Infectious complications of targeted drugs and biotherapies in acute leukemia. Clinical practice guidelines by the European Conference on Infections in Leukemia (ECIL), a joint venture of the European Group for Blood and Marrow Transplantation (EBMT), the European Organization for Research and Treatment of Cancer (EORTC), the International Immunocompromised Host Society (ICHS) and the European Leukemia Net (ELN).

The 9th web-based European Conference on Infections in Leukemia (ECIL-9), held September 16-17, 2021, reviewed the risk of infections and febrile neutropenia associated with more recently approved immunotherapeutic agents and molecular targeted drugs for the treatment of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Novel antibody based treatment approaches (inotuzumab ozogamicin, gemtuzumab ozogamicin, flotetuzumab), isocitrate dehydrogenases inhibitors (ivosidenib, enasidenib, olutasidenib), FLT3 kinase inhibitors (gilteritinib, midostaurin, quizartinib), a hedgehog inhibitor (glasdegib) as well as a BCL2 inhibitor (venetoclax) were reviewed with respect to their mode of action, their immunosuppressive potential, their current approval and the infectious complications and febrile neutropenia reported from clinical studies. Evidence-based recommendations for prevention and management of infectious complications and specific alerts regarding the potential for drug-drug interactions were developed and discussed in a plenary session with the panel of experts until consensus was reached. The set of recommendations was posted on the ECIL website for a month for comments from members of EBMT, EORTC, ICHS and ELN before final approval by the panelists. While a majority of these agents are not associated with a significantly increased risk when used as monotherapy, caution is required with combination therapy such as venetoclax plus hypomethylating agents, gemtuzumab ozogamicin plus cytotoxic drugs or midostaurin added to conventional AML chemotherapy.

Riesgo de infección en pacientes con enfermedades inmunológicas y oncológicas tratados con biológicos: revisión panorámica

Biological medications are effective for the treatment of cancer and inflammatory diseases. The aim of this review is to summarize the available evidence in systematic reviews or meta-analyses about the risk of infection in patients with cancer, arthritis, psoriasis and inflammatory bowel disease who use biological medications. We included systematic reviews or meta-analyses of controlled clinical trials and case/control studies that analyze infections during and after treatment with FDA-approved biological medications for the treatment of cancer, arthritis, inflammatory bowel disease and psoriasis, both in adults and children. The following databases were consulted: PubMed, Epistemonikos, Crochrane reviews, JIB, and Prospero. A quality guideline (AMSTAR) was applied to the selected studies. We included 26 studies. The risk of infections in patients with solid organ cancer is consistent in the literature. In psoriasis there is a risk of non-serious infections. In arthritis and other inflammatory diseases there is a risk of serious infections. In inflammatory bowel disease there is a risk for opportunistic infections. In conclusion, in patients with cancer and inflammatory diseases use biological medications entails a risk of infection. The evidence is different depending on the underlying disease of each patient.

Systematic review with meta-analysis: biologics and risk of infection or cancer in elderly patients with inflammatory bowel disease.

BACKGROUND: Uncertainty exists concerning the risk of infection and cancer associated with biologic therapies in elderly patients with inflammatory bowel disease (IBD). AIMS: To identify, synthesise and critically appraise the available evidence on the topic. METHODS: We systematically searched Medline/PubMed, Embase and Scopus, through October 2019, and recent conference proceedings, to identify studies investigating the risk of serious infections, opportunistic infections, any infection and cancer in elderly IBD patients (>60 years) exposed to biologics as compared to those unexposed to biologics. Two reviewers independently extracted study data and assessed each study's risk of bias. We examined heterogeneity, and calculated summary effect estimates using fixed- and random effects models. Quality of evidence was determined with GRADE. RESULTS: We included 15 studies (one post hoc analysis of a randomised trial, nine cohort and five case-control studies). Elderly IBD patients treated with biologics were at increased risk of developing serious infections (random effects summary relative risk: 2.70, 95% CI: 1.56-4.66; seven studies; I2  = 57%) and opportunistic infections (3.16, 1.09-9.20; four studies; I2  = 73%). The occurrence of any infection (1.67, 0.51-5.43; five studies; I2  = 75%) and cancer (0.90, 0.64-1.26; nine studies; I2  = 0%) was not significantly affected. Nevertheless, our confidence in the effect estimates is rather limited; the quality of evidence is low to very low. CONCLUSIONS: Biologics are likely to increase the risk of serious and opportunistic infections in old IBD patients. Large prospective studies are needed to further assess the biologic treatments' long-term safety profile in this population.

[Risk of infections associated with the use of biological medications; a review]. / Riesgo de infección en pacientes con enfermedades inmunológicas y oncológicas tratados con biológicos: revisión panorámica.

Biological medications are effective for the treatment of cancer and inflammatory diseases. The aim of this review is to summarize the available evidence in systematic reviews or meta-analyses about the risk of infection in patients with cancer, arthritis, psoriasis and inflammatory bowel disease who use biological medications. We included systematic reviews or meta-analyses of controlled clinical trials and case/control studies that analyze infections during and after treatment with FDA-approved biological medications for the treatment of cancer, arthritis, inflammatory bowel disease and psoriasis, both in adults and children. The following databases were consulted: PubMed, Epistemonikos, Crochrane reviews, JIB, and Prospero. A quality guideline (AMSTAR) was applied to the selected studies. We included 26 studies. The risk of infections in patients with solid organ cancer is consistent in the literature. In psoriasis there is a risk of non-serious infections. In arthritis and other inflammatory diseases there is a risk of serious infections. In inflammatory bowel disease there is a risk for opportunistic infections. In conclusion, in patients with cancer and inflammatory diseases use biological medications entails a risk of infection. The evidence is different depending on the underlying disease of each patient.

Trait-specific effects of exogenous triiodothyronine on cytokine and behavioral responses to simulated systemic infection in male Siberian hamsters.

Seasonal changes in day length enhance and suppress immune function in a trait-specific manner. In Siberian hamsters (Phodopus sungorus) winter-like short days (SDs) increase blood leukocyte concentrations and adaptive T cell dependent immune responses, but attenuate innate inflammatory responses to simulated infections. Thyroid hormone (TH) signaling also changes seasonally and has been implicated in modulation of the reproductive axis by day length. Immunologically, TH administration in long days (LD) enhances adaptive immune responses in male Siberian hamsters, mimicking effects of SDs. This experiment tested the hypothesis that T3 is also sufficient to mimic the effects of SD on innate immune responses. Adult male hamsters housed in LDs were pretreated with triiodothyronine (T3; 1 µg, s.c.) or saline (VEH) daily for 6 weeks; additional positive controls were housed in SD and received VEH, after which cytokine, behavioral, and physiological responses to simulated bacterial infection (lipopolysaccharide; LPS) were evaluated. SD pretreatment inhibited proinflammatory cytokine mRNA expression (i.e. interleukin 1ß, nuclear factor kappa-light-chain-enhancer of activated B cells). In addition, the magnitude and persistence of anorexic and cachectic responses to LPS were also lower in SD hamsters, and LPS-induced inhibition of nest building behavior was absent in SD. T3 treatments failed to affect behavioral (food intake, nest building) or somatic (body mass) responses to LPS in LD hamsters, but one CNS cytokine response to LPS (e.g., hypothalamic TNFα) was augmented by T3. Together these data implicate thyroid hormone signaling in select aspects of innate immune responses to seasonal changes in day length.

Phase I trial of selenium plus chemotherapy in gynecologic cancers.

PURPOSE: Preclinical studies performed in our laboratory have shown that high-dose selenium inhibits the development of carboplatin drug resistance in an ovarian cancer mouse xenograft model. Based on these data, as well as the potential serious toxicities of supranutritional doses of selenium, a phase I trial of a combination of selenium/carboplatin/paclitaxel was designed to determine the maximum tolerated dose, safety, and effects of selenium on carboplatin pharmacokinetics in the treatment of chemo-naive women with gynecologic cancers. Correlative studies were performed to identify gene targets of selenium. METHODS: Chemo-naïve patients with gynecologic malignancy received selenious acid IV on day 1 followed by carboplatin IV and paclitaxel IV on day 3. A standard 3 + 3 dose-escalating design was used for addition of selenium to standard dose chemotherapy. Concentrations of selenium in plasma and carboplatin in plasma ultrafiltrate were analyzed. RESULTS: Forty-five patients were enrolled and 291 treatment cycles were administered. Selenium was administered as selenious acid to 9 cohorts of patients with selenium doses ranging from 50 µg to 5000 µg. Grade 3/4 toxicities included neutropenia (66.7%), febrile neutropenia (2.2%), pain (20.0%), infection (13.3%), neurologic (11.1%), and pulmonary adverse effects (11.1%). The maximum tolerated dose of selenium was not reached. Selenium had no effect on carboplatin pharmacokinetics. Correlative studies showed post-treatment downregulation of RAD51AP1, a protein involved in DNA repair, in both cancer cell lines and patient tumors. CONCLUSION: Overall, the addition of selenium to carboplatin/paclitaxel chemotherapy is safe and well tolerated, and does not alter carboplatin pharmacokinetics. A 5000 µg dose of elemental selenium as selenious acid is suggested as the dose to be evaluated in a phase II trial.

Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial.

BACKGROUND: Adjuvant chemotherapy for early breast cancer has improved outcomes but causes toxicity. The UK TACT2 trial used a 2×2 factorial design to test two hypotheses: whether use of accelerated epirubicin would improve time to tumour recurrence (TTR); and whether use of oral capecitabine instead of cyclophosphamide would be non-inferior in terms of patients' outcomes and would improve toxicity, quality of life, or both. METHODS: In this multicentre, phase 3, randomised, controlled trial, we enrolled patients aged 18 years or older from 129 UK centres who had histologically confirmed node-positive or high-risk node-negative operable breast cancer, had undergone complete excision, and were due to receive adjuvant chemotherapy. Patients were randomly assigned to receive four cycles of 100 mg/m2 epirubicin either every 3 weeks (standard epirubicin) or every 2 weeks with 6 mg pegfilgrastim on day 2 of each cycle (accelerated epirubicin), followed by four 4-week cycles of either classic cyclophosphamide, methotrexate, and fluorouracil (CMF; 600 mg/m2 cyclophosphamide intravenously on days 1 and 8 or 100 mg/m2 orally on days 1-14; 40 mg/m2 methotrexate intravenously on days 1 and 8; and 600 mg/m2 fluorouracil intravenously on days 1 and 8 of each cycle) or four 3-week cycles of 2500 mg/m2 capecitabine (1250 mg/m2 given twice daily on days 1-14 of each cycle). The randomisation schedule was computer generated in random permuted blocks, stratified by centre, number of nodes involved (none vs one to three vs four or more), age (≤50 years vs >50 years), and planned endocrine treatment (yes vs no). The primary endpoint was TTR, defined as time from randomisation to first invasive relapse or breast cancer death, with intention-to-treat analysis of standard versus accelerated epirubicin and per-protocol analysis of CMF versus capecitabine. This trial is registered with ISRCTN, number 68068041, and with ClinicalTrials.gov, number NCT00301925. FINDINGS: From Dec 16, 2005, to Dec 5, 2008, 4391 patients (4371 women and 20 men) were recruited. At a median follow-up of 85·6 months (IQR 80·6-95·9) no significant difference was seen in the proportions of patients free from TTR events between the accelerated and standard epirubicin groups (overall hazard ratio [HR] 0·94, 95% CI 0·81-1·09; stratified p=0·42). At 5 years, 85·9% (95% CI 84·3-87·3) of patients receiving standard epirubicin and 87·1% (85·6-88·4) of those receiving accelerated epirubicin were free from TTR events. 4358 patients were included in the per-protocol analysis, and no difference was seen in the proportions of patients free from TTR events between the CMF and capecitabine groups (HR 0·98, 95% CI 0·85-1.14; stratified p=0·00092 for non-inferiority). Compared with baseline, significantly more patients taking CMF than those taking capecitabine had clinically relevant worsening of quality of life at end of treatment (255 [58%] of 441 vs 235 [50%] of 475; p=0·011) and at 12 months (114 [34%] of 334 vs 89 [22%] of 401; p<0·001 at 12 months) and had worse quality of life over time (p<0·0001). Detailed toxicity and quality-of-life data were collected from 2115 (48%) of treated patients. The most common grade 3 or higher adverse events in cycles 1-4 were neutropenia (175 [16%]) and fatigue (56 [5%]) of the 1070 patients treated with standard epirubicin, and fatigue (63 [6%]) and infection (34 [3%]) of the 1045 patients treated with accelerated epirubicin. In cycles 5-8, the most common grade 3 or higher adverse events were neutropenia (321 [31%]) and fatigue (109 [11%]) in the patients treated with CMF, and hand-foot syndrome (129 [12%]) and diarrhoea (67 [6%]) in the 1044 patients treated with capcitabine. INTERPRETATION: We found no benefit from increasing the dose density of the anthracycline component of chemotherapy. However, capecitabine could be used in place of CMF without significant loss of efficacy and with improved quality of life. FUNDING: Cancer Research UK, Amgen, Pfizer, and Roche.

Adverse events resulting in withdrawal of biologic therapy for psoriasis in real-world clinical practice: A Canadian multicenter retrospective study.

BACKGROUND: Safety profiles of biologics for treatment of psoriasis are limited to data from randomized controlled trials. There is a need for comparative safety reports of biologics based on data from clinical practice. OBJECTIVE: We sought to estimate and compare the incidence of adverse events (AEs) leading to withdrawal of biologics (etanercept, infliximab, adalimumab, and ustekinumab) in the treatment of psoriasis. METHODS: We conducted a multicenter retrospective chart review from September 2005 to September 2014. Incidence proportion and rate of AEs leading to withdrawal by biologic agent and AE were calculated. RESULTS: For 545 treatments administered in 398 patients, 22 (4.04%) AEs were associated with withdrawal, for a rate of 1.97/100 patient-years (95% confidence interval [CI] 1.32-2.94). Common AEs were injection-/infusion-site reactions (0.55%, 0.92%, 0%, and 0% for etanercept, infliximab, adalimumab, and ustekinumab, respectively); infections (0%, 0.18%, 0.55%, 0.18%); and malignancies (0.18%, 0.18%, 0%, 0.37%). LIMITATIONS: Possible incompleteness of chart details and small study population limit the conclusiveness of findings. CONCLUSION: Biologic agents for treatment of psoriasis are safe; AEs associated with withdrawal occurred in 4% of all administered biologic therapies. It does not appear that real-world patients encounter more AEs with biologics than patients in clinical trials.

Infecciones en pacientes tratados con antagonistas del factor de necrosis tumoral: incidencia, etiología y mortalidad en el registro BIOBADASER / Infections in patients treated with tumor necrosis factor antagonists: incidence, etiology and mortality in the BIOBADASER registry

Background and objectives: Whether the use of tumor necrosis factor antagonists increases the risk of infection remains a subject of open debate. Developing effective strategies of prevention and empirical treatment entails carefully establishing the etiology and prognosis of the infections.Patients and methods: Analysis of the Spanish registry BIOBADASER (Feb-2000 to Jan-2006), a national drug safety registry of patients with rheumatic diseases. Results: 907 episodes of infection occurring in 6,969 patients were analyzed. The infection incidence observed was 53.09 cases/1,000 patients-years (CI 95% 49.69-56.66). The most frequent infections were skin infection (12.18 cases/1,000 patients-yrs), pneumonia (5.97 cases/1,000 patients-yrs), cystitis (3.92 cases/1,000 patients-yrs), tuberculosis (3.51 cases/1,000 patients-yrs) and arthritis (3.76 cases/1,000 patients-yrs). Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa and Salmonella spp. emerged as important pathogens. Varicella zoster virus and Herpes simplex virus caused most cases of viral infections. Mucocutaneous candidiasis accounted for most fungal infections. Mortality was increased in infected patients (log-rank test p<0.0001). Pneumonia, sepsis, tuberculosis, abdominal infection and endocarditis were associated with significant attributable mortality.Conclusions: A significant number of bacterial, viral and fungal infections occurred in patients with rheumatic diseases treated with TNF antagonists. The information of this study can illuminate clinicians globally on how to address infection in this vulnerable group of patients (AU)

Fundamento y objetivo: El aumento del riesgo de infección en la utilización de los antagonistas del factor de necrosis tumoral (TNF) sigue siendo un tema de debate abierto. El desarrollo de estrategias eficaces de prevención y tratamiento empírico implica establecer la etiología y el pronóstico de las infecciones. Pacientes y métodos: Análisis del registro español BIOBADASER (febrero 2000 a enero 2006), un registro de terapias biológicas en pacientes con enfermedades reumáticas.Resultados: En los 6.969 pacientes registrados a la fecha del análisis, se produjeron 907 episodios de infección. La incidencia de infección observada fue de 53,09 casos/1.000 pacientes-año (IC 95% 49,69-56,66). Las infecciones más frecuentes fueron las de piel (12,18 casos/1.000 pacientes-año), neumonía (5,97 casos/1.000 pacientes-año), cistitis (3,92 casos/1.000 pacientes-año), tuberculosis (3,51 casos/1.000 pacientes-año) y articulares (3,76 casos/1.000 pacientes-año). Emergen como patógenos importantes Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa y Salmonella spp. El virus de la varicela zóster y el virus del herpes simple causaron la mayoría de los casos de infecciones virales con germen identificable. La candidiasis mucocutánea fue la más frecuente entre las infecciones fúngicas. La mortalidad fue mayor en los pacientes infectados (p-log-rank<0,0001). La aparición de una neumonía, sepsis, tuberculosis, infección abdominal y endocarditis se asociaron significativamente con la mortalidad. Conclusiones: Un número significativo de infecciones bacterianas, víricas y fúngicas se produjeron en pacientes con enfermedades reumáticas tratadas con antagonistas del TNF. La información de este estudio puede suponer un avance para la medicina sobre cómo tratar la infección en este grupo vulnerable de pacientes (AU)

CD34+ immunoselection of autologous grafts for the treatment of high-risk neuroblastoma.

BACKGROUND: Graft contamination has been blamed for causing relapse in children with high-risk neuroblastoma (HRNB) after autologous hematopoietic stem cell transplantation (HSCT). PROCEDURE: We report the long-term results of hematopoietic reconstitution, post-transplant complications, and clinical outcome of 44 children with HRNB treated with busulfan/melphalan high-dose chemotherapy followed by transplantation of purged CD34+ immunoselected autologous peripheral HSCT. Minimal residual disease (MRD) of grafts was evaluated by anti-GD2 immunofluorescence or tyrosine hydroxylase reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Contaminating neuroblasts were found in 19/38 grafts (50%) before CD34+ positive selection, and none after (technique sensitivity of one cell in 10(5)). A median of 6.5 × 10(6) CD34+ cells/kg (range 0.8-23.7) were transplanted with only 2% of TRM. Neutrophils and platelet recovery occurred within a median of 12 days (range 9-47) and 44 days (range 12-259), respectively, without any secondary graft failure. Twenty-three percents of patients experienced a sepsis (10/44) and 14% a pyelonephritis (6/44). Recurrence of varicella zoster virus occurred in 21% of patients (9/44). Negative RT-PCR MRD within the leukapheresis product and cis-retinoic acid therapy were significantly and independently associated to a better survival (P < 0.05). Overall and event-free survivals at 5 years post-transplant were at 59.3% and 48.3% respectively. CONCLUSIONS: Besides high rates of manageable infections due to late immune recovery, transplantation with CD34+ immunoselected grafts in HRNB children was feasible and did not affect long-term hematopoiesis.

Pilot Study: effects of parenteral glutamine dipeptide supplementation on neutrophil functions and prevention of chemotherapy-induced side-effects in acute myeloid leukaemia patients.

The effect of parenteral glutamine dipeptide (Gln) supplementation on neutrophil phagocytosis, superoxide anion generation (SAG), prevention of chemotherapy-induced side-effects and cost-effectiveness was examined in a pilot study of acute myeloid leukaemia (AML) patients receiving chemotherapy. Sixteen AML patients were randomized to receive intravenous supplementation with Gln (30 g/day) or an equivalent quantity (25 g/day) of a standard amino acid mixture (control) on days 1 - 5 of chemotherapy. Complete blood count was evaluated twice a week until hospital discharge, and neutrophil phagocytosis and SAG were measured when absolute neutrophil count reached > 500 /microl. Patients were observed for development of infection, mucositis and diarrhoea. In Gln-treated patients, the percentage of neutrophil phagocytosis and the SAG levels were significantly higher than in control patients (20.5 +/- 6.0% and 18.9 +/- 2.9 nmol/10(6) neutrophils per 10 min, respectively). The Gln-treated patients lost significantly less weight, tended to have shorter in-patient duration and had less severe oral mucositis than controls. This pilot study provides preliminary indication that parenteral Gln supplementation enhances neutrophil phagocytic function, maintains nutritional status and is cost effective. Parenteral Gln may also prevent oral mucositis, although further studies involving more patients need to be undertaken to confirm this and the other results.

Registro Español de Acontecimientos Adversos de Terapias Biológicas en Enfermedades Reumáticas (BIOBADASER): informe de la situación, 26 de enero de 2006 / Spanish Registry for Adverse Events of Biological Therapy in Rheumatic Diseases (BIOBADASER): state report, January 26 th, 2006

Objetivo: BIOBADASER es un registro de pacientes reumatológicos en tratamiento con agentes biológicos, para el seguimiento de la supervivencia y la seguridad a largo plazo. Pacientes y métodos: El 26 de enero de 2006, se ha registrado a 6.969 pacientes procedentes de 100 centros, que aportan información de 8.321 tratamientos con terapias biológicas. Resultados: El tratamiento se suspendió en 2.351 ocasiones (28%), principalmente como resultado de un acontecimiento adverso (960; 41%), seguido de ineficacia (942; 40%). Se comunicaron 2.503 acontecimientos adversos, de los cuales el más frecuente fue la infección (909; 36%), seguido de las reacciones infusionales (500; 20%), y los trastornos cutáneos (255; 10%) y cardiovasculares (165; 7%). Conclusiones: El análisis actual de BIOBADASER constata el aumento de las infecciones con el tratamiento, no así el de neoplasias o insuficiencia cardíaca. Las medidas específicas son útiles para la prevención de acontecimientos definidos (AU)

Objective: BIOBADASER is a prospective registry of rheumatic patients treated with biological therapies, which aim is the analysis of long-term survival and safety of these agents. Patients and methods: As of January 26th 2006, 6,969 patients from 100 centers were included in BIOBADASER. In total, 8,321 treatments with biological therapies have been registered. Results: Treatment was discontinued in 2,351 (28%) occasions, mostly as a result of an adverse event (960;41%) or inefficacy (942;40%). A total of 2,503 adverse events were notified. Of these, the most frequent ones were infections (909;36%), followed by postinfusion reactions (500;20%), skin lesions (255;10%) and cardiovascular events (165;7%). Conclusions: The analysis reassures us in the increased rate of infections with biological therapies. Neither the rates of neoplasm nor of cardiac failure are significantly increased with these therapies. Specific measures have proved useful in preventing the occurrence of defined events (AU)

Excessive use of Steroid Hormone & beneficial effects of True St. 36 acupuncture on malignant brain tumors--part I; how to estimate non-invasively presence of excess dose of Steroid Hormone in patients, baseball players & other professional athletes from its toxic effects on heart & pancreas, as well as persistent or recurrent infection--part II.

Using accurate organ representation areas map of the face, originally mapped by the author using Bi-Digital O-Ring Test Resonance Phenomena between two identical substances, one can make quick non-invasive screening of diseases by visual inspection, particularly if it is chronic degenerative disease, as they often develop deep crease or creases or discoloration on the pathological organ representation area. However, even if there are no visible abnormalities in the organ representation areas, the author found that when the individual is using excessive Steroid Hormones for malignant brain tumors, other medical purposes, and competitive sports, not only did the left ventricle and pancreas become very abnormal when examined by the Bi-Digital O-Ring Test, and Steroid Hormone accumulate in these organs with abnormally increased 8-OH-dG & TXB2, and Folic Acid & Telomere markedly reduce, but also the organ representation areas of the pancreas and left ventricle on the face showed similar abnormalities. Thus, using the Bi-Digital O-Ring Test, one can quickly and non-invasively screen the Steroid Hormone induced abnormalities of the heart and pancreas, and their organ representation areas of various parts of the body, including the face, tongue, ears, hands and feet. For malignant tumors including brain tumors, acupuncture on True ST. 36 or ST. 37 was found to be highly beneficial by reducing cancer cell telomere to practically 0, while increasing normal cell telomere moderately. The author's study over the past 15 years indicates that photographs of the human body, including pictures that appear in newspapers and magazines, have almost identical information as the information taken directly from the body surfaces of patients or individual athletes. Some examples of the application of this principle for the noninvasive estimation of the presence of Steroid Hormones using a photograph of the individual receiving the Steroid Hormone for medical reasons, or for the purpose of gaining an advantage in competitive sports, are shown in this article. While excessive Steroid Hormone use damages the heart and pancreas and hides symptoms of infection, additional use of Vitamin C also inhibits antibiotics and antiviral agents and cannot control severe infection, as suspected in the cases of late Pope John Paul II and late Palestinian leader Yasser Arafat.

Intravenous iron as adjuvant therapy: a two-edged sword?

The importance of iron in the manufacture of erythrocytes is self-evident. In recent years, the treatment of anaemia of end-stage renal disease with recombinant human erythropoietin (epoetin) has been optimized by adequate iron supply. Intravenous therapy with dextran-free iron compounds has become the ideal and necessary companion of epoetin therapy. Anxiety has been expressed by clinicians and researchers over the impact of excess levels of iron following i.v. administration. Their concerns have included the potential for short-term side effects such as anaphylactic reactions and response to 'free iron'. Long-term concerns have included the possibility of increased infection, oxidative stress and cardiovascular disease with higher levels of iron. The literature also implies that i.v. iron could be a 'two-edged sword', i.e. on the one hand, it optimizes epoetin therapy, while on the other, it puts the patient at greater risk of other complications. This review assesses the evidence for these concerns and concludes that i.v. therapy with dextran-free iron compounds, such as iron sucrose, optimizes epoetin therapy with no direct evidence of any short-term or long-term complications.

Docetaxel vs 5-fluorouracil plus vinorelbine in metastatic breast cancer after anthracycline therapy failure.

This multicentre, randomised phase III study compared docetaxel with 5-fluorouracil+vinorelbine in patients with metastatic breast cancer after failure of neo/adjuvant or one line of palliative anthracycline-based chemotherapy. One hundred and seventy-six metastatic breast cancer patients were randomised to receive docetaxel (100 mg m(-2)) every 3 weeks or 5-fluorouracil+vinorelbine: 5-fluorouracil (750 mg m(-2) per day continuous infusion) D1-5 plus vinorelbine (25 mg m(-2)) D1 and D5 of each 3-week cycle. Eighty-six patients received 516 cycles of docetaxel; 90 patients received 476 cycles of 5-fluorouracil+vinorelbine. Median time to progression (6.5 vs 5.1 months) and overall survival (16.0 vs 15.0 months) did not differ significantly between the docetaxel and 5-fluorouracil+vinorelbine arms, respectively. Six (7%) complete responses and 31 (36%) partial responses occurred with docetaxel (overall response rate 43%, 95% confidence interval: 32-53%), while 4 (4.4%) complete responses and 31 (34.4%) partial responses occurred with 5-fluorouracil+vinorelbine (overall response rate 38.8%, 95% confidence interval: 29-49%). Main grade 3-4 toxicities were (docetaxel vs 5-fluorouracil+vinorelbine): neutropenia 82% vs 67%; stomatitis 5% vs 40%; febrile neutropenia 13% vs 22%; and infection 2% vs 7%. There was one possible treatment-related death in the docetaxel arm and five with 5-fluorouracil+vinorelbine. In anthracycline-pretreated metastatic breast cancer patients, docetaxel showed comparable efficacy to 5-fluorouracil+vinorelbine, but was less toxic.

Pharmacological therapy of spinal cord injury during the acute phase.

STUDY DESIGN: Prospective, randomized clinical trial. SETTING: France. OBJECTIVES: To evaluate the safety and effect on neurological outcome of nimodipine, methylprednisolone, or both versus no medical treatment in spinal-cord injury during the acute phase. METHOD: One hundred and six patients who had spinal trauma (including 48 with paraplegia and 58 with tetraplegia) were randomly separated into four groups: M=methylprednisolone (30 mg x kg(-1) over 1 h, followed by 5.4 mg x kg(-1) x h(-1) for 23 h), N=nimodipine (0.015 mg x kg(-1) x h(-1) for 2 h followed by 0.03 mg x kg(-1)h(-1) for 7 days), MN (both agents) or P (neither medication). Neurological assessment (ASIA score) was performed by a blinded senior neurologist before treatment and at 1-year follow-up. Early spinal decompression and stabilization was performed as soon as possible after injury. RESULTS: One hundred patients were reassessed at 1 year. Neurological improvement was seen in each group (P<0.0001), however no additional neurological benefit from treatment was observed. Infectious complications occurred more often in patients treated with M. Early surgery (49 patients underwent surgery within 8 h of their accident) did not influence the neurological outcome. The only predictor of the latter was the extent of the spinal injury (complete or incomplete lesion). CONCLUSION: The present study confirms the absence of benefit of pharmacological therapy in this indication. Because of the paucity of clinical studies that demonstrate the efficacy of pharmacological treatment in spinal injury during the acute phase, systematic use of pharmaceutical agents should be reconsidered.