Quality assurance problems in clinical hyperthermia and their impact on therapeutic outcome: a Report by the Radiation Therapy Oncology Group

Since February 1981, 300 patients with superficial measurable tumors were randomized on an RTOG protocol (81-04) involving fractionated radiation therapy (4.00 Gy twice weekly for a total of 32.00 Gy), either alone or followed immediately by hyperthermia (42.5 degrees C, 60 min). This is a report of 218 eligible patients with single lesions: 107 treated with radiotherapy alone (RT), 111 with radiotherapy plus hyperthermia (RT + HT). Only 56% of the 24 tumors less than 3 cm and 36% of the 53 lesions larger than 3 cm received what was felt to be "adequate" therapy (greater than or equal to 29 Gy and 8 heating sessions). Overall complete response (CR) was observed in 28% of the patients treated with RT, and 32% of the patients receiving RT and heat. Response has been found in previous analyses of this and other RTOG studies to be significantly related to both maximum tumor diameter (less than 3 or greater than or equal to 3 cm) and site/histology (breast/adenocarcinoma, head and neck/squamous, or other site/histologies). In the head and neck tumors less than 3 cm in diameter there was no difference in CR with irradiation alone or combined with hyperthermia (46% vs 43%). However, in the breast, and trunk and extremities a better CR rate was noted with irradiation and heat (55% and 67%) than with irradiation alone (33% and 0). In lesions less than 3 cm treated with irradiation and heat the probability of remaining in response was 80% compared with 15% with irradiation alone. In lesions larger than 3 cm no difference in CR was observed in either treatment group. It has been hypothesized that the response rate is higher in patients with smaller lesions (less than 3 cm) and in breast/chest wall, trunk/extremity lesions because these tumors and anatomical sites are easier to heat adequately. Problems encountered in correlating tumor response with quality of heating include less than optimal heating in larger lesions and the limited ability of current thermometry to accurately represent the temperature distribution in a tumor. Furthermore, differences in equipment and treatment practices among institutions add to the variability in heat administration data collected. In addition, tumor response may be difficult to judge because of short survival of some patients and occasionally rapid tumor regression that may cause necrosis which may be misinterpreted as persistent tumor.(ABSTRACT TRUNCATED AT 400 WORDS)     

Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group

BACKGROUND: Inhaled nitric oxide improves gas exchange in neonates, but the efficacy of low-dose inhaled nitric oxide in reducing the need for extracorporeal membrane oxygenation has not been established. METHODS: We conducted a clinical trial to determine whether low-dose inhaled nitric oxide would reduce the use of extracorporeal membrane oxygenation in neonates with pulmonary hypertension who were born after 34 weeks' gestation, were 4 days old or younger, required assisted ventilation, and had hypoxemic respiratory failure as defined by an oxygenation index of 25 or higher. The neonates who received nitric oxide were treated with 20 ppm for a maximum of 24 hours, followed by 5 ppm for no more than 96 hours. The primary end point of the study was the use of extracorporeal membrane oxygenation. RESULTS: Of 248 neonates enrolled, 126 were randomly assigned to the nitric oxide group and 122 to the control group. Extracorporeal membrane oxygenation was used in 78 neonates in the control group (64 percent) and in 48 neonates in the nitric oxide group (38 percent) (P=0.001). The 30-day mortality rate in the two groups was similar (8 percent in the control group and 7 percent in the nitric oxide group). Chronic lung disease developed less often in neonates treated with nitric oxide than in those in the control group (7 percent vs. 20 percent, P=0.02). The efficacy of nitric oxide was independent of the base-line oxygenation index and the primary pulmonary diagnosis. CONCLUSIONS: Inhaled nitric oxide reduces the extent to which extracorporeal membrane oxygenation is needed in neonates with hypoxemic respiratory failure and pulmonary hypertension.     

Managing pain: The Challenge in Underserved Populations: Appropriate Use Versus Abuse and Diversion

ISSUE: Inadequate pain management is a serious public health problem that affects a wide cross-section of Americans. Patients are often denied sufficient medication, because physicians lack training and fear scrutiny from federal and state regulatory agencies. In addition, even the state-financed system of care, Medicaid, has been increasingly denying payment for the best treatment for pain management. These factors are complicated by physician bias about various subgroups and poor physician-patient communication. Comprehensive patient assessment plays a crucial role in determining appropriate treatment and identifying potential abuse problems. Physicians must routinely document medications analgesic effects and screen for potential ill effects and drug abuse. OBJECTIVE: To examine the prevalence of the undertreatment of pain, particularly among African Americans, and to recommend relevant proactive policy and practice changes to aid in eliminating this health problem. CONSENSUS PROCESS: In July 2002, the NMA convened the "Managing Pain: The Challenge in Underserved Populations: Appropriate Use versus Abuse and Diversion" Consensus Meeting in Washington, DC. The country's most renowned experts in the area of pain management and substance abuse reviewed substantial information regarding pain management and substance abuse including the following: --A draft summary paper on pain management and substance abuse that served as briefing material for consensus members; --Annotated bibliographies; --Articles on pain management and substance abuse; and --Key presentations on pain management and substance abuse.     

Histochemical study of RNA content of neurones in the dorsal lateral geniculate nucleus during postnatal development.

Nuclear and cytoplasmic dLGN neurons were investigated by cytophotometric measurements of RNA. This study has been carried out in rats from birth to adulthood. In order to quantify the RNA content a cytophotometer was used. Extinction mean values were obtained which indicated RNA concentrations per surface unit. The nuclear and cytoplasmic surface were calculated simultaneously and from the product of the mean extinction and the surface the RNA total content was calculated. Our results have suggested that the changes are age-related. From day 1 to day 21 the neuronal size and RNA content increase; this may somehow be involved with the differentiation process. Around post-natal day 21 neuronal maturation may begin, reaching its optimal phase around day 42, on which the RNA concentration per surface unit, surface neuronal content and RNA total content are stable.     

Effect of two thymosin fraction 5 polypeptides on human peripheral blood lymphocytes

Thymosin fraction 5 polypeptides beta 4 and alpha 1 were tested for their ability to affect certain immunological parameters of human peripheral blood lymphocytes (PBL). PBL were cultured with various concentrations of the peptides for 24 hours. Thymosin beta 4 was found to induce a significant decrease in the expression of the Fc alpha receptors of PBL, as well as in their ability to express antibody dependent cellular cytotoxic (ADCC) activity. In addition, this peptide had the ability to increase the percentage of T4 lymphocytes in normal and immunosuppressed donors and to decrease the percentage of T8 positive cells in normal donors. Finally, beta 4 peptide caused a small increase in the capacity of peripheral blood lymphocytes to form sheep red blood cell (SRBC) rosettes (ER). In parallel experiments thymosin alpha 1 was found inactive. The results presented here indicate that thymosin beta 4 may be used as an immunoregulatory molecule in patients with immunodeficiencies.     

Changes in EEG activity and hypothalamic temperature as indices for non-REM sleep to REM sleep transitions

A shift of physiological regulations from a homeostatic to a non-homeostatic modality characterizes the passage from non-NREM sleep (NREMS) to REM sleep (REMS). In the rat, an EEG index which allows the automatic scoring of transitions from NREMS to REMS has been proposed: the NREMS to REMS transition indicator value, NIV [J.H. Benington et al., Sleep 17 (1994) 28-36]. However, such transitions are not always followed by a REMS episode, but are often followed by an awakening. In the present study, the relationship between changes in EEG activity and hypothalamic temperature (Thy), taken as an index of autonomic activity, was studied within a window consisting of the 60s which precedes a state change from a consolidated NREMS episode. Furthermore, the probability that a transition would lead to REMS or wake was analysed. The results showed that, within this time window, both a modified NIV (NIV(60)) and the difference between Thy at the limits of the window (Thy(D)) were related to the probability of REMS onset. Both the relationship between the indices and the probability of REMS onset was sigmoid, the latter of which saturated at a probability level around 50-60%. The efficacy for the prediction of successful transitions from NREMS to REMS found using Thy(D) as an index supports the view that such a transition is a dynamic process where the physiological risk to enter REMS is weighted at a central level.     

The polymeric immunoglobulin A receptor is present on hepatocytes in human liver.

A monoclonal antibody raised against human colostrum secretory component produced even staining of hepatocyte plasma membranes, as well as bile duct lining cells, in all sections examined from eight normal and three abnormal human livers. Human bile samples incubated with free secretory component degraded it to varying extents, probably proteolytically; true levels of free secretory component will therefore often be higher than those reported. It seems likely that human liver resembles that of other mammals in transferring polymeric IgA through hepatocytes to the bile by means of the polymeric IgA receptor.     

Stability of Th1 and Th2 populations

Using an in vitro model for the development of IFN-y-producIng(Th1) and IL-4-produclng (Th1) cells from CD4 T lymphocytesexpressing a transgenlc TCR, we show that IL-12 and IL-4 arethe most potent stimuli for the differentiation of naive T cellsto effector populations. When combinations of cytokines arepresent during T cell priming, the effect of IL-4 Is dominant.Furthermore, differentiated Th1 cells can be converted intoIL-4 producers by exposure to IL-4, but the Th2 phenotype Isnot reversible. The stability of Th2 populations may limit theability to regulate Th2-domlnant responses In pathologic situations.