Effectiveness of fentanyl buccal soluble film in cancer patients with inadequate breakthrough pain control.

BACKGROUND: Clinical evidence for the rapidity and effectiveness of fentanyl buccal soluble film (FBSF) in reducing pain intensity of breakthrough cancer pain (BTcP) remains inadequate. This study aimed to evaluate the efficacy of FBSF proportional to the around-the-clock (ATC) opioid regimens in rapidly relieving the intensity of BTcP episodes by determining the percentage of patients requiring further dose titration. METHODS: The study procedure included a dose-finding period followed by a 14-day observation period. Pain intensity was recorded with a Numeric Rating Scale (NRS) at onset and 5, 10, 15, and 30 min after FBSF self-administration. Meaningful pain relief was defined as the final NRS score ≤ 3. Satisfaction survey was conducted for each patient after treatment using the Global Satisfaction Scale. RESULTS: A total of 63 BTcP episodes occurred in 30 cancer patients. Only one patient required rescue medication at first BTcP episode and then achieved meaningful pain relief after titrating FBSF by 200 µg. Most BTcP episodes relieved within 10 min. Of 63 BTcP episodes, 30 (47.6%), 46 (73.0%), and 53 (84.1%) relieved within 5, 10, and 15 min after FBSF administration. Only grade 1/2 adverse events were reported, including somnolence, malaise, and dizziness. Of the 63 BTcP episodes, 82.6% were rated as excellent/good satisfaction with FBSF. CONCLUSION: FBSF can be administrated "on demand" by cancer patients at the onset of BTcP, providing rapid analgesia by achieving meaningful pain relief within 10 min. TRIAL REGISTRATION: This study was retrospectively registered 24 December, 2021 at Clinicaltrial.gov (NCT05209906): https://clinicaltrials.gov/study/NCT05209906 .

Karnofsky Performance Status as A Predictive Factor for Cancer-Related Fatigue Treatment with Astragalus Polysaccharides (PG2) Injection-A Double Blind, Multi-Center, Randomized Phase IV Study.

Fatigue is a common and debilitating symptom in patients with advanced cancer, resulting in poor quality of life and reduced treatment efficacy. Phytotherapeutic agents have shown potential effects to relieve cancer-related fatigue in these patients. The aim of this study was to evaluate the efficacy and safety of Astragalus Polysaccharides injection and identify predictive factors associated with this treatment. Patients with advanced cancer receiving palliative care with moderate to severe cancer-related fatigue were enrolled in this study for two treatment cycles. Fatigue improvement response rates were analyzed as the primary endpoint at the end of the first cycle to determine treatment efficacy. The drug safety profile was evaluated by the reporting of adverse events. Three hundred and ten patients were enrolled in this study and 214 patients were included ITT population. Improvement in fatigue scores by at least 10% was observed in greater than 65% of subjects after one treatment cycle compared to scores at baseline. Patients with higher Karnofsky Performance Status (KPS) responded better to the Astragalus Polysaccharides injection. Drug-related adverse event rates were less than 9%. This study identified KPS as a promising predictive factor for the therapeutic efficacy of Astragalus Polysaccharides injection.

Proportional dose of rapid-onset opioid in breakthrough cancer pain management: An open-label, multicenter study.

BACKGROUND: The management of breakthrough pain (BTP) in cancer patients is a challenge. It is clinically useful to evaluate the effectiveness of rapid-onset opioid at a starting dose in proportional to the background opioid regimen. This open-label, multicenter, noncomparative study aimed to assess the efficacy and safety of proportional doses of fentanyl buccal soluble film (FBSF) in patients with breakthrough cancer pain. METHODS: Thirty patients aged 20 to 70, experiencing 1 to 3 BTP per day, receiving regimens equivalent to 60 to 360 mg/day of oral morphine or 25 to 150 µg/h of transdermal fentanyl ≥1 week, were prospectively recruited. FBSF was administered proportionally based on their current opioid regimen for baseline pain. The percentage of patients requiring dose titration was evaluated. For each BTP episode, changes in pain intensity at 30 minutes (PID30) after dosing, patient's satisfaction, the percentage of episodes requiring rescue medication, and adverse events (AEs) were recorded. RESULTS: The percentage of patients who required dose titration was 21.4% (6/28) and 12.0% (3/25) in the full analysis set and per-protocol populations, respectively. The average PID30 was 3.9, and a pain score ≤3 was achieved in 95.1% of the events. Eight out of 367 (2.2%) BTP episodes needed rescue medication. The majority of subjects (75.8%) rated their experience of pain management as good to excellent. A total of 6 drug-related AEs were reported by 3 (10.7%) patients in the safety population. CONCLUSIONS: FBSF dose in proportional to the regimen of opioid for baseline pain management is efficacious and well tolerated for the treatment of cancer patients with BTP.

Daphnoretin modulates differentiation and maturation of human dendritic cells through down-regulation of c-Jun N-terminal kinase.

Daphnoretin, an active constituent of Wikstroemia indica C.A. Meys, has been shown possessing anti-cancer activity. In this study, we examined the effect of daphnoretin on differentiation and maturation of human myeloid dendritic cells (DCs). After treatment with daphnoretin (0, 1.1, 3.3, 10 and 30µM) to initiate monocytes, the recovery rate of DCs was reduced in a dose-dependent manner. The mature DCs differentiated in the presence of daphnoretin had fewer and shorter dendrites. Daphnoretin modulated DCs differentiation and maturation in terms of lower expression of CD1a, CD40, CD83, DC-SIGN, and HLA-DR. Daphnoretin inhibited the allostimulatory activity of DCs on proliferation of naive CD4+CD45+RA+ T cell. On the mitogen-activated protein kinase, daphnoretin down-regulated the lipopolysaccharide-augmented expression of phosphorylated c-Jun N-terminal kinase (pJNK), but not p38 and extracellular signal-regulated kinase 1/2 (ERK1/2). Activation of JNK by anisomycin reversed the effect of daphnoretin on daphnoretin-inhibited pJNK expression and dendrite formation of DCs. In disease model related to maturation of DCs, daphnoretin suppressed the acute rejection of skin allografts in mice. Our results suggest that daphnoretin modulated differentiation and maturation of DCs toward a state of atypical maturation with impaired allostimulatory function and this effect may go through down-regulation of phosphorylated JNK.

Risk of thyroid cancer in patients with thyroiditis: a population-based cohort study.

BACKGROUND: The causative relationship between autoimmune thyroiditis and thyroid cancer remains a controversial issue. The aim of this population-based study was to investigate the risk of thyroid cancer in patients with thyroiditis. METHODS: From the Longitudinal Health Insurance Database 2005 (LHID2005) of Taiwan, we identified adult patients newly diagnosed with thyroiditis between 2004 and 2009 (n = 1,654). The comparison cohort (n = 8,270) included five randomly selected age- and sex-matched controls for each patient in the study cohort. All patients were followed up from the date of cohort entry until they developed thyroid cancer or to the end of 2010. Multivariate Cox regression was used to assess the risk of developing thyroid cancer. A total of 1,000 bootstrap replicates were created for internal validation. RESULTS: A total of 35 patients developed thyroid cancer during the study period, of whom 24 were from the thyroiditis cohort and 11 were from the comparison cohort (incidence 353 and 22 per 100,000 person-years, respectively). After adjusting for potential confounding factors, the hazard ratio (HR) for thyroid cancer in patients with thyroiditis was 13.24 (95 % CI 6.40-27.39). Excluding cancers occurring within 1 year of follow-up, the HR remained significantly increased (6.64; 95 % CI 2.35-18.75). Hypothyroidism was not an independent factor associated with the occurrence of thyroid cancer. CONCLUSIONS: We found an increased risk for the development of thyroid cancer after a diagnosis of thyroiditis, independent of comorbidities.

Physical activity preferences among patients with lung cancer in Taiwan.

BACKGROUND: Lung cancer is the leading cause of cancer deaths in the world. Physical activity could help lung cancer patients improve their health. OBJECTIVE: The purpose of our study was to investigate lung cancer patients' physical activity preferences and relevant contributing factors, so that we could develop individualized intervention strategies to fit their needs. METHODS: This study used a descriptive and correlational design. Instruments included a physical activity preference survey form, the Physical Activity Social Support Scale, and Physical Activity Self-efficacy Scale. RESULTS: From 81 lung cancer patients' physical activity preferences, our results showed that during the course of their illness, 85.2% of patients wanted to have a physical activity consultation and preferred to obtain advice from their physicians (28.4%) through face-to-face counseling (48.1%). Moreover, patients (70.4%) showed an interest in physical activity programs, and many (69.1%) revealed that they were able to participate. About 88.9% of patients showed a preference for walking, and 54.3% patients preferred moderate physical activity. CONCLUSIONS: This study also revealed that social support and self-efficacy for physical activity effectively predicted moderate physical activity preferences. IMPLICATIONS FOR PRACTICE: The adherence to regular physical activity is improved by understanding the lung cancer patients' unique preferences for physical activity.

Zoledronic acid treatment for cancerous bone metastases: a phase IV study in Taiwan.

AIM OF STUDY: To investigate the features, adverse effects, bone marker changes in patients with breast cancer, prostate cancer, and multiple myeloma with bone metastases under Zometa® therapy. MATERIALS AND METHODS: This post-marketing study included 414 Taiwanese patients with bone metastases secondary to breast cancer, prostate cancer, or multiple myeloma who received Zometa® for 48 weeks. The patients' characteristics, medication and adverse events were recorded, meanwhile changes in four serum bone metabolic markers and pain reduction were assessed every three months for one year. RESULTS: A total of 3,711 doses of Zometa® were infused, accounting for 294.5 patient-years. Adverse events occurred in 9.4% of patients, with bone pain, insomnia, constipation, and pyrexia as the most frequently reported. There was no osteonecrosis of the jaw. The incidence of skeletal-related events decreased significantly from 44.9% to 18.8%. Serum NTx, BAP, and TRACP5b steadily decreased to nadir at six months, but serum OPG was persistently elevated until the end of one year. The average decrease in pain score was 14.1, 14.3, and 16.7 for prostate cancer, breast cancer, and multiple myeloma patients, respectively. CONCLUSION: Zometa® can be safely administered in Taiwanese patients with bone metastases secondary to breast cancer, prostate cancer, and multiple myeloma. There are concomitant decreases in skeletal-related events and bone pain.

A novel infusible botanically-derived drug, PG2, for cancer-related fatigue: a phase II double-blind, randomized placebo-controlled study.

PURPOSE: This study investigated the efficacy of the botanical-derived drug, PG2, a partially purified extract of Astragalus membranaceus, as a complementary and palliative medicine for managing cancer-related fatigue (CRF). METHODS: Patients with advanced cancer and moderate to severe CRF were randomized to receive either PG2 or a placebo (normal saline, NS) in the first treatment cycle (four weeks) in a double-blind manner; thereafter, on the next cycle (four weeks), all patients received open-label treatment with PG2. RESULTS: PG2 significantly improved CRF in the NS-primed group. In the first four week cycle, PG2 administration resulted in a greater fatigue-improvement response rate than seen with NS alone. In addition, approximately 82% of patients who reported an improvement of fatigue symptoms following the first cycle of PG2 experienced sustained benefits after administration of the second treatment cycle. Among patients treated with PG2 who did not report an improvement in symptoms throughout the first treatment cycle, approximately 71% showed significant improvement after the second treatment cycle. No major or irreversible toxicities were observed with PG2 treatment. CONCLUSION: PG2 might be an effective and safe treatment for relieving CRF among advanced cancer patients.

Gender and age differences among youth, in utilization of mental health services in the year preceding suicide in Taiwan.

The primary objective of this study was to explore gender and age differences in the use of medical services during the year preceding suicide. Data were obtained from the mortality dataset of Department of Health and National Health Insurance Database. Included in the sample were 862 persons aged 12-24 years who committed suicide in Taiwan between 2001 and 2004. We compared the records of medical service utilization of adolescents (ages 12-18 years) with young adults (ages 19-24 years). Persons in both age groups contacted general practitioners more often than other types of medical providers in the year preceding suicide, with the exception of the month before suicide. Females made greater use of medical services than males in both age groups. Suicide prevention strategies should increase the emphasis in training non-psychiatric medical practitioners to identify and treat young persons at suicide risk.

The Relationship between Qi Deficiency, Cancer-related Fatigue and Quality of Life in Cancer Patients.

BACKGROUND: Qi ( qì) refers to the vital energy of the body in Traditional Chinese medicines (TCM). Qi deficiency ( qì xu) is the most common symptom in cancer patients according to the concept of TCM. We hypothesized that cancer patients with Qi deficiency suffer from poor quality of life (QOL) and fatigue. METHOD: Among the 256 registered cancer patients screened at our outpatient clinic, a total of 198 were enrolled. The inclusion criteria were (1) age between 18 and 70 years, (2) cancer diagnosis confirmed by the professional physician, (3) being Chinese, and (4) Eastern Cooperative Oncology Group (ECOG) performance status rating (PSR) ≤ 3. The major outcome is the difference in QOL score in cancer patients with and without Qi deficiency. RESULTS: The initial results showed statistically significant differences in WHO-QOL scores in physical, psychological, and social domains between the groups with and without Qi deficiency as well as the groups with and without cancerrelated fatigue (CRF). All patients with CRF present were also diagnosed as Qi deficient. In addition, among the patients with no CRF, 39.9% (69/173) were diagnosed as suffering from Qi deficiency, which led to poor QOL. CONCLUSIONS: The present study showed statistically significant difference in WHO-QOL scores in physical, psychological, and social domains between the groups with and without Qi deficiency as well as the groups with and without CRF. Cancer patients diagnosed with Qi deficiency or CRF have poor QOL. The concept of Qi deficiency in TCM might be applied to cancer health care.

An examination of cancer-related fatigue through proposed diagnostic criteria in a sample of cancer patients in Taiwan.

BACKGROUND: Fatigue among cancer patients has often been reported in the literature; however, great variations have been documented, ranging from 15% to 90%, probably due to the lack of a widely accepted definition and established diagnostic criteria for cancer-related fatigue. The objective of this study was to evaluate the proposed International Statistical Classification of Diseases and Related Health Problems (10th revision) (ICD-10) criteria in a sample of cancer patients from a medical center and a regional teaching hospital in northern Taiwan. More accurate prevalence estimates of CRF may result in improved diagnoses and management of one of the most common symptoms associated with cancer and its treatment. METHODS: Since self-reporting from patients is the most effective and efficient method to measure fatigue, the ICD-10 criteria for fatigue were used. The ICD-10 criteria questionnaire was translated into Chinese and was approved by experts. Patients were recruited from outpatient palliative and oncology clinics and from palliative and oncology inpatient units. RESULTS: Of the 265 cancer patients that were interviewed between 21 October 2008 and 28 October 2009, 228 (86%) reported having at least 2 weeks of fatigue in the past month, and further evaluation with the ICD-10 criteria showed that 132 (49.8%) had cancer-related fatigue. Internal consistency was very good, which was indicated by a Cronbach alpha of 0.843. CONCLUSION: The prevalence of diagnosable CRF in the patients in this sample, of whom most were under palliative treatment, was 49.8%, which was probably somewhat lower than in some of the previous reports that have used less-strict criteria. In addition, among the various criteria of the proposed diagnostic criteria, the most frequently reported symptoms in our sample populations were regarding sleep disturbance and physical factors. Although they will require further replication in other samples, these formal diagnostic criteria can serve as a step toward a common language and a better understanding of the severity range of CRF.

Risk of ovarian cancer in women with pelvic inflammatory disease: a population-based study.

BACKGROUND: Ovarian cancer is commonly fatal and incidence has persistently risen in Taiwan over the past 20 years. Prevention strategies, however, are limited. Pelvic inflammatory disease (PID) has been suggested to increase the risk of developing ovarian cancer, but the results of studies have been inconsistent. Therefore, we investigated whether PID increases the risk of developing ovarian cancer in a large, nationwide cohort. METHODS: From the Longitudinal Health Insurance Database 2005 (LHID2005) in Taiwan, we obtained data for women aged 13-65 years for whom a diagnosis of PID, confirmed by multiple episodes, had been recorded between Jan 1, 2004, and Dec 31, 2005. We also obtained data for two controls per patient, matched for age and the year of first entry into the LHID2005. All patients were followed up from the date of entry in the LHID2005 until they developed ovarian cancer or to the end of 2006, whichever was earlier. We used Cox's regression models to assess the risk of developing ovarian cancer, with adjustment for age, comorbid disorders, and socioeconomic characteristics. FINDINGS: We identified 67,936 women with PID and 135,872 controls. Among these 90 had developed ovarian cancer during the 3-year follow-up period (42 patients with PID and 48 controls, incidence 2·78 and 1·44 per 10,000 person-years, respectively). The adjusted hazard ratio for ovarian cancer in patients with PID was 1·92 (95% CI 1·27-2·92) compared with controls, which rose to 2·46 (1·48-4·09) in women who had had at least five episodes of PID. The adjusted hazard ratio was slightly higher for women aged 35 years or younger with PID than in older women with PID (2·23, 1·02-4·79 vs 1·82, 1·10-3·04). INTERPRETATION: We found an association between PID and ovarian cancer. PID might, therefore, be a useful marker for ovarian cancer, and early treatment could help to improve prognosis. Whether pelvic inflammation itself accelerates the growth of ovarian cancers or affects cancer-cell differentiation in ways that adversely alter prognosis needs to be investigated. FUNDING: None.

Immune impairment in patients with terminal cancers: influence of cancer treatments and cytomegalovirus infection.

Although immunodeficiency is usually considered a prerequisite of oncogenesis, a detailed immune pro- file in cancer has not yet been described. Without such profiling, it is not surprising that there is a vast discrepancy in the responses of cancer patients to immunotherapy. Our results show that the integrity of the immune system deteriorates with cancer progression by displaying a trend toward decreasing levels of functional T cells, including CD4, naïve, and central memory T cells, and an expansion of hyporesponsive populations such as CD28⁻ and CMV-specific T cells. One hundred and one patients constitute the study group for the observational study reported in this paper. Forty-eight patients with newly diagnosed stages III and IV and 53 patients with extensively treated stage IV disease. The costimulatory molecules CD27 and CD28 were downregulated in all patients. Among the proinflammatory cytokines (IL-6, TNF-α, IFN-γ), only IL-6 differed significantly among the groups, increasing as the cancer stage progressed. Plasma IL-7 did not diVer among the participants. The relative deficits of naïve T cells in cancer patients may be associated with the downregulation of IL-7Rα expression rather than changes in the circulating levels of IL-7. The downregulation of IL-7Rα expression was shown to be associated with increased levels of intracellular CMV. The present study suggests that the immune impairment in patients with cancer is associated with multiple factors, such as the stage of cancer, consequence of CMV infection and impact of treatment.

The therapeutic effect of modified Yu Ping Feng San on idiopathic sweating in end-stage cancer patients during hospice care.

End-stage cancer patients frequently suffer from idiopathic sweating of unknown cause. This study was to evaluate the effect (primary endpoint) of modified Yu Ping Feng San on idiopathic sweating and adverse reactions (secondary endpoint). Thirty two end-stage cancer patients receiving hospice care, with exclusion criteria including sweating due to known causes and taking drugs which may affect the sweating threshold were enrolled. Patients received modified Yu Ping Feng San for 10 consecutive days. The quantitative measurement of sweating showed 26 patients (81.3%) had complete remission of sweating, and the average time required to reach 50% reduction was 4.6 days. The visual analog scale (VAS) sweating score estimated by patients and care-givers showed that the mean reductions were 8.4 and 9.1 points, respectively. An increase in appetite was experienced by 65.6% of patients, after administration of modified Yu Ping Feng San. The most prevalent treatment-related complications were nausea (15.6%), diarrhea (9.3%) and allergy (3.1%) without severity greater than grade 2, and these were reversible after cessation of treatment. These results suggest that modified Yu Ping Feng San is a safe and effective treatment for idiopathic sweating of unknown cause in end-stage cancer patients.

Prevalence, detection and treatment of delirium in terminal cancer inpatients: a prospective survey.

BACKGROUND: Delirium is a common syndrome in terminal cancer patients. However, its detection and treatment by palliative care teams are not well documented. This survey aimed to determine the prevalence, detection and treatment of delirium in terminal cancer inpatients. METHODS: The survey was conducted in Mackay Hospice and Palliative Care Center, Taiwan, from August 2006 to January 2007. All terminal cancer inpatients were invited to participate. The Delirium Rating Scale-Chinese Version was used by a research assistant as the screening instrument. Patients detected by screening were reviewed by psychiatrists to verify the diagnosis and determine the sub-type of delirium. The palliative care team members were asked to evaluate all the participants weekly. The medications used for delirium were obtained by a medical chart review. Result Two hundred and twenty eight participants (49.9%) among 457 inpatients were screened. The prevalence of delirium was 46.9% (n = 107). Of these, the most common subtype was hypoactive (68.2%, 95% confidence interval (CI): 59.4-77.0%). The mortality rate of inpatients with delirium (77.6%, 95% CI: 69.7-85.5%) was higher (P < 0.0001) than those without delirium (50.9%, 95% CI: 44.4-57.4%). The overall detection rate by any member of the palliative team was 44.9% (n = 48) (95% CI: 35.5-54.3%). The detection rate of the hypoactive subtype was only 20.5% (95% CI: 11.2-29.8%), which was significantly lower than that of the hyperactive/mixed subtypes (P < 0.0001). Therapy for delirium was prescribed in 42.1% (n = 45) (95% CI: 32.7-51.5%) with haloperidol being the most common medication. CONCLUSION: The prevalence of delirium was high, but the rates of detection and treatment were low. Interventions are recommended to improve the diagnosis and treatment of delirium in palliative care units.

PIK3CA exon 20 mutation is independently associated with a poor prognosis in breast cancer patients.

BACKGROUND: Prognostic factors that could select breast cancer patients with poor survival, and influence clinical trials of targeted therapy, are needed. However, the reported observations regarding the impact of PI3KCA mutation on breast cancers are controversial. METHODS: We analyzed exons 4, 7, 9, and 20 of PI3KCA on a series of 158 patients. Clinicopathological characteristics were correlated with the mutation data. RESULTS: Among 152 patients who were available for follow-up (median follow-up time, 6.57 years), 26% had PIK3CA mutations, more than half of which occurred in exon 20. The five-year survival rate of patients with exon 20 mutations (46%) was significantly lower than that of patients without (75%) (p = 0.0054). Multivariate analysis showed that PIK3CA exon 20 mutations and nodal involvement were independent risk factors for overall survival. The relative risk of death in patients with PIK3CA exon 20 mutations was 2.881 (95% CI, 1.406-5.900; p = 0.0038). CONCLUSIONS: PIK3CA mutations are common in invasive ductal carcinomas of the breast. Our result suggests that PIK3CA exon 20 mutation is an independent risk factor for poor prognosis in breast cancer patients, indicating that differences in patient numbers with PIK3CA exon 20 mutations in study and control arms should be avoided in clinical trials of PI3K inhibitors.

Effects of electromyography biofeedback-assisted relaxation on pain in patients with advanced cancer in a palliative care unit.

Most patients with advanced cancer experience pain. However, many cancer patients do not find satisfaction with conventional treatment of pain relief. This study examined the effect of electromyography (EMG) biofeedback-assisted relaxation on cancer-related pain in advanced cancer patients. We hypothesized that changes in EMG activity in frontal muscles underlie the efficacy of EMG biofeedback-assisted relaxation. This was a randomized control study. The experimental group (n = 12) received 6 EMG biofeedback-assisted relaxation sessions over a 4-week period, whereas the control group (n = 12) received conventional care. The primary efficacy measure was the level of pain, measured by the Brief Pain Inventory. Findings from this study show that relaxation training supplemented with visual and auditory EMG biofeedback signals is effective in reducing cancer-related pain in advanced cancer patients, possibly through a mechanism of attenuation of physiological arousal. Electromyography biofeedback-assisted relaxation training may be used along with medications for effective pain management in patients with advanced cancer.

Grief reactions in family caregivers of advanced cancer patients in Taiwan: relationship to place of death.

Home death has a special cultural meaning for Taiwanese patients who are dying and their family members. However, very limited evidence has been presented on the impact of home death on caregiver bereavement outcomes. The purpose of this study was to explore the preference for place of death by Taiwanese patients dying of cancer and the actual place of death and to investigate the relationship between place of death of a patient and grief reactions of the family caregivers. This study consisted of 46 dying patients and 46 matched family caregivers (N = 92). The grief reaction was measured using the Texas Revised Inventory of Grief. Statistical analyses included descriptive statistics, t tests, logistic regression, and multiple regression. Most of the patients (74%) preferred to die at home; however, only 33% of family caregivers preferred the patient to die at home, and only 17% of patients actually died at home. Of these patients, 43% of their preferences were congruent with the actual place of death, whereas 79% of the family caregivers' preferences were congruent with the patients' actual place of death. Finally, the place of death was not a significant predictor of caregivers' grief reactions immediately after the loss of a loved one or at 1 month after the death occurred. This study provides important implications for future studies and clinical practice.

Chronic intrathecal infusion of minocycline prevents the development of spinal-nerve ligation-induced pain in rats.

BACKGROUND AND OBJECTIVES: Minocycline is a second-generation tetracycline with multiple biological effects, including inhibition of microglial activation. Recently, microglial activation has been implicated in the development of nerve injury-induced neuropathic pain. In this study, the authors examined the effects of continuous intrathecal minocycline on the development of neuropathic pain and microglial activation induced by L5/6 spinal-nerve ligation in rats. METHODS: Under isoflurane anesthesia, male Sprague-Dawley rats (200-250 g) received right L5/6 spinal-nerve ligation and intrathecal catheters connected to an infusion pump. Intrathecal saline or minocycline (2 and 6 microg/h) was given continuously after surgery for 7 days (n = 8 per group). The rat right hind paw withdrawal threshold to von Frey filament stimuli and withdrawal latency to radiant heat were determined before surgery and on days 1 to 7 after surgery. Spinal microglial activation was evaluated with OX-42 immunoreactivity on day 7 after surgery. RESULTS: Spinal-nerve ligation induced mechanical allodynia and thermal hyperalgesia on the affected hind paw of saline-treated rats. Intrathecal minocycline (2 and 6 microg/h) prevented the development of mechanical allodynia and thermal hyperalgesia induced by nerve ligation. It also inhibited nerve ligation-induced microglial activation, as evidenced by decreased OX-42 staining. No obvious histopathologic change was noted after intrathecal minocycline (6 microg/h) infusion. CONCLUSIONS: In this study, the authors demonstrate the preventive effect of continuous intrathecal minocycline on the development of nociceptive behaviors induced by L5/6 spinal-nerve ligation in rats. Further studies are required to examine if continuous intrathecal minocycline could be used safely in the clinical setting.