Publications

BACKGROUND

Electronic referrals can improve access to subspecialty care in safety net settings. In January 2007, San Francisco General Hospital (SFGH) launched an electronic referral portal that incorporated subspecialist triage, iterative communication with referring providers, and existing electronic health record data to improve access to subspecialty care.

OBJECTIVE

We surveyed primary care providers (PCPs) to assess the impact of electronic referrals on workflow and clinical care.

DESIGN

We administered an 18-item, web-based questionnaire to all 368 PCPs who had the option of referring to SFGH.

MEASUREMENTS

We asked participants to rate time spent submitting a referral, guidance of workup, wait times, and change in overall clinical care compared to prior referral methods using 5-point Likert scales. We used multivariate logistic regression to identify variables associated with perceived improvement in overall clinical care.

RESULTS

Two hundred ninety-eight PCPs (81.0%) from 24 clinics participated. Over half (55.4%) worked at hospital-based clinics, 27.9% at county-funded community clinics, and 17.1% at non-county-funded community clinics. Most (71.9%) reported that electronic referrals had improved overall clinical care. Providers from non-county-funded clinics (AOR 0.40, 95% CI 0.14-0.79) and those who spent > or =6 min submitting an electronic referral (AOR 0.33, 95%CI 0.18-0.61) were significantly less likely than other participants to report that electronic referrals had improved clinical care.

CONCLUSIONS

PCPs felt electronic referrals improved health-care access and quality; those who reported a negative impact on workflow were less likely to agree. While electronic referrals hold promise as a tool to improve clinical care, their impact on workflow should be considered.

BACKGROUND

Although physicians sometimes use the futility rationale to limit the use of life-sustaining treatments, little is known about how surrogate decision makers view this rationale. We sought to determine the attitudes of surrogates of patients who are critically ill toward whether physicians can predict futility and whether these attitudes predict surrogates' willingness to discontinue life support when faced with predictions of futility.

METHODS

This multicenter, mixed qualitative and quantitative study took place at three hospitals in California from 2006 to 2007. We conducted semistructured interviews with surrogate decision makers for 50 patients who were critically ill and incapacitated that addressed their beliefs about medical futility and inductively developed an organizing framework to describe these beliefs. We used a hypothetical scenario with a modified time-trade-off design to examine the relationship between a patient's prognosis and a surrogate's willingness to withdraw life support. We used a mixed-effects regression model to examine the association between surrogates' attitudes about futility and their willingness to limit life support in the face of a very poor prognosis. Validation methods included the use and integration of multiple data sources, multidisciplinary analysis, and member checking.

RESULTS

Sixty-four percent of surrogates (n = 32; 95% confidence interval [CI], 49 to 77%) expressed doubt about the accuracy of physicians' futility predictions, 32% of surrogates (n = 16; 95% CI, 20 to 47%) elected to continue life support with a < 1% survival estimate, and 18% of surrogates (n = 9; 95% CI, 9 to 31%) elected to continue treatment when the physician believed that the patient had no chance of survival. Surrogates with religious objections to the futility rationale (n = 18) were more likely to request continued life support (odds ratio, 4; 95% CI, 1.2 to 14.0; p = 0.03) than those with secular or experiential objections (n = 15; odds ratio, 0.95; 95% CI, 0.3 to 3.4; p = 0.90).

CONCLUSIONS

Doubt about physicians' ability to predict medical futility is common among surrogate decision makers. The nature of the doubt may have implications for responding to conflicts about futility in clinical practice.

PURPOSE

The novel topoisomerase I inhibitor karenitecin (KTN) shows activity against melanoma. We examined whether histone deacetylase inhibition could potentiate the DNA strand cleavage, cytotoxicity as well as the clinical toxicity, and efficacy of KTN in melanoma.

EXPERIMENTAL DESIGN

Apoptosis, COMET, and xenograft experiments were carried out as described previously. A phase I/II trial of valproic acid (VPA) and KTN was conducted in patients with stage IV melanoma, with any number of prior therapies, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function.

RESULTS

VPA pretreatment potentiated KTN-induced apoptosis in multiple melanoma cell lines and in mouse A375 xenografts. VPA increased KTN-induced DNA strand breaks. In the phase I/II trial, 39 patients were entered, with 37 evaluable for toxicity and 33 evaluable for response. Somnolence was the dose-limiting toxicity. The maximum tolerated dose for VPA was 75 mg/kg/d; at maximum tolerated dose, serum VPA was approximately 200 microg/mL (1.28 mmol/L). At the dose expansion cohort, 47% (7 of 15) of patients had stable disease; median overall survival and time to progression were 32.8 and 10.2 weeks, respectively. Histone hyperacetylation was observed in peripheral blood mononuclear cells at maximum tolerated dose.

CONCLUSION

VPA potentiates KTN-induced DNA strand breaks and cytotoxicity. VPA can be combined at 75 mg/kg/d for 5 days with full-dose KTN without overlapping toxicities. In metastatic poor prognosis melanoma, this combination is associated with disease stabilization in 47% of patients. Further testing of this combination appears warranted.

PURPOSE

The aim was to study the biological and molecular effects of the histone deacetylase (HDAC) inhibitor, valproic acid, in patients with solid tumor malignancies.

EXPERIMENTAL DESIGN

A phase I dose escalation of valproic acid given on days 1 to 3 followed by epirubicin (day 3) was followed by a dose expansion of valproic acid combined with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC100). Pharmacodynamic and pharmacokinetic studies entailed valproic acid and epirubicin plasma levels and their interaction, the effects of valproic acid on histone acetylation in peripheral blood mononuclear cells (PBMC) and tumor cells at baseline and day 3, and baseline expression of HDAC2 and HDAC6 as therapeutic targets.

RESULTS

Forty-four patients were enrolled in the phase I part, with a disease-specific cohort expansion of 15 breast cancer patients (median age, 55 years; range, 28-66 years) receiving 120 mg/kg/day valproic acid followed by FEC100. Partial responses were seen in 9 of 41 (22%) patients during the phase I part. Objective responses were seen in 9 of 14 (64%) evaluable patients at the dose expansion with a median number of 6 administered cycles. Predominant toxicities were valproic acid-associated somnolence and epirubicin-induced myelosuppression. Valproic acid plasma levels were associated with short-term, reversible depletion of WBC and neutrophils within 48 hours. Histone acetylation in tumor samples and in PBMCs correlated with valproic acid levels and was further linked to baseline HDAC2 but not to HDAC6 expression.

CONCLUSION

Valproic acid is a clinically relevant HDAC inhibitor, and PBMCs may serve as a surrogate for tumor histone acetylation in solid tumor malignancies. HDAC2 should be further considered as a relevant therapeutic target.

PURPOSE

The dose-limiting toxicities, maximum tolerated dose, pharmacokinetic profile, and preliminary antitumor activity of neratinib (HKI-272), an irreversible pan ErbB inhibitor, were determined in patients with advanced solid tumors.

EXPERIMENTAL DESIGN

Neratinib was administered orally as a single dose, followed by a 1-week observation period, and then once daily continuously. Planned dose escalation was 40, 80, 120, 180, 240, 320, 400, and 500 mg. For pharmacokinetic analysis, timed blood samples were collected after administration of the single dose and after the first 14 days of continuous daily administration.

RESULTS

Dose-limiting toxicity was grade 3 diarrhea, which occurred in one patient treated with 180 mg and in four patients treated with 400 mg neratinib; hence, the maximum tolerated dose was determined to be 320 mg. Other common neratinib-related toxicities included nausea, vomiting, fatigue, and anorexia. Exposure to neratinib was dose dependent, and the pharmacokinetic profile of neratinib supports a once-a-day dosing regimen. Partial response was observed for 8 (32%) of the 25 evaluable patients with breast cancer. Stable disease >or=24 weeks was observed in one evaluable breast cancer patient and 6 (43%) of the 14 evaluable non-small cell lung cancer patients.

CONCLUSION

The maximum tolerated dose of once-daily oral neratinib is 320 mg. The most common neratinib-related toxicity was diarrhea. Antitumor activity was observed in patients with breast cancer who had previous treatment with trastuzumab, anthracyclines, and taxanes, and tumors with a baseline ErbB-2 immunohistochemical staining intensity of 2+ or 3+. The antitumor activity, tolerable toxicity profile, and pharmacokinetic properties of neratinib warrant its further evaluation.