E-SHAP: An effective treatment in selected patients with relapsed non-Hodgkin's lymphoma

BACKGROUND:: The optimal treatment of relapsed or refractory non-Hodgkin'slymphoma is unknown. The reported encouraging results of a salvageregimen, E-SHAP (etoposide 40 mg/m²/day x 4, methyl prednisolone500 mg daily x 4, cytosine arabinoside 2 gm/m² one dose andcisplatinum 25 mg/m²/day x 4), at the MD. Anderson Hospitalin Texas, which resulted in a 65% response rate, could not bereproduced in the United Kingdom (0% response). PATIENTS AND METHODS:: Twenty-six patients with relapsed (n = 16) or refractory (n= 10) non-Hodgkin's lymphoma were treated at our Centre by amodified E-SHAP regimen (cytosine arabinoside 1 gm/m² one dose).The treatment was intended as remission induction before BMT(n = 16), as salvage by itself (n = 5) and for palliation ofsymptoms (n = 5). RESULTS:: The overall response rate was 72% (CR = 7 and PR = 11). A comparisonof Kaplan-Meier curves showed a statistically significant improvementin median relapse-free survival in patients who had previouslyachieved CR (p = 0.0012), no bulky disease (P = 0.0006) andno B-symptoms (P = 0.0004). The toxicity was acceptable: 8 instancesof febrile neutropenia, 2 of reversible renal impairment and2 symptomatic electrolyte abnormalities. No fatal toxicitieswere encountered. The median time to treatment failure was 191days and median overall survival was 190 days. CONCLUSIONS:: E-SHAP is an active combination chemotherapy when used as asalvage regimen or for remission induction before bone marrowtransplantation in selected patients with relapsed non-Hodgkin'slymphoma. Patients who previously achieved CR, with low tumourburden and no B-symptoms are the best candidates for this treatment.It has a limited palliative effect. non-Hodgkin's lymphoma, salvage chemotherapy, etoposide, cisplatinum     

P53 mutations in hepatocellular carcinoma patients in Egypt

The p53 gene plays a major role in hepatocellular carcinoma (HCC). Acquired mutations may provide clues to etiology, as some carcinogenic agents are associated with specific genetic changes in p53. Our aim was to analyze the spectrum of p53 mutations in tumor tissues from subjects with HCC in Egypt, where there is a rising incidence of HCC due to hepatitis C virus (HCV). We collected tumor tissues from 41 subjects with HCC diagnosed at the National Cancer Institute of Cairo University during 2000-2003. Sequence mutations were analyzed by the Affymetrix GeneChip technique. HCV RNA was detected in the sera of 37 subjects (90%). Only one patient had a current HBV infection. A total of 17 of the 41 subjects (41%) had p53 mutations. Thirteen of these were in exon 7, of which 10 were in codon 249, but only 8 of the 10 were the R249S mutation, previously reported to be associated with aflatoxin exposure. The other three exon 7 mutations were found in codons 232, 242 and 248. A total of three mutations were detected in exon 5 codons 133, 144 and 176. One mutation was detected in exon 8 codon 275. Unlike previous studies, this population is characterized by a high prevalence of chronic HCV infection. The presence of the R249S mutation in exon 7 may indicate that these subjects with HCC have been exposed to aflatoxin (AFB1), and further investigation is in progress to measure AFB1-albumin adducts in the sera of these subjects.     

Epidemiology of esophageal cancer in Iran,with special reference to nutritional and cultural aspects

A multidisciplinary epidemiological investigation was instituted to find clues to the peculiar geographical distribution of esophageal cancer in the Caspian Littoral of Iran, where in some Turkoman villages, the incidence is among the highest in the world. This article reviews the findings concerning cultural habits, dietary patterns, staple food items, environmental exogenous carcinogens, and cocarcinogens in both high- and low-incidence areas, and their possible association with the disease. This is a good example of the importance of international cooperation in epidemiologic investigations.     

Prevalence of Helicobacter pylori, gastric myoelectrical activity, gastric mucosal changes and dyspeptic symptoms before and after laparoscopic cholecystectomy

BACKGROUND/AIMS: Cholecystectomy may lead to anatomic and functional alterations which eventually induce reflux of duodenal contents with its sequlae. The aim of this study is to evaluate the prevalence of Helicobacter pylori (H. pylori), gastric myoelectrical activities and gastric mucosal changes before and after laparoscopic cholecystectomy. METHODOLOGY: This prospective study has been carried out on 46 patients (20 M & 26 F) with mean age 41.7+/-0.2 years for whom laparoscopic cholecystectomy for gallstones was carried out. Prior to the operation and 1 year after, all patients were subjected to clinical assessment, upper gastrointestinal endoscopy, histopathology of antral mucosa, reflux gastritis score, detection of H. pylori and electrogastrography. RESULTS: There was an increase in the postoperative suggestive symptoms of reflux gastritis compared to the preoperative: epigastric pain increased from 8 (17.4%) to 11 (23.39%) patients, nausea increased from 6 (13%) to 12 (26.1%) and bilious vomiting increased from 3 (6.5%) to 11 (23.9%) patients. Mild antral gastritis was detected endoscopically before laparoscopic cholecystectomy in 20 patients (43.5%) and increased to 27 patients (58.7%) after surgery. Meanwhile, severe antral gastritis and erosions were only detected after the operation in 10 (21.7%) patients, respectively. The histological results showed an increase of the histopathologic score of reflux gastritis after cholecystectomy from 4.28 (+/-1.56) to 9.28 (+/-1.99) (p<0.001). Active chronic superficial gastritis decreased from 23 (50%) to 13 (28.2%) patients while the inactive form increased from 15 (32.6%) to 23 (50%) patients. Also, chronic atrophic gastritis, intestinal metaplasia and dysplasia were detected postoperatively in 4 (8.6%) patients. The incidence of H. pylori infection was decreased from 32 (69.6%) to 19 (41.3%) patients (p<0.0001). Electrogastrography abnormal frequency decreased in fasting from 26.1% to 8.7% (p<0.001), and postprandial from 16.9% to 4.4% recording (p<0.002). On the other hand, there was an increase in the number of patients with decreased electrogastrography amplitude after a meal from 4.3% to 28.3% (p<0.0001). CONCLUSIONS: Our study shows that dyspeptic symptoms, endoscopic and histologic gastric changes as well as electrogastrography abnormalities are present before and increase after cholecystectomy; meanwhile H. pylori colonization in gastric mucosa is decreased after cholecystectomy.     

Vitamin D and its analog EB1089 induce p27 accumulation and diminish association of p27 with Skp2 independent of PTEN in pituitary corticotroph cells

Disruption of the gene for the cyclin dependent kinase inhibitor (CDKI) p27/kip1 results in pituitary corticotroph hyperplasia while diminished expression of this protein has been described in aggressive human pituitary tumors. We have previously shown that 1,25-vitamin D3 (VD) hypophosphorylates p27 and interferes with the degradation of this CDKI in thyroid carcinoma cells. In this study we investigated whether VD/EB1089 can induce p27 accumulation and cause growth arrest of pituitary corticotroph cells. VD and EB1089 exhibited a significant reduction in AtT20 corticotroph but not PRL235 lactotroph cell growth. These changes were accompanied by selective accumulation of p27 in AtT20 but not in PRL235 cells. As p27 levels are highly dependent on protein degradation, we examined the effect of VD/EB1089 on p27 association with factors that target this CDKI to the proteasome. VD/EB1089 significantly restricted the association of p27 with Skp2 as well as with cyclin dependent kinase 2 (CDK2). As the tumor suppressor and phosphatase PTEN has been implicated in p27 regulation, we tested whether the effects of VD/EB1089 on p27 accumulation in corticotrophs could be mediated through this pathway. VD/EB1089 did not appreciably alter PTEN expression. Moreover, transfection of PTEN did not influence the effect of VD on p27 accumulation in corticotrophs. We conclude that VD/EB1089 can selectively arrest pituitary corticotroph growth and induce p27 accumulation.This effect is mediated at least partially through diminished p27 association with Skp2 and with CDK2. In contrast to other cell systems, PTEN does not participate in the regulation of corticotroph p27 and is not involved in mediating the effect of VD on p27 in these cells. Our findings highlight p27 and VD analogs as targets for manipulation and drug development respectively in the treatment of inoperable corticotroph adenomas.     

A pilot trial of combination cisplatin, 5-fluorouracil and interferon-alpha in the treatment of advanced esophageal carcinoma

BACKGROUND/OBJECTIVES: Based on the synergistic effect between cisplatin and 5-fluorouracil (5-FU), and between 5-FU and interferon-alpha, we conducted a trial to assess the response rate and toxicity of the combination of cisplatin, 5-FU and interferon-alpha in patients with advanced esophageal cancer. METHODS: Patients with locally advanced or metastatic squamous cell or adenocarcinoma of the esophagus were eligible. No prior chemotherapy or interferon were allowed. Patients received cisplatin 80 mg/m(2) on day 1, 5-FU 750 mg/m(2)/day by continuous intravenous infusion for 5 days, and interferon-alpha 5 x 10(6) units/m(2)/day by subcutaneous injection on days 1-5 of each cycle. Cycles were repeated every 21 days for a total of 6 cycles. RESULTS: Forty patients were enrolled. Median age was 57.5 years (range 30-70). 33 had squamous carcinoma and 7 adenocarcinoma; 15 were male; the locoregional metastatic ratio was 1:39; median ECOG performance status was 2 (range 1-3). Grade 3-4 toxicities were: leukopenia (9 cases), thrombocytopenia (4), electrolyte imbalance (11), febrile neutropenia (11), vomiting (5), diarrhea (4), and mucositis (11). There were 3 early deaths, most probably related to therapy. Five patients (13%) achieved a complete response and 17 (42%) achieved a partial response, yielding an overall response rate of 55%. Response rates for squamous and adeno histology were 61% and 29%, respectively. Median survival was 6.4 months. CONCLUSION: The combination of cisplatin, 5-FU and interferon-alpha produces a high response rate in advanced squamous cell esophageal carcinoma, but with considerable toxicity. A modified combination of the above agents is presently being evaluated at our institution.     

Short-term safety and efficacy of human GH replacement therapy in 595 adults with GH deficiency: a comparison of two dosage algorithms

The aim of GH replacement therapy in GH-deficient adults is to optimize response with minimum incidence of adverse reactions, but optimal therapy regimens are still to be established. This two-arm parallel study examined effects of two GH dose algorithms in adults with GH deficiency of adult or childhood onset. Patients on low dose (LD; n = 302) received GH at 3 microg/kg per day for 3 months increasing to 6 microg/kg per day for 3 months, and those on conventional dose (CD; n = 293) started on 6 microg/kg per day for 3 months increasing to 12 microg/kg per day for 3 months. The proportion of patients completing therapy was greater for the LD group than the CD group for the first 3 months (93.0% vs. 88.1%; P = 0.037) and overall for the 6 months (90.7% vs. 84.0%; P = 0.013). Both dose groups showed significant increases in lean body mass and decreases in fat mass for all time points. Percent increase in lean body mass was less with LD than CD over the first 3 months (2.43 +/- 4.33 vs. 3.58 +/- 4.69%; P = 0.006) but not overall for the 6-month period (4.38% +/- 5.34% vs. 5.21% +/- 5.99%; P = 0.141). Percent decrease in fat mass was less with LD than CD for the first 3 months (-2.81% +/- 7.81% vs. -5.53% +/- 8.64%; P < 0.001) and overall for the 6-month period (-6.35% +/- 9.42% vs. -9.45% +/- 12.07%; P = 0.006). IGF-I SD score increased less with LD than CD for 0 to 3 and 0 to 6 months, although for IGF-binding protein-3 SD score, there was no significant difference between doses at any time. Arthralgia was the only adverse event that occurred significantly less frequently with LD than with CD. Calculated changes based on gender and onset indicated greater changes in males than females for body composition, but there was little difference in GH-related adverse events between males and females. The lower starting dose with dose titration appeared more favorable, but differences in response between genders and onset of GH deficiency need to be taken into account when setting an individual dose regimen.     

Tumor necrosis factor-alpha inhibits insulin-induced increase in endothelial nitric oxide synthase and reduces insulin receptor content and phosphorylation in human aortic endothelial cells

Insulin exerts a vasodilatory effect through the release of nitric oxide (NO) from the endothelium. We have recently demonstrated that insulin also inhibits the expression of intracellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1), 2 major proinflammatory mediators, by human aortic endothelial cells (HAEC) and the proinflammatory mediator, nuclear factor (NF-kappa B), in the nucleus in parallel with an increase in endothelial nitric oxide synthase (e-NOS) expression. The inhibition of ICAM-1 by insulin is NO dependent. Because tumor necrosis factor-alpha (TNF-a ) is proinflammatory and may thus inhibit the action of insulin at the endothelial cell level, we have now investigated whether TNF-a affects (1) insulin receptor content; (2) insulin receptor (IR) autophosphorylation induced by insulin, and (3) e-NOS expression by the endothelial cells. TNF-alpha (1 to 5 ng/mL) caused e-NOS inhibition in a dose-dependent fashion as measured by Western blotting. This inhibition was reduced with insulin addition. TNF-alpha also inhibited tyrosine autophosphorylation of the IR in HAEC induced by insulin and reduced IR beta-subunit protein expression in HAEC. These effects of insulin and TNF-alpha were independent of cell proliferation, as cell counts did not change with insulin or TNF-alpha. Our data demonstrate that TNF-alpha may exert its effect by inhibiting IR autophosphorylation in HAEC and also by reducing IR protein (IRP) expression. Although the inhibition of IR autophosphorylation by TNF-alpha is known to occur at the adipocyte level, the data on the inhibitory effect of TNF-alpha on insulin-induced e-NOS expression and IRP contents are novel.     

Women awaiting knee replacement have reduced function and growth hormone

Women experience greater functional impairment and occurrence of osteoarthritis than men. We hypothesized that lower levels of serum insulin-like growth factor-I may contribute to gender differences in physical impairments. A cross-sectional comparison (n = 139) was done on candidates having total knee arthroplasty and healthy controls subjects of similar age (range, 55-75 years). Physical function, perceived function, and serum insulin-like growth factor levels were compared across group and gender using analysis of variance. Insulin-like growth factor-I values were markedly reduced in women overall and women having surgery had significantly reduced levels despite lean body mass correction. Values consistent with clinical hormone deficiency were observed in 21% of women and only 4% of men having arthroplasty. Physical function was markedly reduced in women, at times functioning only 33% when compared with healthy women, whereas men's limitations were not as profound. The current findings indicate that physical function is more impaired and serum insulin-like growth factor-I is markedly reduced in women awaiting arthroplasty than their male counterparts. The gender differences observed biochemically and with functional performance indicate that the pathophysiology of end stage osteoarthritis may differ between men and women.