A pilot trial of intravenous pamidronate for chronic low back pain.

Intravenous (i.v.) bisphosphonates relieve pain in conditions such as Paget's disease of bone, metastatic bone disease, and multiple myeloma. Based on positive findings from a prior case series, we conducted a randomized placebo-controlled study to assess the analgesic effect of i.v. pamidronate in subjects with chronic low back pain (CLBP) and evidence of degenerative disease of the spine. Four groups of 11 subjects (7 active, 4 placebo) were enrolled at escalating dose levels of 30, 60, 90, and 180 mg pamidronate (the latter administered as two 90 mg infusions). Primary outcomes were safety and change from baseline in average daily pain scores, recorded at 1, 2, 3, and 6 months postinfusion using electronic diaries. Secondary outcomes included responder rate, daily worst pain, and pain-related interference with daily function. There were no pamidronate-related serious adverse events or other significant safety findings. A statistically significant overall treatment difference in pain scores was observed, with clinically meaningful effects persisting for 6 months in the 180 mg pamidronate group. Least squares mean changes in daily average pain score were -1.39 (SE=0.43) for placebo, and -1.53 (0.71), -1.26 (0.81), -1.42 (0.65), and -4.13 (0.65) for pamidronate 30, 60, 90, and 180 mg, respectively (P=0.012 for pamidronate 180 mg vs placebo). The proportion of responders, changes in worst pain, and pain interference with daily function were also significantly improved for pamidronate 180 mg compared with placebo. In conclusion, i.v. pamidronate, administered as two 90 mg infusions, decreased pain intensity for 6 months in subjects with CLBP.

Effects of foods and beverages on the symptoms of chronic prostatitis/chronic pelvic pain syndrome.

OBJECTIVE: To better elucidate the prevalence of perceived food sensitivity and characterize the sensitivity pattern in patients with clinically diagnosed chronic prostatitis/chronic pelvic pain syndrome. METHODS: A total of 286 men meeting the National Institutes of Health criteria for chronic prostatitis were mailed a validated questionnaire designed to detect the effect of foods, beverages, and/or supplements on pelvic pain symptoms. The questionnaire assessed the effect of 176 individual comestibles on each patient's symptoms. The responses were numerically scored on a scale of -2 to +2, and the mean values were generated for each comestible. In addition, the participants were asked to complete the O'Leary-Sant Symptom and Problem Index and Chronic Prostatitis Symptom Index questionnaires. RESULTS: Of the 286 surveys, 95 were returned, yielding a response rate of 33.2%. Of those subjects who responded, 47.4% reported that the consumption of certain comestibles aggravated their symptoms, with the most aggravating being spicy foods, coffee, hot peppers, alcoholic beverages, tea, and chili. In contrast, the comestibles that alleviated the symptoms the most included docusate, pysllium, water, herbal teas, and polycarbophil. CONCLUSION: Many patients with chronic prostatitis/chronic pelvic pain syndrome have demonstrable food, beverage, and dietary supplement sensitivities. Dietary changes should be considered in the treatment of these patients.

Abusive head trauma in children: a comparison of male and female perpetrators.

OBJECTIVE: To evaluate the effect of perpetrator gender on victim presentation and outcomes, and perpetrator legal outcomes for abusive head trauma (AHT). METHODS: We performed a retrospective chart review of AHT cases from 1998 to 2008. Patient clinical data and information regarding perpetrator legal outcome was obtained. Relationship of brain injury and retinal hemorrhages (RHs) and differences in categorical variables of perpetrator gender were compared by using Fisher's exact test. Differences in continuous variables between perpetrator gender were compared by using the Mann-Whitney Test. RESULTS: There were 34 cases of AHT with identified perpetrators, 17 of each gender. Mean age of the victims was 9.4 months (SD: 7.8). Thirty-two (94%) had intracranial hemorrhages, 14 (41%) had both primary and secondary brain injury, 28 (82%) had RHs, and 6 (18%) died. The severity of RH was related to the severity of brain injuries (P = .01). The median age for female perpetrators (34 years) was higher than that for males (27 years; P = .001). Six categorical variables were associated with male perpetrator gender: acute presenting symptoms of cardiopulmonary or respiratory arrest (P = .025), worse clinical outcome (P = .012), neurosurgical intervention (P = .037), death (P = .018), perpetrator confession (P = .0001), and conviction (P = .005). CONCLUSIONS: There were significant perpetrator gender differences of AHT in children. Male perpetrators were younger and more likely to confess and be convicted. Victims of male perpetrators had more serious acute presentations and neurosurgical intervention and suffered worse clinical outcomes.

Knowledge and attitudes of health care workers regarding MOLST (Medical Orders for Life-Sustaining Treatment) implementation in long-term care facilities.

We studied the impact of knowledge and attitudes of physicians, nurses, and social workers in nursing facilities of the Medical Orders for Life Sustaining Treatment(MOLST)implementation. The results indicate that in the case of advance directives, knowledge influences care.

The histone deacetylase inhibitor panobinostat demonstrates marked synergy with conventional chemotherapeutic agents in human ovarian cancer cell lines.

Although platinum based therapy has improved short term survival of patients with metastatic ovarian cancer, the majority of patients continue to relapse and eventually die of their disease. Currently, a plethora of agents are in development, but how to combine them to enhance efficacy remains largely empiric. We have used short in vitro culture of defined cell lines with application of promising agents and analysis for cell death using a MTT assay to identify potentially useful combinations. Using median effect analysis, curve shift analysis and apoptosis assays, we can identify when agents are synergistic or antagonistic when applied together. Up to three agents can be studied in combination. Using three cell lines: SK-OV3, CaOV-3, and ES-2 (a clear cell tumor), we have identified that panobinostat (LBH-589), a broad histone deacetylase inhibitor in clinical trials, demonstrates global synergy with gemcitabine, with paclitaxel, and additive to synergistic effects with 5'DFUR. The triplet of panobinostat, doxorubicin, and carboplatin is especially synergistic in these cell lines. These effects are cytotoxic and not cytostatic. As all these agents are used clinically, we have identified combinations which warrant further investigation.

Oral and tympanic membrane temperatures are inaccurate to identify Fever in emergency department adults.

INTRODUCTION: Identifying fever can influence management of the emergency department (ED) patient, including diagnostic testing, treatment, and disposition. We set out to determine how well oral and tympanic membrane (TM) temperatures compared with rectal measurements. METHODS: A convenience sample of consecutively adult ED patients had oral, TM, and rectal temperatures performed within several minutes of each other. Descriptive statistics, Bland-Altman agreement matrices with 95% confidence interval (CI), and measures of test performance, including sensitivity, specificity, predictive values, and interval likelihood ratios were performed. RESULTS: A total of 457 patients were enrolled with an average age of 64 years (standard deviation: 19 years). Mean temperatures were: oral (98.3°F), TM (99.6°F), and rectal (99.4°F). The mean difference in rectal and oral temperatures was 1.1°F, although there was considerable lack of agreement between oral and rectal temperatures, with the oral temperature as much as 2.91°F lower or 0.74°F higher than the rectal measurement (95% CI). Although the difference in mean temperature between right TM and rectal temperature was only 0.22°F, the right TM was lower than rectal by up to 1.61°F or greater by up to 2.05°F (95% CI). Test performance varied as the positive predictive value of the oral temperature was 97% and for tympanic temperature was 55% (relative to a rectal temperature of 100.4°F or higher). Comparative findings differed even at temperatures considered in the normal range; among patients with an oral temperature of 98.0 to 98.9, 38% (25/65) were found to have a rectal temperature of 100.4 or higher, while among patients with a TM of 98.0 to 98.9, only 7% (10/134) were found to have a rectal temperature of 100.4 or higher. CONCLUSION: The oral and tympanic temperature readings are not equivalent to rectal thermometry readings. Oral thermometry frequently underestimates the temperature relative to rectal readings, and TM values can either under- or overestimate the rectal temperature. The clinician needs to be aware of the varying relationship between oral, TM, and rectal temperatures when interpreting readings.

Factors influencing older adults to complete advance directives.

OBJECTIVE: The purpose of this study was to determine the factors which influence advance directive (AD) completion among older adults. METHOD: Direct interviews of hospitalized and community-dwelling cognitively intact patients > 65 years of age were conducted in three tertiary teaching settings in New York. Analysis of AD completion focused on its correlation with demographics, personal beliefs, knowledge, attitudes, and exposure to educational media initiatives. We identified five variables with loadings of at least 0.30 in absolute value, along with five demographic variables (significant in the univariate analyses) for multiple logistic regression. The backward elimination method was used to select the final set of jointly significant predictor variables. RESULTS: Of the 200 subjects consenting to an interview, 125 subjects (63%) had completed ADs. In comparing groups with and without ADs, gender (p < 0.0002), age (p < 0.0161), race (p < 0.0001), education (p < 0.0039), and religion (p < 0.0104) were significantly associated with having an AD. Factors predicting AD completion are: thinking an AD will help in the relief of suffering at the end of life, (OR 76.3, p < 0.0001), being asked to complete ADs/ or receiving explanation about ADs (OR 55.2, p < 0.0001), having undergone major surgery (OR 6.3, p < 0.0017), female gender (OR 11.1, p < 0.0001) and increasing age (76-85 vs. 59-75: OR 3.4, p < 0.0543; < 85 vs. 59-75: OR 6.3, p < 0.0263). SIGNIFICANCE OF RESULTS: This study suggests that among older adults, the probability of completing ADs is related to personal requests by health care providers, educational level, and exposure to advance care planning media campaigns.

Patient noncompliance before surgery.

OBJECTIVE: To assess patient compliance with preoperative instructions and to determine causes and factors of noncompliance, as noncompliance might affect surgical outcome and has potential medicolegal implications. PATIENTS AND METHODS: One surgeon counselled 101 consecutive patients before undergoing laparoscopic renal surgery. Deliberate discussions instructed patients to bring their radiograph films on the day of surgery and complete a preoperative bowel preparation. Noncompliance was defined as failure to bring films and/or complete bowel preparation. Patient demographics, socio-economic and clinical variables were analysed, and reasons for failure to comply with instructions were also recorded. RESULTS: Twenty-four of the 101 (24%) patients were not compliant, 13 with films only, seven with bowel preparation only, and four with both sets of instructions. Univariate analysis showed that language and race were factors for noncompliance. Multivariate analysis showed that non-Caucasians had 17 times the risk of noncompliance (P < 0.001); long distance from home to the site of care had five times the risk of noncompliance (P = 0.041), and each day between the initial consultation and the date of surgery had 1.05 times the risk of noncompliance (P < 0.001). The most common reason given by patients for noncompliance was that they were never given the preoperative instructions. CONCLUSIONS: Noncompliance with preoperative surgical instructions is a significant issue and is increased in non-Caucasian patients, those travelling long distances, and those whose surgery date is long after their preoperative consultation. A systems-based approach is needed to address this significant issue.

Hypersensitivity to oxaliplatin: an investigation of incidence and risk factors, and literature review.

BACKGROUND: Hypersensitivity is a well-known complication of the platinum agents cisplatin and carboplatin. Although hypersensitivity to oxaliplatin has been noted, the incidence varies significantly in reports. Risk factors for developing reactions specifically to oxaliplatin have not been evaluated. We report the 5-year incidence of hypersensitivity to oxaliplatin in our clinical program, the patient and disease characteristics associated with its occurrence, and review the literature. METHODS: Clinical information on all patients treated with oxaliplatin between September 2002 and August 2007 was retrospectively reviewed. Data from patients who experienced hypersensitivity were compared to patients treated with this agent who did not. Risk factors investigated included age, sex, diagnosis, disease stage, presence of preexisting allergies, chemotherapy received, and use of oxaliplatin in front-line versus salvage therapy. RESULTS: 247 patients received oxaliplatin, with 29 experiencing hypersensitivity, for an incidence of 11.7% (95% CI 7.7-15.8). Grade 3/4 events occurred in 1.6%. Hypersensitivity was associated with younger mean age (54.9 +/- 12.5 vs. 60.4 +/- 12.4 years with reactions vs. those without, p = 0.02), female gender (17.2% of females vs. 6.4% of males, p = 0.01) and with use of oxaliplatin as salvage therapy (23.9% second-line or higher vs. 9.1% front-line, p = 0.01). CONCLUSIONS: Our data demonstrate an incidence of hypersensitivity to oxaliplatin of 11.7%, with grade 3/4 events in 1.6%. As use of this agent becomes more widespread, increased vigilance for this potentially serious complication should be high, especially amongst younger patients, females, and with the use of oxaliplatin as salvage therapy; three newly recognized potential risk factors.

In-vitro synergism of m-TOR inhibitors, statins, and classical chemotherapy: potential implications in acute leukemia.

Classical chemotherapy has an active, but limited, role in acute leukemia with relapse common in adult patients. Recent evidence has implicated signal transduction pathways in leukemic progression and also in resistance to cytotoxic therapy. We have used a short-term, in-vitro incubation assay with cytotoxic analysis by MTT, confirmed by histone-associated DNA fragmentation, to evaluate both classical and nonclassical combinations of drugs. Isobologram median effect analysis, confirmed by curve shift analysis, was used to identify synergy and antagonism. Fluvastatin, a prenylation inhibitor, demonstrates global enhancement of the effects of classical agents in both AML-193 and KG-1 cell lines. Similarly, the m-TOR inhibitors, RAD-001 (everolimus) and rapamycin, also cause time-dependent global enhancement of cytotoxic agents. At clinically achievable combinations, RAD-001 perturbs the AKT pathway in vitro. The unique combination of fluvastatin and an m-TOR inhibitor was synergistic in both cell lines. These effects were independent of whether or not human plasma was used in the assay system. These studies suggest several novel combinations of agents that need to be evaluated in the management of leukemia.

Can antidepressants be used to treat the schizophrenia prodrome? Results of a prospective, naturalistic treatment study of adolescents.

OBJECTIVE: This study reports the results of a prospective, naturalistic treatment study of adolescents considered to be in the prodromal (i.e., prepsychotic) phase of schizophrenia. METHOD: Forty-eight adolescents (mean age = 15.8 years) participating in the initial phase of the Recognition and Prevention (RAP) program (1998-2005) were included in the current report. Individuals were selected from the overall sample (N = 152) if they had: (1) displayed attenuated positive symptoms, (2) been treated pharmacologically for at least 8 weeks, and (3) been followed up for at least 6 months (mean follow-up = 30.5 months). RESULTS: Two types of medication were naturalistically prescribed: antidepressants (N = 20) or second-generation antipsychotics (N = 28), with polypharmacy common. The 2 treatment groups did not differ in baseline symptom profiles, with the exception of disorganized thinking, which was more severe in second-generation antipsychotic-treated adolescents. Twelve of the 48 adolescents (25%) developed a psychotic disorder, with all converters having been prescribed second-generation antipsychotics. There were no conversions among antidepressant-treated adolescents (log-rank chi(2) = 7.36, df = 1, p = .007). Treatment outcome, however, was confounded, since 11 of the 12 converters were nonadherent. Adolescents, in general, were more likely to be nonadherent to second-generation antipsychotics (61%, 17/28) than to antidepressants (20%, 4/20; chi(2) = 7.86, p = .005). Improvement in 3 of 5 positive symptoms over time was significant (p < .001) and similar for both medications. Disorganized thought, however, did not improve regardless of treatment. CONCLUSIONS: Nonrandom assignment limits comparisons between antidepressants and anti-psychotics in this study. However, with follow-up, a number of adolescents meeting criteria for prodromal schizophrenia were successfully treated with antidepressants. At present, a substantial number of false positives among the antidepressant-treated subgroup cannot be ruled out. However, the findings suggest that, in some cases, it might be preferable to begin treatment with antidepressants and progress to antipsychotics once symptoms intensify, since adherence to the latter is difficult to maintain.

Fluvastatin enhancement of trastuzumab and classical cytotoxic agents in defined breast cancer cell lines in vitro.

The combination of anticancer drugs used in the clinic has been based upon empiricism, and the potential permutations of currently available drugs overwhelm the clinical trials system. Recently, investigators have suggested that the combination of a blockade of vital signal transduction pathways in combination with more standard therapy might enhance anticancer effect. Using a panel of breast cancer cell lines and isobologram median effect analysis, a method of determining synergism or antagonism of drugs, we have investigated in vitro potentially clinically useful combinations of agents with the human cell lines MCF7/wt, MCF7/adr, BT474, and SK-BR-3 grown in log phase. Results were confirmed by curve shift analysis. Cells were exposed to the agent(s) for 72 h and then analyzed for cytotoxicity using a MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyl-tetrazolium bromide) assay. Fluvastatin, an inhibitor of prenylation with excellent tolerability in man, was chosen to disrupt signal transduction pathways and thus potentially enhance the effect of more traditional anticancer agents. Anticancer agents tested were cytotoxics used in the treatment of breast cancer, trastuzumab, and rapamycin as an inhibitor of the AKT pathway. Fluvastatin combined with trastuzumab demonstrates global synergy of cytotoxic effect that is confirmed by apoptosis assay. These effects could only be partially reversed by adding farnesol or geranylgeraniol to restore prenylation. Epirubicin is also synergistic with fluvastatin in three of the four cell lines. Rapamycin, an inhibitor of MTOR, was synergistic with fluvastatin in two of the four cell lines and antagonistic in two other cell lines. The combination of fluvastatin or another inhibitor of prenylation and trastuzumab may be attractive for clinical development as the effect of trastuzumab in Her2/neu positive breast tumors is incomplete as a single agent.

U.S. board-certified pain physician practices: uniformity and census data of their locations.

UNLABELLED: We determined the profiles of the board-certified pain physician workforce and the profiles of those residing near medical pain practices. Data from a mail survey of U.S. pain specialists were compared with U.S. Census data, and different settings and types of practices were contrasted. The 750 respondents (32.1%) were similar to the entire board-certified group in age, geographic distribution, and primary specialty. Although pain practices were underrepresented in rural areas, their prevalence was unrelated to other demographic data. Ninety-six percent of pain physicians treated chronic pain; 84% followed patients longitudinally; 31% worked in an academic environment; 50% had an interdisciplinary practice; and 29% focused on a single modality. Academics were more likely to be neurologists (P < .05) and to have had a pain fellowship (P < or = .0001). Modality-oriented practitioners were more likely to be anesthesiologists (P < or = .0001) and were less likely to follow patients with chronic pain longitudinally (P < or = .0001), provide training to fellows, prescribe controlled substances (P < or = .0001, respectively), or require an opioid contract (P < or = .01). Although boarded specialists learn from similar curricula and must pass a certifying examination, their practices vary considerably. Data are needed to further clarify the nature of workforce variation, its impact on patient care, and the role of other pain management clinicians. PERSPECTIVE: A survey of board-certified pain specialists reveals considerable variation in practice and a total number of specialists that is probably insufficient to meet the needs of the population with chronic pain. The location of pain management practices largely corresponds to census data, with the exception of underrepresentation in rural areas.

Identification of potentially useful combinations of epidermal growth factor receptor tyrosine kinase antagonists with conventional cytotoxic agents using median effect analysis.

Targeted therapy for breast carcinoma has achieved a major advance with the use of trastuzumab in Her2/neu-positive tumors. The epidermal growth factor receptor superfamily thus becomes an attractive target for therapeutic agents. As the epidermal growth factor receptor tyrosine kinase family has a conformational binding site, which allows small molecules to interfere with its function, we have explored the effects of a dual kinase (epidermal growth factor receptor-1 and epidermal growth factor receptor-2) inhibitor (GW282974X) with a variety of cytotoxic agents looking for synergistic effects in vitro. Using a median effect model in four breast cancer cell lines in vitro, cytotoxic agents commonly used in treatment of human malignant disease were combined with trastuzumab or one of two epidermal growth factor receptor tyrosine kinase inhibitors in a 72-h culture and then analyzed for cytotoxic effect by 3-[26]-2,5-diphenyl-tetrazolium bromide assay. Combination index values within one standard deviation of unity were considered additive, less than unity as synergistic and more than unity as antagonistic. Synergistic results were confirmed by curve shift analysis and by an enzyme-linked immunosorbent assay measuring apoptosis by cytoplasmic histone-associated DNA fragments. Quantitative real-time polymerase chain reaction analysis was used to measure the expression of three of the critical enzymes in 5'-deoxy-5-fluorouridine metabolism and activity: thymidine phosphorylase, dihydropyrimidine dehydrogenase and thymidine synthase. 5'-Deoxy-5-fluorouridine with GW282974X demonstrated global synergy, both in high and low expressing epidermal growth factor receptor breast cancer cell lines. These results were confirmed by apoptosis assay and cell counts. RNA quantification following treatment with the dual kinase inhibitor suggested reduction in thymidine synthase levels to be a potential mechanism of synergy. The triplet of trastuzumab, GW282974X and 5'-deoxy-5-fluorouridine, and the triplet of GW282974X, epirubicin and 5'-deoxy-5-fluorouridine were highly synergistic in low expression cells (MCF7/wt) and high expression cells (MCF7/adr). These experiments suggest further studies of the dual kinase inhibitor with selected cytotoxics such as 5'-deoxy-5-fluorouridine are warranted.