Susan Tsai

Sarcopenia negatively impacts short-term outcomes in patients undergoing hepatic resection for colorectal liver metastasis

BACKGROUND As indications for liver resection expand, objective measures to assess the risk of peri-operative morbidity are needed. The impact of sarcopenia on patients undergoing liver resection for colorectal liver metastasis (CRLM) was investigated. METHODS Sarcopenia was assessed in 259 patients undergoing liver resection for CRLM by measuring total psoas area (TPA) on computed tomography (CT). The impact of sarcopenia was assessed after controlling for clinicopathological factors using multivariate modelling. RESULTS Median patient age was 58 years and most patients (60%) were male. Forty-one (16%) patients had sarcopenia (TPA ≤ 500 mm(2) /m(2) ). Post-operatively, 60 patients had a complication for an overall morbidity of 23%; 26 patients (10%) had a major complication (Clavien grade ≥3). The presence of sarcopenia was strongly associated with an increased risk of major post-operative complications [odds ratio (OR) 3.33; P= 0.008]. Patients with sarcopenia had longer hospital stays (6.6 vs. 5.4 days; P= 0.03) and a higher chance of an extended intensive care unit (ICU) stay (>2 days; P= 0.004). On multivariate analysis, sarcopenia remained independently associated with an increased risk of post-operative complications (OR 3.12; P= 0.02). Sarcopenia was not significantly associated with recurrence-free [hazard ratio (HR) = 1.07] or overall (HR = 1.05) survival (both P > 0.05). CONCLUSIONS Sarcopenia impacts short-, but not long-term outcomes after resection of CRLM. While patients with sarcopenia are at an increased risk of post-operative morbidity and longer hospital stay, long-term survival is not impacted by the presence of sarcopenia.

Neoadjuvant FOLFIRINOX for Borderline Resectable Pancreas Cancer: A New Treatment Paradigm?

BACKGROUND Borderline resectable pancreatic cancer is best treated by multimodality therapy. FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, and leucovorin) tripled the response rate and significantly increased median survival for patients with advanced pancreatic cancer and shows promise for neoadjuvant use. Toxicity concerns prompted a careful analysis of our initial FOLFIRINOX experience. METHODS All patients diagnosed with borderline resectable, biopsy-proven pancreatic adenocarcinoma treated with neoadjuvant FOLFIRINOX between July 2010 and December 2012 were reviewed. Primary outcome was surgical resectability. Secondary outcomes were treatment-related toxicities and survival. RESULTS FOLFIRINOX followed by gemcitabine- or capecitabine-based chemoradiation was initiated in 18 patients. The most common grade 3 or 4 toxicities during chemotherapy were gastrointestinal, including nausea/emesis (n = 5), weight loss (n = 3) and diarrhea (n = 2), and hematologic (n = 2; neutropenia); five patients (36%) required a total of six admissions. Neoadjuvant therapy was completed in 15 of 18 patients (83%), and 12 (67%) underwent pancreatectomy (10 Whipple, 2 total pancreatectomy) including portal vein resection/reconstruction in 10 (83%). Disease progression precluded surgery in 6 of the 18 patients (33%). All 12 resected patients had negative (R0) margins. Only 2 of 12 (17%) were node positive (median node count: 26.5 [range: 15-39]). There were no in-hospital or 30-day mortalities and no clinical pancreatic leaks or reoperations. Of the 12 patients who completed all intended therapy, 7 (58.3%) are alive, including 5 who have no evidence of disease (median months from diagnosis: 22 months [range: 18-35 months). The six patients who did not complete all planned therapy are deceased (months from diagnosis: 6.9-17.5 months). CONCLUSION FOLFIRINOX followed by chemoradiation as neoadjuvant therapy for borderline resectable pancreatic adenocarcinoma is safe, and our initial experience suggests favorable resection rates compared with previous reports in this high-risk patient population.

Microwave ablation for hepatic malignancies: a multiinstitutional analysis.

Objective:This study hypothesized that tumor size, number of tumors, surgical approach, and tumor histology significantly affected microwave ablation (MWA) success and recurrence-free survival. Background:Although many hepatobiliary centers have adopted MWA, the factors that influence local control are not well described. Methods:Consecutive patients with hepatic malignancy treated by MWA were included from 4 high-volume institutions (2003–2011) and grouped by histology: hepatocellular carcinoma (HCC), colorectal liver metastases, neuroendocrine liver metastases, and other cancers. Independent significance of outcome variables was established with logistic regression and Cox proportional hazards models. Results:Four hundred fifty patients were treated with 473 procedures (139 HCC, 198 colorectal liver metastases, 61 neuroendocrine liver metastases, and 75 other) for a total of 875 tumors. Median follow-up was 18 months. Concurrent hepatectomy was performed in 178 patients (38%), and when performed was associated with greater morbidity. Complete ablation was confirmed for 839 of 865 tumors (97.0%) on follow-up cross-sectional imaging (10 were unevaluable). A surgical approach (open, laparoscopic, or percutaneous) had no significant impact on complication rates, recurrence, or survival. The local recurrence rate was 6.0% overall and was highest for HCC (10.1%, P = 0.045) and percutaneously treated lesions (14.1%, P = 0.014). In adjusted models, tumor size 3 cm or more predicted poorer recurrence-free survival (hazard ratio: 1.60, 95% CI: 1.02–2.50, P = 0.039). Conclusions:In this large data set, patients with 3 cm or more tumors showed a propensity for early recurrence, regardless of histology. Higher rates of local recurrence were noted in HCC patients, which may reflect underlying liver disease. There were no significant differences in morbidity or survival based on the surgical approach; however, local recurrence rates were highest for percutaneously ablated tumors.

Circulating giant macrophages as a potential biomarker of solid tumors

Significance Using microfiltration as a liquid biopsy for the recovery of circulating tumor cells (CTCs) has revealed an accompanying macrophage subset that we use as a highly sensitive biomarker for solid tumors. We supply evidence that this circulating giant cell is a subset of disseminated tumor-associated macrophages capable of binding CTCs in peripheral blood of cancer patients. The presence of this cell expands the concept of using a liquid biopsy not only to indicate cancer presence but also to track cancer treatment effects sequentially using other circulating blood cells. Further, we supply observational evidence hypothesizing a metastasis pathway model in which CTCs migrate with pro-angiogenic macrophages, linking cancer cell intravasation, migration, and extravasation and the formation of metastatic microenvironments. Tumor-associated macrophages (TAMs) derived from primary tumors are believed to facilitate circulating tumor cell (CTC) seeding of distant metastases, but the mechanisms of these processes are poorly understood. Although many studies have focused on the migration of CTCs, less attention has been given to TAMs that, like CTCs, derive from tumor sites. Using precision microfilters under low-flow conditions, we isolated circulating cancer-associated macrophage-like cells (CAMLs) from the peripheral blood of patients with breast, pancreatic, or prostate cancer. CAMLs, which are not found in healthy individuals, were found to express epithelial, monocytic, and endothelial protein markers and were observed bound to CTCs in circulation. These data support the hypothesis that disseminated TAMs can be used as a biomarker of advanced disease and suggest that they have a participatory role in tumor cell migration.

Two-stage strategy for patients with extensive bilateral colorectal liver metastases.

BACKGROUND Two-stage hepatectomy has been proposed for patients with bilateral colorectal liver metastases. The present study assesses the feasibility and outcome of two-stage hepatectomy for the treatment of colorectal liver metastases. METHODS From January 1994 to December 2008, 720 patients underwent liver resections at two institutions for colorectal liver metastases. The feasibility and outcomes of two-staged hepatectomies were evaluated. RESULTS Forty-five patients were eligible for the two-stage approach and both stages were completed in 35 patients (78%). Reasons for failure included disease progression (n= 7), poor performance status (n= 1) and death after the first stage (n= 2). Patients who completed both stages had significantly fewer lesions than patients who failed to complete the second stage (5 vs. 8; P= 0.02). No differences between the two groups were observed with regard to lesion size, receipt of radiofrequency ablation (RFA) or presence of extrahepatic disease. Post-operative morbidity (24% vs. 26%; P= 0.9) and mortality (4% vs. 5%; P= 0.8) was similar between the first and second stages. Median overall survival was 16 months. Three-year survival was significantly worse for patients failing to complete both stages (18%) compared with patients completing both stages (58%) (P < 0.001). Similar survival rates were observed between patients who completed two-stage vs. patients treated with a planned single-stage hepatectomy (58% vs. 53%; P= 0.34). CONCLUSION The two-stage strategy for colorectal liver metastases can be performed with acceptable morbidity and mortality. The second stage will not be feasible in 20-25% of patients. Patients who are able to complete the two-stage approach, however, may have long-term survival comparable to patients treated with a planned single-stage hepatectomy.

Survival of patients with resectable pancreatic cancer who received neoadjuvant therapy

BACKGROUND Enthusiasm for neoadjuvant therapy is growing from the emerging consensus that pancreatic cancer is a systemic disease at the time of diagnosis. Those who remain in favor of upfront surgery often cite the lack of reported data to support alternative treatment sequencing. We therefore report the results of all patients treated outside of a clinical trial under the direction of a multidisciplinary pancreatic cancer working group. METHODS We reviewed all patients with resectable pancreatic cancer treated with neoadjuvant therapy (NeoTx) from 2009 to 2013; we excluded those patients treated on prospective clinical trials as they will be the subject of subsequent reports. Data regarding demographics, NeoTx, operative outcomes, pathology, and survival data were abstracted from a prospective database. RESULTS NeoTx was initiated in 69 patients; median age was 65 years (interquartile range [IQR]: 11) and median carbohydrate antigen 19-9 at diagnosis was 96.5 (IQR 210). NeoTx consisted of chemotherapy alone (n = 10, 14%), chemotherapy and radiation (chemoradiation, n = 53, 77%), or both (n = 6, 9%). Median carbohydrate antigen 19-9 after NeoTx was 39 (IQR 104) corresponding to a median decrease of 60%. Operative resection was completed in 60 (87%) of the 69 patients. At restaging after NeoTx, 5 (7%) of 69 patients were not considered candidates for surgery because of the development of metastatic disease (n = 4) or an inadequate performance status (n = 1). At the time of surgery, 4 (6%) of 64 patients had metastatic disease found at laparoscopy. Of the 60 patients who underwent surgical resection, a complete pathologic response was observed in 2 (3%) patients; 20 (33%) had positive lymph nodes, and the median number of positive lymph nodes was 2 (IQR 3). R0 resections were achieved in 58 (97%) of the 60 patients. Additional postoperative adjuvant therapy was administered to 37 (62%) of the 60 patients. Median survival of all 69 patients was 31.5 months; 44.9 months for the 60 patients who completed all NeoTx and resection compared with 8.1 months for the 9 patients who were not resected (log rank P < .001). CONCLUSION NeoTx for resectable pancreatic cancer was associated with a median overall survival of 32 months; something not reported for patients treated with surgery first if based on intent-to-treat analysis. Treatment sequencing may provide an oncologic benefit beyond that of the selection bias afforded surgery after a period of induction therapy.

Current staging systems for pancreatic cancer.

Accurate pretreatment staging of pancreatic cancer is a crucial initial step in the development of a stage-specific treatment plan, either on- or off-protocol for any patient with pancreatic cancer. Importantly, current American Joint Committee on Cancer staging utilizes the maximal information available; if surgery has been performed, then pathological information from the resected specimen will provide additional information for both T and N staging. If surgery has not been performed, then staging is based on information from available cross-sectional imaging studies. Although American Joint Committee on Cancer staging was modified in the sixth edition to reflect the survival difference between patients with operable/resectable versus nonoperable/unresectable disease, the precise definitions of resectability continue to evolve. It is essential for clinicians of different specialties to understand the definitions of resectability to facilitate optimal patient care and to allow for accurate interpretation of the literature. This review focuses on important aspects of the pretreatment assessment of patients with particular attention to definitions of resectability. Computed tomography has become the optimal imaging modality for pancreatic cancer staging, but other adjunct studies, including endoscopic ultrasound and laparoscopy, may provide additional staging information especially in circumstances where computed tomography technology is limited. In addition, the process of a standardized pathological review is summarized, with emphasis on assessment of the superior mesenteric artery margin and the definitions of R0, R1, and R2. Finally, the prognostic importance of key components of the pathological report such as lymph node status, lymph node ratio, and treatment effect is reviewed.

Plasma extracellular RNA profiles in healthy and cancer patients.

Extracellular vesicles are selectively enriched in RNA that has potential as disease biomarkers. To systemically characterize circulating extracellular RNA (exRNA) profiles, we performed RNA sequencing analysis on plasma extracellular vesicles derived from 50 healthy individuals and 142 cancer patients. Of ~12.6 million raw reads for each individual, the number of mappable reads aligned to RNA references was ~5.4 million including miRNAs (~40.4%), piwiRNAs (~40.0%), pseudo-genes (~3.7%), lncRNAs (~2.4%), tRNAs (~2.1%), and mRNAs (~2.1%). By expression stability testing, we identified a set of miRNAs showing relatively consistent expression, which may serve as reference control for exRNA quantification. By performing multivariate analysis of covariance, we identified significant associations of these exRNAs with age, sex and different types of cancers. In particular, down-regulation of miR-125a-5p and miR-1343-3p showed an association with all cancer types tested (false discovery rate <0.05). We developed multivariate statistical models to predict cancer status with an area under the curve from 0.68 to 0.92 depending cancer type and staging. This is the largest RNA-seq study to date for profiling exRNA species, which has not only provided a baseline reference profile for circulating exRNA, but also revealed a set of RNA candidates for reference controls and disease biomarkers.

Importance of Lean Body Mass in the Oncologic Patient

Loss of lean body develops from an imbalance in protein synthesis and catabolism and is associated with a variety of different disease and nondisease states, including severe malnutrition, cachexia, and physiologic age-related loss (sarcopenia). Loss of lean body mass is prevalent among a significant proportion of the elderly population and has been associated with increased adverse clinical outcomes. Recognition of individuals at risk for low lean body mass may be difficult due to unequal distribution of losses across muscle and adipose compartments, and individuals who are both obese and sarcopenic demonstrate the highest risk for adverse events. Cross-sectional imaging modalities provide an accessible and easily interpretable means of quantifying lean muscle content and are routine diagnostic tests for cancer patients. As a result, a growing body of literature has developed characterizing the importance of low lean body mass as a poor prognostic factor among cancer patients, regardless of age. Cancer patients, especially those with sarcopenic obesity, are at increased risk for treatment-related toxicities from chemotherapy and increased overall mortality. Further investigations into the pathogenesis of muscle wasting among cancer patients are critical, as therapeutic oncologic interventions may inadvertently accelerate muscle catabolism. This review provides an overview of the definitions of low lean body mass, etiologic causes, clinical significance among cancer patients, and potential therapeutic interventions.

Management of Early Hepatocellular Carcinoma in Patients with Well-Compensated Cirrhosis

Hepatocellular carcinoma (HCC) usually affects patients with chronic liver disease. While resection is the primary treatment of HCC in patients without cirrhosis, in the setting of moderate to severe cirrhosis, liver transplantation is the preferred therapy, as it simultaneously treats the tumor and the underlying liver condition. The optimal management of patients with HCC and early cirrhosis remains controversial. Although liver transplantation for HCC within the Milan criteria has been shown to have excellent long-term survival rates and low recurrence rates, its application is limited by organ availability. Due to the shortage of donors, a portion of patients drop out from the waiting list due to tumor progression. One alternative to transplantation is hepatic resection. In addition to the reported 50% 5-year survival rates, resection allows a better understanding of tumor biology through pathologic examination of the specimen, which may guide decision-making regarding salvage liver transplantation. Other nonsurgical locoregional therapies, such as transarterial chemoembolization and radiofrequency ablation, also serve as primary therapies and as a bridge to transplantation. The management of patients with early HCC is complex and multidimensional. The care of these patients is best served by a multidisciplinary approach, with consideration of the feasibility of transplantation weighed against the aggressiveness of the tumor biology and underlying hepatic dysfunction. All modalities of therapy should be viewed as complementary, not exclusive, therapeutic strategies.