A randomized phase II study comparing capecitabine alone with capecitabine and oral cyclophosphamide in patients with advanced breast cancer-cyclox II.

BACKGROUND: Capecitabine and cyclophosphamide are active in patients with advanced breast cancer, have non-overlapping toxic effects and synergy pre-clinically. We explored the efficacy and toxic effect of an all-oral combination of capecitabine with cyclophosphamide versus capecitabine alone in a multicentre, randomized, phase II study. PATIENTS AND METHODS: Patients with locally advanced or metastatic breast cancer were randomized to treatment with capecitabine given continuously (666 mg/m(2) b.i.d. days 1-28) alone (C) or with oral cyclophosphamide (100 mg/m(2) days 1-14 of a 28-day cycle) (CCy) for up to six cycles. RESULTS: Eighty-two patients were randomized. There was no complete response. The proportions with partial response were 36% on C and 44% on CCy, a difference of 7.9% [95% confidence interval (CI) -13.4 to 29.1]. Significant toxic effect was uncommon: grade ≥3 diarrhoea in 4 (10%) versus 1 (3%) patients; grade ≥3 fatigue in 2 (5%) versus 5 patients (13%) and grade ≥2 hand-foot syndrome in 7 (17%) versus 11 (28%) patients receiving C versus CCy, respectively. Median progression-free survival was 3.1 months on C and 6.9 months on CCy, not significantly different statistically. There was no difference in overall survival. CONCLUSION: The difference in tumour response suggests a reasonable chance that CCy is superior to C alone.

Malaria therapy reinoculation data suggest individual variation of an innate immune response and independent acquisition of antiparasitic and antitoxic immunities.

Malaria therapy reinoculation data were examined for the possible detection of effects attributable to stable individual host-specific factors, through correlation between descriptive variables of first and second infections. Such an effect was demonstrated with respect to the first local maximum of the asexual parasite density, i.e., the density at which a host controls parasite growth. The effect was seen between an individual host's first and second Plasmodium falciparum infection, as well as between an individual host's first malaria infection with P. ovale and second malaria infection with P. falciparum. We give reasons to believe that the main underlying mechanism is individual variation of an innate immune response. The data were also examined for systematic changes from first to second P. falciparum infection, as indicators of acquired immunity. In addition to the well-known reduction in parasite density, the data show the early development of apparent parasite tolerance. We give reasons to interpret the latter as antitoxic immunity.

Population dynamics of untreated Plasmodium falciparum malaria within the adult human host during the expansion phase of the infection.

A retrospective analysis was performed of parasite count data recorded from the first 7 days of blood or mosquito transmitted Plasmodium falciparum infections given for the treatment of neurosyphilis in the USA before 1963. The objective of this study was to characterize initial growth dynamics before host defences have significant effects on the infecting parasite population. Of the 328 patients' data available for analysis, 83 were excluded because they had received anti-malarial treatment during the first 7 days of the patent infection. Nonlinear mixed effects modelling was performed to estimate the parameters of interest; 'parasite multiplication rate per 48 h' (PMR), and length of the parasite life-cycle (periodicity). The parasitaemia versus time profiles showed great variability between patients. The mean population estimate of 'PMR' was approximately 8, and was highly dependent on the P. falciparum 'strain'. PMR also varied significantly between patients with a 90% prediction interval varying from 5.5 to 12.3-fold. Both intrinsic parasite multiplication rate (an intrinsic virulence determinant), and host susceptibility and defence contribute to expansion of the parasite biomass and thus disease severity in falciparum malaria.

Follow-up strategies for patients treated for non-metastatic colorectal cancer.

BACKGROUND: It is common clinical practise to follow patients with colorectal cancer (CRC) for several years following their definitive surgery and/or adjuvant therapy. Despite this widespread practice there is considerable controversy about how often patients should be seen, what tests should be performed and whether these varying strategies have any significant impact on patient outcomes. OBJECTIVES: To review the available evidence concerning the benefits of intensive follow-up of colorectal cancer patients with respect to survival. Secondary endpoints include time to diagnosis of recurrence, quality of life and the harms and costs of surveillance and investigations. SEARCH STRATEGY: Relevant trials were identified by electronic searches of MEDLINE, EMBASE, CINAHL, CANCERLIT, Cochrane Controlled Trials Register, Science Citation Index, conference proceedings, trial registers, reference lists and contact with experts in the field. SELECTION CRITERIA: Only randomised controlled trials comparing different follow-up strategies for patients with non-metastatic CRC treated with curative intent were included. DATA COLLECTION AND ANALYSIS: Trial eligibility and methodological quality were assessed independently by the three reviewers. MAIN RESULTS: Five trials were included. There was evidence that an overall survival benefit at 5 years exists for patients undergoing more intensive follow-up (OR = 0.67, 95% confidence interval 0.53 - 0.84; RD = -0.07, CI -0.12 - -0.02). The absolute number of recurrences was similar (OR = 0.91; 95% confidence interval 0.72 - 1.14; RD = 0.00, CI -0.07 - 0.07) and although the weighted mean difference for the time to recurrence was significantly reduced by 6.75 (95% confidence interval -11.06 - -2.44) there was significant heterogeneity between the studies. Analyses demonstrated a mortality benefit for performing more tests versus fewer tests (OR = 0.66; 95% confidence interval 0.46 - 0.95) and liver imaging versus no liver imaging (OR = 0.66; 95% confidence interval 0.46 - 0.95). However when both these results are expressed as a risk difference this significance is lost (RD = -0.06; CI -0.25 - 0.13). No useful data on quality of life, harms or cost-effectiveness were available for further analysis. REVIEWER'S CONCLUSIONS: The results of our review suggest that there is an overall survival benefit for intensifying the follow-up of patients after curative surgery for colorectal cancer. Because of the wide variation in the follow-up programmes used in the included studies it is not possible to infer from the data the best combination and frequency of clinic (or family practice) visits, blood tests, endoscopic procedures and radiological investigations to maximise the outcomes for these patients. Nor is it possible to estimate the potential harms or costs of intensifying follow-up for these patients in order to adopt a cost-effective approach in this clinical area. Large clinical trials underway or about to commence are likely to contribute valuable further information to clarify these areas of clinical uncertainty.

Genesis, sequestration and survival of Plasmodium falciparum gametocytes: parameter estimates from fitting a model to malariatherapy data.

Plasmodium falciparum malaria is one of mankind's main killers. Part of the parasite's life-cycle is spent in human blood, mainly as asexual stages. A fraction of the asexual parasites develops into gametocytes (gamete precursors) while sequestered in deep tissues. After re-entering the circulation, gametocytes can be picked up by a mosquito to continue the parasite's life-cycle. We present estimates of the conversion probability from asexual parasites to circulating gametocytes and of the gametocytes' sequestration and circulation times, obtained for the first time by fitting a dynamic model to individual patients' histories (daily records of 113 neurosyphilitic patients undergoing malariatherapy). The model assumes that the conversion probability can vary among the successive waves of asexual parasitaemia of a patient, and that gametocytes die at an age-dependent rate which increases under high asexual parasite densities. On average, 1 gametocyte per 156 asexual parasites (range 7.4-3700) is produced. The most remarkable findings are the large individual variation of conversion probabilities and circulation times, the average gametocyte circulation time of 6.4 days (range 1.3-22.2 days) which is more than twice the currently accepted value, and the large variation of conversion probabilities among successive waves of asexual parasitaemia without any particular time pattern. The latter finding could be explained by an association between conversion probability and variation of PfEMP1.

Plasmodium malariae blood-stage dynamics.

We examine the dynamics of parasitemia, fever, and gametocytemia reflected in the preintervention charts of 180 malaria-naive U.S. neurosyphilis patients infected with the USPHS strain of Plasmodium malariae, for malariatherapy, focusing on the 84 charts for which more than 35 days of patency preceded intervention and daily records encompassed 92% or more of the duration of each infection. Inoculum size did not influence any outcome variable. Fevers (days with temperatures > or =101 F) followed patterns that fit recognized brood structures more often than did our approximations of merogony cycles (via local peaks in parasitemia), but neither closely fit textbook quartan patterns. There were no discernable patterns in gametocytemia. Successful transmission to mosquitoes increased following subcurative drug treatment but did not depend on detectable gametocytemia.

Plasmodium falciparum parasitaemia described by a new mathematical model.

A new mathematical model of Plasmodium falciparum asexual parasitaemia is formulated and fitted to 35 malaria therapy cases making a spontaneous recovery after primary inoculation. Observed and simulated case-histories are compared with respect to 9 descriptive statistics. The simulated courses of parasitaemia are more realistic than any previously published. The model uses a discrete time-step of 2 days. Its realistic behaviour was achieved by the following combination of features (i) intra-clonal antigenic variation, (ii) large variations of the variants' baseline growth rate, depending on both variant and case, (iii) innate autoregulation of the asexual parasite density, variable among cases, (iv) acquired variant-specific immunity and (v) acquired variant-transcending immunity, variable among cases. Aspects of the model's internal behaviour, concerning variant dynamics, as well as the respective contributions of the three control mechanisms (iii) - (v), are displayed. Some implications for pathogenesis and control are discussed.

Successful high dose therapy for relapsed mediastinal large B cell lymphoma following surgical repair of anterior chest wall defect.

We describe a man with relapsed large B cell mediastinal lymphoma and associated infected large anterior chest wall defect who required high dose salvage therapy for his underlying disease. An initial mediastinotomy wound, associated with recurrent sepsis, had developed into an abscess, then fistula and eventually a large anterior chest wall defect. Safe use of salvage chemotherapy required reconstructive surgery consisting of a pedicled muscle flap. The subsequent high dose chemotherapy was carried out without complications and 15 months later the patient is alive and well.

Modelling the transition of asexual blood stages of Plasmodium falciparum to gametocytes.

In this paper, we investigate the transition of asexual blood stages of P. falciparum to gametocytes. The study is based on daily data, collected from 262 individual courses of parasitaemia. We propose several mathematical models that follow biological reasoning. The models are fitted with maximum likelihood and are compared with each other. The models differ in the assumptions made about the mortality of circulating gametocytes and about the transition rate of the asexual parasites. Gametocyte mortality is modelled as being (i) constant over time, (ii) linearly increasing over time, (iii) linearly increasing over gametocyte age, and (iv) exponentially increasing over gametocyte age, respectively. The transition rate is either kept constant per patient or piecewise constant within intervals that correspond to waves of asexual parasitaemia which are assumed to be caused by different Pf(emp1)-variants. According to likelihood ratio tests, the models with age-dependent mortality rate and wave-dependent transition rates are superior to the models with constant transition rate and/or constant or time-dependent mortality rate. The best fits are reached for models with exponentially increasing (Gompertz-type) mortality. Furthermore, an impact of high asexual parasite densities on the survival of gametocytes, interpreted as a cytokine-mediated effect, is evident in some cases.

A retrospective examination of sporozoite- and trophozoite-induced infections with Plasmodium falciparum: development of parasitologic and clinical immunity during primary infection.

A retrospective analysis was made of the parasitologic and fever records of 318 patients who had been infected with the El Limon, Santee Cooper, or McLendon strains of Plasmodium falciparum for treatment of neurosyphilis between 1940 and 1963 to determine the development of parasitologic and clinical immunity during primary infection. The presence of fever > or = 101 degrees F and > or = 104 degrees F, asexual parasite counts > or = 1,000 and > or = 10,000/microl, and gametocyte counts > or = 100/microl and > or = 1,000/microl are presented. The frequency of fever (number of patients with fever/number of patients remaining in study) for the first 100 days of patent parasitemia, the frequency of parasite counts > or = 1,000 and > or = 10,000/microl during the first 100 days of patent parasitemia, and the frequency of gametocyte counts > or = 100 and > or = 1,000/microl during the first 100 days of patent parasitemia are presented for 4 groups of patients: 1) sporozoite-induced and 2) trophozoite-induced infections requiring treatment during their primary attack, and 3) sporozoite-induced and 4) trophozoite-induced infections not requiring treatment during the primary attack. For each sporozoite-induced infection, the route of inoculation (bites or syringe), the species of mosquito used, the number of mosquito glands or bites, the intensity of salivary gland infection, and the length of the prepatent period are recorded. Prepatent periods for 109 sporozoite-induced infections ranged from 6 to 28 days. Patients with parasitologic or clinical findings that required suppressive, but non-curative treatment, during the primary attack had higher frequency of fever, parasitemia, and gametocytemia than patients not so treated. Fever was concentrated in the first 2 weeks of patent parasitemia although instances of fever were reported >100 days after infection. High-density parasitemia was also concentrated early in the infection; instances of parasite counts > or = 10,000/microl occurred > 75 days after infection. In conclusion, immunity to infection with P. falciparum was shown to develop rapidly. Following primary infection, clinical and parasitologic immunity was evident within 2-3 weeks following the detection of parasites in the peripheral circulation.

A retrospective examination of secondary sporozoite- and trophozoite-induced infections with Plasmodium falciparum: development of parasitologic and clinical immunity following secondary infection.

A retrospective study was made of clinical records to determine parasitemia and episodes of fever of 59 patients reinfected with Plasmodium falciparum for treatment of neurosyphilis, which was considered standard medical care at the time. Records were collected at the National Institutes of Health laboratories in Columbia, South Carolina and Milledgeville, Georgia during the period 1940 to 1963. Nineteen patients were infected via the bites of Anopheles albimanus, An. quadrimaculatus, or An. freeborni mosquitoes; the median prepatent period was 11.5 days. It was evident that clinical immunity, as measured by the frequency of fever, particularly high intensity fever (> or = 104 degrees F), was increased following reinfection. The parasitologic immunity, as measured by the frequency of asexual parasite counts and gametocyte counts, was also evident. In general, in secondary infections with homologous and/or heterologous strains of P. falciparum, fever episodes > or = 101 degrees F and > or = 104 degrees F were reduced in number, parasitemia was reduced, and gametocyte production was reduced. However, despite long courses of parasitemia during their primary infections, most patients developed fever and, in some cases, high-density parasitemia and gametocytemia following reinfection. The intensity of the secondary response did not appear to be associated with the length of the previous course of parasitemia. In addition, current infection with heterologous strain parasites did not prevent the development of fever or higher density parasite counts following imposition of the new strain of parasite.

A retrospective examination of sporozoite- and trophozoite-induced infections with Plasmodium falciparum in patients previously infected with heterologous species of Plasmodium: effect on development of parasitologic and clinical immunity.

A retrospective examination was made to determine parasitemia and episodes of fever in 97 patients, previously infected with Plasmodium malariae, P. ovale, and/or P. vivax, who were reinfected with P. falciparum for treatment of neurosyphilis, the standard treatment at the time. Data were collected at the National Institutes of Health laboratories in Columbia, South Carolina and Milledgeville, Georgia during the period 1940 to 1963. Results were compared with observations recorded for patients following primary infection with P. falciparum. The mean daily percentage of patients with fever > or = 101 degrees F during the first 20 days of primary infection with P. falciparum was 42.4; the percentage with fever > or = 104 degrees F was 19.9%. Those previously infected with P. ovale, P. vivax, and P. malariae had mean daily percentages of fever > or = 101 degrees F and > or = 104 degrees F of 39.1% and 14.8%, 39.1% and 19.4%, and 28.4%, and 11.3%, respectively. Previous infection with P. ovale or P. vivax had little, if any, effect on subsequent clinical malaria due to P. falciparum, whereas infection with P. malariae resulted in reduced frequencies of fever. A similar comparison was made for parasite counts > or = 1,000/microl and > 10,000/microl. The percentages for 268 patients during the first 20 days of primary infection with P. falciparum parasite counts > or = 1,000/microl and > or = 10,000/microl were 58.2% and 29.9%, respectively. Those previously infected with P. ovale, P. vivax, and P. malariae had mean daily percentages of parasitemia > or = 1,000/microl and > or = 10,000/microl of 58.0% and 24.3%, 57.3% and 31.1%, and 45.9% and 19.0%, respectively. Previous infection with P. malariae resulted in a reduction in the frequency of high-density parasitemia (> or = 10,000/microl) as well as an asexual parasite count > or = 1,000/microl. These results suggest that P. falciparum and P. malariae share common antigens that are able to induce parasitologic and clinical protection when infection with P. falciparum follows that with P. malariae. The results did not suggest that protection to P. falciparum is provided by previous infection with P. ovale or P. vivax.

A retrospective examination of the patterns of recrudescence in patients infected with Plasmodium falciparum.

A retrospective examination was made to determine median intervals between recrudescences of Plasmodium falciparum in 343 neurosyphilitic patients who were given malariatherapy, which was routine care at that time. Data were collected at the National Institutes of Health laboratories in Columbia, South Carolina and Milledgeville, Georgia during the period 1940 to 1963. The geometric mean days of peak parasite count for the patients were 8, 26.5, 43.5, 62, 78.5, and 95.5 days, respectively. The intervals between these peaks of 18.5, 17, 18.5, 16.5, and 17 days suggest a fixed time frame for the appearance of different dominant parasite populations during the first 100 days of patent infection. When the data from these same patients were examined for mean peak parasite counts, the patterns indicated a consistent decrease in parasite count suggestive of increasing immunity, which was sufficient to reduce but not eliminate subsequent parasite populations. The geometric mean peak parasite counts for the 343 patients during the primary attack and the first 5 recrudescences were 40,350, 6,975, 5,090, 3,820, 3,455, and 2,375/microl, respectively.

A historical review of the F-1 strain of Anopheles freeborni as a host and vector for studies of malaria.

A review was made of the use of a specific strain of Anopheles freeborni from California (F-1) that has been used extensively in experimental investigations of malaria for more than 50 years. The F-1 strain of An. freeborni has been shown to be a suitable experimental host and vector for different species of Plasmodium that cause malaria in humans and nonhuman primates for biologic, immunologic, and chemotherapeutic studies. Eleven species of Plasmodium fully completed sporogonic development; development of sporozoites within mature oocysts occurred in an additional 7 species. Transmission through An. freeborni from human to human, monkey to human, or monkey to monkey has been demonstrated for 9 species of Plasmodium.

Sister Joseph's nodule in non-Hodgkin's lymphoma.

Sister Joseph's nodule is traditionally regarded as a sign of poor prognosis in untreatable malignancy. We describe a patient with a metastatic umbilical nodule in non-Hodgkin's lymphoma who had a good outcome. The possible mechanisms of tumour spread to the umbilicus and reasons for its rarity in lymphoma are discussed. The need for histological confirmation to exclude treatable disease is emphasized.

Endobronchial metastasis from rectal adenocarcinoma.

A case of endobronchial metastasis 2 yr following treatment of rectal carcinoma is presented. Endobronchial metastases from extrathoracic primary malignancies are uncommon, the estimated frequency and possible mechanisms underlying this complication are discussed. The importance of recognizing possible endobronchial metastasis is in the approach to management and prognosis.

Primaquine resistance in Plasmodium vivax.

Reports have appeared calling attention to what has been termed primaquine resistance in Plasmodium vivax in several geographic areas. The possibility exists that primaquine tolerant strains (often referred to as the tropical zone type from the South Pacific and Southeast Asian regions characterized by early and frequent relapses) may have become widely disseminated to areas where they had not previously existed through the widespread population mobility that has characterized the last 50 years. The appearance in the relatively recent past of strains of P. vivax, particularly from the South Pacific area, that are resistant to the 4-aminoquinolines has added a new dimension to the resistance problem. While there seems to be little evidence to date of the existence of acquired primaquine resistance in P. vivax, the possibility of its emergence in the future can certainly not be ruled out, and its timely detection and confirmation will be most important, albeit quite difficult because of the relatively covert sites of drug effect. The occurrence of relapses in P. vivax after primaquine therapy would be assumed to be the most reliable indication of resistance. Reports of the sporontocidal or gametocytocidal activity of primaquine when used alone (i.e., without concomitant administration of an effective suppressive) against a P. vivax infection have been few and inconclusive. The establishment of baselines of this activity in P. vivax might be useful in detecting and evaluating primaquine resistance in this species.

Infecting dose and severity of falciparum malaria.

The causes of the wide spectrum of severity in malaria have only partly been elucidated. There are theoretical reasons for thinking that the infecting dose may influence the severity, but evidence is scare. We have analysed the records of 82 non-immune neurosyphilis patients bitten by a known number of mosquitoes infected with one of 3 strains of Plasmodium falciparum, whose treatment was delayed. After controlling for strain, the number of mosquitoes was not associated with the prepatent period nor with any of the outcome measures. For one of the main strains, patients with shorter prepatent periods were more likely to receive treatment during the acute phase of the infection, but no other association with measures of severity was found. This study suggest that infecting dose is unlikely to be an important determinant of severity.

CMV chemotherapy for advanced transitional cell carcinoma.

Between May 1986 and September 1990 a total of 43 patients with metastatic transitional cell carcinoma (TCC) of the urinary tract have been treated at our institution with combination chemotherapy (CMV) consisting of cisplatin 100 mg m-2 i.v. day 2; methotrexate 30 mg m-2 i.v. days 1.8; and vinblastine 4 mg m-2 i.v. days 1.8. Chemotherapy was recycled on day 22 and continued for a maximum of six cycles in responding patients. Of 33 patients with measurable disease 8 (24%) achieved a complete remission (CR). The median survival for patients achieving a CR was 13 months (range 5-29+) whilst the median survival for all 43 patients was 7 months (range 1-29+). Only three patients are still alive--two are disease free. More effective and/or less toxic chemotherapy regimens are needed for the treatment of patients with metastatic TCC.