Measurement of circulating levels of VEGF-A, -C, and -D and their receptors, VEGFR-1 and -2 in gastric adenocarcinoma.

AIM: To analyze the serum levels and prognostic significance of vascular endothelial growth factor (VEGF) -A, -C, and -D, and their receptors, VEGFR-1 and -2 in gastric adenocarcinomas. METHODS: The serum levels of VEGF family members were measured in 76 control subjects and 76 patients with gastric adenocarcinoma using an enzyme-linked immunosorbent assay (ELISA). These measurements were correlated with clinco-pathological features and survival rates. RESULTS: The serum levels of VEGF-A and its receptor, VEGFR-1, were significantly higher in patients with gastric cancer than in healthy donors (t = 2.3, P = 0.02 and t = 4.2, P < 0.0001, respectively). In contrast, the serum levels of VEGF-D were significantly higher in control subjects than in patients (t = 2.9, P = 0.004). There was no significant difference in serum levels of VEGF-C and VEGFR-2 between patients and controls. VEGF-C was associated with advanced tumor stage and presence of metastasis. VEGFR-1 was associated with metastasis, advanced overall stage, tumor differentiation and survival. VEGFR-2 levels were associated with poor tumor differentiation. There was no significant prognostic value for any of the VEGF family members or their receptors except for VEGFR-1 where high levels were associated with a poor overall survival. CONCLUSION: Serum VEGF levels vary significantly in the same cohort of patients with variable clinico-pathological features and prognostic values. The simultaneous measurement of VEGF receptors levels in sera may overcome the limitations of a single biomarker assay.

The prognostic determinants of gastric cancer treatment outcome in Omani Arab patients.

BACKGROUND: Gastric cancer is the most common cancer in Oman and a leading cause of cancer death. The variation in survival rates between countries and ethnic groups has been attributed to early detection policies, differences in clinicopathological features, treatment approaches, and biological characteristics. There were no previous reports on gastric cancer from Oman and very few studies on Asian Arabs. AIM: To evaluate the impact of clinicopathological and treatment variables on the survival prospects of Omani Arab patients diagnosed with gastric cancer. METHODS: The medical records of 339 Omani Arab patients diagnosed with invasive gastric adenocarcinoma during the period 1993-2004 were retrospectively reviewed. The relative importance of clinicopathological features and surgical and medical treatments were assessed using univariate and multivariate analyses. RESULTS: Most patients had distal ulcerating-type gastric cancer and presented at advanced stages. The median survival time for the entire cohort was 12 months (95% CI 9.7-14.4) with a 5-year overall survival rate of 16.7%. On univariate analysis of 237 patients who underwent surgical resection, the following positive prognostic factors emerged as significant: early overall TNM stage, early T stage, negative lymph nodes, tumor size <5 cm, ulcerating macroscopic appearance, and curative surgical attempt. The independent prognostic factors on multivariate analysis were T stage and lymph node involvement. CONCLUSION: The overall T and N stages are the most important determining factor for survival in Omani Arab patients. More efforts need to be made for the early detection of gastric cancer in developing countries such as Oman, while continuing to employ the standard surgical and medical treatments.

The prognostic significance of p53, p27 kip1, p21 waf1, HER-2/neu, and Ki67 proteins expression in gastric cancer: a clinicopathological and immunohistochemical study of 121 Arab patients.

BACKGROUND: The variability of prognosis within a pathological stage of gastric cancer (GC) at presentation, underscores the need for specific biological markers to identify subgroups of patients with aggressive course for intensive treatment. To our knowledge, this is the first study from an Arab population reporting on the relationship of p53, p27 kip1, p21 waf1, HER-2/neu, and Ki67 expression, and clinicopathological features and their prognostic significance. METHODS: Formalin-fixed paraffin-embedded tumors were studied by immunohistochemistry, using monoclonal antibodies to p53, p27 kip1, p21 waf1, HER-2/neu, and Ki67. The results were correlated with clinicopathological features and survival. RESULTS: M:F = 80:41; median age = 60 years; stage III and IV = 71%; and median follow-up = 34.4 months. Positive expression rates of p53, p27 kip1, p21 waf1, Ki67, and HER-2/neu were 54%, 40%, 8.3%, 70%, and 12% respectively. p53 expression correlated with age <60 years (P = 0.03), tumor size >5 cm (P = 0.01), p27 kip1 and Ki67 expression (P = 0.0001), and HER-2/neu (P = 0.04). p21 waf1 correlated inversely with T-stage (P = 0.008) and Her-2/neu expression correlated with histological grade (P = 0.04) and T-stage (P = 0.008). Univariate analysis showed that p53 overexpression (P = 0.01), fungating and infiltrative macroscopic appearance (P = 0.02), size >5 cm (P = 0.0001), lymph node metastasis (P = 0.0001), p T3 and T4 disease (P = 0.01), and overall stage III and IV (P = 0.0001) disease were adverse prognostic factors. Patients with tumor profiles p53 (-)/p27 (+) had better survival than those with p53 (+)/p27 kip1 (-)(P = 0.02). On multivariate analysis by Cox regression model, the expression of p53 (P = 0.03) and lymph node involvement (P = 0.01) were significant adverse prognostic factors for overall survival. CONCLUSIONS: The expression of p53 in Arab patients with GC correlates with aggressive tumor characteristics and is an independent prognostic factor. The combined analysis of p53 and p27 kip1 is of added prognostic value.

Emerging bacterial resistance patterns in febrile neutropenic patients: experience at a tertiary care hospital in Pakistan.

OBJECTIVE: To look at the clinical presentations, spectrum and site of isolation of the organisms, sensitivity patterns of the organisms and the antibiotic prescribing practices for the treatment of febrile neutropenic patients at our hospital. METHODS: The data were collected retrospectively from the records of all neutropenic patients with an absolute neutrophil count (ANC) of less than 500/ml admitted during the period of 3 years from August 1999 to July 2002 at AKUH. RESULTS: Out of the total of 404 patients, 65% had hematological malignancies and around half of them had leukaemia, 86% of the patients presented with fever. A total of 124 bacterial organisms were isolated from 96 patients among which 47% were gram positive and 53% were gram negative organisms; 16.1% of the patients had septicaemia. Coagulase Negative Staphylococci (CoNS) were the most common gram positive and E. coli was the most commonly isolated gram negative organism. Most of the gram positive organisms were isolated from blood (67%). There was emerging resistance to all commonly used antibiotics including imipenem, cloxacillin, vancomycin and amikacin. The average duration of neutropenia was 6.4 days. The mortality rate was 6%. CONCLUSION: There is increasing trend of gram negative organisms developing resistance to commonly used antibiotics. Gram positive bacteria including Enterococcus spp. and CoNS are also showing emerging resistance to vancomycin.

Survival data and prognostic factors seen in Pakistani patients with esophageal cancer.

BACKGROUND: Esophageal cancer is common in Pakistan. An attempt has been made for the first time to look at the survival data and prognostic factors associated with esophageal cancer in this region. PATIENTS AND METHODS: We did a retrospective review of 263 cases seen at the Aga Khan University Hospital in Karachi. Data analysis was done using the Kaplan-Meier method and the Cox proportional hazard model. RESULTS: Squamous cell carcinoma was noted in 81% of the cases, whereas adenocarcinoma was the second most common. At the time of diagnosis, early-stage disease was found in 25%, locally advanced in 41% and metastatic in 34% of all cases. Mean age at diagnosis was 56 years, with 59% males and 41% females. Survival data were available in 89 cases. Median survival was 7 months. On univariate analysis, the following factors were of prognostic significance: obstruction, histology, albumin level at diagnosis, age and platelet count. On multivariate analysis, three factors were found prognostic: presence or absence of obstruction, squamous cell carcinoma versus adenocarcinoma and platelet count. CONCLUSIONS: We found that patients with squamous cell carcinoma and absence of thrombocytopenia and obstruction had a better overall survival. However, this is a limited retrospective analysis; we therefore recommend that these prognostic factors be evaluated in larger studies.

Significance of p53, Bcl-2, and HER-2/neu protein expression in Omani Arab females with breast cancer.

Racial disparity in the presentation of breast cancer and the outcome of its treatment is well established. However, the causes remain unexplained. The scarcity of reports about the prognostic significance of p53, bcl-2, and HER-2/neu in Arab females with breast cancer has been the impetus to this study. We evaluated the prognostic significance of altered expression of p53, bcl-2, HER-2/neu in Omani Arab females with non-metastatic breast cancer with correlation to other established prognostic factors. We have retrospectively analyzed the immunohistochemical expression of p53, HER-2/neu and bcl-2 in paraffin embedded blocks of 72 females diagnosed with invasive breast cancer between 1992 and 2002. The expression of the above proteins was correlated with other prognostic factors and univariate and multivariate analysis was carried out for all prognostic factors. Overexpression of p53 significantly correlated with younger age (<40), pre-menopausal status, poor differentiation with inverse correlation with bcl-2 expression. Expression of bcl-2 immunopostivity significantly correlated to low histological grade and positive estrogen and progesterone receptor status. On univariate and multivariate p53 overexpression and lack of bcl-2 immunostaining resulted in worse survival outcome, but not Her-2/neu overexpression. Expression patterns of p53 and bcl-2 are independent predictors of survival in Omani Arab population which may help to stratify these patients into different risk groups.

Outcome of adult acute lymphoblastic leukemia: a single center experience.

OBJECTIVE: To study the outcomes of adult patients with acute lymphoblastic leukemia. SETTING: Tertiary care hospital. STUDY DESIGN: Retrospective analysis. METHODS: Fifty eight adult patients (age >14 years) diagnosed as cases of acute lymphoblastic leukemia were studied with respect to their clinical, morphological and immunopathological features at presentation and their relationship with treatment outcomes. RESULTS: Forty five (77.5%) of the patients belonged to younger age group with male preponderance. The median age was 20 years and mean age was 25.1 years. Male to female ratio was 3:1. Common presenting signs were lymphadenopathy (17.2%), hepatomegaly (32.7%) and splenomegaly (62%). Laboratory features at presentation revealed: hemoglobin > or = 10 gm/dl in 18 (31%), WBC >50 x 10E9 / L in 18 (31%), LDH more than 1000 IU/L in 44 (75.8%) of patients. Morphology revealed that FAB L1 was seen in 21(37.2%) and L2 in 62 (32.7%). Immunophenotyping showed that 26 (61.9%) were early pre-B ALL, 6 (14.2%) were pre-B ALL and T-ALL were 10 (23.8%). Univariate analysis showed age more than 30 years, male gender, total leucocyte count >50 x 10(9)/L and hemoglobin more than 10 gm/dl to be risk factors for poor outcome. Multivariate analysis revealed age more than 30 years, male sex and total leucocyte count > 50 x 10(9)/L are independent risk factors for poor survival. Patients were treated according to the MRCUKX and XII adult protocols. Thirteen (22.4%) patients died during induction therapy secondary to sepsis and progressive disease whereas 42 (72.4%) patients achieved complete remission. Median survival was 18.6 months and 42% patients were alive at 5-years. CONCLUSION: Overall survival and disease free survival were comparable to those reported in literature. However, age more than 30 years, male gender and total leucocyte count >50 x 10(9)/L had an adverse impact on overall survival.

Effect of methotrexate and folinic acid on accumulation of iron in mice.

A mouse-model was used to investigate the effect of methotrexate (MTX) and folinic acid on accumulation of iron in young growing mice. Four equal groups of Balb/c young male mice were treated (subcutaneously) with either MTX, or folinic acid, or MTX plus folinic acid, or physiological saline on every second day. After 3 weeks of treatment, liver, spleen, kidney, small intestine, brain, skeletal muscle and heart were removed and analyzed for iron contents using a spectrophotometric method. When the mean values of iron in liver of four groups were compared using one way ANOVA followed by Tukey's HSD test, the group receiving MTX alone was found to have significantly (p=0.004) more accumulation of iron in liver. The group receiving MTX plus folinic acid had iron accumulation in the liver similar to the placebo group. However, the mean values of iron in brain, kidney, small intestine, skeletal muscle, heart and spleen in all the groups, were not found to be statistically different. The data indicate that MTX shifts iron from being utilized in hemoglobin synthesis to liver stores. Folinic acid administration 8 h post-MTX, however, prevents this shift of iron to liver. Decreased levels of iron in plasma in mice treated with MTX alone suggest decreased availability of iron to other tissues for their normal growth and development.

Acute myeloid leukemia in children in Pakistan: an audit.

OBJECTIVE: To see the clinical features and treatment of children with Acute Myeloid Leukemia (AML) in Pakistan. SETTING: Tertiary referral at a specialist Hematology/Oncology center. METHODS: Retrospective, chart-based review of children (less than 14 years) admitted to the hospital with a diagnosis of AML between January 1987 and August 1997. RESULTS: A total of 23 patients were admitted. There were 18 males and 5 females. The mean age was 8 +/- 5 years. M3 was the commonest morphological subtype (43%). Twenty-two percent of the patients presented with hyperleucocytosis (TLC > 100 x 10(9)/L) and 95% with an elevated LDH (> 548 IU/L). Pneumonia at presentation was seen in 29%. Of 23 patients 14 were evaluable for responses. Six patients died early (43%); 3 before starting the chemotherapy and 3 during the induction chemotherapy, 8/11 (73%) patients entered remission. The median survival was 9 months. CONCLUSION: The pediatric patients with acute myeloid leukemia present with advanced disease. There is a high early death rate (within 28 days of diagnosis). The long-term outcome was inferior to that reported in the literature.

Tumor-induced hypercalcemia: predictors of early mortality.

OBJECTIVE: To delineate the demographics and predictors of early mortality associated with tumor-induced hypercalcemia (TIH) amongst cancer patients in Pakistan. SETTING: A tertiary care hospital in Pakistan. PATIENTS AND METHODS: Retrospective analysis of patients with cancers, presenting with TIH and admitted to the hospital between January 1988 and December 1997, was carried out. RESULTS: Eighty-four patients (56 males and 28 females) were diagnosed to have TIH. The mean age at the time of presentation was 55 +/- 14 years. Twenty-five percent of the patients each had multiple myeloma and hepatocellular carcinoma whereas 20% of the patients had underlying breast cancer. Other malignancies included lung cancer, gall bladder cancer and colorectal carcinomas. Univariate analysis revealed male sex (p < 0.04), underlying diagnosis other than multiple myeloma (p < 0.025) and a high TLC (p < 0.05) at presentation, as predictors of an early mortality. CONCLUSION: Multiple myeloma, hepatoma and breast carcinoma were common cancers causing TIH. One-third patients died within first few days. Male sex, a high white cell count and an underlying diagnosis other than multiple myeloma predicted early mortality.

Lack of benefit of granulocyte macrophage or granulocyte colony stimulating factor in patients with febrile neutropenia.

OBJECTIVES: To compare the clinical benefits of granulocyte-colony stimulating factor (G-CSF) or granulocyte macrophage-colony stimulating factor (GM-CSF) plus standard supportive care to supportive care alone among cancer patients with febrile neutropenia. METHODS: Clinical data were collected retrospectively from 148 consecutive cancer patients with neutropenia and fever. Patients had hematologic (i.e., acute leukemias or lymphoproliferative disorders) or non-hematologic malignancies (i.e., solid tumors including carcinoma of breast, lung, or colon). Clinical variables analyzed included: age and sex; underlying malignancies; chemotherapy regimens; symptoms at time of presentation; duration of fever prior to study enrollment; days from chemotherapy until administration of GM-CSF or G-CSF; number of previous neutropenic episodes; duration of fever and day of defervescence; absolute neutrophil count on day of defervescence; duration of neutropenia; number and types of antibiotics used; day amphotericin B begun; number of culture-documented infective episodes involving bloodstream, lung, pleura, urinary tract, gastrointestinal tract, intravenous cannulae, or skin; types of antimicrobial isolates; cost of cytokine therapy; length of hospital stay and clinical outcome. RESULTS: The use of myeloid growth factors increased the number of circulating peripheral white blood cells, but no significant effect was noted in terms of duration of neutropenia or fever, number of culture-proven infections (except pneumonia; p < 0.04), length of hospital stay, or survival. CONCLUSION: In areas with limited health care resources, expensive treatment with GM-CSF or G-CSF should be reserved for patients with complicated febrile neutropenia where the expected risk of infection is high and the duration of neutropenia is prolonged, or those with documented infections that are refractory to antibiotic treatment.

Long-term outcomes of acute myeloid leukemia in adults in Pakistan.

OBJECTIVE: To describe the long-term outcomes of Acute Myeloid Leukemia (AML) and to study clinicopathological features at presentation, morphological subtypes and remission rates. METHODS: Demographic information, response to therapy and survival of patients (>14 years of age) admitted between January 1988 to August 1996 with acute myeloid leukaemia was retrieved and analysed. RESULTS: Seventy-four patients were admitted with a diagnosis of AML during the study period. There were 43 males and 31 females. Age ranged between 15 and 70 years with a mean age of 38 years. The most common presenting feature was fever (67.5%) and the morphological subtype according to French-American-British Group (FAB) criteria was M4. Fifty-five patients received treatment and were evaluable for response and outcomes. Thirty-six (65.4%) patients had complete remission. Sixteen (29.1%) died during the first 28 days after starting induction chemotherapy. The median survival was 11 months. Six (11%) patients (4 females, 2 males) are surviving beyond 4 years (long-term survivors). CONCLUSION: Our study suggests that the long-term outcomes of adults with AML are comparable to what has been reported in the literature for patients who do not receive bone marrow transplants.

Lack of correlation between alpha-fetoprotein and tumor size in hepatocellular carcinoma.

OBJECTIVE: To determine whether there was a correlation between tumor size and alpha feto-protein (alpha-FP) levels in hepatocellular carcinoma. SETTING: Retrospective study in tertiary referral center with specialist Oncology services in Southern Pakistan. SUBJECTS: Consecutive patients with biopsy-proven hepatocellular carcinoma diagnosed between January 1994 and June 1998. MAIN OUTCOME MEASURES: Correlation between alpha-FP levels and maximum tumor diameter. RESULTS: The mean tumor size was 8.3 +/- 4.2 cm. The mean alpha-FP level was 17,027 ng/ml. Twenty four percent patients had an alpha-FP level which was within the normal limits (< 10 ng/ml). There was no correlation between tumor size and alpha-FP levels (r = -0.155; p = 0.129). CONCLUSION: There was no correlation between the tumor size and alpha-FP levels.

Induction of white cell proliferation due to haematopoietic growth factors is associated with an increase in multiple forms of dihydrofolate reductase in non-neutropenic cancer patients.

OBJECTIVE: Granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage-colony stimulating factor (GM-CSF) are frequently used in cancer patients to overcome the granulocytopenic effects of chemotherapy, and also to mobilize the stem cells. The mobilized stem cells are collected from the peripheral blood and used for transplantation following high doses of chemotherapy. However, the molecular mechanism by which these colony stimulating factors (CSFs) bring about proliferation of myeloid precursor cells is not clearly known. Dihydrofolate reductase (DHFR), which has an established role in DNA synthesis, could be a link between administration of CSF and stem cell proliferation. The purpose of this study was to investigate whether CSFs induce white cell proliferation by producing multiple forms of DHFR. METHODS: Twelve patients with non-haematological malignancies were treated with either G-CSF or GM-CSF to mobilize stem cells. Nine healthy subjects were treated with placebo as controls. Blood samples were obtained before and after stimulation with CSFs or placebo. White blood cells were separated and concentrations of both active DHFR and immunoreactive nonfunctional form of DHFR were determined in their cytoplasm using methotrexate-binding assay and enzyme-linked immunosorbent assay, respectively. Total leucocytes count (TLC) was also monitored before and after stimulation with CSFs or placebo. RESULTS: There was a significant (P < 0.05) increase in concentration of immunoreactive nonfunctional form of DHFR and TLC following stimulation with CSFs. There was an increase in concentration of active DHFR as well, however, this did not reach statistical significance. In the placebo-treated subjects, no significant increase in active DHFR, immunoreactive nonfunctional form of enzyme or TLC was observed. However, it was noticed that the base-line values of active DHFR and immunoreactive nonfunctional form of enzyme in leucocytes of cancer patients were higher than the base-line values in leukocytes of normal healthy subjects. CONCLUSION: Our data suggest that colony stimulating factors induce white cell proliferation by increasing levels of multiple forms of DHFR.

Complications of in-dwelling venous access devices: a single institution experience.

OBJECTIVE: To determine the complications of venous access devices (VADs) in cancer patients. SETTING: Retrospective study in a tertiary referral center with specialist hematology and oncology services. SUBJECTS: First one hundred consecutive patients who were implanted a VAD. All patients had an underlying cancer and the devices were inserted by the same surgeon. The duration of use of VADs and causes of their premature removal were noted. RESULTS: One hundred VADs (55 port-a-caths and 45 Hickman's lines) were inserted in a total of 89 patients over a 7.5 year period. Majority of patients had acute myeloid leukemia (22) gastrointestinal malignancies (20) breast cancer (19) and genito-urinary cancers (15). The mean duration of use was 110 days; 157 days for the port-a-cath and 53 days for the Hickman's line. Nineteen devices (10 port-a-caths and 9 Hickman's lines) had to be removed prematurely. Two Hickman's lines got removed accidentally. The causes of premature removal included device failure (9), exist site infection (4), luminal infection (3) and tunnel infection (3). CONCLUSION: The mean duration of use and the complication rates are comparable with studies reported in the literature.