Feasibility, safety, and efficacy of dietary or lifestyle interventions for hypothalamic obesity: A systematic review.

BACKGROUND & AIMS: A dysfunctional hypothalamus may result in decreased feelings of satiety (hyperphagia), decreased energy expenditure, and increased fat storage as a consequence of hyperinsulinemia. Hypothalamic dysfunction may thus lead to morbid obesity and can be encountered in childhood as a consequence of congenital, genetic, or acquired disorders. There is currently no effective treatment for hypothalamic obesity (HO). However, comparable to alimentary obesity, dietary and lifestyle interventions may be considered the cornerstones of obesity treatment. We questioned the effect of dietary or lifestyle interventions for HO and systematically searched the literature for evidence on feasibility, safety, or efficacy of dietary or lifestyle interventions for childhood hypothalamic overweight or obesity. METHODS: A systematic search was conducted in MEDLINE (including Cochrane Library), EMBASE, and CINAHL (May 2023). Studies assessing feasibility, safety, or efficacy of any dietary or lifestyle intervention in children with hypothalamic overweight or obesity, were included. Animal studies, studies on non-diet interventions, and studies with no full text available were excluded. Because the number of studies to be included was low, the search was repeated for adults with hypothalamic overweight or obesity. Risk of bias was assessed with an adapted Cochrane Risk of Bias Tool. Level of evidence was assessed using the GRADE system. Descriptive data were described, as pooled-data analysis was not possible due to heterogeneity of included studies. RESULTS: In total, twelve studies were included, with a total number of 118 patients (age 1-19 years) of whom one with craniopharyngioma, one with ROHHAD-NET syndrome, 50 with monogenic obesity, and 66 with Prader-Willi syndrome (PWS). Four studies reported a dietary intervention as feasible. However, parents did experience difficulties with children still stealing food, and especially lowering carbohydrates was considered to be challenging. Seven studies reported on efficacy of a dietary intervention: a well-balanced restrictive caloric diet (30% fat, 45% carbohydrates, and 25% protein) and various hypocaloric diets (8-10 kcal/cm/day) were considered effective in terms of weight stabilization or decrease. No negative effect on linear growth was reported. Four studies reported on specific lifestyle interventions, of which three also included a dietary intervention. Combined dietary and lifestyle intervention resulted in decreased BMI, although BMI returned to baseline values on long-term. One additional study was identified in adults after brain trauma and showed a significant reduction in BMI in one out of eight patients after a combined dietary and lifestyle intervention. CONCLUSIONS: Hypocaloric diet or restrictive macronutrient diet with lower percentage of carbohydrates seems feasible and effective for childhood HO, although most of the studies had a high risk of bias, small cohorts without control groups, and were conducted in children with PWS only, compromising the generalizability. Lifestyle interventions only resulted in BMI decrease in short-term, indicating that additional guidance is needed to sustain its effect in the long-term. Literature on feasibility and efficacy of a dietary or lifestyle intervention for hypothalamic overweight or obesity is scarce, especially in children with acquired HO (following treatment for a suprasellar tumor). There is need for prospective (controlled) studies to determine which dietary and lifestyle intervention are most helpful for this specific patient group.

The levonorgestrel intrauterine system versus endometrial ablation for heavy menstrual bleeding: a cost-effectiveness analysis.

OBJECTIVE: To evaluate the costs and non-inferiority of a strategy starting with the levonorgestrel intrauterine system (LNG-IUS) compared with endometrial ablation (EA) in the treatment of heavy menstrual bleeding (HMB). DESIGN: Cost-effectiveness analysis from a societal perspective alongside a multicentre randomised non-inferiority trial. SETTING: General practices and gynaecology departments in the Netherlands. POPULATION: In all, 270 women with HMB, aged ≥34 years old, without intracavitary pathology or wish for a future child. METHODS: Randomisation to a strategy starting with the LNG-IUS (n = 132) or EA (n = 138). The incremental cost-effectiveness ratio was estimated. MAIN OUTCOME MEASURES: Direct medical costs and (in)direct non-medical costs were calculated. The primary outcome was menstrual blood loss after 24 months, measured with the mean Pictorial Blood Assessment Chart (PBAC)-score (non-inferiority margin 25 points). A secondary outcome was successful blood loss reduction (PBAC-score ≤75 points). RESULTS: Total costs per patient were €2,285 in the LNG-IUS strategy and €3,465 in the EA strategy (difference: €1,180). At 24 months, mean PBAC-scores were 64.8 in the LNG-IUS group (n = 115) and 14.2 in the EA group (n = 132); difference 50.5 points (95% CI 4.3-96.7). In the LNG-IUS group, 87% of women had a PBAC-score ≤75 points versus 94% in the EA group (relative risk [RR] 0.93, 95% CI 0.85-1.01). The ICER was €23 (95% CI €5-111) per PBAC-point. CONCLUSIONS: A strategy starting with the LNG-IUS was cheaper than starting with EA, but non-inferiority could not be demonstrated. The LNG-IUS is reversible and less invasive and can be a cost-effective treatment option, depending on the success rate women are willing to accept. TWEETABLE ABSTRACT: Treatment of heavy menstrual bleeding starting with LNG-IUS is cheaper but slightly less effective than endometrial ablation.

Long-term prognosis for 1-year relapse-free survivors of CD34+ cell-selected allogeneic hematopoietic stem cell transplantation: a landmark analysis.

CD34+ cell selection significantly improves GvHD-free survival in allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, specific information regarding long-term prognosis and risk factors for late mortality after CD34+ cell-selected allo-HSCT is lacking. We conducted a single-center landmark analysis in 276 patients alive without relapse 1 year after CD34+ cell-selected allo-HSCT for AML (n=164), ALL (n=33) or myelodysplastic syndrome (n=79). At 5 years' follow-up after the 1-year landmark (range 0.03-13 years), estimated relapse-free survival (RFS) was 73% and overall survival (OS) 76%. The 5-year cumulative incidence of relapse and non-relapse mortality (NRM) were 11% and 16%, respectively. In multivariate analysis, Hematopoietic Cell Transplantation Comorbidity Index score⩾3 correlated with marginally worse RFS (hazard ratio (HR) 1.78, 95% confidence interval (CI) 0.97-3.28, P=0.06) and significantly worse OS (HR 2.53, 95% CI 1.26-5.08, P=0.004). Despite only 24% of patients with acute GvHD within 1 year, this also significantly correlated with worse RFS and OS, with increasing grades of acute GvHD associating with increasingly poorer survival on multivariate analysis (P<0.0001). Of 63 deaths after the landmark, GvHD accounted for 27% of deaths and was the most common cause of late mortality, followed by relapse and infection. Although prognosis is excellent for patients alive without relapse 1 year after CD34+ cell-selected allo-HSCT, risks of late relapse and NRM persist, particularly due to GvHD.

Clonal B cells in Waldenström's macroglobulinemia exhibit functional features of chronic active B-cell receptor signaling.

Waldenström's macroglobulinemia (WM) is a B-cell non-Hodgkin's lymphoma (B-NHL) characterized by immunoglobulin M (IgM) monoclonal gammopathy and the medullary expansion of clonal lymphoplasmacytic cells. Neoplastic transformation has been partially attributed to hyperactive MYD88 signaling, secondary to the MYD88 L265P mutation, occurring in the majority of WM patients. Nevertheless, the presence of chronic active B-cell receptor (BCR) signaling, a feature of multiple IgM+ B-NHL, remains a subject of speculation in WM. Here, we interrogated the BCR signaling capacity of primary WM cells by utilizing multiparametric phosphoflow cytometry and found heightened basal phosphorylation of BCR-related signaling proteins, and augmented phosphoresponses on surface IgM (sIgM) crosslinking, compared with normal B cells. In support of those findings we observed high sIgM expression and loss of phosphatase activity in WM cells, which could both lead to signaling potentiation in clonal cells. Finally, led by the high-signaling heterogeneity among WM samples, we generated patient-specific phosphosignatures, which subclassified patients into a 'high' and a 'healthy-like' signaling group, with the second corresponding to patients with a more indolent clinical phenotype. These findings support the presence of chronic active BCR signaling in WM while providing a link between differential BCR signaling utilization and distinct clinical WM subgroups.

Sex steroid ablation: an immunoregenerative strategy for immunocompromised patients.

Age-related decline in thymic function is a well-described process that results in reduced T-cell development and thymic output of new naïve T cells. Thymic involution leads to reduced response to vaccines and new pathogens in otherwise healthy individuals; however, reduced thymic function is particularly detrimental in clinical scenarios where the immune system is profoundly depleted such as after chemotherapy, radiotherapy, infection and shock. Poor thymic function and restoration of immune competence has been correlated with an increased risk of opportunistic infections, tumor relapse and autoimmunity. Apart from their primary role in sex dimorphism, sex steroid levels profoundly affect the immune system in general and, in fact, age-related thymic involution has been at least partially attributed to the increase in sex steroids at puberty. Subsequently it has been demonstrated that the removal of sex steroids, or sex steroid ablation (SSA), triggers physiologic changes that ultimately lead to thymic re-growth and improved T-cell reconstitution in settings of hematopoietic stem cell transplant (HSCT). Although the cellular and molecular process underlying these regenerative effects are still poorly understood, SSA clearly represents an attractive therapeutic approach to enhance thymic function and restore immune competence in immunodeficient individuals.

Inducible T-cell receptor expression in precursor T cells for leukemia control.

Co-transplantation of hematopoietic stem cells with those engineered to express leukemia-reactive T-cell receptors (TCRs) and differentiated ex vivo into precursor T cells (preTs) may reduce the risk of leukemia relapse. As expression of potentially self-(leukemia-) reactive TCRs will lead to negative selection or provoke autoimmunity upon thymic maturation, we investigated a novel concept whereby TCR expression set under the control of an inducible promoter would allow timely controlled TCR expression. After in vivo maturation and gene induction, preTs developed potent anti-leukemia effects. Engineered preTs provided protection even after repeated leukemia challenges by giving rise to effector and central memory cells. Importantly, adoptive transfer of TCR-transduced allogeneic preTs mediated anti-leukemia effect without evoking graft-versus-host disease (GVHD). Earlier transgene induction forced CD8(+) T-cell development was required to obtain a mature T-cell subset of targeted specificity, allowed engineered T cells to efficiently pass positive selection and abrogated the endogenous T-cell repertoire. Later induction favored CD4 differentiation and failed to produce a leukemia-reactive population emphasizing the dominant role of positive selection. Taken together, we provide new functional insights for the employment of TCR-engineered precursor cells as a controllable immunotherapeutic modality with significant anti-leukemia activity.

Graft-versus-host disease after double-unit cord blood transplantation has unique features and an association with engrafting unit-to-recipient HLA match.

Manifestations of and risk factors for graft-versus-host disease (GVHD) after double-unit cord blood transplantation (DCBT) are not firmly established. We evaluated 115 DCBT recipients (median age, 37 years) who underwent transplantation for hematologic malignancies with myeloablative or nonmyeloablative conditioning and calcineurin inhibitor/mycophenolate mofetil immunosuppression. Incidence of day 180 grades II to IV and III to IV acute GVHD (aGVHD) were 53% (95% confidence interval, 44 to 62) and 23% (95% confidence interval, 15 to 31), respectively, with a median onset of 40 days (range, 14 to 169). Eighty percent of patients with grades II to IV aGVHD had gut involvement, and 79% and 85% had day 28 treatment responses to systemic corticosteroids or budesonide, respectively. Of 89 engrafted patients cancer-free at day 100, 54% subsequently had active GVHD, with 79% of those affected having persistent or recurrent aGVHD or overlap syndrome. Late GVHD in the form of classic chronic GVHD was uncommon. Notably, grades III to IV aGVHD incidence was lower if the engrafting unit human leukocyte antigen (HLA)-A, -B, -DRB1 allele match was >4/6 to the recipient (hazard ratio, 0.385; P = .031), whereas engrafting unit infused nucleated cell dose and unit-to-unit HLA match were not significant. GVHD after DCBT was common in our study, predominantly affected the gut, and had a high therapy response, and late GVHD frequently had acute features. Our findings support the consideration of HLA- A,-B,-DRB1 allele donor-recipient (but not unit-unit) HLA match in unit selection, a practice change in the field. Moreover, new prophylaxis strategies that target the gastrointestinal tract are needed.

Palifermin is efficacious in recipients of TBI-based but not chemotherapy-based allogeneic hematopoietic stem cell transplants.

Palifermin, a recombinant human keratinocyte growth factor, is commonly given to prevent mucositis following autologous transplantation. In the allogeneic hematopoietic stem cell transplant (allo-HSCT) setting, safety and efficacy data are limited. We conducted a retrospective study in 251 patients undergoing allo-HSCT, 154 of whom received peritransplant palifermin. In all patients, palifermin significantly decreased the mean number of days of total parenteral nutrition (TPN, 13 vs 16 days, P=0.006) and patient-controlled analgesia (PCA, 6 vs 10 days, P=0.023), as well as the length of initial hospital stay (LOS, 32 vs 37 days, P=0.014). However, the effect of palifermin was only significant in patients who received a TBI- but not BU-based chemotherapy conditioning regimen. In TBI recipients, palifermin decreased the mean number of days of TPN (13 vs 17 days, P<0.001) and PCA (7 vs 12 days, P=0.033), and the length of stay (32 vs 38 days, P=0.001). Palifermin did not affect GVHD, graft failure or relapse. Therefore, in the largest analysis with this patient population to date, we demonstrate that palifermin is safe in allo-HSCT patients, decreases TPN and PCA use and decreases LOS following TBI-based but not chemotherapy-based allo-HSCT.

Second-line age-adjusted International Prognostic Index in patients with advanced non-Hodgkin lymphoma after T-cell depleted allogeneic hematopoietic SCT.

T-cell depleted allogeneic hematopoietic SCT (TCD-HSCT) have shown durable disease-free survival with a low risk of GVHD in patients with AML. We investigated this approach in 61 patients with primary refractory or relapsed non-Hodgkin lymphoma (NHL), who underwent TCD-HSCT from January 1992 through September 2004. Patients received myeloablative cytoreduction consisting of hyperfractionated total body irradiation, followed by either thiotepa and cyclophosphamide (45 patients) or thiotepa and fludarabine (16 patients). We determined the second-line age-adjusted International Prognostic Index score (sAAIPI) before transplant transplant. Median follow-up of surviving patients is 6 years. The 10-year OS and EFS were 50% and 43%, respectively. The relapse rate at 10 years was 21% in patients with chemosensitive disease and 52% in those with resistant disease at time of HSCT. Nine of the 18 patients who relapsed entered a subsequent CR. OS (P=0.01) correlated with the sAAIPI. The incidence of grades II-IV acute GVHD was 18%. We conclude that allogeneic TCD-HSCT can induce high rates of OS and EFS in advanced NHL with a low incidence of GVHD. Furthermore, the sAAIPI can predict outcomes and may be used to select the most appropriate patients for this type of transplant.

Adoptive precursor cell therapy to enhance immune reconstitution after hematopoietic stem cell transplantation.

Strategies to enhance post-transplant immune reconstitution without aggravating graft-vs-host disease (GVHD) can improve the outcome of allogeneic hematopoietic stem cell transplantation. Recent preclinical studies demonstrated that the use of T cell depleted allografts supplemented with committed progenitor cells (vs stem cells only) allows enhanced immune reconstitution of specific hematopoietic lineages including myeloid, B, T, and natural killer lineages in the absence of GVHD. This novel adoptive therapy resulted in significantly improved resistance to microbial pathogens and could, in some cases, even mediate tumor immunity. Clinical protocols using adoptive transfer of committed hematopoietic progenitor cells are currently being evaluated.

Novel ways to noninvasively detect inflammation of the myocardium: contrast-enhanced MRI and myocardial contrast echocardiography.

Both contrast-enhanced magnetic resonance imaging (CE-MRI) and myocardial contrast echocardiography (MCE) are promising tools to detect cardiac inflammation. CE-MRI can be used to characterise the location and extent of myocardial inflammation, since areas of abnormal signal enhancement associated with regional wall motion abnormalities reliably indicate areas of active myocarditis. In MCE, chemically composed microbubbles can be visualised by ultrasound and used to determine the status of the cardiac microvasculature. If there is any inflammation the microbubbles will be phagocytosed by neutrophils and monocytes, thus enabling the degree of inflammation to be assessed. These noninvasive techniques may allow early diagnosis and accurate evaluation of myocardial inflammation.

Septic shock and multiple organ failure after hematopoietic stem cell transplantation: treatment with recombinant human activated protein C.

Severe sepsis with multiple organ failure after hematopoietic stem cell transplantation (HSCT) results in extremely high morbidity and mortality. Recent studies have highlighted the importance of sepsis-induced activation of the coagulation system in the pathophysiology of severe sepsis. Activated protein C is an important modulator of coagulation and inflammatory derangements during severe sepsis. Low levels of protein C occur in severe sepsis and are predictive of poor outcome. Recombinant human activated protein C (drotrecogin alfa (activated)) was recently approved by the Food and Drug Administration (FDA) for severe sepsis. The phase III trial that resulted in the approval of this agent, however, enrolled a general sepsis population and excluded patients undergoing HSCT. We report a case of fulminant septic shock and multiple organ failure after HSCT that was treated with drotrecogin alfa (activated) in addition to standard therapy, and recovered. The high mortality rates of patients who develop severe sepsis after HSCT demand that new avenues of treatment be considered for this very high-risk patient population. This case illustrates the potential application of a novel therapeutic approach. Clinical trials are warranted to further investigate the safety and efficacy of drotrecogin alfa (activated) in patients with severe sepsis after HSCT.

Cost-effectiveness analysis of colorectal cancer treatments.

A concise overview is provided of the methodology of cost-effectiveness analyses, followed by a survey of published CEAs of colorectal cancer treatments. To gain credibility, the methodology applied in CEAs must be further improved. Costs are rarely estimated from the societal perspective, and little is known about how colorectal patients value their treatment and health.

Administration of interleukin-7 after allogeneic bone marrow transplantation improves immune reconstitution without aggravating graft-versus-host disease.

Prolonged immunodeficiency after allogeneic bone marrow transplantation (BMT) causes significant morbidity and mortality from infection. This study examined in murine models the effects of interleukin-7 (IL-7) given to young and middle-aged (9-month-old) recipients of major histocompatibility complex (MHC)-matched or -mismatched allogeneic BMT. Although administration of IL-7 from day 0 to 14 after syngeneic BMT promoted lymphoid reconstitution, this regimen was ineffective after allogeneic BMT. However, IL-7 administration from day 14 (or 21) to 27 after allogeneic BMT accelerated restoration of the major lymphoid cell populations even in middle-aged recipients. This regimen significantly expanded donor-derived thymocytes and peripheral T cells, B-lineage cells in bone marrow and spleen, splenic natural killer (NK) cells, NK T cells, and monocytes and macrophages. Interestingly, although recipients treated with IL-7 had significant increases in CD4(+) and CD8(+) memory T-cell populations, increases in naive T cells were less profound. Most notable, however, were the observations that IL-7 treatment did not exacerbate graft-versus-host disease (GVHD) in recipients of an MHC-matched BMT, and would ameliorate GVHD in recipients of a MHC-mismatched BMT. Nonetheless, graft-versus-leukemia (GVL) activity (measured against 32Dp210 leukemia) remained intact. Although activated and memory CD4(+) and CD8(+) T cells normally express high levels of IL-7 receptor (IL-7R, CD127), activated and memory alloreactive donor-derived T cells from recipients of allogeneic BMT expressed little IL-7R. This might explain the failure of IL-7 administration to exacerbate GVHD. In conclusion, posttransplant IL-7 administration to recipients of an allogeneic BMT enhances lymphoid reconstitution without aggravating GVHD while preserving GVL.

Differential use of Fas ligand and perforin cytotoxic pathways by donor T cells in graft-versus-host disease and graft-versus-leukemia effect.

In allogeneic bone marrow transplantation (BMT) donor T cells are primarily responsible for antihost activity, resulting in graft-versus-host disease (GVHD), and for antileukemia activity, resulting in the graft-versus-leukemia (GVL) effect. The relative contributions of the Fas ligand (FasL) and perforin cytotoxic pathways in GVHD and GVL activity were studied by using FasL-defective or perforin-deficient donor T cells in murine parent --> F1 models for allogeneic bone marrow transplantation. It was found that FasL-defective B6.gld donor T cells display diminished GVHD activity but have intact GVL activity. In contrast, perforin-deficient B6.pfp(-/-) donor T cells have intact GVHD activity but display diminished GVL activity. Splenic T cells from recipients of B6.gld or B6.pfp(-/-) T cells had identical proliferative and cytokine responses to host antigens; however, splenic T cells from recipients of B6.pfp(-/-) T cells had no cytolytic activity against leukemia cells in a cytotoxicity assay. In experiments with selected CD4(+) or CD8(+) donor T cells, the FasL pathway was important for GVHD activity by both CD4(+) and CD8(+) T cells, whereas the perforin pathway was required for CD8-mediated GVL activity. These data demonstrate in a murine model for allogeneic bone marrow transplantation that donor T cells mediate GVHD activity primarily through the FasL effector pathway and GVL activity through the perforin pathway. This suggests that donor T cells make differential use of cytolytic pathways and that the specific blockade of one cytotoxic pathway may be used to prevent GVHD without interfering with GVL activity.

The occurrence of recall bias in pediatric headache: a comparison of questionnaire and diary data.

OBJECTIVE: To investigate whether children and adolescents can recall prior headache complaints accurately and to study whether age, gender, headache severity, preferred coping strategies, depression, somatization, and trait anxiety are related to recall errors, causing recall bias. METHODS: A retrospective headache questionnaire and a prospective 4-week headache diary were filled out by 181 children aged 9 to 16 years who experienced headache at least weekly. In addition, several other questionnaires were administered, measuring coping strategies, depression, somatization, and trait anxiety. Headache frequency, intensity, and duration, as scored on the questionnaire and the diary, were compared using Wilcoxon tests. Regression analyses were performed to study whether age, gender, headache severity, preferred coping strategies, depression, somatization, and trait anxiety can predict the size of differences between the diary and the questionnaire. RESULTS: Compared with the diary, headache intensity and headache duration were overestimated on the questionnaire. At group level, median headache frequency as measured by the diary and the questionnaire was equal. Regarding headache frequency and headache intensity, age and headache severity were statistically related to errors in recall. For headache frequency, depression was also predictive of the size of recall error. CONCLUSIONS: Recall errors occur when children are asked to report their headaches on a retrospective questionnaire. As compared to a prospective diary, pain complaints are evaluated more negatively on a questionnaire. Other factors such as age, depression, and headache severity influence the way children and adolescents recall their headaches. To minimize bias, the use of a diary when studying recurrent headache complaints in children is recommended.

Fas ligand-deficient gld mice are more susceptible to graft-versus-host-disease.

BACKGROUND: The Fas/Fas ligand (FasL) pathway plays an important role in a number of apoptotic processes that could be important for the development of graft-versus-host disease (GVHD) after bone marrow transplantation (BMT), such as cytolysis of target cells by cytotoxic T cells, regulation of inflammatory responses, peripheral deletion of autoimmune cells, costimulation of T cells, and activation-induced cell death. METHODS: To study the role of the Fas/FasL pathway in the complex pathophysiology of graft versus host disease (GVHD), we used FasL-deficient B6.gld mice as recipients in a Major Histocompatibility Antigen Complex-matched minor Histocompatibility Antigen-mismatched murine model for GVHD after allogeneic BMT (C3H.SW-->B6). RESULTS: We found a significantly higher morbidity and mortality from GVHD compared to control B6 recipients. Histopathological analysis of the GVHD target organs demonstrated that B6.gld recipients developed significantly more thymic and intestinal GVHD. B6gld recipients with GVHD demonstrated an increased expansion of donor T cells and monocytes/ macrophages compared to control B6 recipients, whereas serum TNF-alpha levels were equivalent in B6.gld recipients and control B6 recipients. CONCLUSION: This study demonstrates that the expression of FasL in the BMT recipient is important for the host's ability to control GVHD.

A phase II pilot trial of concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin 2, and interferon alpha-2B in patients with metastatic melanoma.

In an effort to develop a biochemotherapy regimen for metastatic melanoma suitable for testing in a cooperative group setting, we modified the concurrent biochemotherapy regimen of S. S. Legha et al. (J. Clin. Oncol., 16: 1752-1759, 1998) by providing enhanced supportive care and developing a strict, conservative approach to the management of treatment-related toxicities. Patients received cisplatin, vinblastine, and dacarbazine (CVD: cisplatin (20 mg/m2) and vinblastine (1.2 mg/m2) on days 1-4, dacarbazine (800 mg/m2) on day 1 only) concurrently with interleukin 2 (9 MIU/m2/day) by continuous i.v. infusion on days 1-4 and IFN-alpha (5 MU/m2/day) on days 1-5, 8, 10, and 12. Prophylactic antibiotics and a maximum of four cycles were administered. Routine granulocyte colony-stimulating factor and aggressive antiemetics were initiated after patients 7 and 14, respectively. Forty-four patients were enrolled in this study. No patients had received prior chemotherapy or interleukin 2; however, 23 (53%) had received prior IFN-alpha, mostly in the adjuvant setting. A total of 131 treatment cycles was administered. Significant toxicities requiring dose modification included: hypotension requiring pressors (15 episodes in 11 patients), grades 3/4 vomiting (12 episodes in 15 cycles; 5 episodes in 12 patients (6 episodes in 9 cycles after initiation of the modified antiemetic regimen), transient renal insufficiency (5 episodes in 5 patients), grade 4 thrombocytopenia (24 episodes, 1 associated with bleeding), neutropenia with or without fever (15 instances, only 11 in 112 cycles after routine use of granulocyte colony-stimulating factor), and catheter-related bacteremia (2 patients). Five (16%) of 30 patients who were treated after the last protocol modification experienced what we defined as unacceptable toxicity for a cooperative group setting. Responses were seen in 19 of 40 evaluable patients (relative risk, 48%) with 8 complete responses (20%). The median response duration was 7 months (range, 1-17+ months) with one currently ongoing. The central nervous system was the initial site of relapse in 11 responding patients. The median survival duration was 11 months (range, 2-31 months). This modified, concurrent biochemotherapy regimen is active and tolerable for use in a cooperative group setting. Central nervous system relapse, however, remains a concern for responders. This regimen is being compared with CVD in a Phase III Intergroup Trial (Eastern Cooperative Oncology Group/Southwest Oncology Group 3695).

Graft-versus-host-disease-associated thymic damage results in the appearance of T cell clones with anti-host reactivity.

BACKGROUND: We studied whether T-cell clones, which appear in the periphery as a result of the failure of thymic negative selection during graft-versus-host disease (GVHD), have any in vivo anti-host reactivity and can cause GVHD in an adoptive transfer model. METHODS: We performed our studies in a murine model (B10.BR into CBA/J) for allogeneic bone marrow transplantation with major histocompatibility complex-matched and minor histocompatibility antigen-mismatched unrelated donors and unique Vbeta T-cell deletion patterns in donors and recipients. RESULTS: GVHD resulted in the appearance of Vbeta6+ T cells as a result of a loss of negative selection. We found that Vbeta6+ T cells from normal donors proliferated in vitro and in vivo. Depletion of Vbeta6+ T cells from the donor T-cell inoculum resulted in less GVHD morbidity and a decrease in the loss of thymic cellularity. To test the anti-host reactivity of de novo generated Vbeta6+ T cells in animals with GVHD, we developed an adoptive transfer model of splenic T cells from CBA/J host animals with GVHD into sublethally irradiated CBA/J recipients Depletion of Vbeta6+ T cells from the splenic T cells before adoptive transfer could significantly decrease the transient GVHD morbidity in the sublethally irradiated hosts. CONCLUSIONS: Our data indicate that GVHD-associated thymic damage results in a loss of thymic negative selection, which leads to the appearance of T-cell clones with anti-host reactivity in vitro and in vivo.