Factor VIII Levels and ISTH Disseminated Intravascular Coagulation Scores Do Not Distinguish Disseminated Intravascular Coagulation from the Coagulopathy of Liver Disease.

INTRODUCTION: Distinguishing disseminated intravascular coagulation (DIC) from the coagulopathy of liver disease represents a common clinical challenge. Here, we evaluated the utility of two diagnostic tools frequently used to differentiate between these conditions: factor VIII (FVIII) levels and the International Society on Thrombosis and Hemostasis (ISTH) DIC score. METHODS: To this end, we conducted a retrospective chart review of patients with DIC, liver disease, or both. Multiple logistic regression was performed, and receiver operating characteristic curves were generated to calculate the area under curve (AUC) for distinguishing DIC in the setting of liver disease. RESULTS: Among 123 patients with DIC, liver disease, or liver disease plus DIC, FVIII levels did not differ significantly. ISTH scores were lower in patients with DIC than in liver disease with or without DIC. Addition of several laboratory parameters to the ISTH score, including mean platelet volume, FV, FVIII, international normalized ratio, and activated partial thromboplastin time, improved AUC for distinguishing DIC in liver disease from liver disease alone (AUC = 0.76; p < 0.0001). CONCLUSION: We conclude that FVIII levels do not distinguish DIC from liver disease, and ISTH DIC scores are not predictive of DIC in patients with liver disease. Inclusion of additional lab variables within the ISTH DIC score may aid in identifying DIC in patients with liver disease.

Five-year Long-term Outcomes of Stereotactic Body Radiation Therapy for Operable Versus Medically Inoperable Stage I Non-small-cell Lung Cancer: Analysis by Operability, Fractionation Regimen, Tumor Size, and Tumor Location.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is standard for medically inoperable stage I non-small-cell lung cancer (NSCLC) and is emerging as a surgical alternative in operable patients. However, limited long-term outcomes data exist, particularly according to operability. We hypothesized long-term local control (LC) and cancer-specific survival (CSS) would not differ by fractionation schedule, tumor size or location, or operability status, but overall survival (OS) would be higher for operable patients. PATIENTS AND METHODS: All consecutive patients with stage I (cT1-2aN0M0) NSCLC treated with SBRT from June 2009 to July 2013 were assessed. Thoracic surgeon evaluation determined operability. Local failure was defined as growth following initial tumor shrinkage or progression on consecutive scans. LC, CSS, and OS were calculated using Cox proportional hazards regression. RESULTS: A total of 186 patients (204 lesions) were analyzed. Most patients were inoperable (82%) with Eastern Cooperative Oncology Group performance status of 1 (59%) or 2 (26%). All lesions received biological effective doses ≥ 100 Gy most commonly (94%) in 3 to 5 fractions. The median follow-up was 4.0 years. LC at 2 and 5 years were 95.6% (95% confidence interval, 92%-99%) and 93.7% (95% confidence interval, 90%-98%), respectively. Compared with operable patients, inoperable patients did not have significant differences in 5-year LC (93.1% vs. 96.7%; P = .49), nodal failure (31.4% vs. 11.0%; P = .12), distant failure (12.2% vs. 10.4%; P = .98), or CSS (80.6% vs. 91.0%; P = .45) but trended towards worse OS (34.2% vs. 45.3%; P = .068). Tumor size, location, and fractionation did not significantly influence outcomes. CONCLUSIONS: SBRT has excellent, durable LC and CSS rates for early-stage NSCLC, although inoperable patients had somewhat lower OS than operable patients, likely owing to greater comorbidities.

Disparities in Access to Sorafenib in Communities with Low Socioeconomic Status.

OBJECTIVE: In the United States, hepatocellular carcinoma (HCC) is more common among communities with low socioeconomic status (SES), and these groups tend to be diagnosed with later-stage cancers. Sorafenib is the primary treatment for advanced HCC, however its substantial cost raises concern for access to treatment. METHODS: The newly developed Case-Background method was used to estimate odds ratios for the impacts of various sociodemographic factors on sorafenib access in clinically eligible patients. Socioeconomic status was defined as a factor of median income and education level based on ZIP code of residence. RESULTS: There was a strong association between sorafenib prescription and residence in an area of higher SES. While controlling for age, race/ethnicity, and insurance status, high SES residence doubled the odds of sorafenib prescription (OR=2.05, p<.01). CONCLUSIONS: Low socioeconomic status communities appear to have a reduced chance of receiving the only effective treatment for advanced HCC.

Exploratory analysis using machine learning to predict for chest wall pain in patients with stage I non-small-cell lung cancer treated with stereotactic body radiation therapy.

BACKGROUND AND PURPOSE: Chest wall toxicity is observed after stereotactic body radiation therapy (SBRT) for peripherally located lung tumors. We utilize machine learning algorithms to identify toxicity predictors to develop dose-volume constraints. MATERIALS AND METHODS: Twenty-five patient, tumor, and dosimetric features were recorded for 197 consecutive patients with Stage I NSCLC treated with SBRT, 11 of whom (5.6%) developed CTCAEv4 grade ≥2 chest wall pain. Decision tree modeling was used to determine chest wall syndrome (CWS) thresholds for individual features. Significant features were determined using independent multivariate methods. These methods incorporate out-of-bag estimation using Random forests (RF) and bootstrapping (100 iterations) using decision trees. RESULTS: Univariate analysis identified rib dose to 1 cc < 4000 cGy (P = 0.01), chest wall dose to 30 cc < 1900 cGy (P = 0.035), rib Dmax < 5100 cGy (P = 0.05) and lung dose to 1000 cc < 70 cGy (P = 0.039) to be statistically significant thresholds for avoiding CWS. Subsequent multivariate analysis confirmed the importance of rib dose to 1 cc, chest wall dose to 30 cc, and rib Dmax. Using learning-curve experiments, the dataset proved to be self-consistent and provides a realistic model for CWS analysis. CONCLUSIONS: Using machine learning algorithms in this first of its kind study, we identify robust features and cutoffs predictive for the rare clinical event of CWS. Additional data in planned subsequent multicenter studies will help increase the accuracy of multivariate analysis.

Using machine learning to predict radiation pneumonitis in patients with stage I non-small cell lung cancer treated with stereotactic body radiation therapy.

To develop a patient-specific 'big data' clinical decision tool to predict pneumonitis in stage I non-small cell lung cancer (NSCLC) patients after stereotactic body radiation therapy (SBRT). 61 features were recorded for 201 consecutive patients with stage I NSCLC treated with SBRT, in whom 8 (4.0%) developed radiation pneumonitis. Pneumonitis thresholds were found for each feature individually using decision stumps. The performance of three different algorithms (Decision Trees, Random Forests, RUSBoost) was evaluated. Learning curves were developed and the training error analyzed and compared to the testing error in order to evaluate the factors needed to obtain a cross-validated error smaller than 0.1. These included the addition of new features, increasing the complexity of the algorithm and enlarging the sample size and number of events. In the univariate analysis, the most important feature selected was the diffusion capacity of the lung for carbon monoxide (DLCO adj%). On multivariate analysis, the three most important features selected were the dose to 15 cc of the heart, dose to 4 cc of the trachea or bronchus, and race. Higher accuracy could be achieved if the RUSBoost algorithm was used with regularization. To predict radiation pneumonitis within an error smaller than 10%, we estimate that a sample size of 800 patients is required. Clinically relevant thresholds that put patients at risk of developing radiation pneumonitis were determined in a cohort of 201 stage I NSCLC patients treated with SBRT. The consistency of these thresholds can provide radiation oncologists with an estimate of their reliability and may inform treatment planning and patient counseling. The accuracy of the classification is limited by the number of patients in the study and not by the features gathered or the complexity of the algorithm.

Extrahepatic metastasectomy for hepatocellular carcinoma: Predictors of long-term survival.

INTRODUCTION: We report our institutional experience with extrahepatic metastasectomy (EM) in a cohort of hepatocellular carcinoma (HCC) patients with focus on predictors of survival. METHODS: All patients diagnosed with metastatic HCC from 2001 to 2014 were retrospectively reviewed to identify those who underwent EM with therapeutic intent. Associations among multiple clinicopathological variables and survival after EM were analyzed by univariate and multivariate analyses. RESULTS: Out of 440 metastatic HCC cases, we identified 85 patients (mean age 58.8 ± 11.7 years, 81.2% males) who underwent lung (n = 36), peritoneal (n = 22), lymph node (n = 19), musculoskeletal (n = 18), and adrenal (n = 9) metastasectomy. Most patients (84.7%) underwent metachronous EM following primary liver resection or transplantation. The median follow-up period was 20.9 months, during which 55 patients (64.7%) died. The 1-/2-/5-year overall survival rates after EM were 77.4, 53.1, and 25.1%, respectively. On multivariate analysis, number of metastases resected >2 correlated independently with poor survival (HR = 2.058, P = 0.0099). EM patients had superior median survival compared to all (n = 194) metastatic HCC patients treated with sorafenib without EM during the study period (27.2 vs. 7.4 months, P < 0.001). CONCLUSION: Long-term survival may be achieved in highly selected HCC patients following EM. The presence of greater than two extrahepatic lesions correlates independently with poor survival. J. Surg. Oncol. 2016;114:469-474. © 2016 Wiley Periodicals, Inc.

The effect of locoregional therapies in patients with advanced hepatocellular carcinoma treated with sorafenib.

BACKGROUND & AIMS: It is unknown whether the addition of locoregional therapies (LRTx) to sorafenib improves prognosis over sorafenib alone in patients with advanced hepatocellular carcinoma (HCC). The aim of this study was to assess the effect of LRTx in this population. METHODS: A retrospective analysis was performed of patients with advanced HCC as defined by extrahepatic metastasis, lymphadenopathy >2 cm, or gross vascular invasion. Sorafenib therapy was required for inclusion. Survival of patients who received LRTx after progression to advanced stage was compared to those who did not receive LRTx. RESULTS: Using an intention to treat analysis of 312 eligible patients, a propensity weighted proportional hazards model demonstrated LRTx as a predictor of survival (HR = 0.505, 95% CI: 0.407-0.628; P < 0.001). The greatest benefit was seen in patients with the largest tumor burden (HR = 0.305, 95% CI: 0.236-0.393; P < 0.01). Median survival in the sorafenib arm was 143 days (95% CI: 118-161) vs. 247 days (95% CI: 220-289) in the sorafenib plus LRTx arm (P < 0.001). CONCLUSIONS: These results demonstrate a survival benefit with the addition of LRTx to sorafenib for patients with advanced HCC. These findings should prompt a prospective clinical trial to further assess the role of LRTx in patients with advanced HCC.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with liver involvement.

BACKGROUND: We examined outcomes of patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) combined with liver resection. METHODS: All patients undergoing CRS/HIPEC between 2007 and 2014 were retrospectively reviewed: patients who underwent synchronous liver resection (group 1) were compared with those who did not (group 2) in terms of perioperative and long-term results. RESULTS: Group 1 included 103 patients with colorectal cancer (CRC, n = 28), appendiceal cancer (n = 34), and other malignancies. Compared with group 2 (n = 166), group 1 had higher number of organs resected, increased intraoperative blood loss, and longer hospital stay (all P ≤ 0.004) but similar major morbidity (24.3% vs. 18.1%, P = 0.22) and perioperative mortality rates. Two patients from group 1 developed liver resection-related complications. A comparison between patients who underwent parenchymal liver resection (n = 42) and matched pairs from group 2 with similar extent of cytoreduction did not yield significant differences in morbidity/mortality. CRC patients from group 1 had poorer median overall survival (45.1 vs. 73.5 months from stage IV diagnosis, P = 0.009). CONCLUSIONS: Liver involvement denotes high peritoneal carcinomatosis burden, which often requires resection of multiple organs in order to achieve optimal cytoreduction. However, liver resection-related morbidity is low and overall morbidity/mortality rates are comparable to other extensive CRS/HIPEC procedures. J. Surg. Oncol. 2016;113:432-437. © 2016 Wiley Periodicals, Inc.

Extreme cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: Outcomes from a single tertiary center.

BACKGROUND: Multivisceral resection as part of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) may be required in order to achieve optimal debulking. This study aimed to assess perioperative and long-term outcomes of the most extensive CRS/HIPEC procedures. METHODS: All patients who underwent CRS/HIPEC at our institution between March 2007 and July 2014 were retrospectively reviewed. Patients undergoing extreme cytoreduction (n = 50), defined as a resection of ≥5 organs or ≥3 bowel anastomoses, were compared with patients who underwent less extensive procedures (n = 219). RESULTS: Complete cytoreduction (CC score ≤1) was achieved in 76% of the extreme CRS/HIPEC group, which included patients with colorectal cancer (CRC, n = 17), appendiceal adenocarcinoma (n = 20), gastric cancer (n = 6), and low-grade appendiceal neoplasm (n = 3). When compared with other patients undergoing CRS/HIPEC, the extreme CRS/HIPEC group had higher median PCI score, increased intraoperative blood loss, longer duration of surgery and longer hospital stay (all p values < 0.001). Major 30-day morbidity was significantly higher among the extreme CRS/HIPEC group (34% vs. 17.4%, p = 0.008) and there was also a trend towards higher 90-day mortality (12% vs. 5.1%, p = 0.07). Median disease free survival and overall survival in CRC patients undergoing extreme CRS/HIPEC was poorer (4.1 vs. 14.3 months, p = 0.01 and 10.1 vs. 43.8 months, p < 0.001, respectively). Extreme CRS/HIPEC was found to independently predict decreased overall survival in CRC patients. CONCLUSIONS: Extreme multivisceral resection as part of CRS/HIPEC is associated with higher major morbidity and inferior oncologic outcomes; therefore CRS/HIPEC provides the best outcomes in patients with fewer organs involved.