The efficacy and tolerability of a sunitinib 3-week administration schedule in metastatic renal cell carcinoma patients: report of three cases.

Sunitinib, an orally multitargeted tyrosine kinase inhibitor and standard first-line treatment for metastatic renal cell carcinoma, is usually administered on a 6-week schedule. Toxicities reported with this drug are usually of moderate grade, which results in good treatment tolerability and patients' compliance. However, in some cases high-grade or prolonged toxicities require temporary treatment interruption or dose adjustment, possibly resulting in reduced treatment efficacy. We describe three cases of metastatic renal cell carcinoma patients (a 53-year-old male, a 70-year-old woman, and a 65-year-old woman) who received a shortened 3-week sunitinib administration schedule, 2 weeks daily administration followed by 1 week of rest (2/1) due to toxicities developed on the classic 6-week schedule, which would have required a temporary treatment interruption or a dose reduction. Treatment was generally well tolerated with manageable toxicities. A 3-week administration schedule of sunitinib may represent a valid alternative for managing toxicity while maintaining the planned dose intensity over a 6-weeks period of time. Sunitinib may thus be administered using a flexible dosing schedule to meet individual patient needs, achieving better tolerability and maintaining significant response to treatment.

Congenital transmission of a papovavirus of the stump-tailed macaque.

Stump-tailed macaque virus, a newly recognized papovavirus of the SV40 polyoma subgroup, was demonstrated in kidney cultures from each of five stump-tailed macaque fetuses in the second half of gestation and from six adult stump-tailed macaques. Such regular presence of virus in the fetus is an unusual feature for a papovavirus.

Weekly administration of docetaxel and epirubicin as first-line treatment for hormone-refractory prostate carcinoma.

Androgen-independent prostate carcinoma (AICP) is one of the tumors that continue to respond poorly to chemotherapy. Recently, protocols based on the use of docetaxel have significantly improved survival for patients in this disease. In other types of neoplastic disease, combined therapy with taxanes and anthracycline derivatives has been shown to produce additive effects in terms of growth inhibition, and superior tolerability when associated with weekly administration schedules. These findings prompted us to examine the tolerability and efficacy of weekly treatment of AICP with docetaxel (DOX) plus epirubicin (EPI). We enrolled 35 chemotherapy-naive men with AICP (mean age 72 years, range 68-77) and normal hepatic, renal, and cardiac function. The chemotherapy protocol provided for the IV administration of DOX (30 mg/m2) and EPI (30 mg/m2) on days 1, 8, and 15 every 28 days. Treatment was continued for 6 months or until disease progression and/or unacceptable toxicity was observed. Serum levels of prostate-specific antigen (PSA) were monitored in all patients, and reductions from baseline values of >50% were considered indicative of positive responses to treatment. Thirty-four patients were included in the analysis of toxicity, and objective responses to treatment were assessed in the 28 patients with measurable lesions. Nineteen patients (56%) experienced PSA reductions of >50% that persisted for more than 4 weeks. The response to therapy was classified as complete in 1 of the 28 patients (4%) with measurable disease (at the lymph node level). Thirteen others (13/28, 46%) had partial responses, in nine (32%) the disease remained unchanged, and progression was observed in the remaining five (18%); overall response rate was 50% (CR + PR). Of the 27 patients with pain at the time of enrollment, 16 (59%) experienced pain reduction during treatment. The median time to disease progression was 11.7 months (95% CI: 7.7-15.7) while the median survival time was 18.7 months (95% CI: 12.3-25.1). During the study, four patients developed grade 3 anemia and leukopenia, which was reversible in all cases. Lower grades of asthenia, nausea, vomiting, diarrhea, and peripheral edema were also observed. There were no cases of cardiotoxic effects. Alopecia was frequent but reversible in all cases. The results of this preliminary study indicate that the combined administration of DOX and EPI for treatment of AIPC is effective and well tolerated. The weekly administration of the drug combination appears to be a promising approach to the treatment of these tumors.

Gemcitabine plus irinotecan as first-line weekly therapy in locally advanced and/or metastatic pancreatic cancer.

Single-agent gemcitabine has been established as standard treatment for advanced pancreatic cancer since clinical studies have shown an improvement in overall survival and significant clinical benefit when compared to the best supportive care despite low overall objective response. Several phase II studies have tested other single agents and different gemcitabine-based regimens in pancreatic cancer, but both response and survival rates have remained low. Irinotecan, a topoisomerase I inhibitor currently approved for the treatment of metastatic colon cancer, has also demonstrated improved response rate in patients with pancreatic cancer. Our purpose was to determine the activity and toxicity of this regimen in patients with unresectable or metastatic pancreatic cancer. Patients with histologically confirmed pancreatic adenocarcinoma received gemcitabine 1000 mg/m2 plus irinotecan 100 mg/m2 IV on days 1, 8, and 15 of a 28-day cycle for 6-8 months. From February 2004 to April 2006, 33 patients were entered into this study, 32 of whom were evaluable for treatment response, toxicity, median time to progression, and median survival. Characteristics included a median age of 63 years (range 41-79), 21 males (64%), and 12 females (36%). One patient discontinued treatment due to adverse effects. The total number of cycles administered was 188 and the median number of cycles for patients was 5.6 (range 2-7). Thirty-two patients were assessable for toxicity and response. Grade 3 hematological toxicity occurred in 9% of patients and was primarily neutropenia. No grade >2 gastrointestinal toxicities or death due to treatment were observed. The most frequent nonhematological adverse event was fatigue. Ten patients responded to treatment with two complete responses (6.3%) and eight partial responses (25.0%), for an overall response rate of 31.3%; 11 patients achieved stable disease (34.3%). The median time to tumor progression and the median survival were 9.2 (95% CI: 6.0-12.4) and 11.8 (95% CI: 7.7-15.9) months, respectively, with a 2-year survival of 22%. On the basis of this trial, the combination of gemcitabine plus irinotecan, administered in a weekly schedule and at this dose, is well tolerated and offers encouraging activity in the treatment of advanced and/or metastatic pancreatic cancer.

India's Revised National Tuberculosis Control Programme: looking beyond detection and cure.

SETTING: Pune District, Maharashtra State, India. OBJECTIVES: To examine delays experienced by patients in accessing directly observed treatment. DESIGN: Data were collected from 117 new sputum-positive patients using a semi-structured interview schedule. RESULTS: Patient delays as well as diagnostic and treatment delays, which reflect the performance of a National TB Programme, were minimal. Provider delays, however, contributed significantly to delayed entry into India's Revised National TB Control Programme (RNTCP). Patients had to resort to multiple contacts with providers due to limitations of these providers in diagnosing or directing patients to the RNTCP. Patients who consulted a private provider participating in the public-private mix (PPM) were more likely to be suspected (OR 2.63, 90% CI 1.04-6.64) and referred (OR 6.8, 95%CI 2.08-22.21) to the RNTCP. Once the patients entered the RNTCP, the response of the system was rapid, with diagnosis offered and treatment initiated within on average 7 days. CONCLUSION: Interventions aimed at providers to encourage early suspicion and referral to the RNTCP, such as the PPM, are more important in improving patient access to TB care than those focusing on reducing patient delays.

Grave's Eye disease developing following radioiodine treatment for toxic nodular goitre.

The development of Grave's ophthalmopathy (GO) following radioiodine (RI) treatment for Grave's thyrotoxicosis, though controversial, is well described. The development of ophthalmopathy following RI treatment for toxic nodular goitre is much less recognised. We report a 49 year-old female patient who developed thyrotoxicosis and GO after receiving RI treatment for toxic nodular goitre and we also review the relevant literature.

Once weekly thyroxine treatment as a strategy to treat non-compliance.

Hypothyroidism is a common disorder, which is mainly treated in primary rather than secondary care. Once daily thyroxine replacement restores euthyroidism in most patients; some patients, however, remain hypothyroid despite adequate thyroxine replacement. Non-compliance is the most common cause of lack of response to thyroxine treatment. We describe two cases of primary hypothyroidism in which daily thyroxine treatment did not restore biochemical euthyroidism but once weekly thyroxine treatment was successful. In addition we review the evidence and discuss the differential diagnosis of lack of response to thyroxine treatment. Once weekly thyroxine treatment can be a safe, well-tolerated, and effective therapy for patients with non-compliance.

Oncornavirus particles in lymphoid cultures from a howler monkey with Herpesvirus saimiri-induced disease.

Budding and extracellular oncornavirus particles were observed in cells of lymphoid cultures derived from the spleen, lymph node, and blood of a howler monkey (Alouatta caraya) that developed a malignant lymphoproliferative disease after infection with Herpesvirus saimiri. The various possible sources of origin of these particles are discussed.

Herpesvirus saimiri-induced malignant lymphoma in rabbits.

Of 9 New Zealand White rabbits inoculated at multiple sc and im sites with a single dose of Herpesvirus saimiri (HVS), 2 developed malignant lymphomas 40-50 days post inoculation. At least 1 animal developed a terminal leukemic phase of the disease. HVS was isolated from the oral and conjunctival swabs and blood and tissue lymphocytes, but not from monolayer cell cultures derived from kidney or lung tissues of the diseased animals. The inoculated rabbits developed low titers of neutralizing antibodies against the virus. Antibodies against HVS specific early and late antigens were not detected in the sera of 7 animals that failed to develop clinical disease, but were detected in the serum of the 1 rabbit with lymphoma. The immunologic response of rabbits to HVS infection was compared to similar responses in infected nonhuman primates.

Herpesvirus saimiri-induced lymphoproliferative disease in howler monkeys.

Four of 5 howler monkeys (Alouatta caraya) experimentally infected with Herpesvirus saimiri (HVS) developed a rapidly fatal malignant lymphoma accompanied by peripheral T-cell lymphocytosis. HVS was isolated from fresh and tissue cultured blood and tissue lymphocytes and from cell cultures derived from nonlymphoid organs. Humoral antibodies against HVS-induced antigens were detected in the sera of the animals. The in vitro response of the peripheral blood lymphocytes to mitogenic stimulants was depressed following HVS infection.

Transmissible lymphoma and simian acquired immunodeficiency syndrome in rhesus monkeys.

Four rhesus monkeys (Macaca mulatta) were inoculated with a homogenate of a cutaneous lepromatous leprosy lesion from a mangabey monkey (Cercocebus atys). One died of B-cell lymphoma, and another died of an immunodeficiency syndrome. Cell suspensions prepared from the tumor and spleen of the monkey with lymphoma induced lymphoma or an immunodeficiency syndrome when inoculated into additional young rhesus monkeys. The immunodeficiency syndrome was similar to simian acquired immunodeficiency syndrome and consisted of opportunistic infections, lymphoid hyperplasia or atrophy, wasting, and syncytial cell formation. Mitogen responses and percentages of T4- and T8-positive lymphocytes were normal until the animals were moribund. Lymphoblastoid cell lines became established in vitro from tumor cell suspensions. These cells were infected with a herpesvirus related to Epstein-Barr virus. In addition, a retrovirus morphologically similar to human T-cell lymphotrophic virus type III (HTLV-III) and simian T-lymphotrophic virus type III (STLV-III) was isolated from one of the lymphoblastoid cell lines (LCL). Type D retroviruses could not be demonstrated in the monkeys in the transmission study; however, a retrovirus similar to that in the LCL was isolated from 4 animals by coculture of peripheral blood lymphocytes with the human cell line H9. These results suggest that this retrovirus, STLV-III/Delta, may be associated with the immunodeficiency syndrome in these macaques and may be of mangabey origin.

Immunologic assessment of a cluster of asymptomatic HTLV-I-infected individuals in New Orleans.

PURPOSE: Although clusters of individuals infected with the human T-cell lymphotrophic virus type I (HTLV-I) have been identified in the United States, no systematic evaluation of the immunologic status of these persons has been reported. We therefore studied a group of 11 HTLV-I-infected former intravenous drug abusers who were long-term participants in a methadone maintenance program in New Orleans, Louisiana, to determine the effects of HTLV-I and chronic opiate use on immunity. PATIENTS AND METHODS: Mitogenic responses and results of serologic studies, cell phenotype analysis, and cytotoxicity assays were compared to those in two other HTLV-I seronegative groups: a similar group of 17 methadone users and 15 healthy age-, sex-, and race-matched control subjects. All study participants were seronegative for human immunodeficiency virus type 1. RESULTS: Percentages and numbers of total T lymphocytes (CD2+,CD3+), T-suppressor/cytotoxic lymphocytes (CD8+), cytotoxic lymphocytes (Leu7+, Leu11+, NKH-1+) and B lymphocytes (B4+) were similar among the study groups. Although percentages and numbers of total T-helper lymphocytes (CD4+) were also similar among the groups, HTLV-I-infected subjects had higher percentages and proportions of helper/inducer cells (CD4:4B4+) than did HTLV-I seronegative methadone users. Both methadone using groups had decreased percentages and numbers of suppressor/inducer T lymphocytes (CD4:2H4+). Major histocompatibility complex unrestricted T-cell cytotoxicity (lectin-dependent cellular cytotoxicity), natural killer cell function, and mitogenic responses to the T-cell mitogen phytohemagglutin were similar among the three study groups. Pokeweed mitogen responses were severely depressed in the HTLV-I-infected population. CONCLUSIONS: We conclude that HTLV-I infection is associated with abnormalities in T-cell-dependent B-cell proliferative responses. Furthermore, both long-term methadone use and HTLV-I infection are associated with abnormalities in the distribution of CD4+ cell subpopulations. The increase in the helper/inducer and T-cell cell populations and decrease in the pokeweed mitogenic response noted in HTLV-I-infected subjects appear to be markers for infection with this retrovirus.

The Mumbai experience in building field level partnerships for DOTS implementation.

In February 1999, the Revised National Tuberculosis (TB) Control Programme (RNTCP) was implemented in the city of Mumbai after a pilot phase of 5 years. The city has a population of more than 12 million people and an estimated annual TB incidence of 21,000 cases, 8000 of these being infectious. This paper describes a partnership between the TB programme and a Non Governmental Organization (NGO), which began with a methodological analysis of the problems faced by the programme to help identify other key organizations, who might usefully be involved. The work focussed on "networking" to ensure the optimum use of existing resources. The problems encountered affected all levels of TB control from access to drug supply and treatment. The major issues related to an inadequate public health infrastructure resulting in poor technical and administrative support to field staff. There was confusion over roles of the health personnel in the TB programme and the public health facility, as well as poor technical performance. Partnerships were found to be useful in addressing the following areas: (1) the implementation of an external quality assurance scheme for sputum microscopy through involvement of microbiologists from large hospitals and research organizations; (2) training and capacity strengthening of programme and public health facility staff through innovative training and team building exercises organized by the programme, NGOs and the private sector; (3) development of Information, Education and Communication (IEC) material through partnerships with NGOs, and (4) the involvement of local NGOs and private doctors to increase case finding and to improve access to direct observation of treatment (DOT). The paper discusses the lessons learnt in this process and identifies some of the key issues in urban TB control, for consideration by policy makers.

Synthesis and biological evaluation of prodrugs of zidovudine.

A series of prodrugs of zidovudine (AZT) has been synthesized in an effort to enhance the uptake of the prodrugs by the HIV-1 infected cells and to increase the plasma half-life of AZT. The 5'-OH function of AZT was esterified with various acids in the presence of DCC and 4-(dimethylamino)pyridine (DMAP). The prodrug moieties included (a) morpholine and N-phenylpiperazine-1-acetic acid, (b) 1,4-dihydro-1-methyl-3-nicotinic acid, (c) retinoic acid, and (d) certain amino acids. The anti-HIV-1 activity of the esters was determined in peripheral blood lymphocytes. The IC50 for AZT in this system was 0.12 microM whereas for prodrugs it ranged from 0.05 to 0.2 microM. The prodrugs were generally less cytotoxic than AZT except the retinoic acid ester. In vitro hydrolysis of the various esters in human plasma indicated that these agents were relatively stable toward plasma esterases with t1/2 ranging from 10 to 240 min. Drug uptake studies in H9 cells with radiolabeled analogues demonstrated that the retinoic acid ester achieved approximately 4-fold higher intracellular concentration than [3H]AZT. However, 1,4-dihydro-1-methyl-3-[(pyridylcarbonyl)oxy] ester (5) was the most active agent of this series and had a higher therapeutic index than AZT.

Enhanced frequency of spontaneous B cell lines from Epstein-Barr virus (EBV) seropositive donors 80 years and older.

Based on the well-recognized decline in immunocompetence which develops with advancing age, we have evaluated the effect of age on the frequency of development of spontaneous Epstein-Barr virus (EBV)-infected B cell lines. Blood mononuclear cells were isolated from 38 clinically healthy seropositive donors. The cells were maintained in vitro according to routine culture conditions for lymphocytes. Eight spontaneously EBV-infected B lymphoblastoid cell lines (LCL) were isolated. The LCL developed in 12.5, 14.3, or 6.3% of the samples derived from donors in the three age groups 20-39, 40-59, 60-79, respectively. In contrast, samples from five of seven (71%) donors 80 years and older yielded LCL. Although the reason(s) for the increased frequency of occurrence of spontaneous LCL from the older adults is yet to be explored, the possible role of the virus-specific T lymphocytes as a contributing factor is discussed.

Tuberculosis patients and practitioners in private clinics in India.

SETTING: Rural and urban areas of Maharashtra, a large state in Western India. OBJECTIVE: To understand tuberculosis (TB) management practices among private medical practitioners (PPs) and the treatment behaviour of the patients they manage. DESIGN: Prospective study of help-seeking patterns and treatment behaviour among 173 pulmonary TB patients diagnosed in private clinics, and the TB management practices of 122 PPs treating these patients. RESULTS: The first source of help for 86% of patients was a PP. The diagnostic and treatment practices of PPs were inadequate; 15% did not consider sputum examination to be necessary, and 79 different treatment regimens were prescribed by 105 reporting PPs. Sixty-seven percent of the patients diagnosed in private clinics remained with the private sector, and the rest shifted to public health services within six months of treatment. The treatment adherence rate among the patients in private clinics was 59%. There were discrepancies between the reported management practices of the PPs and what their patients actually followed. CONCLUSION: The study identifies and highlights the need to educate PPs and their TB patients, and indicates ways in which PPs could be meaningfully involved in efforts to revitalize the national TB control programme.

Shifting the paradigm in tuberculosis control: illustrations from India.

Drawing on literature from India and key contributions from social science, this paper asks and attempts to answer the question 'who is to blame for treatment failures in TB'? Some key lessons emerge: effective tuberculosis control cannot be achieved so long as the disease is considered in isolation from the social processes that maintain it, create the conditions facilitating its spread and act as barriers to care. Insights into the economic and social burdens incurred with a diagnosis of TB are essential to understand why many patients, especially the most disadvantaged, are unable to comply with treatment regimens. TB and health care interventions need to be appropriate to the health service contexts in which they are applied, and sensitive to the competing demands, needs and priorities of people's lives. The paper argues for the need to reorient TB control programmes towards enabling patients to obtain care. The problem of access emerges as central to people's ability to obtain and maintain appropriate therapy. Examples and characteristics of successful non-governmental projects, from which policy makers, programmers and practitioners could learn, are outlined and contrasted with more rigid directly observed treatment approaches. We conclude that treatment failures are not patient failures, and that TB control programmes need to address the social dimensions of TB, and adhere to the principles of good TB care, with the same commitment that is devoted to ensuring patients follow treatment guidelines. We suggest a paradigm shift away from a focus on diseased patients towards enabling health in the community.

Attention to gender issues in tuberculosis control.

Although a seventy per cent excess of male over female TB cases are reported globally each year, the reasons for this difference are unclear. Generally, women in poor countries confront more barriers than men in accessing health care services. Yet, research is lacking to explain the impact of gender inequalities in access to care on reported sex ratios for TB. A review of the limited available literature and field visits to TB programmes offered insights and suggested a framework to study gender differentials in TB. This paper considers the role of gender at various steps in effective TB care. A research strategy to study and account for gender differences in TB control is proposed.

Tuberculosis control in rural India: lessons from public-private collaboration.

SETTING: A rural tuberculosis (TB) Unit (population 350 794) in Pune district, Maharashtra State, India. OBJECTIVE: To develop a 'model' partnership between rural private medical practitioners (PMPs) and the Revised National Tuberculosis Control Programme (RNTCP). DESIGN: A partnership was developed between 100 PMPs in the study area and the district health and tuberculosis staff through facilitation by a non-governmental organisation (NGO). Participatory research methods were used to plan and implement the partnership. The process of creation and implementation of the partnership was analysed using quantitative and qualitative research methods. RESULTS: The partnership contributed to 30% of the cases detected in the TB Unit over a 5-month period. Six months after withdrawal of the NGO, referrals from the private sector to the RNTCP were continuing to a lesser extent, but there was a breakdown of the communication and documentation systems. CONCLUSION: The project highlights the importance of organisational and individual commitment to these partnerships, the key roles of the District Health Officer and the District Tuberculosis Officer in guiding and supporting these initiatives from the public sector, the potential role of process and outcome 'indicators' in monitoring partnerships and the important role of NGOs as intermediaries and facilitators.

Comparison of methods for HIV isolation from monocytes and lymphocytes of seropositive asymptomatic hemophiliacs and homosexuals.

1. Since monocyte-macrophages have been recognized as HIV targets in addition to CD4+ T-lymphocytes, we have evaluated HIV infection of purified peripheral blood mononuclear cell fractions obtained from 10 seropositive asymptomatic hemophiliacs and compared it with that of 10 asymptomatic homosexual patients. 2. HIV was isolated more frequently from the lymphocytes than the monocytes of both groups of patients. 3. HIV preferentially replicated in phytohemagglutinin-stimulated lymphocytes compared with growth factor-treated monocytes. Monocytes did not preferentially harbour HIV in either group.