[show abstract][hide abstract] ABSTRACT: Lung cancer is the leading cause of cancer mortality worldwide and tobacco smoking has been established as its biggest risk factor. Cigarette smoke contains several carcinogens. Most of them need to be activated by phase I enzymes, such as cytochrome P450 (CYP), while phase II enzymes, such as glutathione S-transferases are responsible for the detoxification of activated forms. The present study aimed to determine the role of CYP1A1, GSTP1 and GSTM1 gene polymorphisms in smoking-related lung cancer risk. It also aimed to investigate the association of the above polymorphisms with clinicopathological parameters, as well as their effect on survival. One hundred newly diagnosed lung cancer patients with advanced disease and 125 healthy controls with a smoking history participated in the study. The participants were screened for the presence of the following polymorphisms: MspI (CYP1A1), Ile105Val (GSTP1) and GSTM1 deletion. The above polymorphisms were also examined with regards to gender, age, histological type and survival. GSTP1 Ile/Val and GSTM1-null genotypes were associated with increased lung cancer risk and the presence of the combination of the three non-wild-type genotypes increases susceptibility to lung cancer (OR 3.328, 95% CI=1.681-6.587, p=0.001). In the non-small cell lung cancer group, the GSTP1 homozygous variant was significantly associated with increased lung cancer risk (p=0.008) and shorter survival. The results of this study suggest that the GSTP1 Ile/Val genotype and GSTM1 deletion contribute to increased lung cancer susceptibility. Moreover, GSTP1 Val/Val genotype is associated with increased lung cancer risk and shorter survival in non-small cell lung cancer patients.
[show abstract][hide abstract] ABSTRACT: More aggressive treatment approaches (methotrexate, cytarabine, cyclophosphamide, vincristine, prednisone, and bleomycin [the MACOP-B regimen] or consolidation with high-dose therapy and autologous stem cell transplantation) have been considered to be superior to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with primary mediastinal large B-cell lymphoma (PMLBCL). Rituximab-CHOP (R-CHOP) is the standard of care for diffuse large B-cell lymphoma, whereas efficacy in PMLBCL has not been adequately confirmed.
Seventy-six consecutive PMLBCL patients who received R-CHOP with or without radiotherapy (RT) were compared with 45 consecutive historical controls treated with CHOP with or without RT. Baseline characteristics of the two groups were balanced.
The rate of early treatment failure was much lower with R-CHOP with or without RT (9% versus 30%; p = .004). The 5-year freedom from progression rate after R-CHOP with or without RT was 81%, versus 48% for CHOP with or without RT (p < .0001). The 5-year event-free survival rates were 80% and 47% (p < .0001) and the 5-year overall and lymphoma-specific survival rates were 89% and 69% (p = .003) and 91% and 69% (p = .001), respectively, with only seven of 76 lymphoma-related deaths. Among R-CHOP responders, 52 of 68 received RT.
Based on these results, most patients with PMLBCL appear to be cured by R-CHOP in 21-day cycles with or without RT, which could be the current standard of care. Therefore, the need for more aggressive treatment strategies is questionable unless high-risk patients are adequately defined. Further studies are required to establish the precise role of RT.
The Oncologist 01/2012; 17(2):239-49. · 4.10 Impact Factor
[show abstract][hide abstract] ABSTRACT: The treatment of Waldenström's macroglobulinemia (WM) has changed over the last decades, mainly because of the introduction of nucleoside analogues and of rituximab while novel agents such as bortezomib have been recently introduced. We performed an analysis to investigate whether the outcome of patients with WM has improved over the last years, compared to that of patients who started treatment before new drugs became widely available, especially as part of the frontline treatment. We analyzed 345 symptomatic patients with WM: 130 who initiated treatment before and 215 who started treatment after January 1, 2000. Patients who started treatment in the latter group were older and had more often elevated beta2-microglobulin but the other characteristics were similar between the two groups. Most patients who started treatment before January 1, 2000 were treated upfront with alkylating agent-based regimens and most patients who started treatment after January 1, 2000 received rituximab-based regimens as initial treatment. Objective response (63 and 59%, respectively) and median overall survival, OS, (106.5 months for Group A and is estimated at 94 months for Group B, P = 0.327) were similar. There was also no difference regarding OS or cause specific survival (CSS) in each risk group according to IPSSWM. Our observation may be explained by the indolent course of WM in several patients and by the lack of profound cytoreduction in patients with high-risk disease. Possible differences in the 15- or 20-year survival rate between the two groups may be detected with further follow-up of these patients.
American Journal of Hematology 06/2011; 86(6):479-83. · 4.00 Impact Factor
[show abstract][hide abstract] ABSTRACT: Waldenström's macroglobulinemia is characterized by a protracted course in most patients and the median survival may be long. However, a subset of patients may present with more aggressive disease that is associated with short survival. In order to better characterize these "poor-risk" patients, we identified patients who died within 2 years from the initiation of front-line treatment. These patients were older and had more often features of aggressive disease, such as elevated LDH and low serum albumin than the standard-risk population. Furthermore, only a minority of poor-risk patient had a response to initial therapy. However, conventional clinical factors or even the lack on response could not adequately identify poor-risk patients, indicating the need for novel molecular or other markers that would be able to effectively recognize patients at greatest need for aggressive therapies.
[show abstract][hide abstract] ABSTRACT: Anthracyclines have contributed to a marked increase in survival in different types of cancer [1,2]. Unfortunately, they are associated with dose-dependent cardiotoxicity and heart failure (HF) [3–8]. Change to a weekly dosage schedule with slow infusions has been tested, a strategy that requires more frequent hospital visits and increased storage resources[7,9]. Liposomal anthracycline formulations with reduced drug exposure and lower plasma concentrations may still be cardiotoxic at higher cumulative doses . Beta-blockers and angiotensin converting enzyme(ACE) inhibitors have been shown to reduce anthracycline-induced cardiotoxicity,but have not been tested in long-term prospective, randomized,controlled studies with well defined cardiotoxicity criteria and careful cardiac function monitoring [11–16]. We investigated doxorubicin-induced clinical or subclinical cardiotoxicity in lymphoma patients after concomitant prophylactic therapy with metoprolol or enalapril or no concomitant treatment. We examined whether cardiotoxicity was related to the treatment or any other variable. We found that HF was less frequent under concomitant treatment than no treatment, especially in the metoprolol group, but the differences were not significant. No association was found between the presence of cardiotoxicity and concomitant treatment or other variable apart of age that had a significant impact. The marginal benefit seen with metoprolol should be investigated further.
American Journal of Hematology 11/2010; 85(11):894-6. · 4.00 Impact Factor
[show abstract][hide abstract] ABSTRACT: The recently proposed, ISSWM staging system for symptomatic patients with WM was based on patients treated with alkylating agents and nucleoside analogs and has not been externally validated nor has been validated for cause-specific survival (CSS). We independently validated ISSWM both for overall survival (OS) and for CSS and assessed whether addition of elevated serum LDH may add to the strength of ISSWM in 335 patients treated upfront mainly with alkylating agents (43%), and rituximab-based therapies (47%). ISSWM could discriminate three groups with significantly different OS and CSS (p<0.01 for both). High serum LDH was predictive of shorter OS and CSS (p<0.01). The combination of high risk according to ISSWM and elevated serum LDH identified a subset of patients for whom innovative treatment approaches are needed.
Leukemia research 05/2010; 34(10):1340-3. · 2.36 Impact Factor
[show abstract][hide abstract] ABSTRACT: Jumping translocations (JT) are rare cytogenetic aberrations in hematological malignancies that include unbalanced translocations involving a donor chromosome arm or chromosome segment that has fused to two or more different recipient chromosomes in different cell lines. We report five cases associated with different hematologic disorders and JT to contribute to the investigation of the origin, pathogenesis, and clinical significance of JT. These cases involve JT of 1q in a case of acute myeloblastic leukemia (AML)-M1, a case of Burkitt lymphoma, and a case of BCR/ABL-positive acute lymphoblastic leukemia, as well as a JT of 13q in a case of AML-M5, and a JT of 11q segment in a case of undifferentiated leukemia. To our knowledge, with regard to hematologic malignancies, this study presents the first case of JT associated with AML-M1, the first case of JT involving 13q as a donor chromosome, and the first report of JT involving a segment of 11q containing two copies of the MLL gene, jumping on to two recipient chromosomes in each cell line and resulting in six copies of the MLL gene. Our investigation suggests that JT may not contribute to the pathogenesis but rather to the progression of the disease, and it demonstrates that chromosome band 1q10 as a breakpoint of the donor chromosome 1q is also implicated in AML, not only in multiple myeloma as it has been known until now.
Cancer genetics and cytogenetics 01/2009; 187(2):85-94. · 1.54 Impact Factor
[show abstract][hide abstract] ABSTRACT: Pure infradiaphragmatic Hodgkin's lymphoma (HL) is a rare disease. The prognostic impact of a purely infradiaphragmatic localization of this lymphoma is controversial. We aimed to evaluate the baseline clinicopathologic features, prognostic factors and outcome of a large series of consecutive patients with pure infradiaphragmatic HL.
We analyzed 131 patients with clinical stage I/II infradiaphragmatic HL treated with ABVD or equivalent regimens with or without radiotherapy, and compared 54 of them with 444 patients with pure supradiaphragmatic disease, who were treated at the same center.
Older age, clinical stage II (borderline), involvement of > or =3 sites, lymphocyte predominant histology, elevated serum beta2-microglobulin and higher International Prognostic Score were more frequent in patients with infradiaphragmatic disease than in those with supradiaphragmatic disease, while nodular sclerosis was less frequent. The complete remission rate was 100%, 97% and 82% for stages I, IIA and IIB, respectively. Only B-symptoms independently predicted for inferior failure-free survival, while inferior overall survival was independently associated with the involvement of > or =3 sites. At 10 years failure-free survival was 82+/-6% (vs. 85+/-2% for patients with supradiaphragmatic disease, p=0.45), overall survival was 74+/-8% (vs. 91+/-2%, p=0.0006), and disease-specific survival 87+/-5% (vs. 94+/-1%, p=0.04). In multivariate analysis the differences between infradiaphragmatic and supradiaphragmatic disease were obscured by older age and B-symptoms.
Pure infradiaphragmatic HL presents with distinct clinicopathologic characteristics. The previously reported poorer outcome may be explained by the unfavorable profile of the patients rather than the infradiaphragmatic presentation per se. Patients with stage IIB disease should probably be classified as having advanced HL because of the unacceptable rate of primary refractory disease.
[show abstract][hide abstract] ABSTRACT: We developed a clinical prediction rule for bone marrow involvement (BMI) in Hodgkin lymphoma based on 826 patients and validated it in 654 additional patients. Independent prognostic factors for BMI were x1, B symptoms; x2, stage III/IV prior to bone marrow biopsy; x3, anemia; x4, leukocytes fewer than 6 x 10(9)/L; x5, age 35 years or older; and x6, iliac/inguinal involvement. Each factor was graded as x(i)=1, if present, or x(i)=0, if absent. A simplified score Zs=8x1+6x2+5x3+5x4+3x5+3x6-8 was assigned to each patient. The sensitivity, specificity, and positive and negative predictive value of this prediction rule was 97.8%, 51.5%, 10.6%, and 99.8%, respectively. In the validation group, they were 98.1%, 40.3%, 12.7%, and 99.6%. According to Zs value, 3 risk groups for BMI were defined: low risk (Zs<0, 44% of patients, 0.3% risk), standard risk (Zs, 0-9; 37% of patients; 4.2% risk), and high risk (Zs>or=10, 20% of patients, 25.5% risk). Patients with low risk (stage IA/IIA without anemia and leukopenia; stage IA/IIA, younger than 35 years, with either anemia or leukopenia but no inguinal/iliac involvement; and stage IIIA/IVA without any of these 4 risk factors) do not need bone marrow (BM) biopsy. Patients with standard risk should be staged with unilateral biopsy, but patients with high risk may benefit from bilateral biopsy.
[show abstract][hide abstract] ABSTRACT: To investigate hypothalamic-pituitary-adrenal axis function in patients requiring mechanical ventilation for traumatic brain injury and to assess the relation of hypothalamic-pituitary-adrenal axis abnormalities with vasopressor dependence and peripheral cytokine levels.
General intensive care unit in a university teaching hospital.
Forty patients (33 men and 7 women) with moderate to severe traumatic brain injury (mean age, 37 +/- 16 yrs) were studied the day after termination of mechanical ventilation (7-60 days after trauma).
First, a morning blood sample was obtained to measure baseline cortisol, corticotropin, interleukin-6, and tumor necrosis factor alpha. Subsequently, 1 microg of synthetic corticotropin was injected intravenously, and 30 mins later, a second blood sample was drawn to determine stimulated plasma cortisol. Based on data derived from healthy volunteers, patients having stimulated cortisol levels <18 microg/dL were defined as nonresponders to the low-dose stimulation test. Thirty-one patients underwent also a human corticotropin releasing hormone test.
In traumatic brain injury patients, mean baseline and low-dose stimulation test-stimulated cortisol levels were 17.2 +/- 5.4 microg/dL and 24.0 +/- 6.6 microg/dL, respectively. The median increment in cortisol was 5.9 microg/dL. Basal corticotropin levels ranged from 3.9 to 118.5 pg/mL. Six of the 40 patients (15%) failed the low-dose stimulation test. The human corticotropin releasing hormone test (performed in 26 responders and five nonresponders) revealed diminished cortisol release only in the low-dose stimulation test nonresponder patients. Corticotropin responses to corticotropin releasing hormone were consistent with both primary (three patients) and/or secondary (two patients) adrenal dysfunction. In retrospect, nonresponders to the low-dose stimulation test more frequently required vasopressors (6/6 [100%] vs. 16/34 [47%]; p =.02) and for a longer time interval (median, 0 vs. 293 hrs; p =.006) compared with responders. Furthermore, nonresponders had higher interleukin-6 levels compared with responders (56.03 vs. 28.04 pg/mL; p =.01), whereas tumor necrosis factor alpha concentrations were similar in the two groups (2.42 vs. 1.55 pg/mL; p =.53).
Adrenal cortisol secretion after dynamic stimulation is deficient in a subset of critically ill patients with moderate to severe head injury. This disorder is associated with prior vasopressor dependency and higher interleukin-6 levels.
Critical Care Medicine 02/2004; 32(2):404-8. · 6.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: The standard CHOP regimen may cure 30-40% of patients with advanced aggressive non-Hodgkin's lymphoma (ANHL). Mitoxantrone is an anthracenedione, which is active in NHL and its toxicity profile may be more favorable than doxorubicin with respect to alopecia, mucositis and cardiotoxicity. This study was designed to compare the effectiveness of an escalated dose of mitoxantrone with that of standard doxorubicin, used in the CHOP regimen in patients with ANHL. One hundred and forty three eligible patients with ANHL were randomized to receive 6 cycles of either CHOP (n = 71) or intensified CNOP (iCNOP) (n = 72), with mitoxantrone 20 mg/m2, i.v., d.1 instead of doxorubicin. Complete responders (CR) were again randomized either to receive interferon-alpha (IFN-alpha) maintenance (3 MU t.i.w., s.c.) or not. The CR rate was 70 vs. 76% for iCNOP and CHOP (p = 0.45), and the overall response rate was 81 vs. 83%, respectively (p = 0.71). The 5-year failure free survival (FFS) was 48 and 50% in the iCNOP and CHOP arm, respectively (p = 0.45), and the 5-year overall survival (OS) was 61 vs. 64% (p = 0.56). IFN-alpha did not prolong relapse free survival (p = 0.91). iCNOP produced less alopecia (p = 0.001) but more febrile episodes (p = 0.04) than CHOP, while requiring more frequent G-CSF support (p = 0.01). Two cases of acute myelogenous leukemia (AML) were recorded, both in the iCNOP arm (p = 0.14). In conclusion, iCNOP was equally effective to CHOP in patients with ANHL, producing more leukopenia and febrile episodes, but less alopecia. The development of two cases of secondary AML in th e iCNOP arm is of concern.
Leukemia and Lymphoma 05/2003; 44(4):635-44. · 2.30 Impact Factor
[show abstract][hide abstract] ABSTRACT: To assess the association of serum CA 125 in patients with non-Hodgkin's lymphoma (NHL) with prognostic parameters of the disease, response to treatment, and survival.
Sixty-eight patients [38 males, median age 56 (range 17-82) yr] with NHL were evaluated. CA 125 was measured by an enzyme immunoradiometric assay at diagnosis and at the end of first-line treatment.
Median overall CA 125 was 49 (1-963) U mL-1, whereas 49 patients had initially abnormal (>35 U mL) CA 125 levels. High CA 125 was found to correlate with failure of treatment (P = 0.001) and relapse (P = 0.01), and to be independently associated with bulky disease, effusions, LDH, and the International Prognostic Index (IPI) score (P<0.01 for each of these four variables). An initially abnormal CA 125 value was associated with poorer 5-yr survival [median survival of patients with CA 125>35 U mL-1 33 (18-72) months compared to 58 (20-77) months for those with CA 125 = 35 U mL-1, P = 0.012]. Moreover, CA 125>35 U mL-1 (among stage III/IV and LDH>460 mU mL-1) emerged as an independent predictor of death within 5 yr from diagnosis (Relative Risk (RR) 3.1, 95% CI 1.5-12.8, P = 0.02).
Measurement of serum CA 125 is useful for staging, monitoring, and estimating prognosis in patients with NHL.
European Journal Of Haematology 10/2002; 69(4):221-6. · 2.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: To investigate the adrenal function in non-septic, long-stay critically ill patients.
Prospective, consecutive study.
General intensive care unit in a university hospital.
Forty-three non-septic patients with protracted critical illness.
A morning blood sample was first obtained to measure baseline plasma cortisol. Subsequently, 1 micro g of corticotropin (ACTH, Synacthene) was injected intravenously and 30 min later a second blood sample was drawn to determine stimulated plasma cortisol. Patients having a stimulated cortisol level of at least 18 micro g/dl were defined as responders. In 36 patients, morning interleukin-6 (IL-6) was also measured.
Baseline and stimulated plasma cortisol were 16.8+/-4.1 micro g/dl and 21.2+/-5.1 micro g/dl, respectively. Interleukin-6 was high (median 39.3 pg/ml, interquartile range 24.9-86.6 pg/ml) and correlated negatively with stimulated plasma cortisol (r=-0.40, p<0.05). Of the 43 patients studied, 31 patients (72%) were responders and 12 patients (28%) were non-responders to the ACTH stimulation test. Overall, 18 patients died and 25 patients survived to hospital discharge. Non-responders had significantly higher IL-6 levels compared to responders (106+/-73 versus 48+/-42 pg/ml, p<0.05), whereas mortality rate was comparable in the two groups (50% versus 38%, p=0.74).
Circulating plasma IL-6 levels are high during protracted critical illness, and are partially responsible for the relative adrenal insufficiency found in a subset of severely ill patients.
Intensive Care Medicine 08/2002; 28(8):1168-71. · 5.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: The aim of this study was to investigate the relationship of pretreatment serum IL-10 (sIL-10) levels with known prognostic factors and with failure-free survival (FFS) in patients with Hodgkin's lymphoma (HL).
Interleukin-10 (IL-10) levels were measured in the sera of 36 untreated patients with HL and were subsequently correlated with clinical and laboratory prognostic parameters as well as with FFS.
36 untreated HL patients (21 men, median age 31 (18-62) years) were studied. Of the subjects, 19 (52.7%) had elevated IL-10 levels (> or = 10 pg/ml). High IL-10 correlated with bulky disease, high serum lactate dehydrogenase (LDH) and leukocytosis (P = 0.015 for all three variables). High IL-10 (P = 0.015) and low serum albumin (P = 0.001) were associated with worse FFS, but only high IL-10 emerged as an independent predictor of inferior FFS in multivariate analysis (P = 0.04, hazard ratio 2.21, 95% CI 1.12-14.67). Median FFS of IL-10-positive patients (30 (12-47) months) was significantly shorter compared to that of IL-10-negative ones (39 (12-58) months, log-rank test P = 0.0185).
IL-10 was found to be elevated in approximately half of untreated patients with HL, to correlate with bulky disease, high LDH and leukocytosis and to be an independent predictor of FFS.
[show abstract][hide abstract] ABSTRACT: We evaluated the safety and efficacy of the new BP ibandronate, given as a rapid infusion.
We administered 4 mg of ibandronate as an intravenous infusion over 30 minutes. Thirty patients (16 breast cancers, 4 prostate cancers, 10 multiple myelomas) with bone metastases received 4 mg of ibandronate injected intravenously over 30 minutes in normal saline 0.9%, 250cc every 3 or 4 weeks. The patients were followed-up over 2 hours after infusion. A total of 198 infusions were administered over a period of 24 months and the patients were followed-up for long-term ibandronate-related side-effects, as well as for any potential clinical benefit.
Following the first administration of ibantronate, serum levels of calcium, phosphate and alkaline phosphatase were significantly decreased and the difference was statistically significant (p < 0.001) for all three parameters examined. The reduced time of infusion (30 minutes vs 2 hours) did not correlate with any side-effects during or post-administration. Serum levels of creatinine and urea nitrogen did not increase significantly, while changes in temperature and blood pressure were not detected in the patients examined. With regard to efficacy, all the patients, after repeated administrations, reduced the doses of analgesics needed; 26 out of 30 patients had stable disease in the bones while 1 out of 30 patients had significant improvement of bone lesions in consecutive bone scans.
Infusional administration of ibandronate is efficient in the management of hypercalcaemia of malignancy and it results in a reduced need for analgesics. The rapid infusion over 30 minutes is safe and could be given in the setting of a day care unit.
In vivo (Athens, Greece) 01/2002; 16(5):361-3. · 1.22 Impact Factor