Use Of Experimental Therapies Research Articles

Clinical impact of minimal residual disease in blood and bone marrow of children with acute myeloid leukemia.

The prognostic significance of bone marrow minimal residual disease (MRD) in pediatric patients with acute myeloid leukemia (AML) is well characterized, but the impact of blood MRD is not known. We, therefore, used flow cytometric assessment of leukemia-specific immunophenotypes to measure levels of MRD in both the blood and bone marrow of patients treated in the AML08 (NCT00703820) clinical trial. Blood samples were obtained on days 8 and 22 of therapy, whereas bone marrow samples were obtained on day 22. Among patients who tested as having MRD-negative bone marrow on day 22, neither day-8 nor day-22 blood MRD was significantly associated with the outcome. However, day-8 blood MRD was highly predictive of the outcome among patients who tested as having MRD-positive bone marrow on day 22. Although the measurement of blood MRD on day 8 cannot be used to identify patients who have day-22 MRD-negative bone marrow who are likely to relapse, our findings suggest that day-8 blood MRD results can identify patients with MRD-positive bone marrow who have a dismal prognosis and may be candidates for the early use of experimental therapy.

(361) Novel treatments for Erectile Dysfunction and Peyronie’s Disease - A Survey of Clinics Across the USA

Abstract Introduction Over the past several years there has been a rise in the number of clinics offering novel treatments for erectile dysfunction and Peyronie’s disease such as stem cell therapy, platelet rich plasma, and shockwave therapy Objective In this study, we attempt to identify to identify experimental treatment approaches for ED and PyD used by various clinics across the country. Methods Using a systematic search of online website directories, we identified 26 clinics were surveyed for PRP treatment, 27 for shockwave therapy, and 26 for stem cell therapy A standard questionnaire was used to retrieve information from all clinics regarding cost of treatment, duration of therapy, medical staff involved, and patient outcome data. Results We found that the cost of treatment varied widely between groups. PRP cost between $500 to $2400, Shockwave total cost was between $1500 - $7500, and stem cell therapy cost ranged between $3,800 to $16,000 USD. Across all clinics surveyed, a physician was involved in 67% of treatments and over 75% of clinics reported patient satisfaction following treatment. Conclusions Although the number of human clinical trials evaluating novel treatments for ED and PyD are limited, several clinics are offering these therapies with promises of success without evidence to support the claims. Our data demonstrates the wide use of experimental therapies for ED and PyD across the US. Clinical outcome data available for patients is largely up to the clinics discretion, and was only given to us in subjective measurements and testimonials. Disclosure No

Treatments, resource utilization, and outcomes of COVID-19 patients presenting to emergency departments across pandemic waves: an observational study by the Canadian COVID-19 Emergency Department Rapid Response Network (CCEDRRN)

BackgroundTreatment for coronavirus disease 2019 (COVID-19) evolved between pandemic waves. Our objective was to compare treatments, acute care utilization, and outcomes of COVID-19 patients presenting to emergency departments (ED) across pandemic waves.MethodsThis observational study enrolled consecutive eligible COVID-19 patients presenting to 46 EDs participating in the Canadian COVID-19 ED Rapid Response Network (CCEDRRN) between March 1 and December 31, 2020. We collected data by retrospective chart review. Our primary outcome was in-hospital mortality. Secondary outcomes included treatments, hospital and ICU admissions, ED revisits and readmissions. Logistic regression modeling assessed the impact of pandemic wave on outcomes.ResultsWe enrolled 9,967 patients in 8 provinces, 3,336 from the first and 6,631 from the second wave. Patients in the second wave were younger, fewer met criteria for severe COVID-19, and more were discharged from the ED. Adjusted for patient characteristics and disease severity, steroid use increased (odds ratio [OR] 7.4; 95% confidence interval [CI] 6.2–8.9), and invasive mechanical ventilation decreased (OR 0.5; 95% CI 0.4–0.7) in the second wave compared to the first. After adjusting for differences in patient characteristics and disease severity, the odds of hospitalization (OR 0.7; 95% CI 0.6–0.8) and critical care admission (OR 0.7; 95% CI 0.6–0.9) decreased, while mortality remained unchanged (OR 0.7; 95% CI 0.5–1.1).InterpretationIn patients presenting to cute care facilities, we observed rapid uptake of evidence-based therapies and less use of experimental therapies in the second wave. We observed increased rates of ED discharges and lower hospital and critical care resource use over time. Substantial reductions in mechanical ventilation were not associated with increasing mortality. Advances in treatment strategies created health system efficiencies without compromising patient outcomes.Trial registrationClinicaltrials.gov, NCT04702945.

Regulatory oversight on the use of experimental therapies during a pandemic: The case of early access to convalescent plasma therapy in three LMICs

Clinicians, especially in low- and middle-income countries (LMICs), contend with limited economic and healthcare resources in deciding appropriate and feasible care for their patients. Some of the LMICs affected by COVID-19 implemented convalescent plasma therapy without sufficient regulatory guidance. Based on this experience, there are several requirements going forward, including: the need for an immediately accessible data gathering and processing system; the necessity of establishing regulatory pathways for early access to experimental treatment during emergency situations; and the accompanying reporting and monitoring requirements must be set. The different stakeholders must also be properly incorporated in the system that such a pathway will create, without neglecting to properly inform the public of the patient rights especially during an emergency situation.

Cardiac arrhythmias in patients presenting with COVID-19 treated in Portuguese hospitals: A national registry from the Portuguese Association of Arrhythmology, Pacing and Electrophysiology

Introduction and objectivesIn December 2019, SARS-CoV-2, was discovered as the agent of COVID-19 disease. Cardiac arrhythmias have been reported as frequent but their incidence is unknown. The aim of this research was to assess the real incidence of cardiac arrhythmias among COVID-19 patients admitted to Portuguese hospitals and to understand the underlying prognostic implications. MethodsThe Portuguese Association of Arrhythmology, Pacing and Electrophysiology (APAPE) conducted a survey in Portuguese hospitals to assess the occurrence of arrhythmias in COVID-19 patients, their clinical characteristics, the use of experimental therapies and the impact on QT interval. ResultsTwenty hospitals participated, reporting 692 hospitalized patients. An arrhythmic episode occurred in 81 (11.7%) and 64 (79%) had detailed information on these episodes. New onset arrhythmias occurred in 41 (64%) patients, 45 (70.3%) male, median age 73.5 (61-80.3) years. There were 51 (79.7%) with associated comorbidities, mainly arterial hypertension (41, 64.1%). Of 53 patients (82.3%) on experimental therapy, 7 (10.9%) had an increased QTc interval. Regarding arrhythmias, two patients (3.1%) had ventricular tachycardia, 5 (7.8%) sinus bradycardia, 17 (26.6%) paroxysmal supraventricular tachycardia and 40 (62.5%) atrial fibrillation or flutter. At the time of reporting, there had been no deaths due to arrhythmic syndrome or related complications. ConclusionsIn a population of COVID-19 patients. The incidence of cardiac arrhythmias is high but not associated with increased cardiac mortality although it does though occur frequently in extremely ill patients and with multiple organ failure. Regardless of the use of experimental drugs, the incidence of ventricular arrhythmias is low and atrial fibrillation and other supraventricular arrhythmias are the most prevalent arrythmias.

Treatment Patterns and Outcomes in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: Experience from a Single UK Centre

Introduction: First-line (1L) therapy for diffuse large B-cell lymphoma (DLBCL) can cure ~60% of patients (pts), but ~10-15% do not respond and 20-25% relapse. Salvage chemotherapy with autologous stem cell transplant (ASCT) is standard for 'fit' pts with relapsed or refractory (R/R) disease. However ~50% of pts are ineligible for transplant and most who undergo ASCT will relapse; for these pts options are extremely limited. Here we evaluated R/R DLBCL treatment patterns and outcomes for pts managed at a single UK center to create a detailed 'real-world' comparator for novel therapies. Methods: A detailed retrospective analysis of medical records was undertaken for pts with DLBCL 2006-2017 and a R/R event 2011-2017. Additional eligibility criteria were: age ≥18 years; ≥1 prior anti-CD20 antibody-containing chemo-immunotherapy regimen; no history of high-grade transformation; and no lymphomatous CNS involvement. Pt characteristics, treatments, responses, and overall survival (OS) were reported by line (L) of therapy (2L, 3L, 4L+) in all pts and in refractory pts (defined as no response to or relapse within 6 months of last treatment). Results: Of 2025 pts diagnosed with DLBCL 2006-2017, 89 fulfilled eligibility including a R/R event 2011-2017: 89, 63, and 41 received 2L, 3L, and 4L+ treatment. Median age at 2L was 66 years (range 58-72). 58.4% (n=52) were male and 64.0% (n=57) were stage III/IV; 49.4% (n=44) were ABC subtype and 29.2% (n=26) were GCB. Systemic 2L therapies (≥5% incidence) included R-DHAP (20.2%; n=18), R-GDP (20.2%; n=18), DHAP (10.1%; n=9), R-GCVP (7.9%; n=7), and gemcitabine (5.6%; n=5). In 2L, 23.6% (n=21) of pts underwent ASCT. With each line, regimens became more diverse, with increased use of experimental therapies. Overall response rate was 46.1% in 2L, 27.0% in 3L, and 9.8% in 4L+. In refractory pts, it was 34.8%, 21.2%, and 7.9% (Table). OS is shown in the Figure and Table; 2-year OS was 30.6% in all R/R pts and 20.5% in refractory pts. Median OS was reduced in pts with low ECOG performance status or high LDH. Two-year OS was 71.4% in transplanted pts (n=23) and 16.3% in non-transplanted pts. Conclusions: Despite multiple treatment options, pts with R/R DLBCL have a very poor prognosis, highlighting the need for rapid introduction of more effective therapies. This can be facilitated by robust data such as these, which may be used for comparing outcomes of novel therapies with those expected at a given line of treatment in the 'real world', unrestricted by the requirements of a trial protocol. Results will be compared with those from the SCHOLAR-1 study (Crump et al. Blood 2017;130:1800-8) to provide greater clarity regarding R/R DLBCL treatment outcomes in the 'real world' setting. Disclosures Radford: Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Research Funding; AstraZeneca: Equity Ownership, Research Funding; GSK: Equity Ownership; BMS: Consultancy, Honoraria. Castro:F. Hoffmann-La Roche Ltd: Employment. Chaturvedi:Christie Hospital NHS Trust: Employment. Spielewoy:F. Hoffmann-La Roche Ltd: Employment. Gibb:Takeda: Research Funding. Surinach:Genesis Research: Employment. Shang:F.Hoffmann-La Roche AG: Employment. Wenger:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. OffLabel Disclosure: "Atezolizumab (atezo) is a programmed death-ligand 1 (PD-L1) blocking antibody. In the United States, atezo is approved for treatment of pts with locally advanced or metastatic urothelial carcinoma who are: not eligible for cisplatin-containing chemotherapy (chemo) and whose tumors express PDL-1, or are not eligible for any platinum-containing chemo regardless of PD L1 status; or have disease progression during or following any platinum-containing chemo, or within 12 months of neoadjuvant or adjuvant chemo. Atezo is also approved: in combination with bevacizumab, paclitaxel and carboplatin for first-line treatment of pts with metastatic non-squamous non-small-cell lung carcinoma (NSCLC) with no EGFR or ALK genomic tumor aberrations, and for pts with metastatic NSCLC who have disease progression during or following platinum-containing chemo; in combination with paclitaxel protein-bound for the treatment of adults with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1; and in combination with carboplatin and etoposide, for the first-line treatment of adults with extensive-stage small cell lung cancer. Atezo is not approved for treatment of pts with multiple myeloma."

Compassionate use of experimental therapies: who should decide?

In addition to being an example of unsubstantiated hype about regenerative medicine, the controversy around the Italy-based Stamina Foundation's unproven stem cell therapy represents another chapter in a continuing debate about how to balance patients' requests for early access to experimental medicines with requirements for demonstrating safety and effectiveness. Compassionate use of the Stamina therapy arguably should not have been permitted under Italy's laws, but public pressure was intense and judges ultimately granted access. One lesson from these events is that expert regulatory agencies may be the institutions most competent to make compassionate use decisions and that policies should include more specific criteria for authorizing compassionate use. But even where regulatory agencies make decisions based on clear rules, difficult questions will arise.

A Case of Severe Ebola Virus Infection Complicated by Gram-Negative Septicemia

Ebola virus disease (EVD) developed in a patient who contracted the disease in Sierra Leone and was airlifted to an isolation facility in Hamburg, Germany, for treatment. During the course of the illness, he had numerous complications, including septicemia, respiratory failure, and encephalopathy. Intensive supportive treatment consisting of high-volume fluid resuscitation (approximately 10 liters per day in the first 72 hours), broad-spectrum antibiotic therapy, and ventilatory support resulted in full recovery without the use of experimental therapies. Discharge was delayed owing to the detection of viral RNA in urine (day 30) and sweat (at the last assessment on day 40) by means of polymerase-chain-reaction (PCR) assay, but the last positive culture was identified in plasma on day 14 and in urine on day 26. This case shows the challenges in the management of EVD and suggests that even severe EVD can be treated effectively with routine intensive care.

Glimmers of hope on the Ebola front.

Daniel Bausch has been assisting with patient care during the current Ebola virus disease outbreak in western Africa and - as part of a WHO-led international collaboration - is exploring the possible use of experimental therapies and vaccines. He tells Fiona Fleck why this outbreak is different.

Ebolavirus in West Africa, and the use of experimental therapies or vaccines.

Response to the current ebolavirus outbreak based on traditional control measures has so far been insufficient to prevent the virus from spreading rapidly. This has led to urgent discussions on the use of experimental therapies and vaccines untested in humans and existing in limited quantities, raising political, strategic, technical and ethical questions.

Twenty years of chemotherapy for colorectal cancer (CRC): Progress made, insights gleaned.

596 Background: The past 20 years have seen progress in CRC therapy with more effective agents and better medical, surgical and supportive care. Methods: We conducted a systematic review of 101 phase III and large phase II trials in CRC to quantify benefit over time with first-line and subsequent therapies. Outcomes examined in the experimental (EA) and control arms (CA) included progression-free survival (PFS), overall response rate (ORR), stable disease (SD), overall survival (OS) and post-treatment survival (PTS). Data were analyzed according to dates of publication and median enrollment. Results: Significant outcomes are reported; most had R2 values > 0.6. OS of EA improved 0.83 mos/yr. Importantly the OS of CA improved 0.58 mos/yr likely reflecting use of experimental therapies in CA in subsequent studies and improvement in CRC care over time as suggested by: (1) modest improvements of PFS: 0.33 [EA] and 0.26 [CA] mos/yr; (2) PTS gains of 0.48 [EA] and 0.29 [CA] mos/yr, accounting for majority of OS gains; and (3) lack of OS improvement in 14 second/subsequent line trials. Using logistic regression to examine all drugs as class predictors of increasing OS, oxaliplatin [OX], bevacizumab [BEV], and irinotecan [IRI] were significant in the EA, but only OX and BEV were significant in the CA. Capecitabine [CAP] and cetuximab/panitumumab [CET/PAN] were not significant in EA or CA, with CAP odds ratio towards null and CET/PAN odds ratio away from null. The lack of IRI effect in CA concurs with observation that only IRI regimens had worse OS in CA compared with EA. The CET/PAN results likely reflect lack of efficacy/harm in patients with WT KRAS tumors. As expected PFS and PTS correlate highly with OS, but importantly ORR had very high correlations with both PFS and OS. SD emerged as an “adverse” outcome, OS decreasing as SD rates increase. Conclusions: OS of CRC patients has improved gradually over past two decades, with gains from chemotherapy but also other factors, such as lead-time bias, more loco-regional approaches and improved supportive care. IRI performed better in EA than in CA. CET/PAN had negative effects in the entire population. In CRC, ORR correlates highly with OS, while SD portends a poor outcome.

Prognostic Factors After Relapse in Nonmetastatic Rhabdomyosarcoma: A Nomogram to Better Define Patients Who Can Be Salvaged With Further Therapy

Previous studies suggest poor outcome in children with relapsed rhabdomyosarcoma (RMS). A better understanding is needed of which patients can be salvaged after first relapse. The analysis included children with nonmetastatic RMS and embryonal sarcoma enrolled onto the International Society of Paediatric Oncology (SIOP) Malignant Mesenchymal Tumor (MMT) 84, 89, and 95 studies who relapsed after achieving complete local control with primary therapy. All patients included in the analysis had follow-up for ≥ 3.0 years after the last event. The clinical features, initial treatment characteristics, and features of the relapse were correlated with survival in univariate and multivariate analyses. In all, 474 eligible patients were identified for the study. At ≥ 3.0 years from the last event, 176 (37%) were alive ("cured"). In a full-model multivariate analysis, the factors identified at first relapse that most strongly associated with poor outcome were metastatic relapse (odds ratio [OR], 4.19; 95% CI, 2.0 to 8.5), prior radiotherapy treatment (OR, 3.64; 95% CI, 2.1 to 6.4), initial tumor size > 5 cm (OR, 2.53; 95% CI, 1.5 to 4.1), and time of relapse < 18 months from diagnosis (OR, 2.20; 95% CI, 1.3 to 3.6). Unfavorable primary disease site, nodal involvement at diagnosis, alveolar histology, and previous three- or six-drug chemotherapy were also independently associated with poor outcome. To estimate chance of cure for individual patients, a nomogram was developed, which allowed for weighting of these significant factors. Some children with relapsed RMS remain curable. It is now possible to estimate the chance of salvage for individual children to direct therapy appropriately toward cure, use of experimental therapies, and/or palliation.

Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline

We developed clinical practice guidelines for congenital adrenal hyperplasia (CAH). The Task Force included a chair, selected by The Endocrine Society Clinical Guidelines Subcommittee (CGS), ten additional clinicians experienced in treating CAH, a methodologist, and a medical writer. Additional experts were also consulted. The authors received no corporate funding or remuneration. Consensus was guided by systematic reviews of evidence and discussions. The guidelines were reviewed and approved sequentially by The Endocrine Society's CGS and Clinical Affairs Core Committee, members responding to a web posting, and The Endocrine Society Council. At each stage, the Task Force incorporated changes in response to written comments. We recommend universal newborn screening for severe steroid 21-hydroxylase deficiency followed by confirmatory tests. We recommend that prenatal treatment of CAH continue to be regarded as experimental. The diagnosis rests on clinical and hormonal data; genotyping is reserved for equivocal cases and genetic counseling. Glucocorticoid dosage should be minimized to avoid iatrogenic Cushing's syndrome. Mineralocorticoids and, in infants, supplemental sodium are recommended in classic CAH patients. We recommend against the routine use of experimental therapies to promote growth and delay puberty; we suggest patients avoid adrenalectomy. Surgical guidelines emphasize early single-stage genital repair for severely virilized girls, performed by experienced surgeons. Clinicians should consider patients' quality of life, consulting mental health professionals as appropriate. At the transition to adulthood, we recommend monitoring for potential complications of CAH. Finally, we recommend judicious use of medication during pregnancy and in symptomatic patients with nonclassic CAH.

Efeitos do Foscarnet sobre a infecção pelos herpesvírus bovino tipos 1 e 5 em coelhos

O efeito antiviral do Foscarnet (PFA) foi demonstrado anteriormente em células de cultivo infectadas com três herpesvírus bovino (BoHV). No presente estudo, investigaram-se os seus efeitos sobre a infecção e doença causadas pelo BoHV-1 e BoHV-5 em coelhos infectados experimentalmente. Coelhos inoculados com o BoHV-5 pela via intraconjuntival (IC) e tratados com o PFA (100mg/kg/dia) a partir do dia 1 pós-inoculação (pi) apresentaram uma redução nos títulos de vírus excretados entre os dias 2 e 6 pi em comparação com o grupo não-tratado; essa diferença foi significativa no dia 3 pi [F(9,108) = 2,23; P&lt;0,03)]. Os coelhos inoculados com o BoHV-5 e tratados com o PFA apresentaram uma redução significativa nos índices de morbidade e mortalidade (95,4% [21/22] nos controles; 50% [11/22] nos tratados; [P&lt;0,0008]). Em coelhos inoculados com o BoHV-1 pela via IC, o tratamento com o PFA resultou em redução nos títulos de vírus excretados, entre os dias 1 e 4, e 6 e 7 pi. Esses animais apresentaram um período de incubação mais curto e um curso clínico mais longo comparando-se com o grupo controle não tratado (P&lt;0,005 e P&lt;0,04, respectivamente). O PFA também reduziu a freqüência e severidade da doença ocular nos coelhos inoculados com o BoHV-1. Esses resultados demonstram que o PFA possui atividade frente ao BoHV-1 e BoHV-5 in vivo e são promissores para o uso desse fármaco em terapias experimentais das infecções herpéticas dos animais domésticos.

Use of experimental therapy outside of clinical trials among U.S. oncologists

6047 Background: Investigational cancer therapies being tested in clinical trials may be available outside of trials, or “off-protocol” (OPRx). There are no published data on either the frequency of OPRx or the attitudes of physicians towards OPRx. Methods: In spring 2005, we surveyed a random sample of American medical oncologists chosen from the ASCO directory regarding their attitudes and practices surrounding OPRx. We evaluated the correlation between demographic factors, attitudes, use of OPRx, and response to hypothetical cases. All statistical tests were two-sided. Results: 146 of 471 (31%) oncologists responded. 93% reported ever discussing OPRx and 81% ever prescribing OPRx. 66% reported prescribing OPRx ≥ once/year and 12% ≥ once/month. 68% reported denying requests for OPRx ≥ once/year and 6% ≥ once/month. Academic oncologists were simultaneously more likely than community oncologists to have ever provided OPRx (89% v. 75%, p = 0.06 by Fisher’s exact test), to discuss OPRx ≥ 1 month (45% v. 12%, p = .003), and to deny requests for OPRx ≥ 1 month (15% v. 2%, p = 0.02). While 61% of oncologists believe that patients should be discouraged from OPRx, only 31% felt it should not be available. 53% felt that patients considering trial enrollment should be informed if OPRx is available, whereas 34% disagreed. 26% felt that patients considering enrollment have a right to OPRx, whereas 56% disagreed. Neither practice setting nor other demographic factors predicted attitudes towards OPRx. For hypothetical cases, there was little consensus regarding when to prescribe OPRx. For example, prior to the release of data from recent trials, 41% reported that they would prescribe adjuvant trastuzumab OPRx at a patient’s request. Factors correlating with willingness to provide OPRx included non-academic practice setting (p = 0.04), &gt; 15 years in practice (p = 0.08), belief that non-trial care and trial care are equivalent (p = 0.01) and belief that patients have a right to OPRx (p = 0.004). Conclusion: American oncologists commonly discuss and provide OPRx. Attitudes towards and utilization of OPRx vary substantially in the oncology community. Further discussion of OPRx and guideline development appear warranted. No significant financial relationships to disclose.

Effect of Awareness of a Randomized Controlled Trial on Use of Experimental Therapy

Use of experimental therapies during but outside of randomized controlled trials (RCTs) has not been studied. To determine whether initiation of an RCT leads to increased use of the experimental therapy outside the trial. Data on national apheresis use during 3 Canadian RCTs for multiple sclerosis (1986-1988), thrombotic thrombocytopenic purpura (1982-1988), and myeloma cast nephropathy (1998-2000) were obtained from 19 major medical centers in Canada. The multiple sclerosis and myeloma cast nephropathy trials had data on apheresis use for 3 years prior to and during the trials, which permitted a time-series analysis to determine the impact of the RCTs on the use of apheresis. The ongoing myeloma cast nephropathy trial provided data on the number of patients inside and outside of the RCTs in trial and nontrial centers. Initial and follow-up questionnaires were sent to 24 Canadian physicians in trial and nontrial centers to determine if they had noted an increase in apheresis activity during the trials and, if so, their explanation for it. Change in number of patients undergoing apheresis for thrombotic thrombocytopenic purpura, multiple sclerosis, and myeloma cast nephropathy prior to and during the respective RCTs compared with all patients undergoing apheresis during the same periods. During all 3 RCTs, there were large increases in use of apheresis. The majority of the increased use of apheresis was outside of the trials: for multiple sclerosis, 30 of 49 patients per year (61% of increase); thrombotic thrombocytopenic purpura, 49 of 56 patients per year (72% of increase); and myeloma cast nephropathy, 60 of 72 patients per year (57% of increase). The myeloma cast nephropathy study noted that this increase occurred in both nontrial and trial centers. Among questionnaire respondents (n = 22; 92% response rate), most physicians noted an increase in apheresis activity during the trials and attributed it to a "jumping-the-gun" phenomenon. During 3 Canadian RCTs, apheresis increased, but most of the increase occurred outside the trials. This behavior during an RCT, in the absence of clear efficacy, can be termed jumping the gun.

'Hitting you over the head': oncologists' disclosure of prognosis to advanced cancer patients.

The disclosure of prognosis to terminally ill patients has emerged as a recent concern given greater demands for patient involvement in medical decision-making in the United States. As part of the informed consent process, American physicians are legally and ethically obligated to provide information to such patients about risks, benefits, and alternatives of all available treatment options including the use of experimental therapies. Although not legally required, the disclosure of terminal prognosis is ethically justified because it upholds the principle of self-determination and enables patients to make treatment decisions consistent with their life goals. To understand oncologists' attitudes about disclosing prognostic information to cancer patients with advanced disease, we interviewed fourteen oncologists and conducted one focus group of medical fellows. Although oncologists reported to disclose prognosis in terms of cancer not being curable, they tend to avoid using percentages to convey prognosis. Oncologists' reported reluctance to disclosing prognosis was conveyed through the use of metaphors depicting the perceived violent impact of such information on patients. Oncologists' reluctance to disclose prognosis and preserve patient hope are held in check by their need to ensure that patients have 'realistic expectations' about therapy. We discuss these data in light of the cultural, ethical, and legal dimensions of prognosis disclosure, patient hope and the doctor-patient relationship, and recommend ways to enhance the communication process.

Formulation study for the antitumor drug camptothecin: liposomes, micellar solutions and a microemulsion

In the present paper we describe the production and characterization of specialized delivery systems for camptothecin, namely liposomes, micellar solutions and microemulsion. For instance, liposomes were prepared by reverse phase evaporation technique followed by extrusion through polycarbonate filters. Liposomes were characterized in term of dimensions, morphology and encapsulation efficacy. All the formulations were designed firstly to increase the solubility of camptothecin in aqueous environment and secondly to reduce the toxicity problems related to the administration of this drug. The analysis of their in vitro antiproliferative activity on cultured human leukemic K562 cells demonstrated that liposomes, micellar solutions and microemulsion containing camptothecin exert similar or slightly enhanced effect as compared to that shown by the free drug. Based on these results, the specialized delivery systems here proposed typify an interesting starting point for a future use in experimental therapy.

2 Smoke inhalation and airway injury

Respiratory tract injury makes a significant contribution to the morbidity and mortality of burned patients. Injury may be thermal damage to the upper airway, leading to potential airway obstruction, or damage to the lower airway from smoke inhalation, leading to increased capillary permeability. The burned patient may also develop sepsis and respiratory infection. The combination of insults also leads to respiratory failure, which is the leading cause of death in burns patients. The use of sophisticated diagnostic and management techniques does not appear to have reduced the associated mortality rate. The improved knowledge of the pathophysiology of smoke inhalation and the use of experimental therapies in animals allows a more rational approach to the management of smoke inhalation.

Criteria for standard versus experimental therapy.

This paper demarcates the boundaries between experimental and standard therapy and the influence of this division on policy, payment, and practice. It proposes a new category, crossover therapy, to deal with the many therapies that fall in between. It establishes four criteria to separate these categories: (1) the populations and conditions for which use is helpful; (2) the expected outcomes of care; (3) the skill, personnel, and site requirements and the economic, ethical, and legal understandings essential for use; and (4) the level of knowledge needed to certify that prospective users can apply it well. The paper then explores the use of experimental therapy in desperate situations and of standard therapies in new areas and gives policy recommendations to facilitate these actions.