Prediction of Mortality After ALPPS Stage-1: An Analysis of 320 Patients From the International ALPPS Registry.

OBJECTIVES: The aim of this study was to identify predictors of 90-day mortality after Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS), available after stage-1, either to omit or delay stage-2. BACKGROUND DATA: ALPPS is a two-stage hepatectomy for patients with extensive liver tumors with predicted small liver remnants, which has been criticized for its high mortality rate. Risk factors for mortality are unknown. METHODS: Patients in the International Registry undergoing ALPPS from April 2011 to July 2014 were analyzed. Primary outcome was 90-day mortality. Liver function after stage-1 was assessed using the criteria of the International Study Group for Liver Surgery (ISGLS) after stage-1 among others. A multivariable model was used to identify independent predictors of 90-day mortality. RESULTS: Three hundred twenty patients registered by 55 centers worldwide were evaluated. Overall 90-day mortality was 8.8% (28/320). The predominant cause for 90-day mortality was postoperative liver failure in 75% of patients. Fourteen percent of patients developed liver failure according to ISGLS criteria already after stage-1 ALPPS. Those and patients with a model of end-stage liver disease (MELD) score more than 10 before stage-2 were at significantly higher risk for 90-day mortality after stage-2 with an odds ratio (OR) 3.9 [confidence interval (CI) 1.4-10.9, P = 0.01] and OR 4.9 (CI 1.9-12.7, P = 0.006), respectively. Other factors, such as size of future liver remnant (FLR) before stage-2 and time between stages, were not predictive. CONCLUSIONS: This analysis of the largest cohort of ALPPS patients so far identifies those patients in whom stage-2 ALPPS surgery should be delayed or even denied. These findings may help to make ALPPS safer.

PREDICTORS OF INFLAMMATORY LOCAL RECURRENCE AFTER BREAST-CONSERVING THERAPY FOR BREAST CANCER: MATCHED CASE-CONTROL STUDY.

BACKGROUND: Inflammatory local recurrence (ILR) after breast-conserving surgery for noninflammatory breast cancer (BC) is associated with dismal prognosis. Risk factors for ILR are not well defined. METHODS: Between 2001 and 2010, twelve patients at our hospital developed ILR after breast-conserving surgery, adjuvant chemotherapy, and radiotherapy for BC. We compared their clinico-pathological characteristics to those of 24 patients with noninflammatory local recurrence (non-ILR), 24 patients with distant metastases, and 48 disease-free controls, matched for age and observation period. RESULTS: The median time to ILR was 10 months. In univariate analysis, extent of lymph node involvement (p < 0.05), multifocality (p < 0.05), c-erbB2 overexpression (p < 0.05), and lymphovascular invasion (LVI) (p < 0.001) affected the risk of ILR. Conditional logistic regression analysis showed a significant association between ILR and combined LVI and high histopathological grade. The odds ratio (OR) for ILR versus non-ILR was 6.14 (95% confidence interval [CI] 1.48-25.38) and for ILR versus distant metastases it was 3.05 (95% CI 0.09-97.83) when both LVI and high histopathological grade were present. Patients with family history of BC were more likely to present with ILR than non-ILR (OR 5.47; 95% CI 1.55-19.31) or distant relapse (OR 5.62; 95% CI 0.26-119.95). CONCLUSIONS: Pre- and postmenopausal women with high-grade BC and LVI are at increased risk to develop ILR, especially in the presence of family history of BC. Identification of risk factors for this lethal form of recurrent BC may lead to more effective preventive treatment strategies in properly selected patients.

Proliferation and differentiation of human adipose-derived mesenchymal stem cells (ASCs) into osteoblastic lineage are passage dependent.

OBJECTIVE: The effect of in vitro expansion of human adipose-derived stem cells (ASCs) on stem cell properties is controversial. We examined serial subcultivation with expansion on the ability of ASCs to grow and differentiate into osteoblastic lineages. DESIGN: Flow cytometric analysis, growth kinetics, cell population doubling time, light microscopy and confocal analysis, and osteogenesis induction were performed to assess growth and osteogenic potential of subcultivated ASCs at passages 2 (P2), P4 and P6. RESULTS: Flow cytometric analysis revealed that ASCs at P2 express classical mesenchymal stem cell markers including CD44, CD73, and CD105, but not CD14, CD19, CD34, CD45, or HLA-DR. Calcium deposition and alkaline phosphatase activity were the highest at P2 but completely abrogated at P4. Increased passage number impaired cell growth; P2 cultures exhibited exponential growth, while cells at P4 and P6 showed near linear growth with cell population doubling times increased from 3.2 at P2 to 4.8 d at P6. Morphologically, cells in various subcultivation stages showed flattened shape at low density but spindle-like structures at confluency as judged by phalloidin staining. CONCLUSIONS: Osteogenic potential of ASCs is impaired by successive passaging and may not serve as a useful clinical source of osteogenic ASCs past P2.

Residual tumor thickness at the tumor-normal tissue interface predicts the recurrence-free survival in patients with liver metastasis of breast cancer.

Tumor response to neoadjuvant therapy is a significant predictive indicator of recurrence-free survival. We measured tumor response using residual tumor thickness at the tumor-normal tissue interface (TNI) and evaluated its association with outcome in patients with liver metastasis of breast cancer. We included 48 patients who underwent neoadjuvant therapy followed by partial liver resection at MD Anderson Cancer Center between 1997 and 2010. The hematoxylin-eosin-stained tumor sections were evaluated for both pathologic response and the residual tumor thickness at the TNI by 3 pathologists who were blinded to the clinical information, treatment regimen, and patient outcome. The residual tumor thickness at the TNI was correlated with recurrence-free survival using Kaplan-Meier method and log-rank test. Cox proportional hazard model was used to identify predictors of recurrence-free survival. All patients were women with a median age of 43 years. The median duration of follow-up was 52.1 months. Residual tumor thickness less than or equal to 3 mm at the TNI correlated with major pathologic response and was associated with longer recurrence-free survival in both univariate and multivariate analyses. Residual tumor thickness at the TNI predicts recurrence-free survival and provides an objective outcome end point in patients who underwent neoadjuvant therapy and liver resection of metastatic breast cancer. We suggest using both the pathologic response and the residual tumor thickness at the TNI to measure tumor response to therapy to improve accuracy.

Treatment sequencing strategy for hepatic epithelioid haemangioendothelioma.

BACKGROUND: The biology of hepatic epithelial haemangioendothelioma (HEHE) is variable, lying intermediate to haemangioma and angiosarcoma. Treatments vary owing to the rarity of the disease and frequent misdiagnosis. METHODS: Between 1989 and 2013, patients retrospectively identified with HEHE from a single academic cancer centre were analysed to evaluate clinicopathological factors and initial treatment regimens associated with survival. RESULTS: Fifty patients with confirmed HEHE had a median follow-up of 51 months (range 1-322). There was no difference in 5-year survival between patients presenting with unilateral compared with bilateral hepatic disease (51.4% versus 80.7%, respectively; P = 0.1), localized compared with metastatic disease (69% versus 78.3%, respectively; P = 0.7) or an initial treatment regimen of Surgery, Chemotherapy/Embolization or Observation alone (83.3% versus 71.3% versus 72.4%, respectively; P = 0.9). However, 5-year survival for patients treated with chemotherapy at any point during their disease course was decreased compared with those who did not receive any chemotherapy (43.6% versus 82.9%, respectively; P = 0.02) and was predictive of a decreased overall survival on univariate analysis [HR 3.1 (CI 0.9-10.7), P = 0.02]. CONCLUSIONS: HEHE frequently follows an indolent course, suggesting that immediate treatment may not be the optimal strategy. Initial observation to assess disease behaviour may better stratify treatment options, reserving surgery for those who remain resectable/transplantable. Prospective cooperative trials or registries may confirm this strategy.

Margin status remains an important determinant of survival after surgical resection of colorectal liver metastases in the era of modern chemotherapy.

OBJECTIVE: To determine the impact of surgical margin status on overall survival (OS) of patients undergoing hepatectomy for colorectal liver metastases after modern preoperative chemotherapy. BACKGROUND: In the era of effective chemotherapy for colorectal liver metastases, the association between surgical margin status and survival has become controversial. METHODS: Clinicopathologic data and outcomes for 378 patients treated with modern preoperative chemotherapy and hepatectomy were analyzed. The effect of positive margins on OS was analyzed in relation to pathologic and computed tomography-based morphologic response to chemotherapy. RESULTS: Fifty-two of 378 resections (14%) were R1 resections (tumor-free margin <1 mm). The 5-year OS rates for patients with R0 resection (margin ≥1 mm) and R1 resection were 55% and 26%, respectively (P = 0.017). Multivariate analysis identified R1 resection (P = 0.03) and a minor pathologic response to chemotherapy (P = 0.002) as the 2 factors independently associated with worse survival. The survival benefit associated with negative margins (R0 vs R1 resection) was greater in patients with suboptimal morphologic response (5-year OS rate: 62% vs 11%; P = 0.007) than in patients with optimal response (3-year OS rate: 92% vs 88%; P = 0.917) and greater in patients with a minor pathologic response (5-year OS rate: 46% vs 0%; P = 0.002) than in patients with a major response (5-year OS rate: 63% vs 67%; P = 0.587). CONCLUSIONS: In the era of modern chemotherapy, negative margins remain an important determinant of survival and should be the primary goal of surgical therapy. The impact of positive margins is most pronounced in patients with suboptimal response to systemic therapy.

Morbidity of staged proctectomy after hepatectomy for colorectal cancer: a matched case-control analysis.

BACKGROUND: Proctectomy after hepatectomy, or the reverse approach, is an alternative to traditional sequencing for advanced liver metastases with asymptomatic colorectal primary tumors. We sought to evaluate the surgical morbidity of proctectomy for colorectal cancer after previous liver surgery. METHODS: A single-institution colorectal database was queried for patients treated with proctectomy after previous hepatectomy from 2003 to 2011. Reverse-approach patients (n = 31) were matched 1:2 with a cohort of standard proctectomy patients (n = 62) using operation, age, gender, and surgeon. Perioperative factors were analyzed by univariate/multivariate models for associations with complications graded by Dindo-Clavien criteria. RESULTS: Thirty-one patients with adenocarcinoma ≤ 20 cm from the anal verge underwent proctectomy after hepatectomy. Median time from hepatectomy to proctectomy was 5.1 months. Median tumor distance was 8.5 cm. Before proctectomy, patients underwent 28 (90 %) major hepatectomies and 7 (22 %) portal vein embolizations. There were no perioperative deaths. Reverse-approach patients did not differ from control patients in operation, demographics, body mass index (BMI), comorbidities, tumor distance, operative time, estimated blood loss, length of stay, or complication rates (p > 0.05). Grade 2 or higher complications developed in 42 % of reverse-approach and 27 % of standard proctectomies (p = 0.17). Grade 3 or higher complications developed in 10 % and 8 %, respectively (p = 1.00). Independent predictors of complications of grade 2 or higher were BMI ≥30 kg/m(2) (p = 0.007), operative time ≥300 min (p = 0.012), intraoperative transfusion (p = 0.044), concurrent procedures (p = 0.024), and age ≥50 years (p = 0.030). CONCLUSIONS: Risk factors for morbidity of staged proctectomy are similar to those for standard proctectomy. In selected patients, the reverse-approach proctectomy is safe with acceptable morbidity.

Resection of at-risk mesenteric lymph nodes is associated with improved survival in patients with small bowel neuroendocrine tumors.

BACKGROUND: Neuroendocrine tumors of the small intestine commonly metastasize to regional lymph nodes (LNs). Single-institution reports suggest that removal of LNs improves outcome, but comprehensive data are lacking. We hypothesized that the extent of lymphadenectomy reported in a large administrative database would be associated with overall survival for jejunal and ileal neuroendocrine tumors. METHODS: A search of the Surveillance Epidemiology and End Results database was performed for patients with jejunal and ileal neuroendocrine tumors from 1977 to 2004. Descriptive patient characteristics were collected to include age at diagnosis, sex, race, grade, primary tumor size, LN status, number of LNs resected, presence of distant metastasis, and the type of operation. Statistical analyses were limited to patients with only one primary tumor to exclude patients with other malignancies. Univariate and multivariate analyses were performed to analyze the number of LNs resected and the LN ratio (number of positive LNs/total number of LNs removed) to determine the effect on cancer-specific survival. RESULTS: Altogether, 1,364 patients were included in this analysis. Removal of any LNs was associated with improved cancer-specific survival when compared to patients with no LN removal reported (p = 0.0027) on univariate analysis. Among those who had any LNs removed, a median of eight LNs were identified in resection specimens with a median LN ratio of 0.29 (range 0-1). On multivariate analysis (adjusting for age and tumor size), patients with >7 LNs removed experienced better cancer-specific survival than those with ≤ 7 LNs removed (median survival not reached vs. 140 months): hazard ratio and 95 % confidence interval were 0.573 (0.402, 0.817) (p = 0.002). CONCLUSIONS: This review of a large number of surgical patients demonstrates that regional mesenteric lymphadenectomy in conjunction with resection of the primary tumor is associated with improved survival of patients with small bowel neuroendocrine tumors.

Locoregional surgical and interventional therapies for advanced colorectal cancer liver metastases: expert consensus statements.

Selection of the optimal surgical and interventional therapies for advanced colorectal cancer liver metastases (CRLM) requires multidisciplinary discussion of treatment strategies early in the trajectory of the individual patient's care. This paper reports on expert consensus on locoregional and interventional therapies for the treatment of advanced CRLM. Resection remains the reference treatment for patients with bilateral CRLM and synchronous presentation of primary and metastatic cancer. Patients with oligonodular bilateral CRLM may be candidates for one-stage multiple segmentectomies; two-stage resection with or without portal vein embolization may allow complete resection in patients with more advanced disease. After downsizing with preoperative systemic and/or regional therapy, curative-intent hepatectomy requires resection of all initial and currently known sites of disease; debulking procedures are not recommended. Many patients with synchronous primary disease and CRLM can safely undergo simultaneous resection of all disease. Staged resections should be considered for patients in whom the volume of the future liver remnant is anticipated to be marginal or inadequate, who have significant medical comorbid condition(s), or in whom extensive resections are required for the primary cancer and/or CRLM. Priority for liver-first or primary-first resection should depend on primary tumour-related symptoms or concern for the progression of marginally resectable CRLM during treatment of the primary disease. Chemotherapy delivered by hepatic arterial infusion represents a valid option in patients with liver-only disease, although it is best delivered in experienced centres. Ablation strategies are not recommended as first-line treatments for resectable CRLM alone or in combination with resection because of high local failure rates and limitations related to tumour size, multiplicity and intrahepatic location.

Post-therapy pathologic stage and survival in patients with pancreatic ductal adenocarcinoma treated with neoadjuvant chemoradiation.

BACKGROUND: Neoadjuvant chemoradiation before surgery is an emerging treatment modality for pancreatic ductal adenocarcinoma (PDAC). However, analysis of prognostic factors is limited for patients with PDAC treated with neoadjuvant chemoradiation and pancreaticoduodenectomy (PD). METHODS: The study population was comprised of 240 consecutive patients with PDAC who received neoadjuvant chemoradiation and PD and was compared with 60 patients who had no neoadjuvant therapy between 1999 and 2007. Clinicopathologic features were correlated with disease-free survival (DFS) and overall survival (OS). RESULTS: Among the 240 treated patients, the 1-year and 3-year DFS rates were 52% and 32%, with a median DFS of 15.1 months. The 1-year and 3-year OS rates were 95% and 47%, with a median OS of 33.5 months. By univariate analysis, DFS was associated with age, post-therapy tumor stage (ypT), lymph node status (ypN), number of positive lymph nodes, and American Joint Committee on Cancer (AJCC) stage, whereas OS was associated with intraoperative blood loss, margin status, ypT, ypN, number of positive lymph nodes, and AJCC stage. By multivariate analysis, DFS was independently associated with age, number of positive lymph nodes, and AJCC stage, and OS was independently associated with differentiation, margin status, number of positive lymph nodes, and AJCC stage. In addition, the treated patients had better OS and lower frequency of lymph node metastasis than those who had no neoadjuvant therapy. CONCLUSIONS: In patients with PDAC who received neoadjuvant chemoradiation and subsequent PD, post-therapy pathologic AJCC stage and number of positive lymph nodes are independent prognostic factors.

Identification of cancer stem cells in human gastrointestinal carcinoid and neuroendocrine tumors.

BACKGROUND & AIMS: Metastatic gastrointestinal neuroendocrine tumors (NETs) frequently are refractory to chemotherapy. Chemoresistance in various malignancies has been attributed to cancer stem cells (CSCs). We sought to identify gastrointestinal neuroendocrine CSCs (N-CSCs) in surgical specimens and a NET cell line and to characterize novel N-CSC therapeutic targets. METHODS: Human gastrointestinal NETs were evaluated for CSCs using the Aldefluor (Stemcell Technologies, Vancouver, Canada) assay. An in vitro, sphere-forming assay was performed on primary NET cells. CNDT2.5, a human midgut carcinoid cell line, was used for in vitro (sphere-formation) and in vivo (tumorigenicity assays) CSC studies. N-CSC protein expression was characterized using Western blotting. In vivo, systemic short interfering RNA administration targeted Src. RESULTS: By using the Aldefluor assay, aldehyde dehydrogenase-positive (ALDH+) cells comprised 5.8% ± 1.4% (mean ± standard error of the mean) of cells from 19 patient samples. Although many primary cell lines failed to grow, CNDT96 ALDH+ cells formed spheres in anchorage-independent conditions, whereas ALDH- cells did not. CNDT2.5 ALDH+ cells formed spheres, whereas ALDH- cells did not. In vivo, ALDH+ CNDT2.5 cells generated more tumors, with shorter latency than ALDH- or sham-sorted cells. Compared with non-CSCs, ALDH+ cells demonstrated increased expression of activated Src, Erk, Akt, and mammalian target of rapamycin (mTOR). In vivo, anti-Src short interfering RNA treatment of ALDH+ tumors reduced tumor mass by 91%. CONCLUSIONS: CSCs are present in NETs, as shown by in vitro sphere formation and in vivo tumorigenicity assays. Src was activated in N-CSCs and represents a potential therapeutic target in gastrointestinal NETs.

Defined clinical classifications are associated with outcome of patients with anatomically resectable pancreatic adenocarcinoma treated with neoadjuvant therapy.

BACKGROUND: We previously introduced a classification system for patients with localized pancreatic adenocarcinoma that integrates assessments of tumor anatomy, cancer biology, and patient physiology. By means of this system, we sought to analyze outcomes of patients with resectable anatomy but heterogeneous biology and physiology who were treated with neoadjuvant therapy. METHODS: We evaluated consecutive patients (2002-2007) with anatomically potentially resectable cancers treated with chemotherapy or chemoradiation before potential pancreatectomy. We compared clinical factors and outcomes of patients classified as having disease that was clinically resectable (CR; no extrapancreatic disease, preserved performance status); suspicion for extrapancreatic disease (BR-B); or marginal performance status or significant comorbidity (BR-C). Patients with borderline resectable anatomy (BR-A) were excluded. RESULTS: Resection rates for 138 CR, 41 BR-B, and 38 BR-C patients were 75, 46, and 37%, respectively (P < 0.001). Metastases, detected during treatment in 23% of patients, were the most common contraindication to resection among CR (15%) and BR-B (46%) patients. Performance status rarely precluded surgery except among BR-C (32%) patients. Factors associated with selection against surgery were older age, poor performance status, pain, and therapeutic complications (P < 0.05). The median overall survival of all patients was 21 months. Resected and unresected BR-B and BR-C patients had median overall survival durations similar to those of resected and unresected CR patients, respectively (P > 0.22). CONCLUSIONS: This system describes discrete clinical subgroups of patients with pancreatic cancer who have similar, potentially resectable tumor anatomy but heterogeneous physiology and cancer biology. It may be used with neoadjuvant therapy to predict outcomes, individualize treatment algorithms, and optimize survival.

Risk of venous thromboembolism outweighs post-hepatectomy bleeding complications: analysis of 5651 National Surgical Quality Improvement Program patients.

BACKGROUND: Historically, liver surgeons have withheld venous thromboembolism (VTE) chemoprophylaxis due to perceived postoperative bleeding risk and theorized protective anticoagulation effects of a hepatectomy. The relationships between extent of hepatectomy, postoperative VTE and bleeding events were evaluated using the National Surgical Quality Improvement Program (NSQIP) database. METHODS: From 2005 to 2009, all elective open hepatectomies were identified. Factors associated with 30-day rates of VTE, postoperative transfusions and returns to the operating room (ROR), were analysed. RESULTS: The analysis included 5651 hepatectomies with 3376 (59.7%) partial, 585 (10.4%) left, 1134 (20.1%) right, and 556 (9.8%) extended. Complications included deep vein thrombosis (DVT) (1.93%), pulmonary embolism (PE) (1.31%), venous thromboembolism (VTE) (2.88%), postoperative transfusion (0.76%) and ROR with transfusion (0.44%). VTE increased with magnitude of hepatectomy (partial 2.13%, left 2.05%, right 4.15%, extended 5.76%; P < 0.001) and outnumbered bleeding events (P < 0.001). Other factors independently associated with VTE were aspartate aminotransferase (AST) ≥27 (P= 0.022), American Society of Anesthesiologists (ASA) class ≥3 (P < 0.001), operative time >222 min (P= 0.043), organ space infection (P < 0.001) and length of hospital stay ≥7 days (P= 0.004). VTE resulted in 30-day mortality of 7.4% vs. 2.3% with no VTE (P= 0.001). CONCLUSIONS: Contrary to the belief that transient postoperative liver insufficiency is protective, VTE increases with extent of hepatectomy. VTE exceeds major bleeding events and is strongly associated with mortality. These data support routine post-hepatectomy VTE chemoprophylaxis.

Study Protocol: Efficacy and Safety of Radioembolization (REM) as an Early Modality (EM) Therapy for Metastatic Breast Cancer (BR) to the Liver with Y90 (REMEMBR Y90).

PURPOSE: The primary objective of the REMEMBR Y90 study is to evaluate the efficacy of Yttrium-90 (Y90) radioembolization in patients with breast cancer metastases to the liver as a 2nd or 3rd line treatment option with systemic therapy by assessing liver-specific and overall progression-free survival. Secondary objectives include quality of life, overall survival benefit, and toxicity in relation to patients' tumor biology. MATERIALS AND METHODS: This trial is a multi-center, prospective, Phase 2, open-label, IRB-approved, randomized control trial in the final phases of activation. Eligible patients include those over 18 years of age with metastatic breast cancer to the liver with liver-only or liver-dominant disease, and history of tumor progression on 1-2 lines of chemotherapy. 60 patients will be randomized to radioembolization with chemotherapy versus chemotherapy alone. Permissible regimens include capecitabine, eribulin, vinorelbine, and gemcitabine within 2 weeks of enrollment for every patient. Patients receiving radioembolization will receive lobar or segmental treatment within 1-6 weeks of enrollment depending on their lesion. After final radioembolization, patients will receive clinical and imaging follow-up every 12-16 weeks for two years, including contrast-enhanced computed tomography or magnetic resonance imaging of the abdomen and whole-body positron emission tomography/computed tomography. DISCUSSION: This study seeks to elucidate the clinical benefit and toxicity of Y90 in patients with metastatic breast cancer to the liver who are receiving minimal chemotherapy. Given previous data, it is anticipated that the use of Y90 and chemotherapy earlier in the metastatic disease course would improve survival outcomes and reduce toxicity. LEVEL OF EVIDENCE: Level 1b, Randomized Controlled Trial. TRIAL REGISTRATION NUMBER: NCT05315687 on clinicaltrials.gov.

Is resection of colorectal liver metastases after a second-line chemotherapy regimen justified?

BACKGROUND: Patient outcomes following resection of colorectal liver metastases (CLM) after second-line chemotherapy regimen is unknown. METHODS: From August 1998 to June 2009, data from 1099 patients with CLM were collected prospectively. We retrospectively analyzed outcomes of patients who underwent resection of CLM after second-line (2 or more) chemotherapy regimens. RESULTS: Sixty patients underwent resection of CLM after 2 or more chemotherapy regimens. Patients had advanced CLM (mean number of CLM ± standard deviation, 4 ± 3.5; mean maximum size of CLM, 5 ± 3.2 cm) and had received 17 ± 8 cycles of preoperative chemotherapy. In 54 (90%) patients, the switch from the first regimen to another regimen was motivated by tumor progression or suboptimal radiographic response. All patients received irinotecan or oxaliplatin, and the majority (42/60 [70%]) received a monoclonal antibody (bevacizumab or cetuximab) as part of the last preoperative regimen. Postoperative morbidity and mortality rates were 33% and 3%, respectively. At a median follow-up of 32 months, 1-year, 3-year, and 5-year overall survival rates were 83%, 41%, and 22%, respectively. Median chemotherapy-free survival after resection or completion of additional chemotherapy administered after resection was 9 months (95% confidence interval, 4-14 months). Synchronous (vs metachronous) CLM and minor (vs major) pathologic response were independently associated with worse survival. CONCLUSIONS: Resection of CLM after a second-line chemotherapy regimen was found to be safe and was associated with a modest hope for definitive cure. This approach represents a viable option in patients with advanced CLM.

I-CLIP: improved stratification of advanced hepatocellular carcinoma patients by integrating plasma IGF-1 into CLIP score.

OBJECTIVE: Improving the prognostic stratification of unresectable hepatocellular carcinoma (HCC) patients is critically needed. Since patients' survival is closely linked to the severity of the underlying liver disease, and insulin-like growth factor-1 (IGF-1) is produced predominantly in the liver, we hypothesized that IGF-1 may correlate with patients' survival and hence improve the prognostic ability of the Cancer of the Liver Italian Program (CLIP) score. METHODS: Baseline plasma IGF-1 and clinicopathologic parameters were available from 288 patients. Multivariate Cox regression models, Kaplan-Meier curves, and the log-rank test were applied. Recursive partitioning was used to determine the optimal cut point for IGF-1 using training/validation samples. Prognostic ability of the I-CLIP (I = IGF) was compared to CLIP using C-index. RESULTS: IGF-1 significantly correlated with the clinicopathologic features. With an optimal IGF-1 cut point of 26 ng/ml, the overall survival of patients with IGF-1 >26 was 17.7 months (95% CI 13.6-22.8), and with IGF-1 ≤26 was 5.8 months (95% CI 4.0-12.5), p < 0.0001. The concordance probabilities for CLIP and I-CLIP were 0.7037 and 0.7096, respectively (p < 0.0001). CONCLUSIONS: Our preliminary results indicate that I-CLIP significantly improved prognostic stratification of patients with advanced HCC. However, independent validation of our study is warranted.

Radiation treatment outcomes for unresectable hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma is one of the most common cancers worldwide. Data regarding the use of radiotherapy is limited in patients from populations without endemic viral hepatitis. We examine the outcomes for patients treated with radiotherapy in the modern era at a single institution. MATERIAL AND METHODS: A total of 29 patients with localized hepatocellular carcinoma treated from 2000-2010 were reviewed. Patients with metastatic disease at the time of radiation were excluded. Median radiation dose was 50 Gy (range 30 to 75 Gy) with a median biologically effective dose of 80.6 (range 60 to 138.6). Median tumor size at the time of radiation was 5.2 cm (range 2 to 25 cm). RESULTS: Eighty three percent of all patients had either stable disease or a partial response to radiation, based on RECIST criteria. Median change in tumor size following radiation was -17% (range -73.5 to 177.8%). Estimated one-year overall survival and in-field progression-free survival rates for the study population were 56% and 79%, respectively. One-year overall survival in patients treated to a biologically effective dose <75 was significantly lower than in patients treated to a biologically effective dose ≥75 (18% vs. 69%). One-year in-field progression-free survival rate (60% vs. 88%) and biochemical progression-free survival duration (median 6.5 vs. 1.6 months) were also significantly improved in patients treated to a biologically effective dose ≥75. Grade 3 toxicity was seen in 13.8% of patients. DISCUSSION: In a population without endemic viral hepatitis, unresectable hepatocellular carcinoma demonstrates significant response to radiotherapy with minimal toxicity. Furthermore, our findings suggest that increased biologically effective dose is associated with improved survival and local tumor control.

Repeat hepatectomy for recurrent colorectal liver metastases is associated with a high survival rate.

BACKGROUND: The outcome after a repeat hepatectomy for recurrent colorectal liver metastases (CLM) is not well defined. The present study examined the morbidity, mortality and long-term survivals after a repeat hepatectomy for recurrent CLM. METHODS: Data on patients who underwent surgery for recurrent CLM between 1993 and 2009 were retrospectively evaluated. Patients who underwent radiofrequency ablation at the time of first treatment or at recurrence of CLM were excluded. RESULTS: Forty-three patients underwent a repeat hepatectomy for recurrent CLM. At the time of recurrence, patients had a median of 1 (1-3) lesions and the median tumour size was 2 (0.5-8.7) cm. The post-operative morbidity and mortality rates were 12% and 0%, respectively. After a median follow-up of 33 months from a repeat hepatectomy, 5-year overall and progression-free survival rates were 73% and 22%, respectively. Using multivariate analysis, the largest initial CLM ≥5 cm and positive surgical margins at initial resection were independently associated with a worse survival after surgery for recurrent CLM. Positive surgical margins at repeat hepatectomy were a predictive factor for an increased risk of further recurrence. DISCUSSION: A repeat hepatectomy for recurrent CLM was associated with excellent survival, low morbidity and no mortality. Surgeon-controlled variables, including margin-negative resection at first and repeat hepatectomy, contribute to good oncological outcome.

Association between hypothyroidism and hepatocellular carcinoma: a case-control study in the United States.

Thyroid hormones play an essential role in lipid mobilization, lipid degradation, and fatty acid oxidation. Hypothyroidism has been associated with nonalcoholic steatohepatitis; however, the association between thyroid diseases and hepatocellular carcinoma (HCC) in men and women has not been well established. We investigated the association between hypothyroidism and HCC risk in men and women in a case-control study, which included 420 eligible patients with HCC and 1104 healthy controls. We used multivariate unconditional logistic regression models to control for the confounding effects of established HCC risk factors. A long-term history of hypothyroidism (>10 years) was associated with a statistically significant high risk of HCC in women; after adjusting for demographic factors, diabetes, hepatitis, alcohol consumption, cigarette smoking, and family history of cancer, the odds ratio (OR) was 2.9 (95% confidence interval [CI], 1.3-6.3). Restricted analyses among hepatitis virus-negative subjects, nondrinkers, nondiabetics, nonsmokers, and nonobese individuals indicated a significant association between hypothyroidism and HCC, with an approximate two-fold to three-fold increased risk of HCC development. We observed risk modification among women with diabetes mellitus (OR = 9.4; 95% CI = 2.7-32.7) and chronic hepatitis virus infection (OR = 31.2; 95% CI = 6.3-153.2). A history of hyperthyroidism was not significantly related to HCC (OR = 1.7; CI = 0.6-5.1). We noted significant elevated risk association between hypothyroidism and HCC in women that was independent of established HCC risk factors. Experimental investigations are necessary for thorough assessment of the relationship between thyroid disorders and HCC.

Extended preoperative chemotherapy does not improve pathologic response and increases postoperative liver insufficiency after hepatic resection for colorectal liver metastases.

BACKGROUND: The optimal duration, safety, and benefit of preoperative chemotherapy in patients with colorectal liver metastases (CLM) are unclear. We evaluated the association between the duration of preoperative chemotherapy with 5-fluorouracil (5-FU), leucovorin, oxaliplatin (FOLFOX) ± bevacizumab, pathologic response, and hepatotoxicity after hepatic resection for CLM. METHODS: A total of 219 patients underwent hepatic resection following FOLFOX with or without bevacizumab and were divided into 2 groups according to the chemotherapy duration: 1-8 cycles (short duration [SD]; N = 157) and ≥9 cycles (long duration [LD]; N = 62). The frequency of complete or major pathologic response, sinusoidal injury, and major postoperative morbidity were compared. RESULTS: Treatment consisting of ≥9 cycles was not associated with an increase in complete or major pathologic response (SD vs. LD, 57% vs. 55%; P = .74). The incidence of sinusoidal injury was higher in the LD group (26% vs. 42%; P = .017). The incidence of liver insufficiency was higher in the LD group (4% vs. 11%; P = .035). Sinusoidal injury did not predict postoperative liver insufficiency; multivariate analysis revealed ≥9 cycles was the only independent predictor of postoperative liver insufficiency (P = .031; odds ratio = 3.90). Chemotherapy including bevacizumab was associated with a significantly higher frequency of complete or major response in both SD and LD groups. CONCLUSIONS: Extended preoperative chemotherapy increases the risk of hepatotoxicity in CLM without improving the pathologic response. The type of chemotherapy (FOLFOX with bevacizumab) has more impact on pathologic response than the duration of chemotherapy.