Impact of reconceptualization response shift on rating of quality of life over time among people with advanced cancer.

BACKGROUND: People with cancer may experience change in what constitutes quality of life (QOL) over time as a result of the cancer progression (true change) or adaptation to the experience, considered as a response shift phenomenon. As individualized measures are ideally suited to explore response shift, this study aimed to estimate the extent to which reconceptualization response shift occurred over time in a cancer population and the impact of this response shift on estimates of change on QOL measures. METHODS: Ninety-seven people with advanced cancer completed the study measures including the Patient-Generated Index (PGI) at diagnosis (T0) and 1 year later (T1). The response shift indicator was the change in the number of areas nominated (range - 4 to + 3). Multivariate linear regression was used to estimate the effect of changing areas on change in the PGI score, single indicators of global QOL, and the EQ-5Dindex adjusted for age and sex. RESULTS: Approximately 72% of people in this sample either added or dropped areas over time. People who dropped more than two areas had higher PGI scores at T1 than T0 while people who added areas showed low PGI score. CONCLUSION: The results are consistent with the PGI framework as areas nominated tend to focus on negative aspects of QOL.

Agreement between personally generated areas of quality of life concern and standard outcome measures in people with advanced cancer.

PURPOSE: People with advanced cancer experience different sequelae which have unique effects on quality of life (QOL). The patient-generated index (PGI) is a personalized measure that allows patients to nominate, rate, and value areas that have the most impact on QOL. Fatigue, pain, and aspects of physical function are among the top 10 areas with QOL impact. An area of validation that is lacking for the PGI is the extent to which spontaneously nominated areas of QOL that patients are concerned with, agree with ratings obtained from standard patient reported outcomes (PROs). METHODS: Data from 192 patients were used to compare ratings on fatigue, pain, and physical function obtained from PGI to those from standard outcome measures. RESULTS: Within one severity rating, agreement ranged from 32.1 to 76.9 % within the fatigue domain, 34.2 to 95.24 % for pain, and between 84.2 and 94.7 % for physical function. Of the 10 items where the PGI had the highest agreement, 7 came from the RAND-36. At the domain level, people nominating an area scored in the more impaired range on standard measures than people who did not. CONCLUSION: PGI gives comparable information as do standard measures. IMPLICATIONS FOR CANCER: PGI provides important information to guide clinical care of the patient and also produces a legitimate total score suitable for research.

Canadian recommendations for the management of breakthrough cancer pain.

Breakthrough cancer pain (btcp) represents an important element in the spectrum of cancer pain management. Because most btcp episodes peak in intensity within a few minutes, speed of medication onset is crucial for proper control. In Canada, several current provincial guidelines for the management of cancer pain include a brief discussion about the treatment of btcp; however, there are no uniform national recommendations for the management of btcp. That lack, accompanied by unequal access to pain medication across the country, contributes to both regional and provincial variability in the management of btcp. Currently, immediate-release oral opioids are the treatment of choice for btcp. This approach might not always offer optimal speed for onset of action and duration to match the rapid nature of an episode of btcp. Novel transmucosal fentanyl formulations might be more appropriate for some types of btcp, but limited access to such drugs hinders their use. In addition, the recognition of btcp and its proper assessment, which are crucial steps toward appropriate treatment selection, remain challenging for many health care professionals. To facilitate appropriate management of btcp, a group of prominent Canadian specialists in palliative care, oncology, and anesthesiology convened to develop a set of recommendations and suggestions to assist Canadian health care providers in the treatment of btcp and the alleviation of the suffering and discomfort experienced by adult cancer patients.

Using a personalized measure (Patient Generated Index (PGI)) to identify what matters to people with cancer.

PURPOSES: Patient Generated Index (PGI) is designed to both ask and document quality of life (QOL) concerns. Its validity with respect to standard QOL measures has not been fully established for advanced cancer when QOL concerns predominate. The specific objective of this study is to identify, for people with advanced cancer, similarities and differences in ratings of global QOL between personalized and standard measures. METHODS: A total of 192 patients completed five QOL measures at study entry: PGI, generic measures (SF-6D, EQ-5D), and cancer-specific measures of QOL (McGill Quality of Life Questionnaire and Edmonton Symptoms Assessment Scale). Comparisons among total scores were compared using Generalized Estimating Equations (GEE). RESULTS: Patients voiced 114 areas of QOL concerns by the PGI with the top three being fatigue, sleep, and pain (39.2, 22.6, and 21.6%, respectively). PGI total QOL score was 25 to 30 percentage points lower than those documented by the other measures, particularly when QOL was poor. Correlations between PGI and other measures were low. CONCLUSION: PGI allowed patients to express a wide range of QOL concerns, many that were not assessed by other QOL measures. If only one QOL measure is to be included, either in a clinical setting or for research, the PGI would satisfy many of the criteria for "best choice." PGI could be considered a cancer-specific QOL measure. IMPLICATIONS FOR CANCER: This study provides evidence that the PGI would be a good measure for patients and clinicians to use together to identify areas of concern that require attention and monitor changing needs.

A prospective evaluation of an interdisciplinary nutrition-rehabilitation program for patients with advanced cancer.

BACKGROUND: Cancer can affect many dimensions of a patient's life, and in turn, it should be targeted using a multimodal approach. We tested the extent to which an interdisciplinary nutrition-rehabilitation program can improve the well-being of patients with advanced cancer. METHODS: Between January 10, 2007, and September 29, 2010, 188 patients with advanced cancer enrolled in the 10-12-week program. Body weight, physical function, symptom severity, fatigue dimensions, distress level, coping ability, and overall quality of life were assessed at the start and end of the program. RESULTS: Of the enrolled patients, 70% completed the program. Patients experienced strong improvements in the physical and activity dimensions of fatigue (effect sizes: 0.8-1.1). They also experienced moderate reductions in the severity of weakness, depression, nervousness, shortness of breath, and distress (effect sizes: 0.5-0.7), and moderate improvements in Six Minute Walk Test distance, maximal gait speed, coping ability, and quality of life (effect sizes: 0.5-0.7) Furthermore, 77% of patients either maintained or increased their body weight. CONCLUSIONS: Interdisciplinary nutrition-rehabilitation can be advantageous for patients with advanced cancer and should be considered an integrated part of standard palliative care.

Montreal prognostic score: estimating survival of patients with non-small cell lung cancer using clinical biomarkers.

BACKGROUND: For evidence-based medical practice, well-defined risk scoring systems are essential to identify patients with a poor prognosis. The objective of this study was to develop a prognostic score, the Montreal prognostic score (MPS), to improve prognostication of patients with incurable non-small cell lung cancer (NSCLC) in everyday practice. METHODS: A training cohort (TC) and a confirmatory cohort (CC) of newly diagnosed patients with NSCLC planning to receive chemotherapy were used to develop the MPS. Stage and clinically available biomarkers were entered into a Cox model and risk weights were estimated. C-statistics were used to test the accuracy. RESULTS: The TC consisted of 258 patients and the CC consisted of 433 patients. Montreal prognostic score classified patients into three distinct groups with median survivals of 2.5 months (95% confidence interval (CI): 1.8, 4.2), 8.2 months (95% CI: 7.0, 9.4) and 18.2 months (95% CI: 14.0, 27.5), respectively (log-rank, P<0.001). Overall, the C-statistics were 0.691 (95% CI: 0.685, 0.697) for the TC and 0.665 (95% CI: 0.661, 0.670) for the CC. CONCLUSION: The MPS, by classifying patients into three well-defined prognostic groups, provides valuable information, which physicians could use to better inform their patients about treatment options, especially the best timing to involve palliative care teams.

Independent contributors to overall quality of life in people with advanced cancer.

BACKGROUND: The definition of health for people with cancer is not focused solely on the physiology of illness and the length of life remaining, but is also concerned with improving the well-being and the quality of the life (QOL) remaining to be lived. This study aimed to identify the constructs most associated with QOL in people with advanced cancer. METHODS: Two hundred three persons with recent diagnoses of different advanced cancers were evaluated with 65 variables representing individual and environmental factors, biological factors, symptoms, function, general health perceptions and overall QOL at diagnosis. Three independent stepwise multiple linear regressions identified the most important contributors to overall QOL. R(2) ranking and effect sizes were estimated and averaged by construct. RESULTS: The most important contributor of overall QOL for people recently diagnosed with advanced cancer was social support. It was followed by general health perceptions, energy, social function, psychological function and physical function. CONCLUSIONS: We used effect sizes to summarise multiple multivariate linear regressions for a more manageable and clinically interpretable picture. The findings emphasise the importance of incorporating the assessment and treatment of relevant symptoms, functions and social support in people recently diagnosed with advanced cancer as part of their clinical care.

A multicentre open-label safety and efficacy study of tetrodotoxin for cancer pain.

BACKGROUND: Cancer pain is highly prevalent, and existing treatments are often insufficient to provide adequate relief. OBJECTIVES: We assessed the long-term safety and efficacy of subcutaneous tetrodotoxin treatment in reducing the intensity of chronic cancer-related pain. METHODS: In this multicentre open-label longitudinal trial, 30 µg tetrodotoxin was administered subcutaneously twice daily for 4 days in a heterogeneous cohort of patients with persistent pain despite opioids and other analgesics. "Responder" was defined as a mean reduction of 30% or more in pain intensity from baseline; and "clinical responder" as some pain reduction, but less than 30%, plus agreement on the part of both the patient and the physician that a meaningful analgesic response to treatment had occurred. RESULTS: Of 45 patients who entered the longitudinal trial, 41 had sufficient data for analysis. Of all 45 patients, 21 (47%) met the criteria for "responder" [16 patients (36%)] or "clinical responder" [5 patients (11%)]. Onset of pain relief was typically cumulative over days, and after administration ended, the analgesic effect subsided over the course of a few weeks. No evidence of loss of analgesic effect was observed during subsequent treatments (2526 patient-days in total and a maximum of 400 days in 1 patient). One patient withdrew from the study because of adverse events. Toxicity was usually mild (82%) or moderate (13%), and remained so through subsequent treatment cycles, with no evidence of cumulative toxicity or tolerance. CONCLUSIONS: Long-term treatment with tetrodotoxin is associated with acceptable toxicity and, in a substantial minority of patients, resulted in a sustained analgesic effect. Further study of tetrodotoxin for moderate-to-severe cancer pain is warranted.

Flexible modeling improves assessment of prognostic value of C-reactive protein in advanced non-small cell lung cancer.

BACKGROUND: C-reactive protein (CRP) is gaining credibility as a prognostic factor in different cancers. Cox's proportional hazard (PH) model is usually used to assess prognostic factors. However, this model imposes a priori assumptions, which are rarely tested, that (1) the hazard ratio associated with each prognostic factor remains constant across the follow-up (PH assumption) and (2) the relationship between a continuous predictor and the logarithm of the mortality hazard is linear (linearity assumption). METHODS: We tested these two assumptions of the Cox's PH model for CRP, using a flexible statistical model, while adjusting for other known prognostic factors, in a cohort of 269 patients newly diagnosed with non-small cell lung cancer (NSCLC). RESULTS: In the Cox's PH model, high CRP increased the risk of death (HR=1.11 per each doubling of CRP value, 95% CI: 1.03-1.20, P=0.008). However, both the PH assumption (P=0.033) and the linearity assumption (P=0.015) were rejected for CRP, measured at the initiation of chemotherapy, which kept its prognostic value for approximately 18 months. CONCLUSION: Our analysis shows that flexible modeling provides new insights regarding the value of CRP as a prognostic factor in NSCLC and that Cox's PH model underestimates early risks associated with high CRP.

El lugar de muerte en pacientes con cáncer: ¿qué sabemos y qué entendemos? Una revisión sistemática y crítica de la literatura / No disponible

Introducción: se reconoce que los pacientes en fase terminal prefieren generalmente morir en su domicilio. Una organización de los servicios de salud que respeten este deseo podría mejorar la calidad de los cuidados en sus últimos días. Objetivo: quisimos identificar los factores asociados con una muerte en casa para pacientes con cáncer basándonos exclusivamente en estudios poblacionales que consideran a todos los sujetos fallecidos de cáncer en una zona geográfica dada y con una metodología estadística apropiada. Material y métodos: realizamos una revisión sistemática de la literatura usando cuatro bases de datos electrónicas y las palabras «place of death» o «site of death» o «location of death» con «cancer» y «population» o «registry». Se incluyeron ocho estudios del efecto de variables pre-existentes sobre el lugar de muerte, que se aplicaban a una población adulta de pacientes con cáncer, de registros poblacionales y que utilizaban buenos métodos estadísticos para el análisis de sus resultados. Resultados y conclusiones: los datos representan a un total de 455.176 muertes por cáncer de 1985 a 2003 en Taiwán, Inglaterra, Australia e Italia. Las variables individuales asociadas con el lugar de muerte por cáncer en casa eran: ser nativo de la región o autóctono, un nivel socioeconómico y de educación alto, estar casado y un tiempo largo de supervivencia desde el diagnóstico. Hubo más heterogeneidad en el año de muerte y la edad por tener categorías de variables difícilmente comparables, aunque tener una edad entre 70 y 79 años fue asociado con una muerte encasa en casi todos los estudios. Se observó una heterogeneidad de las asociaciones reportadas en cuanto al origen del cáncer, el año de muerte y el género del sujeto. Las asociaciones de variables ecológicas con el lugar de muerte en casa eran un entorno rural y haber obtenido servicios paliativos. Cuando se examinaron las asociaciones de las variables con una muerte en casa y las metodologías empleadas, se observó que pocas variables se pueden considerar como asociadas con un lugar de muerte y manteniendo una buena metodología epidemiológica (AU)

Background: patients with terminal disease report that they would rather die at home. A healthcare organization respectful of these patients' wishes to die in their homes would ensure improved quality of care at the end of life. Objective: we wanted to assess factors associated with home death inpatients with cancer by strictly reviewing population-based studies using sound epidemiological methodology. Material and methods: we performed a systematic review of the literature using four electronic databases and the keywords «place of death» or «site of death» or «location of death» together with «cancer» and «population» or «registry». We included all studies that reported the effect of preexisting variables on place of death, that were based on an adult cancer population database, and with a good statistical analysis of their results, which resulted in a total of 8 studies. Results and conclusions: data included represented a total of 455,176 deaths because of cancer from 1985 to 2003 in Taiwan, England, Australia, and Italy. Individual variables associated with home death included being native or indigenous, a high socioeconomic and educational level, being married, and long survival time since diagnosis. More heterogeneity was seen for year of death and age because categories were not easily comparable, even though being between 70 and 79 years of age was associated with home death in almost all studies. There was also heterogeneity in the association with cancer origin and subject gender. Ecological variables associated with home death included living in a rural environment and having received palliative care services. However, when examining the strength of associations and the methods employed, few variables can be considered as associated with place of death while maintaining epidemiological relevance (AU)

The impact of delirium on the circadian distribution of breakthrough analgesia in advanced cancer patients.

Most cancer patients will experience pain requiring opioid therapy during their illness. Standard opioid therapy includes fixed scheduled doses and so-called "rescue" doses for breakthrough pain. Circadian rhythms seem to influence the expression of pain and the responsiveness to analgesic medication. Delirium is a common complication in advanced cancer patients and it also may modify the expression of pain and the use of analgesic medication. We reviewed the circadian distribution of breakthrough analgesia (BTA) doses in 104 advanced cancer patients who were part of a prospective study of the occurrence of delirium. We found that the circadian distribution of BTA is significantly different from a random distribution in the case of patients with and without delirium. Patients without delirium tended to use more BTA (P < 0.001) in the morning, whereas patients with delirium tended to use more BTA in the evening and at night (P = 0.02). We conclude that delirium is associated with changes in the circadian distribution of BTA, which is possibly related to reversal of the normal circadian rhythm.

Clinical utility, factor analysis, and further validation of the memorial delirium assessment scale in patients with advanced cancer: Assessing delirium in advanced cancer.

BACKGROUND: Delirium is a common neuropsychiatric complication in patients with advanced cancer. The Memorial Delirium Assessment Scale (MDAS) is a recently developed 10-item severity rating instrument. The purpose of the current prospective study was to further assess the clinical utility, factor structure, and validity of the MDAS in a relatively homogeneous population of patients with advanced cancer. METHODS: Study entry of 104 patients occurred on their consecutive admission to a tertiary-level, acute palliative care unit in a university-affiliated teaching hospital. Patients underwent regular cognitive screening using the Mini-Mental State Examination, and serial monitoring of delirium using standardized semistructured interviews and MDAS ratings, up to the study endpoints of either patient discharge or death. RESULTS: Seventy-one patients met Diagnostic and Statistical Manual (of Mental Disorders)-IV criteria for a first episode of delirium. In 15 of 71 (21%) patients with a first episode of delirium, the first MDAS ratings were prorated because of dyspnea, fatigue, or profound delirium. In the remaining 56 patients (79%), the first MDAS ratings were rated fully and therefore evaluable. Correlations among the scale items ranged from moderate to low (correlation coefficient [r] = 0.68-0.02). Analysis of the pattern of factor loadings identified two primary correlated factors: global cognitive (Factor I) and neurobehavioral (Factor II) (r = 0.33). Cronbach alpha coefficients for Factors I and II were 0.8 and 0.66, respectively, indicating a relatively high level of correlation for items within each. The Cronbach alpha coefficient for all 10 items was 0.78, suggesting a general underlying factor. In a larger sample of complete MDAS ratings (n = 330) a cutoff total MDAS score of 7 of 30 yielded the highest sensitivity (98%) and specificity (96%) for delirium diagnosis. The MDAS was correlated moderately with the Mini-Mental State Examination (r = 0.55). CONCLUSIONS: The authors concluded that the MDAS structure is representative of the many features of delirium, broadly grouped as global cognitive and neurobehavioral dimensions. Prorating item scores is necessary in approximately 20% of advanced cancer patients with delirium. This poses potential limitations on the applicability of the MDAS in research. Conversely, the ability to prorate item scores confers a clinical advantage to the instrument when assessing delirium in a patient population with advanced cancer.

Occurrence, causes, and outcome of delirium in patients with advanced cancer: a prospective study.

CONTEXT: Delirium impedes communication and contributes to symptom distress in patients with advanced cancer. There are few prospective data on the reversal of delirium in this population. OBJECTIVES: To evaluate the occurrence, precipitating factors, and reversibility of delirium in patients with advanced cancer. DESIGN: Prospective serial assessment in a consecutive cohort of 113 patients with advanced cancer. Precipitating factors were examined using standardized criteria; 104 patients met eligibility criteria. SETTING: Acute palliative care unit in a university-affiliated teaching hospital. MAIN OUTCOME MEASURES: Delirium occurrence and reversal rates, duration, and patient survival. Strengths of association of various precipitating factors with reversal were expressed as hazard ratios (HRs) in univariate and multivariate analyses. RESULTS: On admission, delirium was diagnosed in 44 patients (42%), and of the remaining 60, delirium developed in 27 (45%). Reversal of delirium occurred in 46 (49%) of 94 episodes in 71 patients. Terminal delirium occurred in 46 (88%) of the 52 deaths. In univariate analysis, psychoactive medications, predominantly opioids (HR, 8.85; 95% confidence interval [CI], 2.13-36.74), and dehydration (HR, 2.35; 95% CI, 1.20-4.62) were associated with reversibility. Hypoxic encephalopathy (HR, 0.39; 95% CI, 0.19-0.80) and metabolic factors (HR, 0.44; 95% CI, 0.21-0.91) were associated with nonreversibility. In mulitivariate analysis, psychoactive medications (HR, 6.65; 95% CI, 1.49-29.62), hypoxic encephalopathy (HR, 0.32; 95% CI, 0.15-0.70), and nonrespiratory infection (HR, 0.23; 95% CI, 0.08-0.64) had independent associations. Patients with delirium had poorer survival rates than controls (P<.001). CONCLUSIONS: Delirium is a frequent, multifactorial complication in advanced cancer. Despite its terminal presentation in most patients, delirium is reversible in approximately 50% of episodes. Delirium precipitated by opioids and other psychoactive medications and dehydration is frequently reversible with change of opioid or dose reduction, discontinuation of unnecessary psychoactive medication, or hydration, respectively.

The impact of a regional palliative care program on the cost of palliative care delivery.

In July 1995 the Edmonton Regional Palliative Care Program (ERPCP) was established in the City of Edmonton to increase the access of patients with terminal cancer to palliative care services, decrease the number of cancer deaths in acute-care facilities, and increase the participation of family physicians in the care of terminally ill patients. The objective of this retrospective study was to determine the cost of implementation of the ERPCP and savings in acute-care facility costs after its implementation. We did this by comparing the cost of care for patients during 1992-93 (prior to the ERPCP) and 1996-97 (with the ERPCP). The main outcome measures were the cost of care and the total hospital stay in days for all patients during their last acute-care hospital admission. The increased funding for the ERPCP was offset by a significant decrease in the overall cost of palliative care in the acute-care facilities. There was a substantial decrease in the palliative care costs in acute facilities from 11,963,846 dollars in 1992/93 to 3,449,055 dollars in 1996/97. This can be explained by the significant decrease in the number of palliative care patient days in acute-care facilities from 22,608 during 1992/93 to 6085 during 1996/97. Physician billings were slightly higher for 1996 as compared to 1992. In 1992, 90% (195,117/427,780) of the billings were made by the specialists (internists, surgeons, and other specialists), while in 1996/97 67% (359,869/537,342) of the payments were made to primary care practitioners (p < 0.0001). Overall, there were estimated saving of 1,650,689 dollars for palliative care costs in 1996/97 as compared to 1992/93. Our results suggest that the establishment of an integrated palliative care program reduced the cost of care. Prospective cost measurement studies are required.

Differences in the ratios of morphine to methadone in patients with neuropathic pain versus non-neuropathic pain.

The use of methadone in the treatment of cancer pain is becoming more attractive mainly because of its known efficacy, lack of active metabolites, and low cost. Methadone also blocks the n-methyl-D-aspartate (NMDA) receptor, and this property may result in other clinical advantages. Because of this capacity of methadone to block the NMDA receptors, we have hypothesized that the equianalgesic dose ratio of hydromorphone or morphine to methadone will be different in patients with neuropathic pain than in patients with non-neuropathic pain. To explore this hypothesis, we reviewed computerized patient records and determined the ratio of morphine and hydromorphone (expressed as morphine subcutaneous equivalent dose) to methadone in patients who underwent rotation from morphine or hydromorphone to methadone. We found that the ratio of morphine subcutaneous equivalent dose to methadone is between 5 and 7, which is different from previously described dose ratios. However, our study failed to show a difference in the ratios of patients with neuropathic or non-neuropathic pain syndromes.

Edmonton Regional Palliative Care Program: impact on patterns of terminal cancer care.

The Edmonton Regional Palliative Care Program was established in July 1995 to measure the access of patients with terminal cancer to palliative care services, decrease the number of cancer-related deaths in acute care facilities and increase the participation of family physicians in the care of terminally ill patients. In this retrospective study the authors compared the pattern of care and site of deaths before establishment of the program (1992/93) and during its second year of operation (1996/97). Significantly more cancer-related deaths occurred in acute care facilities in 1992/93 than in 1996/97 (86% [1119/1304] v. 49% [633/1279]) (p < or = 0.001). The number of inpatient days decreased, from 24,566 in 1992/93 to 6960 in 1996/97. More cancer patients saw a palliative care consult team in 1996/97 than in 1992/93 (82% v. 22%). The shift from deaths in acute care facilities to palliative hospices suggests that the establishment of an integrated palliative care program has increased access of patients with terminal cancer to palliative care.

The use of intermittent subcutaneous injections of oxycodone for opioid rotation in patients with cancer pain.

Oxycodone is a strong opioid that has been available for at least 70 years. At present, commercially prepared parenteral oxycodone is only available in Finland. We report in this paper our experience of administering oxycodone s.c. From 21 October 1996 to 31 July 1998, 63 advanced cancer patients received intermittent s.c. injections of oxycodone via the Edmonton Injector, a simple, low-cost mechanical device. Local tolerance and systemic toxicity were followed prospectively. Only 2 patients developed s.c. injection site intolerance, and in both cases doses of 50 mg/ml or more were being administered. Most of the patients in this study were rotated to oxycodone because of opioid toxicity, and in 34% of those patients their delirium subsided. A subgroup of 19 patients who underwent rotation to oxycodone SC from morphine and hydromorphone were studied for equivalent analgesia with oxycodone. We found a ratio (mean +/- SD) of 1.2+/-0.4 for morphine s.c. to oxycodone s.c. and a mean ratio of 0.5+/-0.4 for hydromorphone s.c. to oxycodone s.c. When hydromorphone s.c. was converted to a morphine s.c. equivalent dose and the results for these patients were added to those for the morphine s.c. group, the mean and median overall ratios of morphine s.c. equivalent dose to oxycodone were 1.9+/-1.5 and 1.4, respectively. The cost of the oxycodone s.c. was also evaluated and was found to be comparable to that of morphine s.c. and lower than that of hydromorphone s.c. We conclude that s.c. oxycodone can be an effective, safe and inexpensive alternative opioid agonist.

Suggestive evidence for a susceptibility gene near the vitamin D receptor locus in idiopathic calcium stone formation.

Calcium is the principal crystalline constituent in up to 80% of kidney stones. Epidemiologic studies have suggested that genetic predisposition plays a major role in the etiology of this condition. This study evaluates by a candidate-gene approach whether the vitamin D receptor (VDR) locus on chromosome 12q12-14 is implicated in idiopathic hypercalciuria and calcium nephrolithiasis in a cohort of 47 French Canadian pedigrees. These comprised 54 sibships with a total of 303 pairs of siblings concordant for > or =1 stone episode. Evidence is provided for linkage to nephrolithiasis with microsatellite marker D12S339 (near the VDR locus, P = 0.01), as well as with flanking markers (D12S1663: P = 0.03 and D12S368: P = 0.01). Inclusion of unaffected sibs in the analyses also supported evidence for linkage. Quantitative trait linkage analysis of urinary calcium excretion yielded linkage to some, but not all, markers. This appears to be the first study to suggest linkage for idiopathic calcium stone formation.

A review of the drug treatment of cachexia associated with cancer.

In the past 20 years, cachexia in cancer patients has attracted increasing interest from both clinicians and basic researchers. It is now clear that the cachexia is secondary to major metabolic abnormalities due to tumour by-products and cytokine release. These metabolic abnormalities produce numerous symptoms such as cachexia, anorexia and asthenia. There are now effective drugs such as corticosteroids and progestational drugs that have been shown to improve appetite, food intake and sensation of well-being, and which elicit bodyweight gain. While hydrazine (hydrazine sulfate) has received much attention, unfortunately it has been shown to be ineffective in improving the symptoms of the patient with cancer cachexia. A new group of drugs, such as thalidomide and melatonin because of their effects on tumour necrosis factor-alpha, and beta 2-adrenoceptor agonists because of their effects on muscle metabolism, and other agents, is presently reaching the clinical trial stage. There is now the possibility of addressing this fascinating syndrome at a different level and an opportunity for combined therapy to try to improve the quality of life of these patients.

The 1 alpha-hydroxylase locus is not linked to calcium stone formation or calciuric phenotypes in French-Canadian families.

Calcium urolithiasis is often associated with increased intestinal absorption and urine excretion of calcium, and has been suggested to result from increased vitamin D production. The role of the enzyme 1 alpha-hydroxylase, the rate-limiting step in active vitamin D production, was evaluated in 36 families, including 28 sibships with at least a pair of affected sibs, using qualitative and quantitative trait linkage analyses. Sibs with a verified calcium urolithiasis passage (n = 117) had higher 24-h calciuria (P = 0.03), oxaluria (P = 0.02), fasting and postcalcium loading urine calcium/creatinine (Ca/cr) ratios (P = 0.008 and P = 0.002, respectively), and serum 1,25(OH)2 vitamin D levels (P = 0.02) compared with nonstone-forming sibs (n = 120). Markers from a 9-centiMorgan interval encompassing the VDD1 locus on chromosome 12q13-14 (putative 1 alpha-hydroxylase) were analyzed in 28 sibships (146 sib pairs) of single and recurrent stone formers and in 14 sibships (65 sib pairs) with recurrent-only (> or = 3 episodes) stone-forming sibs. Two-point and multipoint analyses did not reveal excess in alleles shared among affected sibs at the VDD1 locus. Linkage of stone formation to the VDD1 locus could be excluded, respectively, with a lambda d of 2.0 (single and recurrent stone formers) and 3.25 (recurrent stone formers). Quantitative trait analyses revealed no evidence for linkage to 24-h calciuria and oxaluria, serum 1,25(OH)2 vitamin D levels, and Ca/cr ratios. This study shows absence of linkage of the putative 1 alpha-hydroxylase locus to calcium stone formation or to quantitative traits associated with idiopathic hypercalciuria. In addition, there is coaggregation of calciuric and oxaluric phenotypes with stone formation.