Changes in Apparent Diffusion Coefficient (ADC) in Serial Weekly MRI during Radiotherapy in Patients with Head and Neck Cancer: Results from the PREDICT-HN Study.

Background: The PREDICT-HN study aimed to systematically assess the kinetics of imaging MR biomarkers during head and neck radiotherapy. Methods: Patients with intact squamous cell carcinoma of the head and neck were enrolled. Pre-, during, and post-treatment MRI were obtained. Serial GTV and ADC measurements were recorded. The correlation between each feature and the GTV was calculated using Spearman's correlation coefficient. The linear mixed model was used to evaluate the change in GTV over time. Results: A total of 41 patients completed the study. The majority (76%) had oropharyngeal cancer. A total of 36 patients had intact primary tumours that can be assessed on MRI, and 31 patients had nodal disease with 46 nodes assessed. Median primary GTV (GTVp) size was 14.1cc. The rate of GTVp shrinkage was highest between pre-treatment and week 4. Patients with T3-T4 tumours had a 3.8-fold decrease in GTVp compared to T1-T2 tumours. The ADC values correlated with residual GTVp. The median nodal volume (GTVn) was 12.4cc. No clinical features were found to correlate with GTVn reduction. The overall change in ADC for GTVn from pre-treatment was significant for 35th−95th percentiles in weeks 1−4 (p < 0.001). Conclusion: A discrepancy in the trajectory of ADC between primary and nodal sites suggested that they exhibit different treatment responses and should be analysed separately in future studies.

A randomised controlled trial of clinical pharmacy intervention versus standard care to improve medication adherence in outpatients with head and neck cancer receiving radiotherapy.

PURPOSE: Patient understanding of medicines information and adherence to medication instructions are important variables for ensuring optimal cancer care. This randomised controlled trial (RCT) aimed to evaluate the impact of an outpatient clinical pharmacy service on medication adherence and symptom burden in cancer patients. METHODS: In this single-centre RCT, 115 patients were randomised 1:1 to a pharmacist-led pharmaceutical care program (intervention, n = 59) versus standard of care (control, n = 56) within an outpatient multidisciplinary radiotherapy clinic. The primary endpoint was medication adherence as assessed by Medication Understanding and Use Self-Efficacy (MUSE) scale and Teach-Back assessment. Secondary endpoints were patient-reported symptom burden assessed by the Edmonton Symptom Assessment Scale (ESAS). Patients were assessed at baseline (weeks 1-2) and at discharge from radiotherapy (weeks 5-7). RESULTS: Polypharmacy (use of five or more medications) was observed in 26% of patients at baseline compared to 97% at discharge. Patient self-efficacy and medication adherence was higher in the intervention arm compared to the control arm, with a mean MUSE score difference of 2.70 (95% CI 1.24, 4.17) after adjustment for baseline, and a higher proportion of patients with average Teach-Back score of four or more (86% vs 14%; odds ratio (OR) 46.09, 95% CI 14.49, 146.56). The mean (SD) scores for aggregate ESAS (0-100) at discharge were 26.2 (14.0) in the intervention arm and 32.0 (15.8) in the control arm demonstrating lower overall symptom burden associated with the intervention (mean score difference adjusted for baseline - 0.52; 95% CI - 1.03, - 0.01). CONCLUSION: A structured outpatient clinic pharmacy service significantly improved medication adherence and reduced overall symptom burden in patients receiving radiotherapy.

Assessment of Ovarian Function in Phase III (Neo)Adjuvant Breast Cancer Clinical Trials: A Systematic Evaluation.

BACKGROUND: Loss of ovarian function is a recognized adverse effect of chemotherapy for breast cancer and of great importance to patients. Little is known about the ovarian toxicity of newer cancer treatments. This study examined whether breast cancer clinical trials include assessment of the impact of trial interventions on ovarian function. METHODS: Eligible trials were phase III (neo)adjuvant trials of pharmacologic treatments for breast cancer, recruiting between June 2008 and October 2019, which included premenopausal women. MEDLINE, EMBASE, Clinicaltrials.gov, and EudraCT were searched. Data were extracted from trial publications, protocols, databases, and a survey sent to all trial chairs. Tests of statistical significance were 2-sided. RESULTS: Of 2354 records identified, 141 trials were eligible. Investigational treatments included chemotherapy (36.9%), HER2 targeted (24.8%), endocrine (12.8%), immunotherapy (7.8%), cyclin-dependent kinase 4/6 inhibitors (5.0%), and poly-ADP-ribose polymerase inhibitors (2.8%). Ovarian function was a prespecified endpoint in 13 (9.2%) trials. Forty-five (31.9%) trials collected ovarian function data, but only 33 (23.4%) collected posttrial-intervention data. Common postintervention data collected included menstruation (15.6%), pregnancy (13.5%), estradiol (9.9%), and follicle-stimulating hormone levels (8.5%). Only 4 (2.8%) trials collected postintervention anti-müllerian hormone levels, and 3 (2.1%) trials collected antral follicle count. Of 22 trials investigating immunotherapy, cyclin-dependent kinase 4/6 inhibitors, or poly-ADP-ribose polymerase inhibitors, none specified ovarian function as an endpoint, but 4 (18.2%) collected postintervention ovarian function data. CONCLUSIONS: The impact of pharmacologic interventions on ovarian function is infrequently assessed in phase III breast cancer (neo)adjuvant trials that include premenopausal women. Trialists should consider inclusion of ovarian function endpoints when designing clinical trials, given its importance for informed decision making.

Efficacy of immune checkpoint inhibitors for in-transit melanoma.

BACKGROUND: The efficacy of immune checkpoint inhibitors (ICI) in metastatic melanoma is well established. However, there are limited data regarding their efficacy in in-transit melanoma (ITM). This study assessed the efficacy of ICI in patients with ITM. METHODS: A retrospective review of patients with ITM commenced on an ICI between March 2013 and February 2018 at three tertiary centers in Australia. Patients were excluded if they had previous or synchronous distant metastases. Overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were based on a composite of radiological and clinical assessments. RESULTS: Fifty-four patients were included: 27 (50%) female; median age 75 (range 26-94); 12 (22%) stage IIIB, 40 (74%) stage IIIC and 2 (4%) stage IIID; 10 (19%) BRAF mutant. Forty (74%) received single-agent anti-PD-1 (pembrolizumab or nivolumab), 8 (15%) single agent anti-CTLA-4 (ipilimumab), 5 (9%) combination anti-PD-1/anti-CTLA-4 (ipilimumab and nivolumab or pembrolizumab) and 1 (2%) combination anti-PD-L1 (atezolizumab) and MEK inhibitor (cobimetinib). The median follow-up was 15 months (2-46).ORR to ICI was 54%: 14 (26%) complete responses; 15 (28%) partial responses; 9 (17%) stable disease; 16 (30%) progressive disease. Thirteen (46%) responders had only one ITM lesion. ORR was 58% for single-agent anti-PD-1, 38% for single-agent anti-CTLA4 and 40% for anti-PD-1/anti-CTLA-4. The median PFS was 11.7 months (6.6-not reached). 1-year and 2-year PFS were 48% and 39%, respectively,. Fourteen progressed locoregionally and 11 progressed distantly. The median OS was not reached. 1-year and 2-year OS were 85% and 63%, respectively. No clinicopathological features were associated with ORR. CONCLUSIONS AND RELEVANCE: ICI produce objective responses in ITM and should be considered in patients with unresectable ITM or disease recurrence.

Correlation between percutaneous biopsy and final histopathology for retroperitoneal sarcoma: a single-centre study.

BACKGROUND: Retroperitoneal sarcomas are rare soft tissue tumours accounting for 10-15% of soft tissue sarcomas. Patient prognosis and treatment recommendations (including extent of surgery and neoadjuvant strategies) are determined by the pre-operative histopathological subtype and grade obtained from biopsy and thus it is important to understand the accuracy of biopsy in retroperitoneal masses. METHODS: This study presents a case series of primary retroperitoneal sarcomas managed at Peter MacCallum Cancer Centre (PMCC) between 2008 and 2019. Statistical analyses were performed to determine correlation between histopathology from percutaneous biopsy and surgical excision. RESULTS: A total of 117 patients who underwent percutaneous core biopsy and surgical excision of retroperitoneal sarcoma were included. Diagnostic accuracy varied with histopathological diagnosis, but overall precise concordance between biopsy and final histopathology was seen in 61% (κ = 0.57). Biopsy was most sensitive for identifying well-differentiated liposarcoma (WDLPS) (sensitivity 85%, 95% CI 0.06-0.96) and leiomyosarcoma (sensitivity 81%, 95% CI 0.54-0.96) and was least sensitive for identifying de-differentiated liposarcoma (DDLPS) (sensitivity 40%, 95% CI 0.25-0.56). Overall agreement between biopsy and final histopathology increased with use of PET/CT scan pre-biopsy and with use of fluorescence in situ hybridisation testing on biopsy, however, neither test improved recognition of de-differentiated components within WD/DDLPS on core biopsy. CONCLUSIONS: Pre-operative biopsy is important for clinical decision making in the treatment of retroperitoneal sarcoma. A significant portion of patients with a WDLPS will have a de-differentiated component identified at the time of resection that was not identified on initial biopsy.

The Prognosis and Natural History of In-Transit Melanoma Metastases at a High-Volume Centre.

BACKGROUND: Patients with in-transit melanoma metastases (ITM) experience a diverse spectrum of clinical presentations and a highly variable disease course. There is no standardized treatment protocol for these patients due to the limited data comparing treatment modalities for ITM. This is the first study to describe the disease trajectory and natural history of a large cohort of patients with ITM. METHODS: A retrospective study of patients treated for ITM between 2004 and 2018 at the Peter MacCallum Cancer Centre was performed. Clinical and pathological characteristics for primary and in-transit episodes were analyzed for predictors of relapse-free survival (RFS), distant metastasis-free survival (DMFS), and melanoma-specific survival. RESULTS: A total of 109 patients with 303 episodes of ITM were identified: 52 (48%) females, median age 70.1 years (range 35-92). The median RFS for all episodes was 5 months (95% confidence interval [CI] 4.2-5.7). Eighty-seven percent of episodes involving isolated in-transit lesions underwent surgical excision, compared with 17% involving more than five in-transit lesions. A trend was seen between a greater number of lesions and shorter RFS (p = 0.055). The median DMFS was 34.8 months (95% CI 22.8-51.6). Factors associated with shorter DMFS included primary tumor thickness (hazard ratio [HR] 1.08, 95% CI 1.01-1.15; p = 0.026), site of primary tumor (p = 0.008), and BRAF mutation (HR 2.12, 95% CI 1.14-3.94; p = 0.018). CONCLUSIONS: Locoregional relapse is common in patients with ITM regardless of treatment modality. Characteristics of the ITM may predict for RFS, while primary tumor characteristics remain important predictors of DMFS.

Negative Sentinel Lymph Node Biopsy in Patients with Melanoma: The Patient's Perspective.

BACKGROUND: The majority of patients undergoing sentinel lymph node biopsy (SLNB) for melanoma will have a negative SLN. The long-term sequelae of a negative result are important when discussing this staging investigation with patients. The objective of this study was to assess rates of lymphoedema and quality of life for these patients. METHODS: A prospective, cross-sectional study was performed on patients under routine follow-up with a history of melanoma, who had undergone sentinel lymph node biopsy where no metastasis was found (N0) at a high-volume melanoma centre. Relevant limbs were measured to assess for lymphoedema and patients completed the FACT-M quality of life instrument and a study specific questionnaire. RESULTS: A total of 102 patients were recruited. Wound complications were observed in 25% and lymphoedema in 2% of patients. Physical and functional well-being scores were lowest in patients seen within 3 months of their SLNB. Functional well-being and quality of life improved over the 2 years following the procedure. CONCLUSIONS: SLNB has low complication rates. The procedure is associated with a short-term impact on patient quality of life and well-being. The vast majority of patients are pleased with the outcomes of this procedure and the information that it provides.

The RAPID-CTCA trial (Rapid Assessment of Potential Ischaemic Heart Disease with CTCA) - a multicentre parallel-group randomised trial to compare early computerised tomography coronary angiography versus standard care in patients presenting with suspected or confirmed acute coronary syndrome: study protocol for a randomised controlled trial.

BACKGROUND: Emergency department attendances with chest pain requiring assessment for acute coronary syndrome (ACS) are a major global health issue. Standard assessment includes history, examination, electrocardiogram (ECG) and serial troponin testing. Computerised tomography coronary angiography (CTCA) enables additional anatomical assessment of patients for coronary artery disease (CAD) but has only been studied in very low-risk patients. This trial aims to investigate the effect of early CTCA upon interventions, event rates and health care costs in patients with suspected/confirmed ACS who are at intermediate risk. METHODS/DESIGN: Participants will be recruited in about 35 tertiary and district general hospitals in the UK. Patients ≥18 years old with symptoms with suspected/confirmed ACS with at least one of the following will be included: (1) ECG abnormalities, e.g. ST-segment depression >0.5 mm; (2) history of ischaemic heart disease; (3) troponin elevation above the 99th centile of the normal reference range or increase in high-sensitivity troponin meeting European Society of Cardiology criteria for 'rule-in' of myocardial infarction (MI). The early use of ≥64-slice CTCA as part of routine assessment will be compared to standard care. The primary endpoint will be 1-year all-cause death or recurrent type 1 or type 4b MI at 1 year, measured as the time to such event. A number of secondary clinical, process and safety endpoints will be collected and analysed. Cost effectiveness will be estimated in terms of the lifetime incremental cost per quality-adjusted life year gained. We plan to recruit 2424 (2500 with ~3% drop-out) evaluable patients (1212 per arm) to have 90% power to detect a 20% versus 15% difference in 1-year death or recurrent type 1 MI or type 4b MI, two-sided p < 0.05. Analysis will be on an intention-to-treat basis. The relationship between intervention and the primary outcome will be analysed using Cox proportional hazard regression adjusted for study site (used to stratify the randomisation), age, baseline Global Registry of Acute Coronary Events score, previous CAD and baseline troponin level. The results will be expressed as a hazard ratio with the corresponding 95% confidence intervals and p value. DISCUSSION: The Rapid Assessment of Potential Ischaemic Heart Disease with CTCA (RAPID-CTCA) trial will recruit 2500 participants across about 35 hospital sites. It will be the first study to investigate the role of CTCA in the early assessment of patients with suspected or confirmed ACS who are at intermediate risk and including patients who have raised troponin measurements during initial assessment. TRIAL REGISTRATION: ISRCTN19102565 . Registered on 3 October 2014. ClinicalTrials.gov: NCT02284191.

Regimen selection in the OPTIONS trial of HIV salvage therapy: drug resistance, prior therapy, and race-ethnicity determine the degree of regimen complexity.

BACKGROUND: Regimen selection for highly treatment-experienced patients is complicated. METHODS: Using a web-based utility, study team members reviewed antiretroviral (ARV) history and resistance data and recommended individual ARV regimens and nucleoside reverse transcriptase inhibitor (NRTI) options for treatment-experienced participants consisting of 3-4 of the following agents: raltegravir (RAL), darunavir (DRV)/ritonavir, tipranavir (TPV)/ritonavir, etravirine (ETR), maraviroc (MVC), and enfuvirtide (ENF). We evaluated team recommendations and site selection of regimen and NRTIs. Associations between baseline factors and the selection of a complex regimen (defined as including four ARV agents or ENF) were explored with logistic regression. RESULTS: A total of 413 participants entered the study. Participants initiated the first or second recommended regimen 86% of the time and 21% of participants started a complex regimen. In a multivariable model, ARV resistance to NRTI (odds ratio [OR] = 2.2), non-nucleoside reverse transcriptase inhibitor (NNRTI, OR = 6.2) or boosted protease inhibitor (PI, OR = 6.6), prior use of integrase strand transfer inhibitor (INSTI, OR = 25), and race-ethnicity (all P ≤ 0.01) were associated with selection of a complex regimen. Black non-Hispanic (OR = 0.5) and Hispanic participants from the continental US (OR = 0.2) were less likely to start a complex regimen, compared to white non-Hispanics. CONCLUSIONS: In this multi-center trial, we developed a web-based utility that facilitated treatment recommendations for highly treatment-experienced patients. Drug resistance, prior INSTI use, and race-ethnicity were key factors in decisions to select a more complex regimen.

Comparison of the metabolic effects of ritonavir-boosted darunavir or atazanavir versus raltegravir, and the impact of ritonavir plasma exposure: ACTG 5257.

BACKGROUND: Metabolic effects following combination antiretroviral therapy (cART) vary by regimen type. Changes in metabolic effects were assessed following cART in the AIDS Clinical Trials Group (ACTG) A5257 study, and correlated with plasma ritonavir trough concentrations (C24). METHODS: Treatment-naive adult subjects were randomized to ritonavir-boosted atazanavir or darunavir, or raltegravir-based cART. Changes in lipids and other metabolic outcomes over time were estimated. Differences between arms were estimated with 97.5% confidence intervals and compared using pairwise Student t tests. Associations between ritonavir C24 and lipid changes at week 48 were evaluated via linear regression. RESULTS: Analyses included 1797 subjects with baseline fasting data. Baseline lipid profiles and metabolic syndrome rates (approximately 21%) were similar across arms. Comparable increases occurred in total cholesterol, triglycerides, and low-density lipoprotein cholesterol with the boosted protease inhibitors (PIs); each PI had greater increases relative to raltegravir (all P ≤ .001 at week 96). Metabolic syndrome incident rates by week 96 (approximately 22%) were not different across arms. Ritonavir C24 was not different by arm (P = .89) (median, 69 ng/mL and 74 ng/mL in the atazanavir and darunavir arms, respectively) and were not associated with changes in lipid measures (all P > .1). CONCLUSIONS: Raltegravir produced the most favorable lipid profile. Metabolic syndrome rates were high at baseline and increased to the same degree in all arms. Ritonavir C24 was not different in the PI arms and had no relationship with the modest but comparable increases in lipids observed with either atazanavir or darunavir. The long-term clinical significance of the lipid changes noted with the PIs relative to raltegravir deserves further evaluation. CLINICAL TRIALS REGISTRATION: NCT 00811954.

Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial.

BACKGROUND: Nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons. OBJECTIVE: To evaluate 3 nonnucleoside reverse transcriptase inhibitor-sparing initial antiretroviral regimens to show equivalence for virologic efficacy and tolerability. DESIGN: A phase 3, open-label study randomized in a 1:1:1 ratio with follow-up for at least 96 weeks. (ClinicalTrials.gov: NCT00811954). SETTING: 57 sites in the United States and Puerto Rico. PATIENTS: Treatment-naive persons aged 18 years or older with HIV-1 RNA levels greater than 1000 copies/mL without resistance to nucleoside reverse transcriptase inhibitors or protease inhibitors. INTERVENTION: Atazanavir, 300 mg/d, with ritonavir, 100 mg/d; raltegravir, 400 mg twice daily; or darunavir, 800 mg/d, with ritonavir, 100 mg/d, plus combination emtricitabine, 200 mg/d, and tenofovir disoproxil fumarate, 300 mg/d. MEASUREMENTS: Virologic failure, defined as a confirmed HIV-1 RNA level greater than 1000 copies/mL at or after 16 weeks and before 24 weeks or greater than 200 copies/mL at or after 24 weeks, and tolerability failure, defined as discontinuation of atazanavir, raltegravir, or darunavir for toxicity. A secondary end point was a combination of virologic efficacy and tolerability. RESULTS: Among 1809 participants, all pairwise comparisons of incidence of virologic failure over 96 weeks showed equivalence within a margin of equivalence defined as -10% to 10%. Raltegravir and ritonavir-boosted darunavir were equivalent for tolerability, whereas ritonavir-boosted atazanavir resulted in a 12.7% and 9.2% higher incidence of tolerability discontinuation than raltegravir and ritonavir-boosted darunavir, respectively, primarily because of hyperbilirubinemia. For combined virologic efficacy and tolerability, ritonavir-boosted darunavir was superior to ritonavir-boosted atazanavir, and raltegravir was superior to both protease inhibitors. Antiretroviral resistance at the time of virologic failure was rare but more frequent with raltegravir. LIMITATION: The trial was open-label, and ritonavir was not provided. CONCLUSION: Over 2 years, all 3 regimens attained high and equivalent rates of virologic control. Tolerability of regimens containing raltegravir or ritonavir-boosted darunavir was superior to that of the ritonavir-boosted atazanavir regimen. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases.

Association between efavirenz as initial therapy for HIV-1 infection and increased risk for suicidal ideation or attempted or completed suicide: an analysis of trial data.

BACKGROUND: The relationship between efavirenz use and suicidality is not well-defined. OBJECTIVE: To compare time to suicidality with efavirenz-containing versus efavirenz-free antiretroviral regimens for initial treatment of HIV. DESIGN: Participant-level data were analyzed from 4 AIDS Clinical Trials Group, antiretroviral-naive studies conducted from 2001 to 2010. Within each study, participants were randomly assigned to an efavirenz-containing (n = 3241) or efavirenz-free (n = 2091) regimen. (ClinicalTrials.gov: NCT00013520 [A5095], NCT00050895 [A5142], NCT00084136 [A5175], and NCT00118898 [A5202]). SETTING: AIDS Clinical Trials Group sites; 74% of participants enrolled in the United States. PATIENTS: Antiretroviral-naive participants. INTERVENTION: Efavirenz versus efavirenz-free regimens. MEASUREMENTS: Suicidality was defined as suicidal ideation or attempted or completed suicide. Groups were compared with a hazard ratio and 95% CI estimated from a Cox model, stratified by study. RESULTS: Seventy-three percent of participants were men, the median age was 37 years, and 32% had documented psychiatric history or received psychoactive medication within 30 days before entering the study. Median follow-up was 96 weeks. Suicidality incidence per 1000 person-years was 8.08 (47 events) in the efavirenz group and 3.66 (15 events) in the efavirenz-free group (hazard ratio, 2.28 [95% CI, 1.27 to 4.10]; P = 0.006). Incidence of attempted or completed suicide was 2.90 (17 events) and 1.22 (5 events) in the efavirenz and efavirenz-free groups, respectively (hazard ratio, 2.58 [CI, 0.94 to 7.06]; P = 0.065). Eight suicides in the efavirenz group and 1 in the efavirenz-free group were reported. LIMITATION: There was not a standardized questionnaire about suicidal ideation or attempt. Efavirenz was open-label in 3 of 4 studies. CONCLUSION: Initial treatment with an efavirenz-containing antiretroviral regimen was associated with a 2-fold increased hazard of suicidality compared with a regimen without efavirenz. PRIMARY FUNDING SOURCE: National Institutes of Health.

Postoperative Recovery Outcomes in Adult Scoliosis: A Prospective Multicenter Database With 5-Year Follow-Up.

STUDY DESIGN: Retrospective review of a prospective, multi-institutional database. OBJECTIVES: To determine postoperative quality of life outcomes in scoliosis patients using the Oswestry Disability Index (ODI) at defined time points. SUMMARY OF BACKGROUND DATA: Spinal surgery provides significant improvement in both pain and disability in adults with scoliosis compared with conservative treatment; however, the postoperative timing of improvements in quality of life outcomes has not been studied. METHODS: This was a retrospective review of a prospective, multi-center database with 1,750 patients. All patients completed the ODI at first encounter and at 6 follow-ups (6 weeks, 6 months, and 1, 2, 3, and 5 years). The authors stratified by age, primary versus revision, staged surgery, anatomical region of surgery, complexity (osteotomy and levels), and complications (intraoperative and postoperative). RESULTS: At baseline and most follow-up visits, older patients, those with revision surgeries, and those who had an osteotomy had significantly higher ODI scores than did young patients, those with primary surgeries, and those who did not have an osteotomy. All stratified groups showed a significant ODI score decrease between 6 weeks' and 6 months' follow-up. However, most of the stratified group patients' outcomes remained unchanged throughout the postoperative recovery period from 1 to 5 years. CONCLUSIONS: Surgical treatment has the potential to significantly improve the quality of life of patients with adult scoliosis. An understanding of the timing of improvement after surgery will improve both the counseling of surgical candidates and patient care pathways.

Pitfalls of calculating hospital readmission rates based on nonvalidated administrative data sets: : presented at the 2012 Joint Spine Section Meeting: clinical article.

OBJECT: Administrative databases are increasingly being used to establish benchmarks for quality of care and to compare performance across peer hospitals. As proposals for accountable care organizations are being developed, readmission rates will be increasingly scrutinized. The purpose of the present study was to assess whether the all-cause readmissions rate appropriately reflects the University of California, San Francisco (UCSF) Medical Center hospital's clinically relevant readmission rate for spine surgery patients and to identify predictors of readmission. METHODS: Data for 5780 consecutive patient encounters managed by 10 spine surgeons at UCSF Medical Center from October 2007 to June 2011 were abstracted from the University HealthSystem Consortium (UHC) using the Clinical Data Base/Resource Manager. Of these 5780 patient encounters, 281 patients (4.9%) were rehospitalized within 30 days of the previous discharge date. The authors performed an independent chart review to determine clinically relevant reasons for readmission and extracted hospital administrative data to calculate direct costs. Univariate logistic regression analysis was used to evaluate possible predictors of readmission. The two-sample t-test was used to examine the difference in direct cost between readmission and nonreadmission cases. RESULTS: The main reasons for readmission were infection (39.8%), nonoperative management (13.4%), and planned staged surgery (12.4%). The current all-cause readmission algorithm resulted in an artificially high readmission rate from the clinician's point of view. Based on the authors' manual chart review, 69 cases (25% of the 281 total readmissions) should be excluded because 39 cases (13.9%) were planned staged procedures; 16 cases (5.7%) were unrelated to spine surgery; and 14 surgical cases (5.0%) were cancelled or rescheduled at index admission due to unpredictable reasons. When these 69 cases are excluded, the direct cost of readmission is reduced by 29%. The cost variance is in excess of $3 million. Predictors of readmission were admission status (p < 0.0001), length of stay (p = 0.0001), risk of death (p < 0.0001), and age (p = 0.021). CONCLUSIONS: The authors' findings identify the potential pitfalls in the calculation of readmission rates from administrative data sets. Benchmarking algorithms for defining hospitals' readmission rates must take into account planned staged surgery and eliminate unrelated reasons for readmission. When this is implemented in the calculation method, the readmission rate will be more accurate. Current tools overestimate the clinically relevant readmission rate and cost.