a unique therapy for this group of patients, intense immune suppression followed by autologous hematopoietic stem cell transplantation (HSCT). The response to this approach in our first four patients has been excellent, with there being no significant untoward event from the transplantation and with each patient entering clinical remission in terms of the Crohn's Disease Activity Index off all therapy for CD and no diarrhea or abdominal pain. However, some evidence of minor laboratory abnormalities and slight inflammation of the colon on colonoscopic evaluation persist up to 1 year post-transplant. It is suggested that HSCT should be considered a reasonable option for patients who have failed standard CD therapy, although long-term follow-up will be necessary to confirm the duration of the induced clinical remission.

Allogeneic stem cell transplantation for autoimmune diseases: nonmyeloablative conditioning regimens.

Hematopoietic stem cell transplantation (HSCT) for autoimmune diseases have been, because of safety reasons, overwhelmingly autologous. Results are, in general, encouraging with improvement in quality of life, a remission of up to several years, and perhaps in some diseases improved survival. This indicates that further study of autologous HSCT especially under phase III design is warranted. However, the ultimate goal of HSCT is cure of otherwise incurable autoimmune diseases. For this reason, allogeneic HSCT in carefully selected high-risk patients with autoimmune diseases using strategies to minimize both regimen-related toxicity and graft-versus-host disease (GVHD) is ongoing at Northwestern University and will be reviewed briefly.

Allogeneic hematopoietic stem cell transplantation for advanced mycosis fungoides: evidence of a graft-versus-tumor effect.

Allogeneic hematopoietic stem cell transplantation should be considered as a therapeutic option for patients with generalized erythoderma or tumor stage MF. Indeed, the only curative option for MF may be an allogeneic transplant. Bone Marrow Transplantation (2000) 25, 111-113.