Recurrence patterns and prognostic factors in patients with hepatocellular carcinoma in noncirrhotic liver: a multi-institutional analysis.

BACKGROUND: Hepatocellular carcinoma (HCC) primarily affects patients with a cirrhotic liver. Reports on the characteristics of patients with HCC in noncirrhotic liver, as well as predictors of recurrence and survival, are scarce. METHODS: Between 1992 and 2011, 334 patients treated for HCC in noncirrhotic liver were identified from three major hepatobiliary centers. Clinicopathological characteristics were analyzed and independent predictors of recurrence and overall survival were identified using Cox proportional hazards models. RESULTS: Median patient age was 58 years and 77 % were male. Most patients had a solitary (81 %) and poorly or undifferentiated tumor (56 %); median size was 6.5 cm. The majority of patients (96 %) underwent liver resection (microscopically negative margins in 94 %), whereas a few had transarterial chemoembolization or transplantation (4 %). Median recurrence-free survival (RFS) was 2.5 years, and 1- and 5-year RFS was 71.1, and 35 %, respectively. Elevated alkaline phosphatase levels [hazards ratio (HR) = 1.82], poor tumor differentiation (HR = 1.4), macrovascular invasion (HR = 2.18), and the presence of satellite lesions (HR = 1.9), or intrahepatic metastases (HR = 2.59) were independently associated with shorter RFS; in contrast, an intact tumor capsule independently prolonged RFS (HR = 0.46). Median overall survival was 5.9 years, and 1- and 5-year overall survival was 86.9, and 54.5 %, respectively. Tumor size ≥5 cm (HR = 2.27), macrovascular (HR = 2.72) or adjacent organ invasion (HR = 3.34), and satellite lesions (HR = 2.18) were independently associated with shorter overall survival, whereas an intact tumor capsule showed a protective effect (HR = 0.51). CONCLUSIONS: Following resection of HCC in the setting of no cirrhosis, more than one-half of patients were alive after 5 years. However, even among patients with no cirrhosis, recurrence was common. Factors associated with RFS and overall survival included tumor characteristics, such as tumor capsule, satellite lesions, and vascular invasion.

Phase I study of intra-osseous co-transplantation of a single-unit cord blood and mesenchymal stromal cells with reduced intensity conditioning regimens.

Cord blood (CB) is a valuable graft source for patients undergoing allogeneic hematopoietic cell transplant (HCT) who lack human leukocyte antigen (HLA)-matched donors. However, single-unit CB-HCT is limited by the insufficient cell dose and slow engraftment. To overcome these limitations, we combined a single-unit CB with third-party healthy donors' bone marrow (BM) derived mesenchymal stromal cells (MSCs) to improve engraftment and injected intra-osseously (IO) to enhance homing. In this phase I clinical trial, six patients with high-risk hematologic malignancies were enrolled and received allogeneic HCT using reduced intensity conditioning regimens. The primary objective was to determine the engraftment rate at day 42. The median age of enrolled patients was 68 years, and only one patient was in complete remission at the time of HCT. The median CB total nucleated cell dose was 3.2x107/kg. No serious adverse events were reported. Two patients had early deaths due to persistent disease and multi-drug resistant bacterial infection, respectively. Of the remaining four evaluable patients, all had successful neutrophil engraftment in a median of 17.5 days. No grade 3 or higher acute graft-versus-host disease (GvHD) was observed, and only one patient developed moderate-extensive chronic GvHD. In conclusion, IO co-transplantation of a single-unit CB and MSCs was feasible and resulted in a reasonable engraftment rate in these very high-risk patients.

Diffuse infiltrative hepatocellular carcinoma: assessment of presentation, treatment, and outcomes.

BACKGROUND: Data on infiltrating hepatocellular carcinoma (HCC) are limited. We sought to define treatment and outcome of patients treated with infiltrating HCC compared with patients who had advanced multifocal HCC. METHODS: Between January 2000 and July 2011, a total of 147 patients with advanced HCC were identified from the Johns Hopkins Hospital database (infiltrative, n = 75; multifocal, n = 72). Clinicopathologic data were compared by HCC subtype. RESULTS: Patients with infiltrating HCC had higher alfa-fetoprotein levels (median infiltrative, 326.5 ng/mL vs. multifocal, 27.0 ng/mL) and larger tumors (median size, infiltrating, 9.2 cm vs. multifocal, 5.5 cm) (P < 0.05). Imaging failed to reveal a discrete lesion in 42.7 % of patients with infiltrating HCC. Most infiltrating HCC lesions presented as hypointense on T1-weighted images (55.7 %) and hyperintense on T2-weighted images (80.3 %). Among patients with infiltrating HCC, most (64.0 %) were treated with intra-arterial therapy (IAT), and periprocedural morality was 2.7 %. Patients treated with IAT had longer survival versus patients receiving best support care (median survival, IAT, 12 months vs. best supportive care, 3 months; P = 0.001). Survival after IAT was similar among patients treated with infiltrating HCC versus multifocal HCC (hazard ratio 1.29, 95 % confidence interval 0.82-2.03; P = 0.27). Among infiltrating HCC patients, pretreatment bilirubin >2 mg/dL and alfa-fetoprotein >400 ng/mL were associated with worse survival after IAT (P < 0.05). Patients with progressive disease after IAT had higher risk of death versus patients who had stable/responsive disease (hazard ratio 3.53, 95 % confidence interval 1.49-8.37; P = 0.004). CONCLUSIONS: Patients with infiltrative HCC often present without a discrete lesion on imaging. IAT for infiltrative HCC was safe and was associated with survival comparable to IAT outcomes for patients with multifocal HCC. Infiltrative HCC morphology is not a contraindication to IAT therapy in select patients.

Management and recurrence patterns of desmoids tumors: a multi-institutional analysis of 211 patients.

BACKGROUND: Desmoid tumors are rare soft-tissue neoplasms with limited data on their management. We sought to determine the rates of recurrence following surgery for desmoid tumors and identify factors predictive of disease-free survival. METHODS: Between January 1983 and December 2011, 211 patients with desmoid tumors were identified from three major surgical centers. Clinicopathologic and treatment characteristics were analyzed to identify predictors of recurrence. RESULTS: Median age was 36 years; patients were predominantly female (68 %). Desmoid tumors most commonly arose in extremities (32 %), abdominal cavity (23 %) or wall (21 %), and thorax (15 %); median size was 7.5 cm. Most patients had an R0 surgical margin (60 %). The 1- and 5-year recurrence-free survival was 81.3 and 52.8 %, respectively. Factors associated with worse recurrence-free survival were: younger age (for each 5-year increase in age, hazard ratio [HR] = 0.90, 95 % confidence interval [95 % CI] 0.82-0.98) and extra-abdominal tumor location (abdominal wall referent: extra-abdominal site, HR = 3.28, 95 % CI, 1.46-7.36) (both P < 0.05). CONCLUSIONS: Recurrence remains a problem following resection of desmoid tumors with as many as 50 % of patients experiencing a recurrence within 5 years. Factors associated with recurrence included age, tumor location, and margin status. While surgical resection remains central to the management of patients with desmoid tumors, the high rate of recurrence highlights the need for more effective adjuvant therapies.

Socioeconomic Factors and Survival of Multiple Myeloma Patients.

BACKGROUND: Outcome of Multiple Myeloma (MM) patients has improved as the result of the introduction of novel medications and use of autologous hematopoietic cell transplantation. However, this improvement comes at the expense of increased financial burden. It is largely unknown if socioeconomic factors influence MM survival. METHODS: We used the National Cancer Database, a database that houses data on 70% of cancer patients in the US, to evaluate the effect of socioeconomic factors on the survival of 117,926 MM patients diagnosed between 2005 and 2014. RESULTS: Patients aged ≥65 years who were privately insured lived longer than patients with Medicare (42 months vs. 31 months, respectively, p < 0.0001). Treatment in academic institutions led to better survival (HR: 1.49, 95% CI: 1.39, 1.59). Younger age, fewer comorbidities, treatment in academic centers, and living in a higher median income area were significantly associated with improved survival. After adjusting for confounders, survival of Medicare patients was similar to those with private insurance. However, the hazard of death remained higher for patients with Medicaid (HR: 1.59, 95% CI: 1.36, 1.87) or without insurance (HR: 1.62, 95% CI: 1.32, 1.99), compared to privately insured patients. CONCLUSION: Economic factors and treatment facility type play an important role in the survival of MM patients.

A risk model to predict 90-day mortality among patients undergoing hepatic resection.

BACKGROUND: Reliable criteria to predict mortality after hepatectomy remain poorly defined. We sought to identify factors associated with 90-day mortality, as well as validate the "50-50" and peak bilirubin of >7 mg/dL prediction rules for mortality after liver resection. In addition, we propose a novel integer-based score for 90-day mortality using a large cohort of patients. STUDY DESIGN: Data from 2,056 patients who underwent liver resection at 2 major hepatobiliary centers between 1990 and 2011 were identified. Perioperative laboratory data, as well as surgical and postoperative details, were analyzed to identify factors associated with liver-related 90-day death. RESULTS: Indications for liver resection included colorectal metastasis (39%), hepatocellular carcinoma (19%), benign mass (17%), or noncolorectal metastasis (14%). Most patients had normal underlying liver parenchyma (71%) and resection involved ≥3 segments (36%). Overall morbidity and mortality were 19% and 2%, respectively. Only 1 patient fulfilled the 50-50 criteria; this patient survived and was discharged on day 8. Twenty patients had a peak bilirubin concentration >7 mg/dL and 5 died within 90 days; the sensitivity and specificity of the >7-mg/dL rule were 25% and 99.3%, respectively, but overall accuracy was poor (area under the curve 0.574). Factors associated with 90-day mortality included international normalized ratio (odds ratio = 11.87), bilirubin (odds ratio = 1.16), and serum creatinine (odds ratio = 1.87) on postoperative day 3, as well as grade of postoperative complications (odds ratio = 5.08; all p < 0.05). Integer values were assigned to each factor to develop a model that predicted 90-day mortality (area under the curve 0.89). A score of ≥11 points had a sensitivity and specificity of 83.3% and 98.8%, respectively. CONCLUSIONS: The 50-50 and bilirubin >7-mg/dL rules were not accurate in predicting 90-day mortality. Rather, a composite integer-based risk score based on postoperative day 3 international normalized ratio, bilirubin, creatinine, and complication grade more accurately predicted 90-day mortality after hepatectomy.

Cadmium exposure and liver disease among US adults.

BACKGROUND: Effects of chronic cadmium exposure on liver disease and liver-related mortality are unknown. We evaluated the association of creatinine-corrected urinary cadmium levels with hepatic necroinflammation, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver-related mortality, and liver cancer mortality in the US general population. METHODS: We analyzed the relationship of individuals in the top quartile for urinary cadmium measured in 12,732 adults who participated in the Third National Health and Nutrition Examination Survey in 1988-1994 (NHANES III), and hepatic necroinflammation, NAFLD, and NASH. Associations between cadmium, liver-related mortality, and liver cancer mortality were evaluated in the NHANES III mortality follow-up study. RESULTS: The cutoffs for highest quartile of urinary cadmium per gram of urinary creatinine were 0.65 and 0.83 µg/g for men and women, respectively (P < 0.001). After multivariate adjustment for other factors including smoking, the odds ratios [95 % confidence intervals (CI)] for hepatic necroinflammation, NAFLD, and NASH associated with being in the top quartile of cadmium levels by gender, were 2.21 (95 % CI, 1.64-3.00), 1.30 (95 % CI, 1.01-1.68) and 1.95 (95 % CI, 1.11-3.41) for men and 1.26 (95 % CI, 1.01-1.57), 1.11 (95 % CI, 0.88-1.41) and 1.34 (95 % CI, 0.72-2.50) for women, respectively. The hazard ratios for liver-related mortality and liver cancer mortality for both genders were 3.42 (95 % CI, 1.12-10.47) and 1.25 (95 % CI, 0.37-4.27). CONCLUSIONS: Environmental cadmium exposure was associated with hepatic necroinflammation, NAFLD, and NASH in men, and hepatic necroinflammation in women. Individuals in the top quartile of creatinine-corrected urinary cadmium had over a threefold increased risk of liver disease mortality but not in liver cancer related mortality.

Impact of sarcopenia on outcomes following intra-arterial therapy of hepatic malignancies.

BACKGROUND: Assessment of patient performance status is often subjective. Sarcopenia--measurement of muscle wasting--may be a more objective means to assess performance status and therefore mortality risk following intra-arterial therapy (IAT). METHODS: Total psoas area (TPA) was measured on cross-sectional imaging in 216 patients undergoing IAT of hepatic malignancies between 2002 and 2012. Sarcopenia was defined as TPA in the lowest sex-specific quartile. Impact of sarcopenia was assessed relative to other clinicopathological factors. RESULTS: Indications for IAT included hepatocellular carcinoma (51 %), intrahepatic cholangiocarcinoma (13 %), colorectal liver metastasis (7 %), or other metastatic disease (30 %). Median TPA among men (568 mm(2)/m(2)) was greater than women (413 mm(2)/m(2)). IAT involved conventional chemoembolization (54 %), drug-eluting beads (40 %), or yttrium-90 (6 %). Median tumor size was 5.8 cm; most patients had multiple lesions (74 %). Ninety-day mortality was 9.3 %; 3-year survival was 39 %. Factors associated with risk of death were tumor size (HR = 1.84) and Child's score (HR = 2.15) (all P < 0.05). On multivariate analysis, sarcopenia remained independently associated with increased risk of death (lowest vs. highest TPA quartile, HR = 1.84; P = 0.04). Sarcopenic patients had a 3-year survival of 28 vs. 44 % for non-sarcopenic patients. CONCLUSIONS: Sarcopenia was an independent predictor of mortality following IAT with sarcopenic patients having a twofold increased risk of death. Sarcopenia is an objective measure of frailty that can help clinical decision-making regarding IAT for hepatic malignancies.

Impact of sarcopenia on outcomes following resection of pancreatic adenocarcinoma.

INTRODUCTION: Assessing patient-specific risk factors for long-term mortality following resection of pancreatic adenocarcinoma can be difficult. Sarcopenia--the measurement of muscle wasting--may be a more objective and comprehensive patient-specific factor associated with long-term survival. METHODS: Total psoas area (TPA) was measured on preoperative cross-sectional imaging in 557 patients undergoing resection of pancreatic adenocarcinoma between 1996 and 2010. Sarcopenia was defined as the presence of a TPA in the lowest sex-specific quartile. The impact of sarcopenia on 90-day, 1-year, and 3-year mortality was assessed relative to other clinicopathological factors. RESULTS: Mean patient age was 65.7 years and 53.1 % was male. Mean TPA among men (611 mm²/m²) was greater than among women (454 mm²/m²). Surgery involved pancreaticoduodenectomy (86.0 %) or distal pancreatectomy (14.0 %). Mean tumor size was 3.4 cm; 49.9 % and 88.5 % of patients had vascular and perineural invasion, respectively. Margin status was R0 (59.0 %) and 77.7 % patients had lymph node metastasis. Overall 90-day mortality was 3.1 % and overall 1- and 3-year survival was 67.9 % and 35.7 %, respectively. Sarcopenia was associated with increased risk of 3-year mortality (HR = 1.68; P < 0.001). Tumor-specific factors such as poor differentiation on histology (HR = 1.75), margin status (HR = 1.66), and lymph node metastasis (HR = 2.06) were associated with risk of death at 3-years (all P < 0.001). After controlling for these factors, sarcopenia remained independently associated with an increased risk of death at 3 years (HR = 1.63; P < 0.001). CONCLUSIONS: Sarcopenia was a predictor of survival following pancreatic surgery, with sarcopenic patients having a 63 % increased risk of death at 3 years. Sarcopenia was an objective measure of patient frailty that was strongly associated with long-term outcome independent of tumor-specific factors.