Nir Lubezky

The role and limitations of 18-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) scan and computerized tomography (CT) in restaging patients with hepatic colorectal metastases following neoadjuvant chemotherapy: comparison with operative and pathological findings.

BackgroundRecent data confirmed the importance of 18-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) in the selection of patients with colorectal hepatic metastases for surgery. Neoadjuvant chemotherapy before hepatic resection in selected cases may improve outcome. The influence of chemotherapy on the sensitivity of FDG-PET and CT in detecting liver metastases is not known.MethodsPatients were assigned to either neoadjuvant treatment or immediate hepatic resection according to resectability, risk of recurrence, extrahepatic disease, and patient preference. Two-thirds of them underwent FDG-PET/CT before chemotherapy; all underwent preoperative contrast-enhanced CT and FDG-PET/CT. Those without extensive extrahepatic disease underwent open exploration and resection of all the metastases according to original imaging findings. Operative and pathological findings were compared to imaging results.ResultsTwenty-seven patients (33 lesions) underwent immediate hepatic resection (group 1), and 48 patients (122 lesions) received preoperative neoadjuvant chemotherapy (group 2). Sensitivity of FDG-PET and CT in detecting colorectal (CR) metastases was significantly higher in group 1 than in group 2 (FDG-PET: 93.3 vs 49%, Pu2009<u20090.0001; CT: 87.5 vs 65.3, Pu2009=u20090.038). CT had a higher sensitivity than FDG-PET in detecting CR metastases following neoadjuvant therapy (65.3 vs 49%, Pu2009<u20090.0001). Sensitivity of FDG-PET, but not of CT, was lower in group 2 patients whose chemotherapy included bevacizumab compared to patients who did not receive bevacizumab (39 vs 59%, Pu2009=u20090.068).ConclusionsFDG-PET/CT sensitivity is lowered by neoadjuvant chemotherapy. CT is more sensitive than FDG-PET in detecting CR metastases following neoadjuvant therapy. Surgical decision-making requires information from multiple imaging modalities and pretreatment findings. Baseline FDG-PET and CT before neoadjuvant therapy are mandatory.

Response to chemotherapy predicts survival following resection of hepatic colo-rectal metastases in patients treated with neoadjuvant therapy

Prognosis of patients following resection of CRC metastases to the liver has traditionally been predicted by clinical risk factors. In the era of neoadjuvant chemotherapy, determination of new prognostic indicators of outcome are necessary.

Pancreaticoduodenectomy in Elderly Adults: Is It Justified in Terms of Mortality, Long-Term Morbidity, and Quality of Life?

To evaluate long‐term morbidity, mortality, and quality of life (QoL) after pancreaticoduodenectomy (PD) in elderly adults.

Perioperative Complications After Neoadjuvant Chemotherapy With and Without Bevacizumab for Colorectal Liver Metastases

PurposeBevacizumab has been shown to increase progression free and overall survival in patients with metastatic colorectal cancer. Neoadjuvant bevacizumab is commonly used in patients undergoing liver resection. Our purpose was to evaluate whether bevacizumab is associated with increased rate of perioperative complications in patients undergoing hepatic resection for colorectal liver metastases (CRLM).MethodsRetrospective analysis of patients undergoing hepatic resection for CRLM who received chemotherapy and bevacizumab (group 1, nu2009=u2009134), or chemotherapy alone (group 2, nu2009=u200957). We compared demographics, surgical characteristics, and perioperative course.ResultsPerioperative complications developed in 35xa0% of patients in group 1, and 47xa0% in group 2 (pu2009=u20090.11). Of those complications, 15 (11.2xa0%) in group 1, and 5 (8.8xa0%) in group 2 were considered major (pu2009=u20090.617). Four patients, all of whom received preoperative bevacizumab, developed enteric leaks following combined liver and bowel resection. The rate of anastomotic leak in group 1 was 10xa0%, compared with 0 in group 2, pu2009=u20090.56.ConclusionNeoadjuvant chemotherapy along with bevacizumab was not associated with an increased risk of postoperative complications after hepatic resection. Possible association of increased morbidity with simultaneous bowel and liver resections following bevacizumab administration was found and we recommend avoiding such treatment combination.

Solid pseudopapillary neoplasm of the pancreas: Management and long-term outcome

BACKGROUNDnSolid pseudopapillary neoplasm (SPN) of pancreas is a rare pancreatic neoplasm with a low metastatic potential. Our aim was to study the clinical-pathological characteristics, and long-term outcome of this tumor.nnnMATERIALSnRretrospective single center study of patients operated for SPN of pancreas. Clinical and pathological data were collected.nnnRESULTSnFrom 1995 to 2016, 1320 patients underwent pancreatic resection. SPN was confirmed in 32 cases (2.46%), including 29 (90.6%) female and three (9.4%) male, with a mean age of 28.4xa0±xa012.2 years. SPN was the most common pathology among female patients under age of 40 (72.4%). Abdominal pain was the most frequent presenting symptom (48%), whereas none of the patients presented with jaundice. Mean tumor diameter was 5.9xa0cm (range, 0.9-14xa0cm). All patients underwent margin-negative surgical resection. Two patients demonstrated gross malignant features, including liver metastases at presentation (nxa0=xa01), and adjacent organ and vascular invasion (nxa0=xa01). Microscopic malignant features were present in thirteen patients (40.6%). Recurrence occurred in the retroperitoneal lymph nodes (nxa0=xa01, 7 years post resection) and in the liver (nxa0=xa02, 1 and 5 years post resection). Mean follow-up was 49.2 months (range, 1-228 months). Five and 10-year disease-free survival was 96.5% and 89.6% respectively.nnnCONCLUSIONSnSPNs are low-grade tumors with a good prognosis. Margin-negative surgical resection is curative in most patients. However, almost 15% of patients demonstrate malignant features including invasion of adjacent organs or metastatic disease. Patients with malignant disease are still expected to have long survival, and aggressive surgical approach is advocated.

Epithelial-to-mesenchymal transition (EMT) in intraductal papillary mucinous neoplasm (IPMN) is associated with high tumor grade and adverse outcomes.

AbstractBackgroundnEpithelial-to-mesenchymal transition (EMT) is generally associated with increased tumor aggressiveness and poor prognosis. We evaluated EMT characteristics in intraductal papillary mucinous neoplasm (IPMN) tumor specimens and their potential role as biomarkers for malignancy, metastasis, and adverse patient outcomes.MethodsnIPMN surgical specimens were identified and reviewed by two gastrointestinal pathologists. Immunohistochemical analysis of E-cadherin, vimentin, and ZEB-1 was performed. Samples were linked to clinicopathologic and outcome data for these patients. Western blot test was used to evaluate ZEB-1 expression in IPMN samples; 846 human miRNAs were profiled, and EMT-related differentially expressed miRNAs were validated using quantitative real-time polymerase chain reaction.ResultsFifty-eight IPMN specimens and five normal pancreatic tissue samples were immunohistochemically stained and scored. E-cadherin expression was significantly lower in malignant versus low-grade IPMN (pxa0<xa00.05). Vimentin expression was increased in malignant IPMN tumor samples (pxa0<xa00.05). EMT was associated with increased lymph node metastasis and decreased survival of malignant IPMN patients (pxa0<xa00.05). ZEB-1, an imperative EMT regulator, was exclusively expressed by malignant IPMN tumors. miRNA hierarchical clustering demonstrated grouping of two main IPMN subgroups: low-grade IPMN versus high-grade IPMN and carcinoma. Twenty-four miRNAs were differentially expressed (14 up-regulated, 10 down-regulated). The EMT-regulatory miRNAs, miR-200c and miR-141, were down-regulated (twofold and 1.8-fold decrease, respectively) in malignant versus low-grade IPMN (pxa0<xa00.05).ConclusionsEMT may play a role in IPMN tumorigenesis and metastasis. EMT molecular deregulations could be utilized as potential novel biomarkers for the identification of high-risk IPMN patients.

Number of evaluated lymph nodes and positive lymph nodes, lymph node ratio, and log odds evaluation in early-stage pancreatic ductal adenocarcinoma: numerology or valid indicators of patient outcome?

BackgroundWe evaluated the prognostic significance and universal validity of the total number of evaluated lymph nodes (ELN), number of positive lymph nodes (PLN), lymph node ratio (LNR), and log odds of positive lymph nodes (LODDS) in a relatively large and homogenous cohort of surgically treated pancreatic ductal adenocarcinoma (PDAC) patients.MethodsProspectively accrued data were retrospectively analyzed for 282 PDAC patients who had pancreaticoduodenectomy (PD) at our institution. Long-term survival was analyzed according to the ELN, PLN, LNR, and LODDS.ResultsOf these patients, 168 patients (59.5xa0%) had LN metastasis (N1). Mean ELN and PLN were 13.5 and 1.6, respectively. LN positivity correlated with a greater number of evaluated lymph nodes; positive lymph nodes were identified in 61.4xa0% of the patients with ELNu2009≥u200913 compared with 44.9xa0% of the patients with ELNu2009<u200913 (pu2009=u20090.014). Median overall survival (OS) and 5-year OS rate were higher in N0 than in N1 patients, 22.4 vs. 18.7xa0months and 35 vs. 11xa0%, respectively (pu2009=u20090.008). Mean LNR was 0.12; 91 patients (54.1xa0%) had LNRu2009<u20090.3. Among the N1 patients, median OS was comparable in those with LNRu2009≥u20090.3 vs. LNRu2009<u20090.3 (16.7 vs. 14.1xa0months, pu2009=u20090.950). Neither LODDS nor various ELN and PLN cutoff values provided more discriminative information within the group of N1 patients.ConclusionsOur data confirms that lymph node positivity strongly reflects PDAC biology and thus patient outcome. While a higher number of evaluated lymph nodes may provide a more accurate nodal staging, it does not have any prognostic value among N1 patients. Similarly, PLN, LNR, and LODDS had limited prognostic relevance.

Visceral Fat Content Correlates with Retroperitoneal Soft Tissue Sarcoma (STS) Local Recurrence and Survival

BackgroundOur aim was to evaluate the association between visceral fat content with soft tissue sarcoma (STS) local recurrence and survival.MethodsOne hundred and one computed tomography imaging studies of primary STS patients who had complete macroscopic resection at our institution between 2002 and 2012 were reviewed, and retroperitoneal and circumferential fat contents were measured. Correlations between imaging findings and clinical data were analyzed.ResultsFifty-seven STS tumors (56.4xa0%) were retroperitoneal; of them, 65xa0% were high grade, median size was 15xa0cm (range 3–49), and the most common histological subtype was high grade liposarcoma (31.6xa0%). Median follow-up length for the entire cohort was 64xa0months (range 6–95). High visceral fat (VF) content ≥15 versus <15xa0mm was identified as a risk factor for retroperitoneal STS local recurrence; 65.1 versus 26.7xa0%, respectively (pxa0=xa00.04); VF content did not correlate with distant metastasis. Median overall survival (OS) length of patients with VF ≥15 versus <15xa0mm was 57xa0months (range 2–144) versus not reached, respectively (pxa0=xa00.007). Multivariable analysis identified VF ≥15xa0mm as an independent risk factor for decreased OS (HR: 4.2, 95xa0% CI 1.07–16.67). In contrast, circumferential fat content did not correlate with retroperitoneal STS patient outcomes.ConclusionHigh VF content is an independent adverse prognosticator associated with significantly higher rates of retroperitoneal STS local recurrence and decreased patients survival. Local tumor biology may be affected by the presence of adipose cells. Further clinical and molecular research is needed to establish this premise.

Adipose-Induced Retroperitoneal Soft Tissue Sarcoma Tumorigenesis: A Potential Crosstalk between Sarcoma and Fat Cells

Previous data demonstrated that high retroperitoneal visceral fat content increases retroperitoneal soft-tissue sarcoma (RSTS) local recurrence and patients mortality. Most RSTS tumors initiate and recur within visceral fat. The objective of the current study was to evaluate potential paracrine effects of visceral fat on RSTS. A xenograft model was used to evaluate in vivo effects of human visceral fat on STS growth. Tissue explants were prepared from visceral fat, and their conditioned medium (CM) was utilized for various in vitro experiments designed to evaluate growth, survival, migration, and invasion of STS and endothelial cells. Visceral fat–secreted protumorigenic factors were identified by mass spectrometry. The in vivo experiments demonstrated a significant increase in STS tumor growth rate when SK-LMS-1 leiomyosarcoma cells were colocalized with human visceral fat compared with subcutaneous injection of cancer cells only. The in vitro model demonstrated that visceral fat CM increased STS cellular growth and reduced doxorubicin-induced apoptosis. Visceral fat also enhanced STS cellular migration and invasion. In addition, visceral fat CM significantly increased endothelial cell tube formation, suggesting its role as a proangiogenic factor in the STS tumor microenvironment (TME). Using a robust proteomic approach, liquid chromatography and tandem mass spectrometry resolved various molecules within the visceral fat CM, of which a subset was associated with protumorigenic biologic processes. These results suggest that visceral fat directly interacts with STS cells by secreting specific adipokines into the TME, thus augmenting STS tumor cell proliferation and invasiveness. Fat-induced STS molecular deregulations should be studied to identify new potential prognostic and therapeutic targets. Implications: Visceral fat induces protumorigenic effects, in STS, through various secreted factors that should be investigated to improve our understanding of adipose–cancer cell interactions. Mol Cancer Res; 14(12); 1254–65. ©2016 AACR.

Neoadjuvant FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer: An intention to treat analysis

OBJECTIVEnTo assess clinical and pathologic efficacy of neoadjuvant FOLFIRINOX for locally advanced (LAPC) and borderline resectable pancreatic cancer (BRPC).nnnMETHODSnPatients receiving neoadjuvant FOLFIRINOX for LAPC and BRPC treated between 2014 and 2017 were identified. Post-treatment patients achieving resectability were referred for surgery, whereas unresectable patients continued chemotherapy. Clinical and pathological data were retrospectively compared with control group consisting of 47 consecutive patients with BRPC undergoing pancreatic and portal vein resection between 2008 and 2017.nnnRESULTSnThirty LAPC and 23 BRPC patients were identified. Reasons for unresectability included disease progression (70%), locally unresectable disease (18%), and poor performance status (11%). Three patients (10%) with LAPC, and 20 (87%) with BRPC underwent curative surgery. Compared with control group, perioperative complication rate (4.3% versus 28.9%, pxa0=xa00.016), and pancreatic fistula rate (0 versus 14.8%, pxa0=xa00.08) were lower. Peripancreatic fat invasion (52.2% vs 97.8%, pxa0=xa00.001), lymph node involvement (22% vs 54.3%, pxa0=xa00.01), and surgical margin involvement (0 vs 17.4%, pxa0=xa00.04) were higher in the control group. Median survival was 34.3 months in BRPC patients operated after FOLFIRINOX and 26.1 months in the control group (pxa0=xa00.07). Three patients (13%) with complete pathological response are disease-free after mean follow-up of 19 months.nnnCONCLUSIONSnWhereas neoadjuvant FOLFIRINOX rarely achieves resectability in patients with LAPC (10%), most BRPC undergo resection (87%). Neoadjuvant FOLFIRINOX leads to complete pathological response in 13% of cases, tumor downstaging, and a trend towards improved survival compared with patients undergoing up-front surgery.