Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop.

OBJECTIVE: Our objective was to summarize important advances in the management of children with idiopathic short stature (ISS). PARTICIPANTS: Participants were 32 invited leaders in the field. EVIDENCE: Evidence was obtained by extensive literature review and from clinical experience. CONSENSUS: Participants reviewed discussion summaries, voted, and reached a majority decision on each document section. CONCLUSIONS: ISS is defined auxologically by a height below -2 sd score (SDS) without findings of disease as evident by a complete evaluation by a pediatric endocrinologist including stimulated GH levels. Magnetic resonance imaging is not necessary in patients with ISS. ISS may be a risk factor for psychosocial problems, but true psychopathology is rare. In the United States and seven other countries, the regulatory authorities approved GH treatment (at doses up to 53 microg/kg.d) for children shorter than -2.25 SDS, whereas in other countries, lower cutoffs are proposed. Aromatase inhibition increases predicted adult height in males with ISS, but adult-height data are not available. Psychological counseling is worthwhile to consider instead of or as an adjunct to hormone treatment. The predicted height may be inaccurate and is not an absolute criterion for GH treatment decisions. The shorter the child, the more consideration should be given to GH. Successful first-year response to GH treatment includes an increase in height SDS of more than 0.3-0.5. The mean increase in adult height in children with ISS attributable to GH therapy (average duration of 4-7 yr) is 3.5-7.5 cm. Responses are highly variable. IGF-I levels may be helpful in assessing compliance and GH sensitivity; levels that are consistently elevated (>2.5 SDS) should prompt consideration of GH dose reduction. GH therapy for children with ISS has a similar safety profile to other GH indications.

Phase II study of single-agent pegylated liposomal doxorubicin HCl (PLD) in metastatic breast cancer after first-line treatment failure.

OBJECTIVES: Aim of this study was to evaluate the clinical benefit and the toxicity of pegylated liposomal doxorubicin. PATIENTS AND METHODS: Patients with metastatic breast cancer (n = 30) who failed a prior chemotherapy regimen for metastatic disease received 45 mg/m2 pegylated liposomal doxorubicin (PLD) every 4 weeks following prophylactic administration of metoclopramide (10 mg) and dexamethasone (8 mg). RESULTS: 29 of 30 patients were assessed for clinical benefit and time to progression. All patients were assessed for toxicity and analysis of overall survival. 9 patients (31%) had a partial response, and 16 patients (55%) responded with stable disease, resulting in a clinical benefit rate of 86% (n = 25). Median time to progression was 4 months (95% CI: 2.8-5.2), median duration of response was 7 months (95% CI: 4.7-8.2), and median survival was 12 months (95% CI: 6.7-17.2). Skin toxicity was the most common adverse event (30%, all < or = grade 2). Other toxicities were remarkably low in occurrence. CONCLUSION: PLD is a well-tolerated, second-line monotherapy with a high rate of clinical benefit.

Cellular adhesion of primary Sertoli cells affects responsiveness of the extracellular signal-regulated kinases 1 and 2 to follicle-stimulating hormone but not to epidermal growth factor.

The cellular adhesion status and the exposure to soluble growth factors both contribute to mitogen-activated protein (MAP) kinase activation. To date, however, whether mitogens acting through G-protein-coupled receptors (GPCRs) need cell adhesion to activate MAP kinases/extracellular signal-regulated kinases (ERK) 1, 2 has been poorly investigated. We addressed this point in primary cultures of Sertoli cells experimentally maintained in suspension, considering that follicle-stimulating hormone (FSH) activates ERK1, 2 in attached Sertoli cells by acting through a GPCR. We found that FSH actively repressed ERK1, 2, in a cAMP-dependent but cAMP-dependent protein kinase (PKA)-independent manner, and this inhibition required the activity of a tyrosine phosphatase. In comparison, in the absence of anchorage, ERK1, 2 were still activated by epidermal growth factor, in a PKA-dependent manner. Altogether, these data suggest that sensitivity of the MAP kinase response toward cell adhesion may depend, at least in part, on the class of receptor, GPCR or receptor with tyrosine kinase activity, by which it is triggered.

The ERK-dependent signalling is stage-specifically modulated by FSH, during primary Sertoli cell maturation.

Primary cultures of Sertoli cells provide an interesting model to study how signalling pathways induced by a single hormone in a single cell type evolve, depending on the developmental stage. In vivo, follicle-stimulating hormone (FSH) induces proliferation of Sertoli cells in neonate and controls the subsequent differentiation of the entire population. Molecular mechanisms underlying Sertoli cell pleiotropic responses to FSH have long been investigated. But to date, only cAMP-dependent kinase (PKA) activation has been reported to account for most FSH biological activities in male. Here, we demonstrate that FSH activates the ERK MAP kinase pathway following dual coupling of the FSH-R both to Gs and to Gi heterotrimeric proteins, in a PKA- and also Src-dependent manner. This activation is required for FSH-induced proliferation of Sertoli cells isolated 5 days after birth. Consistently, we show that the ERK-mediated FSH mitogenic effect triggers upregulation of cyclin D1. In sharp contrast, at 19 days after birth, as cells proceed through their differentiation program, the ERK pathway is dramatically inhibited by FSH treatment. Taken together, these results show that FSH can exert opposite effects on the ERK signalling cascade during the maturation process of Sertoli cells. Thus, signalling modules triggered by the FSH-R evolve dynamically throughout development of FSH natural target cells.

Cost effectiveness of computer tailored and non-tailored smoking cessation letters in general practice: randomised controlled trial.

OBJECTIVES: To develop and evaluate, in a primary care setting, a computerised system for generating tailored letters about smoking cessation. DESIGN: Randomised controlled trial. SETTING: Six general practices in Aberdeen, Scotland. PARTICIPANTS: 2553 smokers aged 17 to 65. INTERVENTIONS: All participants received a questionnaire asking about their smoking. Participants subsequently received either a computer tailored or a non-tailored, standard letter on smoking cessation, or no letter. MAIN OUTCOME MEASURES: Prevalence of validated abstinence at six months; change in intention to stop smoking in the next six months. RESULTS: The validated cessation rate at six months was 3.5% (30/857) (95% confidence interval 2.3% to 4.7%) for the tailored letter group, 4.4% (37/846) (3.0% to 5.8%) for the non-tailored letter group, and 2.6% (22/850) (1.5% to 3.7%) for the control (no letter) group. After adjustment for significant covariates, the cessation rate was 66% greater (-4% to 186%; P=0.07) in the non-tailored letter group than that in the no letter group. Among participants who smoked <20 cigarettes per day, the cessation rate in the non-tailored letter group was 87% greater (0% to 246%; P=0.05) than that in the no letter group. Among heavy smokers who did not quit, a 76% higher rate of positive shift in "stage of change" (intention to quit within a particular period of time) was seen compared with those who received no letter (11% to 180%; P=0.02). The increase in cost for each additional quitter in the non-tailored letter group compared with the no letter group was pound 89. CONCLUSIONS: In a large general practice, a brief non-tailored letter effectively increased cessation rates among smokers. A tailored letter was not effective in increasing cessation rates but promoted shift in movement towards cessation ("stage of change") in heavy smokers. As a pragmatic tool to encourage cessation of smoking, a mass mailing of non-tailored letters from general practices is more cost effective than computer tailored letters or no letters.

Impact of olfactory impairment on quality of life and disability.

OBJECTIVE: To determine whether olfactory loss affects patients' quality of life or level of disability. DESIGN: Retrospective survey using questionnaire data and clinic database review. SETTING: Two university medical center smell and taste clinics. PATIENTS: A total of 1407 patients were tested for smell and taste disturbances from 1984 through 1998. Surveys were mailed to 1093 patients who had abnormal test scores; 420 (38.4%) returned completed surveys. Patients were grouped by self-rated ability to smell as "impaired" (those reporting persisting deficits) or "improved" (those reporting no smell problem when surveyed). MAIN OUTCOME MEASURES: Response frequencies were compared between the 2 groups for questions regarding ability to perform common activities of daily living and quality-of-life issues. RESULTS: Mean (+/-SD) number of activities of daily living affected by olfactory loss was 4.70 +/- 3.56 for the impaired group and 0.61 +/- 1.58 for the improved group (P < .001). Among specific activities, the most common cited impairments were ability to detect spoiled food (impaired vs improved groups, 75% vs 12%; P < .001), gas leaks (61% vs 8%; P < .001), or smoke (50% vs 1%; P < .001); eating (53% vs 12%; P < .001); and cooking (49% vs 12%; P < .001). Differences in quality-of-life issues were reported primarily in the areas of safety and eating. Overall satisfaction with life was reported by 87% of the improved group but only 50% of the impaired group (P < .001). CONCLUSIONS: Patients reporting persistent olfactory impairment after previously documented olfactory loss indicate a higher level of disability and lower quality of life than those with perceived resolution of olfactory compromise.

Early initiation of growth hormone treatment allows age-appropriate estrogen use in Turner's syndrome.

Because estrogen (E) accelerates skeletal maturation it can decrease final height attainable with GH therapy in girls with Turner's syndrome (TS). Nonetheless, as age-appropriate E administration does have psychobehavioral benefits for such patients, we asked whether E treatment in TS could occur without adverse impact on final adult height if GH therapy were started at an earlier age. Near adult height (NAH) was assessed in 344 girls with TS, who had received both GH and E and were followed in the National Cooperative Growth Study database. The groups were divided into quartiles based on age at initiation of GH (2-10, 10-12, 12-14, and 14-18 yr). The longest total and E-free period of GH treatment occurred in the girls who had started treatment in the youngest quartile (mean age, 8.2 +/- 1.5 (SD) yr); they were also exposed to E at the youngest age (12.7 +/- 1.6 yr). Although the girls in the youngest group received E at an earlier age, they had a significantly greater increase (1.8 +/- 0.8) in Lyon height SD score at NAH over Lyon predicted adult height than those in the oldest GH-treated group (0.8 +/- 0.6), which first received E at 15.9 +/- 1.3 yr. Multiple linear regression equations for gain in Lyon height SD score and in height (cm) showed greater increments with a longer period of E-free GH therapy. All four GH age groups had the same NAH, but the youngest quartile was youngest at NAH and likely still having more growth potential. Comparable data were found in 127 TS girls with spontaneous puberty. In conclusion, girls with TS starting GH at an early age have a greater gain in Lyon SD score at NAH compared with those starting later, even though they received E at a younger age. If GH therapy were started early, E treatment could be initiated at a younger, more age-appropriate time without compromising adult height.

A novel messenger ribonucleic acid homologous to human MAGE-D is strongly expressed in rat Sertoli cells and weakly in Leydig cells and is regulated by follitropin, lutropin, and prolactin.

We have cloned a novel complementary DNA whose expression was decreased in rat Sertoli cell cultures after treatment with FSH. This complementary DNA encodes a protein of 570 amino acids and shares 92% homology with the human MAGE-D protein. In contrast to other MAGE genes (A, B, or C), we have shown that MAGE-D expression was ubiquitous in healthy rat tissues. In the seminiferous tubules, the MAGE-D was expressed in Sertoli cells but not in germ cells as demonstrated by RT-PCR and in situ hybridization, whereas for the other MAGE genes, expression has been shown to be restricted to germ cells. Interestingly, MAGE-D was also detected for the first time in the female gonad by Northern blotting. In MLTC-1 cells (mouse Leydig tumor cell line-1), LH and PRL stimulated MAGE-D expression. Using hypophysectomized rats, it was confirmed that FSH decreased MAGE-D expression, whereas LH and PRL increased MAGE-D messenger RNA level in the whole testis most probably through a direct action on Leydig cells. As MAGE-D is present in both the seminiferous compartment and interstitium and hormonally regulated in each, it is possible that it has specific functions in each compartment during the development and the maintenance of the testis.

Low curative potential of bone marrow transplantation for highly aggressive acute myelogenous leukemia with inversioin inv (3)(q21q26) or homologous translocation t(3;3) (q21;q26).

Structural rearrangements of the long arm of chromosome 3 involving bands 3q21 and 3q26 and leading either to a paracentric inversion inv (3)(q21q26) or a translocation between both homologous chromosomes--t(3;3)(q21q26)-- have been reported in patients with acute myelogenous leukemia (AML), myelodysplastic syndromes, myeloproliferative disorders, and chronic myelogenous leukemia in blast crisis. We describe three patients with de novo AML with these structural abnormalities who received multiple courses of conventional chemotherapy followed by unrelated donor (n=2) and autologous (n = 1) bone marrow transplantation (BMT). All three patients had early relapse: patients 1 and 2 had relapse 69 days and 306 days after BMT, respectively, and patient 3 immediately after autologous BMT. Despite further chemotherapy, they died without achieving another remission. These findings, together with other recorded similar cases, show that AML with structural abnormalities of the long arm of chromosome 3 as described has an extremely poor prognosis even with the most potent anti-leukemic treatment modalities.

Regeneration of erythropoiesis after related- and unrelated-donor BMT or peripheral blood HPC transplantation: a major ABO mismatch means problems.

BACKGROUND: Blood group incompatibility in allogeneic BMT is common but does not appear to affect the outcome in terms of incidence of graft rejection or delayed engraftment. However, major ABO incompatibility may be associated with prolonged erythroid aplasia. STUDY DESIGN AND METHODS: In a retrospective analysis of 286 allogeneic transplant recipients, the prevalence of prolonged erythroid aplasia, including pure RBC aplasia, was determined. RESULTS: Patients receiving major ABO-incompatible grafts showed a significant delay in reticulocyte engraftment (median, 32 days; range, 12-347) from that in patients receiving ABO-identical (20; 10-152) or minor ABO-incompatible (21; 12-47) grafts. Pure RBC aplasia occurred in 7 (3%) of 240 evaluable recipients and was observed only in the major ABO-incompatible group (7/43, 16%). Treatment of pure RBC aplasia consisted of either plasma exchange, which resulted in a response within 16 to 68 days, or immunoadsorption, in which the response occurred between Days 119 and 204 after initiation of treatment. CONCLUSION: Major ABO incompatibility may lead to delayed reticulocyte engraftment, resulting in prolonged transfusion dependency and increased risks of transmission of infection and iron overload. Therefore, therapeutic strategies should be taken into consideration to allow erythroid reconstitution in these patients.

Relapse of chronic myelogenous leukemia 12 years after allogeneic marrow transplantation: successful second transplantation with allogeneic peripheral blood progenitor cells.

We report on a 31-year old female patient who relapsed with CML in blast crisis 12 years after a successful BMT for CML in chronic phase from her HLA-identical sister. Because of her good performance status and the long time elapsed since her first BMT, PBPC transplantation of the originial donor was planned. Therefore, the patient was conditioned with busulfan and cyclophosphamide and then received unmanipulated PBPCs from her sister. GVHD prophylaxis consisted of MTX and CsA. She had early engraftment but considerable hepatotoxicity which resolved after more than six months. Furthermore, she developed acute GVHD of the skin grade 2, which responded to corticosteroids. Fifteen months after second transplantation the patient is alive and well in molecular remission and without signs of chronic GVHD.

Long-term follow-up of patients after related- and unrelated-donor bone marrow transplantation for chronic myelogenous leukemia.

Between January 1983 and December 1997, 88 patients (36 female, 52 male, median age 37 years, range 19-57) with chronic myelogenous leukemia (CML) underwent allogeneic bone marrow transplantation (BMT) at the University Hospital of Vienna. Sixty patients were in chronic phase, 18 in accelerated phase, and ten in blast crisis. Marrow donors were HLA-identical siblings for 64 patients (BM 58, PBSC 6), 2-antigen-mismatched related donors (RD) for two, HLA-identical unrelated donors (URD) for 17, and 1-antigen-mismatched URD for five. The median time from diagnosis to BMT was 22 months (range 2-91), and 63 patients had received prior interferon (IFN)-alpha therapy, 46 (73%) for more than 6 months. Conditioning therapy consisted of cyclophosphamide (CY) and total body irradiation (TBI) in 71 patients and CY and busulfan (BU) in 16. One patient received etoposide and TBI. For graft-versus-host disease (GVHD) prophylaxis methotrexate (MTX) was given to 12 patients, MTX and cyclosporin A (CSA) to 67, CSA alone to four, and CSA and methylprednisolone to five. Durable engraftment was documented in 80 of 82 patients (98%). As of December 31, 1997, 52 patients (59%) were alive, 38 (58%) after sibling transplantation with a median observation time of 73 months and 14 (64%) after URD transplantation with a median observation time of 12 months. Probability of overall survival is 59%, for patients undergoing transplantation in chronic phase and 44% for patients undergoing transplantation in advanced stage CML. Probability of disease-free survival (DFS) after sibling and URD BMT is 55% and 59%, respectively. Ten patients (12%) experienced relapse of CML. Transplant-related mortality was 32% both after RD and after URD transplantation. Acute GVHD occurred in 53 of 80 evaluable patients (66%), consisting of grade III or IV in 14 patients (18%). Chronic GVHD developed in 40 of 63 eligible patients (63%), including extensive disease in 26 patients (41%). Thus, sibling and URD BMT offer high cure rates with acceptable toxicity to patients with CML.

A novel gene overexpressed in the prostate of castrated rats: hormonal regulation, relationship to apoptosis and to acquired prostatic cell androgen independence.

We have identified a novel complementary DNA (cDNA) corresponding to a gene overexpressed in the rat ventral prostate after castration. This cDNA displays 89.4% identity with 453 bp of a mouse EST and 81.5% identity with 157 bp of a human EST and was named PARM-1 for prostatic androgen-repressed message-1. The complete cDNA is 1187 bp long and codes for a protein of 298 amino acids that contains four potential glycosylation sites and three half cystinyl residues. The PARM-1 gene was found to be expressed at quite low levels in most rat tissues including those of the urogenital tract. The kinetic of induction of PARM-1 gene in the prostate was highly correlated to the development of apoptosis in the whole organ. Supplementation of castrated animals with androgens reversed both the process of apoptosis and the overexpression of PARM-1 gene. Supplementation with estrogens did not result in an increase in the PARM-1 messenger RNA levels when compared with the castration alone. However, the treatment resulted in a more rapid return to intact levels in the castrated plus estrogen group. When apoptosis of testis and prostate was induced in vivo by hypophysectomy, it was found that PARM-1 was only overexpressed in the prostate. Therefore, PARM-1 seems to be regulated by androgens only in the prostate. Using in situ hybridization and immunohistological techniques, we have shown that PARM-1 gene product is found exclusively in the epithelial cells of involuting prostate. Analysis by flow cytometry of MAT LyLu epithelial cells transiently expressing PARM-1 protein did not allow us to demonstrate a direct effect of PARM-1 gene overexpression on the programmed death of the transfected cells. Treatment of MAT LyLu cells by transforming growth factor-beta induced apoptosis but had no effect on PARM-1 production. However PARM-1 protein has been detected by Western blotting in various cell lines such as MAT LyLu, MAT Lu, and PIF, which are androgen independent. This would suggest that PARM-1 gene product would be a marker for acquired androgen-independence of these tumor cells.

Involvement of G protein-coupled receptor kinases and arrestins in desensitization to follicle-stimulating hormone action.

FSH rapidly desensitizes the FSH-receptor (FSH-R) upon binding. Very little information is available concerning the regulatory proteins involved in this process. In the present study, we investigated whether G protein-coupled receptor kinases (GRKs) and arrestins have a role in FSH-R desensitization, using a mouse Ltk 7/12 cell line stably overexpressing the rat FSH-R as a model. We found that these cells, which express GRK2, GRK3, GRK5, and GRK6 as well as beta-arrestins 1 and 2 as detected by RT-PCR and by Western blotting, were rapidly desensitized in the presence of FSH. Overexpression of GRKs and/or beta-arrestins in Ltk 7/12 cells allowed us to demonstrate 1) that GRK2, -3, -5, -6a, and -6b inhibit the FSH-R-mediated signaling (from 71% to 96% of maximal inhibition depending on the kinase, P < 0.001); 2) that beta-arrestins 1 or 2 also decrease the FSH action when overexpressed (80% of maximal inhibition, P < 0.01) whereas dominant negative beta-arrestin 2 [319-418] potentiates it 8-fold (P < 0.001); 3) that beta-arrestins and GRKs (except GRK6a) exert additive inhibition on FSH-induced response; and 4) that FSH-R desensitization depends upon the endogenous expression of GRKs, since there is potentiation of the FSH response (2- to 3-fold, P < 0.05) with antisenses cDNAs for GRK2, -5, and -6, but not GRK3. Our results show that the desensitization of the FSH-induced response involves the GRK/arrestin system.

Pneumatosis [correction of Pneumocystis] cystoides intestinalis with pneumoperitoneum and pneumoretroperitoneum in a patient with extensive chronic graft-versus-host disease.

Pneumatosis cystoides intestinalis is a rare finding of intramural gasfilled cysts in the bowel wall and sometimes free air in the abdomen. A few conditions are reported to cause this disease, one of them being immunosuppression. We describe a 50-year-old Caucasian male with extensive chronic graft-versus-host disease (GVHD) of the gut and skin who developed PCI with pneumoperitoneum and pneumoretroperitoneum. To our knowledge, this is the first report of PCI occurring in a patient with active chronic GVHD which resolved spontaneously.

Anaplastic squamous cell carcinoma (SCC) in a patient with chronic cutaneous graft-versus-host disease (GVHD).

We describe an allogeneic bone marrow (BM) recipient who developed aggressive, metastasizing squamous cell cancer (SCC) of the skin, and discuss possible risk factors in the development of this secondary solid tumor. The patient had been treated with cyclosporine (CsA), methyl-prednisolone and thalidomide for 3 years because of extensive de novo chronic cutaneous GVHD occurring 1 year after BMT. Ten years after BMT a locally invasive and metastasizing SCC occurred on the patient's neck, and diagnosis was confirmed by H&E histopathology and cytokeratin-immunohistochemistry. Analysis of genomic DNA did not reveal p53 mutations nor were HPV sequences detectable. Risk factors included conditioning for BMT with total body irradiation (TBI) and cyclophosphamide (Cy), immunosuppressive treatment for GVHD, and extensive exposure to UV radiation before and after BMT. Despite surgery and adjuvant chemotherapy with 5-fluorouracil (5-FU) the patient died 1 year after the diagnosis of SCC.

Effect of high-dose melphalan and peripheral blood stem cell transplantation on renal function in patients with multiple myeloma and renal insufficiency: a case report and review of the literature.

Multiple myeloma with IgG-lambda monoclonal gammopathy and severe renal impairment with light-chain deposit disease was diagnosed in a 51-year-old man. Following conventional therapy with VAD (vincristine, adriamycin, dexamethasone) a partial remission was achieved. Peripheral blood stem cells (PBSC) were then collected following mobilization with cyclophosphamide and recombinant human granulocyte colony-stimulating factor and enriched for CD34-positive cells by immunoaffinity column. Fourteen months after diagnosis high-dose melphalan was given, followed by infusion of CD34-positive PBSC. Aside from mild oral mucositis and trigonitis, high-dose therapy was tolerated well. After he underwent PBSC transplantation his renal function improved, and the patient has been in in continuous complete remission for 1 year. Thus, high-dose chemotherapy can be safely administered to patients with multiple myeloma and severe renal impairment. Our findings confirm previous reports summarized in the current presentation.

Low transplant-related mortality in patients receiving unrelated donor marrow grafts for leukemia.

Transplantation with unrelated donor (UD) marrow has been shown to potentially cure patients with leukemia. Between January 1991 and April 1998, 54 patients with leukemia have received an UD BMT at our institution. Five patients received their UD BMT as a second transplant after a preceding autologous or syngeneic BMT and were excluded from further analysis. Forty-nine patients with leukemia (acute leukemia n = 26; CML n = 23) and a median age of 36 years (range 19-51) were analyzed. For conditioning, all patients received a combination of fractionated TBI and CY. GVHD prophylaxis consisted of MTX and CsA in all patients. As of 30 April 1998, 27 of 49 (55%) patients survive after a median observation time of 18 months. The probability of overall survival for standard risk and high risk patients is 54% and 31% (P = 0.05). Probability of transplant-related mortality (TRM) is 27%, 24% in standard risk and 31% in high risk patients (P = 0.44). Patients younger than 40 years (n = 33) had a similar TRM as patients 40 years and older (n = 16). The probability of relapse is 41% for the whole group, 29% for standard risk and 55% for high risk pts (P<0.05). Our data confirm that UD BMT is an effective treatment for patients with leukemia. TRM is almost similar to related sibling BMT, most probably due to improvements in HLA typing technology, conditioning regimen and supportive patient care.