NEWS
| 1. | Methadone versus morphine as a first-line strong opioid for cancer pain: A randomized double-blind study |
This was the first randomized study designed to compare the effectiveness and tolerability of methadone (7.5 mg orally every 12 hours and 5 mg every 4h as needed) and morphine (15 mg slow-release every 12 hours and 5 mg every 4 h as needed), as a first-line opioid for severe pain caused by advanced cancer.
More than 80% of cancer patients develop pain before death. Morphine is the standard first-line strong opioid according to the WHO. Methadone is an alternative second-line strong opioid. Methadone has been stated to have a number of potential advantages over morphine: improved pain control (particularly in patients with neuropathic pain), decreased toxicity (particularly constipation) and lower development of tolerance. In addition, the cost of treatment with methadone is also lower, which is important for low-income countries. So far, no studies have directly compared methadone and morphine on a double-blind basis.
A total of 103 patients, from 7 international research centers, were randomized after stratification by characteristics of the pain (neuropathic vs. non-neuropathic) to receive methadone (49 patients) or morphine (54 patients). The study duration was 4 weeks. The Institute for Oncology and Radiology of Serbia participated with 34 patients and was nominated the best research center on the basis of the quality of data. The primary objective of the study was to evaluate the difference in pain intensity and opioid-induced toxicity (sedation, nausea and vomiting, confusion and constipation), comparing the baseline score with the score at week 4 for each study arm. Methadone did not produce superior analgesic efficiency or overall tolerability at 4 weeks compared with morphine. The blind global satisfaction ratings of both drugs by patients and investigators did not show any difference between methadone and morphine. However, patients receiving methadone had more opioid toxicity-related dropouts. Methadone is a useful alternative strong opioid in developing countries because of its lower cost. Two-times daily dosing regimen of methadone used in the study proved to be effective and feasible. Close monitoring of patients in the first week after initiation of methadone treatment is mandatory.
References:
1. Bruera E, Palmer JL, Bosnjak S, Rico MA, Moyano J, Sweeney C et al. Methadone versus morphine as a first-line strong opioid for cancer pain: A randomized double-blind study. J Clin Oncol 2004;22:185-92.
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Snezana
BOSNJAK
Snezana SUSNJAR |
| 2. | HPV-prophylactic vaccine: A new way of prevention against cervical carcinoma |
Cervical cancer is a major cause of death in women in reproductive age, in parts of the developing world (1). According to many researchers HPV infections have an important role in the development of cervical neoplasm (2). Persisting infection of the anogenital epithelium -over five years to a lifetime - with one of more than ten high-risk genotypes of HPV is causally linked to cervical cancer; other anogenital malignancies are also, to some degree, caused by HPV infection. Infection with HPV16 - the highest risk genotype - is responsible for more than 50% of cervical cancers worldwide. Nevertheless, more than 95% of incident HPV infections of the anogenital tract resolve over three to five years, and cancer can be estimated to develop in less than 5% of HPV16-infected individuals over their lifetime (3-5).
High-risk types of HPV are often observed in association with moderate dysplasia (CIN II) and severe dysplasia or carcinoma in situ (CIN III). These high-risk types are also observed in the majority of patients with cervical cancer (6,7). Today, vaccines are available against many serious human pathogens such as bacteria, viruses and about half of the parasites. As it is universally accepted that cervical carcinoma is a consequence of infection with HPV viruses it would be reasonable to assume that vaccine that prevents infection will reduce incidence of cervical cancer (8).
HPV-prophylactic vaccine
Recombinant DNA technology allows expression of the L1 major capsid protein of papillomavirus by various cell types, and expression of L1 protein by eukaryotic cells is followed by self-assembly of the recombinant L1 into virus-like particles (VLPs) (9,10). L1 VLPs mimic the natural virus structurally and, unlike denatured L1 protein, elicit high titres of virus-neutralizing anti-bodies in animals and humans. VLPs were found to bind very well to human and mouse immune cells that expressed markers of antigen-presenting cells (APC) such as MHC class II, CD80 and CD86, including dendritic cells, macrophages and B cells. MoAb blocking studies identified Fc gamma RIII (CD16) as one of the molecules to which the VLP can bind both on immune cells and 79 foreskin epithelium (11). Koutsky L et al. performed a controlled trial of a human papillomavirus type 16 vaccine. In a double-blind study, randomly assigned 2392 young women (defined as females 16 to 23 years of age) received three doses of placebo or HPV-16 virus-like-particle vaccine, given at day 0, month 2, and month 6. HPV-16 L1 virus-like-particle vaccine (Merck Research Laboratories) consists of highly purified virus-like particles of L1 capsid of HPV-16. The HPV-16 L1 polypeptide is expressed in yeast (Saccharomyces cerevisiae). Virus-like particles are isolated with the use of standard techniques to achieve purity of more than 97 percent and adsorbed onto amorphous aluminum hydroxyphosphate sulfate adjuvant without preservative. Among 2392 women enrolled in the study, 1194 received vaccine and 1198 received placebo. Altogether, 1533 women (64 percent of the study cohort) were included in the primary analysis. These women were followed for a median of 17.4 months after completion of the vaccination regimen. The most common reason for exclusion was evidence of HPV-16 infection at enrollment or antibodies in samples collected during the visit at day 0 or month 7. The reason for these exclusions is based on the fact that the vaccine was designed to prevent HPV-16 infection. If patients were infected before vaccination, vaccine was not able to protect these patients for infection. This controlled trial showed evidence of a highly efficacious prophylactic vaccine against HPV infection. A three-dose regimen of HPV-16 vaccine reduced the incidence of persistent HPV-16 infection; all 41 cases of new HPV-16 infection, including 9 cases of HPV-16-related cervical intraepithelial neoplasia occurred among placebo recipients (vaccine efficacy of 100%). Only 6 cases in which tests were positive at a single visit occurred among vaccine recipients, whereas 27 cases were expected on the basis of the observed rate in the placebo group. Among women who received HPV-16 vaccine, 99.7 percent were seroconverted. At month 7, geometric mean titer of HPV-16 antibodies in these women was 58.7 times as high as the geometric mean titer among women with serologic evidence of natural HPV-16 infection at enrollment (12).
References:
1. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001. CA Cancer J Clin 2001;50:7-33.
2. Bosch FX, Lorincz A, Munoz N, Meijer CJ, Shah KV. The causal relation between human papillomavirus and cervical cancer. J Clin Pathol 55, 2002;55:244-65.
3. Munoz N et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518-27.
4. Schlecht NF et al. Human papillomavirus infection and time to progression and regression of cervical intraepithelial neoplasia. J Natl Cancer Inst 2003;95:1336-43.
5. Goldie SJ et al. A comprehensive natural history model of HPV infection and cervical cancer to estimate the clinical impact of a prophylactic HPV-16/18 vaccine. Int J Cancer 2003;106:896-904.
6. Stanimirovic B, Kuljic-Kapulica N, Antic N, Stanimirovic V, Vasiljevic M, Popovic-Lazic J. HPV typing in cervical squamous intraepithelial lesions(SIL)- our experience after 1000 studied patiens. Archive of Oncology 1999;7(2):43-8.
7. Koutsky LA, Holmes KK, Critchlow CW et al. A cohort study of the risk of cer- vical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infec- tion. N Engl J Med 1992;327:1272-8.
8. Mandic A, Vujkov T. Human papillomavirus vaccine as a new way of pre- venting cervical cancer: A dream or the future. Ann Oncol 2004;15:197-200.
9. Zhou J, Sun XY, Stenzel DJ, Frazer IH. Expression of vaccinia recombinant HPV 16 L1 and L2 ORF proteins in epithelial cells is sufficient for assembly of HPV virion-like particles. Virology 1991;185:251-7 .
10. Kirnbauer R, Booy F, Cheng N, Lowy DR, Schiller JT. Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immuno- genic. Proc Natl Acad Sci USA 1992;89:12180-4.
11. Da Silva DM, Velders MP, Nieland JD, Schiller JT, Nickoloff BJ, Kast WM. Physical interaction of human papillomavirus virus-like particles with immune cells. Int Immunol 2001;13(5):633-41.
12. Koutsky L, Ault K, Wheeler C, Brown D, Barr E, Alvarez F et al. A controlled trial of human papillomavirus type 16 vaccine. N Engl J Med 2002;347/21:1645-51.
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Aljosa
MANDIC
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| 3. | Diagnostic and therapeutic management of primary cardiac lymphoma |
Primary cardiac lymphoma (PCL) can be defined as non-Hodgkin's lymphoma (NHL) that involves e heart and/pericardium, or as NHL with tumor mass localized in heart (1,2). Primary cardiac lymphoma accounts for 1.3% to 2% of all cardiac tumors and 0.5% of extranodal lymphomas (1). Primary and secondary lymphomas appear most frequently in case of immunocompromised HIV-infected persons (3). In HIV-infected persons the risk of development of systemic non-Hodgkin's lymphoma is 60 to 200 times that in the general population. A meta-analysis of cohort studies that included 14 936 HIV-infected persons showed that the relative risk in the era of highly active antiretroviral therapy (HAART), as compared with the pre-HAART era, was 0.58 (4). Primary cardiac lymphomas are most often localized in the right atrium and rarely in other heart cavities or in valves. As a rule neoplasia always involves pericardium also. However, secondary lymphoma always involves pericardium, epicardium or infiltrates into myocardium (3,4). Pathognomonic clinical presentation of PCL is not typical and depends on the size and localization of primary lesion. Prognostic factors are also difficult for identification. Retrospective analysis of 60 immunocompetent patients showed that the disease was presented as right heart insufficiency (20%), pericardial pain (17%), cardiac tamponade (12%), heart rhythm abnormalities, vena cava superior syndrome (8%), acute myocardial infarction, dyspnea, etc. (3). Systemic symptoms were found in 17% of patients, and elevated laboratory values for LDL and ESR were registered in case of 16% and 20% of patients, respectively. To diagnose the disease following techniques can be used: cytological analysis of pericardial exudates, echocardiography, CT, MRI, and scintigraphy with Tc99mSESTAMIB. When indicated angiography can also be used (3). Transesophageal echocardiography and MRI are the techniques of high specificity and sensitivity (Figure 1,2) (4). ECG-gated MRI provides the image of cardiac tumor mass that is isointensive with the signal of normal myocardium T1W and T2W images. The application of gadolinium contrast medium elevates the signal intensity (Figure 3) (4).
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Figure 1. Echocardiogram Obtained at the Time of Diagnosis. The apical four-chamber view (Panel A) and the subcostal four-chamber view (Panel B) show that right atrial cavity is filled by mass of echoes, indicating the presence of a tumor. RA denotes right atrium, LA left atrium, RV right ventricle, and LV left ventricle. |
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Figure 2. Cardiac MRI Studies. One frame from a cine acquisition (in which the blood appears bright), obtained in a paraseptal long-axis view to the right of the intreventricular septum (Panel A), shows a large, lobulated mass extending into the right atrial cavity from its attachment along the floor of the chamber (straight arrow). The mass protrudes partially into the tricuspid orifice, which is demarcated by the closed tricuspid-valve leaflet (curved arrow). A small pericardial effusion is also visible (arrowhead). A spin-echo image with T2 weighting (in which the blood appears black), acquired in the orientation of the four-chamber view near the inferior surface of the heart (Panel B), shows a bulky mass lesion (straight arrow) yhat occupies most of the right atrial cavity at this level. A small pericardioal effusion, probably with some deposition of fibrin along the pericardial surfaces, may be contributing to apparent thickening of the right atrial free wall (curved arrow). A short-axis spin-echo image obtained after the intravenous administration of 0.1 mmol of gadolinium per kilogram (Panel C) shows extension of the tumor underneath the basal portion of the interventricular septum (arrow). The signal intensity in the tumor is less strongly enhanced that of the normal myocardium. AO denotes ascendings aorta, SVC superior vena cava, RVO right ventricular outflow tract, RA right atrium, RV right ventricle, and LV left ventricle. |
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Figure 3. Endomyocardial -Biopsy Specimen. There is a diffuse infiltrateof neoplastic cells under the endocardium (Panel A, hematoxylin and eosin, x125). Examination at a higher magnification (Panel B) shows that the cells have a high nuclear-to-cytoplasmic ratio (hematoxylin and eosin, x500). In situ hybridization studies show that most of the lymphoma cells contain nuclear Epstein-Barr virus-encoded RNA (Panel C, x125). |
Endomocardial biopsy was performed in 50% of patients to obtain histologically confirmed diagnosis. Centroblasts and B-cell immunoblasts (CD20+, Ki67+, CD3-, and EBV-) were predominant (4).
The shown characteristics are typical for diffuse B-cell NHL of high-grade malignancy. The prognosis of disease course in patients with PCL associated with HIV infection is poor. The results of present clinical researching show that 50% to 73% of patients affected with PCL, after the treatment with poly-chemotherapy, develop CR that persists longer than 33 months in 20% of all cases. The applied treatment regimen consists of CHOP (cyclophosphamide, hydroxydaunomicin [doxorubicin], Oncovin [vincristine], prednisone) or CHOP combined with Rituximab (CD20 monoclonal antibody) (4).
References:
1. McAllister HA, Fengolio JJ. Tumors of the cardiovascular systems. In: Atlas of tumor pathology. 2nd Series. Fascicle 15. Washington, DC: Armed Forces Institute of Pathology; 1978. p. 99-100.
2. Caiirins P, Butany J, Fulop J, Rakowski H, Hasram S. Cardiac presentation of non-Hodgkin's lymphoma. Arch Pathol Lab Med 1978;111:80-3.
3. Ceresoli GL, Ferreri AJM, Bucc E, Ripa C, Ponzoni M, Villa E. Primary cardiac lymphoma in immunocompetent patient. Cancer 1997;80:1497-506.
4. Kaplan LD, Afridi NA, Holmvang G, Yukerberg LR. Case 31-2003: A 44-year- old man with HIV infection and right atrial mass. N Engl J Med 2003,349:14;1367-77.
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Vladimir
BALTIC
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| 4. | Application of MCC-465 or doxorubicin (DXR) encapsulated in PEG immunolyposome, in patients with metastatic stomach cancer |
Goren et al. prepared immunoliposome for the first time in 1996 (Figure 1). This liposome was conjugated to MoAb against HER-2 positive tumors. On the basis of their and other authors' experience Matsamura et al. (2003) prepared immunoliposome-encapsulated form of DXR (Figure 1). The liposome was chemically conjugated to PEG and F(ab')2 fragments of the human monoclonal antibody GAH, which can recognize antigen molecules on plasmatic membranes of different types of tumor cells. The anti-tumor activity of MCC-465 against GAH-positive human stomach cancer B37 cells was clearly shown in pharmacokinetic studies phase I.
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Figure
1. Schematic diagram of MCC-465 Taken from: Ann Oncol 2004;15(3):518. |
MTD for MCC-465 is 45.5 mg/m2 using the 3-week schedule. The authors recommend MCC-465 dose of 32.5 mg/m2 for phase II study.
References:
1. Matsumura Y, Goth M, Muro K et al. Phase I and pharmacokinetics study of MCC-465. a doxorubicin (DXR) encapsulated in PEG immunoliposome, in patients with metastatic stomach cancer. Ann Oncol 2004;15:517-25.
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Vladimir
BALTIC
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© Institute of
Oncology Sremska Kamenica, Last updated May 5, 2004