Selective increase of potassium permeability in red blood cells exposed to acetylphenylhydrazine

Normal human red blood cells, when exposed briefly to acetylphenylhydrazine (APH), acquire Heinz bodies and a propensity for net ion and water loss upon subsequent incubation in an APH-free medium of physiologic sodium and potassium (K) content. The cells can be protected from APH damage by previous deoxygenation. The ion and water loss depend on the presence of a K gradient from cell to medium. In contradistinction to some other types of membrane perturbation in which K permeability is increased, the APH effect is not dependent on calcium. The meaning of these observations is discussed in relation to the vulnerability of the K permeability barrier.     

High-dose chemotherapy with or without total body irradiation followed by autologous bone marrow and/or peripheral blood stem cell transplantation for patients with relapsed and refractory Hodgkin's disease: results in 85 patients with analysis of prognostic factors

Eight-five consecutive patients with relapsed or refractory Hodgkin's disease (HD) underwent high-dose chemotherapy or chemo/radiotherapy followed by autologous bone marrow (ABMT) and/or peripheral blood stem cell (PBSC) transplantation. Two preparative regimens were used. Twenty- two patients (26%) without prior radiation received fractionated total body irradiation (FTBI) 1,200 Gy in combination with high-dose etoposide (VP-16) 60 mg/kg and cyclophosphamide (CTX) 100 mg/kg. Sixty- three patients (74%) with prior radiotherapy received carmustine (BCNU) 450 mg/m2 instead of FTBI. The median age was 32 years (range, 16 to 56). The median number of prior chemotherapy regimens was three (range, 1 to 7). Forty-three patients (51%) received transplants in first relapse or second complete remission (CR), whereas 33 (39%) received transplants after second or subsequent relapse. All relapsed patients, except one, received conventional salvage chemotherapy and/or radiotherapy in an attempt to reduce tumor bulk before transplant. At the time of analysis in April 1994, fifty-seven patients (67%) are alive, including 44 (52%) in continuous CR, with a median follow-up for the surviving patients of 28 months (range, 7 to 66). Thirty patients (35%) relapsed at a median of 9 months (range, 1 to 43). Eleven patients (13%) died of transplant-related complications including veno- occlusive disease of the liver (VOD) in five, acute and late interstitial pneumonitis in three, graft failure in one, cerebral hemorrhage in one, and therapy-induced myelodysplasia (MDS)/acute leukemia in one patient. At a median follow-up of 25 months (range, 0.6 to 66), the cumulative probability of 2-year overall and disease-free survival (DFS) of all 85 patients is 75% (95% confidence interval [CI] 64% to 84%) and 58% (95% CI 47% to 69%), respectively. Three independent prognostic variables were identified by univariate analysis: number of prior chemotherapy regimens, prior radiotherapy, and extranodal disease at ABMT. Multivariate stepwise Cox regression identified the number of prior chemotherapy regimens as the only significant prognostic factor predicting for both relapse and DFS. There were no significant differences in the outcome of the treatment between the two preparative regimens. Our results confirm that high- dose therapy and ABMT is an effective therapy for patients with relapsed or refractory HD. Earlier transplantation is recommended before the development of drug resistance and end organ damage that results from repeated attempts of salvage therapy.     

Emergence of a clinical daptomycin-resistant Staphylococcus aureus isolate during treatment of methicillin-resistant Staphylococcus aureus bacteremia and osteomyelitis

The emergence of a clinically daptomycin-resistant Staphylococcus aureus isolate occurred during treatment of methicillin-resistant S. aureus bacteremia and probable vertebral osteomyelitis. The breakthrough isolate was indistinguishable from pretreatment daptomycin-susceptible isolates by pulsed-field gel electrophoresis. Daptomycin nonsusceptibility was confirmed by MIC and time-kill curve analyses.     

Clinical and genetic analysis of 18 pancreatic carcinoma/melanoma‐prone families

Bartsch DK, Langer P, Habbe N, Matthäi E, Chaloupka B, Sina M, Hahn SA, Slater EP. Clinical and genetic analysis of 18 pancreatic carcinoma/melanoma‐prone families. Families with both melanoma and pancreatic cancer are extremely rare and some are affected with the autosomal dominant inherited familial atypical multiple mole melanoma‐pancreatic cancer (FAMMM‐PC) syndrome. The phenotypic and genotypic expressions of such pancreatic cancer–melanoma prone families are not well defined. The National Case Collection of Familial Pancreatic Cancer of the Deutsche Krebshilfe includes 110 pancreatic cancer families, 18 of which (16%) show an association of pancreatic cancer and melanoma. These 18 families were analysed regarding their phenotype and the prevalence of germline mutations in the candidate genes CDKN2A, BRCA2, CHEK2, NOD2, ARL11 and Palladin (PALLD). There were two types of families: five families with the FAMMM‐PC phenotype and 13 PC/melanoma families without the multiple mole phenotypes (PCMS). The prevalences of PC and melanoma in the two types of families were similar. The prevalence of other tumour types, especially breast carcinoma, was higher (11%) in PCMS‐ than in FAMMM‐PC families (2.4%, p = 0.02). CDKN2A mutations were identified in 2 of 18 (11%) PCMS families. A cosegregating BRCA2 mutation was detected in one PCMS family without breast cancer. None of the reported germline mutations in the NOD2, Palladin, ARL11 or CHEK2 genes were detected in either type of family. In conclusion, families with an accumulation of PC and melanoma show a large variety of phenotypic expression, which is not always consistent with the FAMMM‐PC phenotype. More PC/melanoma‐prone families need to be analysed to clarify whether such families represent variations of the FAMMM‐PC syndrome or two distinct hereditary cancer syndromes.     

Membrane progesterone receptors (mPRs) mediate progestin induced antimorbidity in breast cancer cells and are expressed in human breast tumors

Membrane progesterone receptors (mPRs) have been detected in breast cancer cells and tissues, but their roles in cancer progression remain unclear. Here, we demonstrate the localization, signaling, and antiapoptotic actions of mPRs in two nuclear progesterone receptor (PR)-negative breast cancer cell lines, SKBR3 and MDA-MB-468 (MB468), and mPR expression in human breast tumor biopsies. mPRα, mPRβ, and mPRγ subtypes were detected in both cell lines as well as in breast tumor tissues from 13 individuals irrespective of nuclear steroid receptor expression. Competitive receptor binding studies with a selective PR ligand, R5020, and an mPR agonist, Org OD 02-0 confirmed the presence of functional mPRs on both cancer cell lines. Progesterone treatment of either cell line caused rapid activation of an inhibitory G protein, as well as activation of p42/44 MAP kinase. Treatment with progesterone or Org OD 02-0 significantly decreased cell death and apoptosis in response to serum starvation, whereas testosterone, 17β-estradiol, dexamethasone, and R5020 and RU486 were ineffective. Progesterone treatment of MB468 cells also increased mitochondrial membrane potential and Akt activity, but no decrease in caspase 3 activity was observed. Knockdown of mPRα expression in MB468 cells by siRNA transfection blocked the inhibitory effects of progesterone on cell death. The results indicate that progesterone can act through mPRs to inhibit apoptosis in breast cancer cells. The involvement of mPRs in the development or progression of breast tumor growth through inhibition of cell death is an intriguing possibility and requires further investigation.     

Lower costs associated with hematopoietic cell transplantation using reduced intensity vs high-dose regimens for hematological malignancy

We compared inpatient and outpatient costs alongside clinical outcomes associated with hematopoietic cell transplantation between 2000 and 2003 with high-dose regimens (HDCT, n=185) and with reduced intensity regimens (RICT, n=90) from human leukocyte antigen (HLA)-matched donors for patients with hematological malignancies. With a comparable median follow-up of 3 years, long-term clinical outcomes, including cumulative incidence of chronic graft-vs-host disease, disease-free survival and overall survival, were similar between the two groups. In the univariate analysis, median costs for the first 100 days ($104,380 vs $42,149) and 1 year ($128,253 vs $80,499) in the HDCT group were higher than those in the RICT group. Median days of hospitalization are also higher for HDCT recipients (39 vs 21), although the number of outpatient clinic visits for HDCT recipients were fewer compared to that for RICT recipients (16 vs 25) during the first year. Adjusting for patient characteristics, RICT recipients had approximately 16 fewer days of hospitalization and cost $53,030 less than HDCT recipients within the first year after transplantation. Our data suggest that substantially lower costs and fewer days of hospitalization within the first year after RICT procedures can be obtained with no compromise of long-term clinical outcomes compared to HDCT procedures.