Search

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.amjmed.2005.02.009 Byline: Libuse Tauchmanova (a), Carmine Selleri (b), Gennaro De Rosa (b), Mariarosaria Esposito (b), Carolina Di Somma (a), Francesco Orio (a), Stefano Palomba (c), Gaetano Lombardi (a), Bruno Rotoli (b), Annamaria Colao (a) Keywords: Bone marrow transplantation; Gonadal failure; Thyroiditis; Low T.sub.3 syndrome; Subclinical hyperthyroidism; IGF-1; Adrenal insufficiency Abstract: Frequent endocrine disorders have been reported after allogeneic stem-cell transplant, but data on adult survivors of autologous transplants are still scarce. Author Affiliation: (a) Department of Molecular and Clinical Endocrinology and Oncology, 'Federico II' University of Naples, Italy (b) Division of Hematology, 'Federico II' University of Naples, Italy (c) Chair of Gynecology and Obstetrics, University 'Magna Graecia' of Catanzaro, Italy Article History: Received 3 May 2004; Accepted 15 November 2004 Article Note: (footnote) This study was partially supported by grant number 2003069821 from MURST, Rome, Italy.

Developmental cysts are very rare lesions occurring in the retrorectal space, and include epidermoid, dermoid, tailgut cysts and teratomas. There is little information on their natural history and biologic behavior, although a recent paper reported a greater incidence of malignant transformation than previously thought. The diagnosis requires high-resolution imaging, and complete surgical excision is the treatment of choice. In this paper we analyzed short- and long-term results of surgical excision of six retrorectal developmental cysts observed at our institution over a period of 11 years. All patients were women, three were referred with an infected perineal fistula/pelvic abscess after having undergone drainage surgery elsewhere. In these three patients, excision was attempted through a trans-perineal approach, which was technically demanding and ultimately incomplete because of the intense surrounding inflammation. Multiple re-interventions were required for tumor recurrence, and two of them still present an occasional perineal discharge. In the other three patients, a trans-perineal or trans-anal route was employed according to tumor location, without any recurrence at a median follow-up of 118.5 months. Final pathologic diagnosis included five tailgut cysts and one teratoma. This paper shows that the treatment of developmental cysts may be very challenging, especially when they are associated with a concomitant fistula/abscess and are not correctly diagnosed at presentation. In our experience, healing was finally achieved in four patients out of six. All the lesions were benign, and no malignant transformation was observed during follow-up, even in tumors partially resected.Developmental cysts are very rare lesions occurring in the retrorectal space, and include epidermoid, dermoid, tailgut cysts and teratomas. There is little information on their natural history and biologic behavior, although a recent paper reported a greater incidence of malignant transformation than previously thought. The diagnosis requires high-resolution imaging, and complete surgical excision is the treatment of choice. In this paper we analyzed short- and long-term results of surgical excision of six retrorectal developmental cysts observed at our institution over a period of 11 years. All patients were women, three were referred with an infected perineal fistula/pelvic abscess after having undergone drainage surgery elsewhere. In these three patients, excision was attempted through a trans-perineal approach, which was technically demanding and ultimately incomplete because of the intense surrounding inflammation. Multiple re-interventions were required for tumor recurrence, and two of them still present an occasional perineal discharge. In the other three patients, a trans-perineal or trans-anal route was employed according to tumor location, without any recurrence at a median follow-up of 118.5 months. Final pathologic diagnosis included five tailgut cysts and one teratoma. This paper shows that the treatment of developmental cysts may be very challenging, especially when they are associated with a concomitant fistula/abscess and are not correctly diagnosed at presentation. In our experience, healing was finally achieved in four patients out of six. All the lesions were benign, and no malignant transformation was observed during follow-up, even in tumors partially resected.

Women undergoing stem cell transplantation (SCT) are mostly young and have more than 90% probability of ovarian failure, which is often permanent. A woman's age, use of radiotherapy and alkylating chemotherapy, and the allogeneic type of transplant are associated with a higher rate of premature ovarian failure and worse residual ovarian function. Premature ovarian failure has serious systemic and psychological effects that may need treatment and should be managed by practitioners trained to treat this particular population of women. Ultrasonographic evidence of ovarian follicles is often associated with a future resumption of cycles, but there are no serum markers to predict the return of ovarian function in these patients. In our center, the rate of ovarian function recovery was 7% after allogeneic SCT and 25% after autologous SCT (P< 0.05). There are no guidelines on how to manage premature ovarian failure induced by myeloablative treatments followed by SCT. Because of the likelihood of the need for long-lasting estrogen plus progestin therapy (EPT) and the increased risk of secondary neoplasia after SCT, the EPT should be as physiological as possible. In our experience, the cyclical sequential combination of estradiol (2 mg daily) plus dydrogesterone (10 mg for 14 d/mo) was associated with excellent compliance because of its simple administration and few adverse effects. Such a treatment led to a dramatic improvement in vasomotor, urogenital, and psychological symptoms related to estrogen deficiency. However, in the allogeneic transplantation setting, up to 25% of women may suffer from gynecological chronic graft-versus-host disease, which may become apparent as hematocolpometra after introduction of EPT. Thus, accurate pretreatment evaluation and frequent monitoring during treatment are required. Moreover, EPT absorption may be reduced in patients who received allotransplants and have gastrointestinal or skin chronic graft-versus-host disease.

Increased serum leptin has been described after various organ transplants, with a mechanism that is still unclear.

Comparison of the gene expression repertoire in human hematopoietic progenitors and mature leukocytes led to identification of a transcript expressed in CD34+cells and undetectable in differentiated cells. Sequencing of the cDNA (termed EHZF: early hematopoietic zinc finger) revealed 30 zinc fingers with 96% homology to mouse Evi3, a recently identified gene associated with the retroviral integration site in AKXD-27 B-cell lymphomas. EHZF and Evi3 share high homology with the transcription cofactor OAZ, implicated in the control of olfactory epithelium and B-lymphocyte differentiation and in the bone morphogenic protein (BMP) signal transduction. Here we show that (1) EHZF expression is abundant in human CD34+ progenitors and declines rapidly during cytokine-driven differentiation; (2) significant mRNA levels are found in most acute myelogenous leukemias; (3) in response to BMPs EHZF complexes SMADs 1 and 4, binds to, and enhances the transcriptional activity of, a BMP2/4 responsive element; (4) EHZF inhibits the transcriptional activity of early B-cell factor (EBF), a transcription factor essential for specification of the B-cell lineage. Taken together, our data suggest that EHZF is likely to play a relevant role in the control of human hematopoiesis and might be implicated in the development of hematopoietic malignancies.

In the European Organization for Research and Treatment of Cancer Leukemia Group and Gruppo Italiano Malattie Ematologiche dell' Adulto (EORTC-LG/GIMEMA) acute myeloid leukemia (AML)–10 trial, patients in first complete remission (CR1) received a single intensive consolidation (IC) course. Subsequently, those patients younger than 46 years with an HLA-identical sibling donor were assigned to undergo allogeneic (allo) stem cell transplantation (SCT), and patients without such a donor were planned for autologous (auto) SCT. Between November 1993 and December 1999, of 1198 patients aged younger than 46 years, 822 achieved CR. The study group constituted 734 patients who received IC: 293 had a sibling donor and 441 did not. Allo-SCT and auto-SCT were performed in 68.9% and 55.8%, respectively. Cytogenetic determination was successfully performed in 446 patients. Risk groups were good (t(8;21), inv16), intermediate (NN or –Y only), and bad/very bad (all others). Median follow-up was 4 years; 289 patients relapsed, 66 died in CR1, and 293 died. Intention-to-treat analysis revealed that the 4-year disease-free survival (DFS) rate of patients with a donor versus those without a donor was 52.2% versus 42.2%, P = .044; hazard ratio = 0.80, 95% confidence interval (0.64, 0.995), the relapse incidence was 30.4% versus 52.5%, death in CR1 was 17.4% versus 5.3%, and the survival rate was 58.3% versus 50.8% (P = .18). The DFS rates in patients with and without a sibling donor were similar in patients with good/intermediate risk but were 43.4% and 18.4%, respectively, in patients with bad/very bad risk cytogenetics. In younger patients (15-35 years), the difference was more pronounced. The strategy to perform early allo-SCT led to better overall results than auto-SCT, especially for younger patients or those with bad/very bad risk cytogenetics.

Thiotepa (N,N'N'-triethylenethiophosphoramide), which is an alkylating compound, has an antineoplastic activity and has been used in oncology (e.g. breast-, ovarian- and bladder cancer) for decades. In the recent years, and because of its good safety profile, Thiotepa has been increasingly used both for autologous and allogeneic hematopoietic stem cell transplantation conditioning. Interestingly, this agent has a very active myeloablative activity but also its mechanism of action can mimick the effect of radiation.With this background, the aim of this study was to compare outcome of patients receiving a myeloablative conditioning consisting of either high dose TBI or Thiotepa-based chemotherapy.Inclusion criteria were adults with AML, first allograft in CR1 from an HLA-matched sibling donor (MSD) or an unrelated donor (UD) between 2000 and 2011 and myeloablative conditioning. We first compared patient and transplant characteristics between the two types of conditioning, and then performed a pair-matched analysis.The number of patients was 2833 in the TBI group and 102 in the Thiotepa group. Patients who received Thiotepa were older (49y vs 40y, p<10-4), transplanted more recently (2009 vs 2006, p<10-4) and later after the diagnosis of AML (183 days vs 143 days, p<10-4). The percentage of secondary AML was also higher in the Thiotepa group (14% vs 6%; p=0.0002). There was no difference regarding patient/donor gender, type of donor and source of stem cells.In this cohort, we were able to match 96 patients who received Thiotepa with 185 patients who received high dose TBI. Matching factors were: age at transplantation (10 years classes), year of transplant, interval from diagnosis to transplant (less or more than median day), secondary AML and type of donor (MSD/UD). The characteristics of the 2 groups are summarized in Table 1.Median dose of TBI was 12 Gy (range, 8-16). In this group, TBI was combined with Cyclophosphamide (84% of cases), Fludarabine (14%) or other compounds (2%). On the other hand, Thiotepa was administered with Cyclophosphamide (45%), Fludarabine (54%) with/without Busulfan and other combinations (1%).Engraftment occurred in 96% of patients using Thiotepa-based conditioning versus 99% after TBI (p=0.11). The interval from transplant to neutrophils count>500/µL was 16 days (range, 9-42) versus 17 days (range, 9-81) in the 2 groups, respectively (p=0.23). Acute GvHD grade II+ was observed in 25 patients (27%) after Thiotepa-containing regimen versus 42 patients (25%) after TBI (p=0.78). 2-years cumulative incidence of chronic GVHD was 48±4% and 41±6% in the 2 groups, respectively (p=0.15). The 2-year cumulative incidences of non-relapse mortality (NRM) was 21±4% versus 27±4% (p=0.57) and relapse incidence (RI) was 18±4% versus 21±3% (p=0.71) in the Thiopeta and TBI groups, respectively. The 2-year leukemia-free survival (LFS) and overall survival (OS) were 61±5% and 64±5% in the Thiotepa group versus 51±4% and 52±4% in the TBI group (LFS: p=0.40; OS: p=0.25).This pair-matched analysis suggests that a Thiotepa-based myeloablative conditioning regimen prior to allogeneic HSCT in AML in first CR, can allow achieving similar results to high-dose TBI-based myeloablative conditioning. Also, given the deleterious long term side effects of TBI, it is likely that a Thiotepa-based myeloablative conditioning would represent an attractive and valid alternative to TBI. Prospective trials are currently planned in this setting.Bacigalupo: ADIENNE : Speakers Bureau. Mohty:Riemser : Research Funding.

Risitano: Alexion: Membership on an entity's Board of Directors or advisory committees, Research Funding.