Liposomal bupivacaine reduces narcotic use and time to flatus in a retrospective cohort of patients who underwent laparotomy.

INTRODUCTION: Sustained release liposomal bupivacaine (LB) is a new pain control option that can reduce opioid use after laparotomy, which is known to prolong ileus, length of stay. METHODS: Sixty-one consecutive patients undergoing laparotomy were treated with a standardized multi-modal therapy (MMT) consisting of IV tylenol, toradol, and morphine/dilaudid PCA. Thirty-one of those patients were additionally treated with LB infiltrated during fascial closure. Endpoints were opioid use, time to flatus, length of stay, and complications. RESULTS: Overall opioid use for 72 h was 78 mg of morphine for the MMT + LB group and 112 mg in the MMT control group (p = 0.04). During 0-24 h s PCA use was similar. However, during 24-48 h PCA use was decreased by 46% in the MMT + LB group (p = 0.038), and decreased by 55% during the 48-72 h period (p = 0.019). Time to flatus was decreased by 1.0 days in the MMT + LB group (p = 0.005). CONCLUSION: Use of LB in laparotomy patients decreases opioid use, time to flatus, and should be considered as a component of post-operative pain control.

Genome and transcriptome profiling of fibrolamellar hepatocellular carcinoma demonstrates p53 and IGF2BP1 dysregulation.

Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare variant of HCC that most frequently affects young adults. Because of its rarity and an absence of preclinical models, our understanding of FL-HCC is limited. Our objective was to analyze chromosomal alterations and dysregulated gene expression in tumor specimens collected at a single center during two decades of experience with FL-HCC. We analyzed 38 specimens from 26 patients by array comparative genomic hybridiziation (aCGH) and 35 specimens from 15 patients by transcriptome sequencing (RNA-seq). All tumor specimens exhibited genomic instability, with a higher frequency of genomic amplifications or deletions in metastatic tumors. The regions encoding 71 microRNAs (miRs) were deleted in at least 25% of tumor specimens. Five of these recurrently deleted miRs targeted the insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) gene product, and a correlating 100-fold upregulation of IGF2BP1 mRNA was seen in tumor specimens. Transcriptome analysis demonstrated intrapatient tumor similarity, independent of recurrence site or time. The p53 tumor suppressor pathway was downregulated as demonstrated by both aCGH and RNA-seq analysis. Notch, EGFR, NRAS, and RB1 pathways were also significantly dysregulated in tumors compared with normal liver tissue. The findings illuminate the genomic and transcriptomic landscape of this rare disease and provide insight into dysregulated oncogenic pathways and potential therapeutic targets in FL-HCC.

Gastric adenocarcinoma: clinicopathologic differences among Hispanics and non-Hispanic whites. A single Institution's experience over 14 years.

BACKGROUND: Gastriccancer is a leading cause of cancer death worldwide and has significant ethnic and socioeconomic differences in distribution. The aim of this study was to compare clinicopathologic characteristics and survival between Hispanics (H) and non-Hispanic whites (NHW) with gastric cancer. METHODS: We reviewed the records of all patients diagnosed with gastric cancer between 1999 and 2013 at our institution. A total of 638 patients were studied. Demographics, tumor characteristics and survival rate were analyzed. Kaplan-Meier was used for survival analysis. RESULTS: There were 101 H and 537 NHW. The median age at diagnosis was 63 years in H and 69 years in NHW. At diagnosis, 48 (48%) of H patients had stage IV disease compared with 195 (36%) of NHW (P<0.03). H were more likely to have distal cancers and poorly differentiated tumors compared to NHW (44% vs. 15%, P<0.0001; 70% vs. 50%, P<0.0002, respectively). There was a significant difference in median overall survival between the two groups, being 51 months for H (95% CI: 34.6-66.9) and 99 months for NHW (95% CI: 77.3-120.7) P<0.0001. In multivariate analysis, age (OR: 1.02, 95% CI: 1.02-1.03, P<0.0001), poor differentiation (OR: 1.21, 95% CI: 1.02-1.43, P<0.02), ethnicity (OR: 1.69, 95% CI: 1.07-2.55, P<0.02), and stage (OR: 1.95, 95% CI: 1.77-2.15, P<0.0001) were independent predictors of survival. CONCLUSIONS: H patients were diagnosed with gastric cancer at a younger age, to present with advanced disease at diagnosis, and had shorter overall survival compared to NHW.

Massive malignant solitary fibrous tumor arising from the bladder serosa: a case report.

INTRODUCTION: Solitary fibrous tumors are rare neoplasms of mesenchymal origin. They are often of low malignant potential and rarely metastasize. While they frequently arise from the pleura, they can occur at any soft tissue site in the body. We present a case of a large (28 × 21 cm) malignant solitary fibrous tumor arising from the bladder serosa. In addition, the clinicopathologic features, differential diagnosis, cytogenetics and management of this rare disease are discussed, along with a review of the existing literature on this topic. CASE PRESENTATION: An otherwise healthy 41-year-old Caucasian man presented with weight loss and progressive abdominal bloating. A subsequent computed tomography scan of his chest, abdomen and pelvis revealed a 26.8 × 21 cm intra-abdominal mass occupying most of his abdominal cavity. The inferior vena cava was compressed, and the mass extended inferiorly to his upper pelvis abutting the superior dome of his bladder. He underwent operative resection and the resected mass measured 28 × 21 × 18 cm and weighed 4.8 kg. The cut surface revealed a gray-white mass with an ill-defined whorled-like pattern, with randomly assorted tan fleshy nodules. A histologic evaluation revealed variable, alternating hypercellular and hypocellular areas, with areas of necrosis. The tumor cells varied from spindle to epithelioid within a hyalinized stroma. In the hypercellular areas, the tumor cells showed moderate atypia with high mitotic activity. The histological features combined with immunophenotyping were suggestive of a malignant solitary fibrous tumor that grossly appeared to be growing from the bladder serosa, specifically the intraperitoneal superior dome of the bladder. Our patient is currently eight months post-surgery without evidence of recurrence. CONCLUSIONS: Extrapleural occurrences of solitary fibrosis tumors are being increasingly observed. Malignant solitary fibrosis tumors of the urinary bladder, however, are very rare. As there are no pathognomonic features of malignancy, surgical resection is often both diagnostic and therapeutic, as was the case in our report.

Enlarging Pancreatic Schwannoma: A Case Report and Review of the Literature.

A 72-year-old female presented with dyspepsia for 2 years and an incidental mass in the head of the pancreas on abdominal computed tomography (CT) scan. Patient had multiple negative endoscopic ultrasound guided biopsies. She was followed up for 3 years with serial imaging until an abdominal CT scan showed an increase in size of the pancreatic mass. Physical examination was unremarkable. Laboratory tests including tumor markers were normal. Given the enlarging size of the mass and its impingement on the portal vein, the consensus was to proceed with surgery. Histology revealed a 3.5 cm mass showing a spindle cell neoplasm with mild atypia. The lesion was well defined and nerve tissue was noted at the periphery. On immuno-stains, the spindle cells were positive for S-100 protein and negative for pan-cytokeratin, CD-34, CD-117, smooth muscle actin and Melan A, consistent with the diagnosis of a pancreatic schwannoma.

Predicting the development of brain metastases in patients with local/regional melanoma.

BACKGROUND: The brain is a common site of recurrence in melanoma patients. Brain recurrence may present as a seizure, hemorrhage, or death. We sought to determine predictors of brain metastases in patients with primary and regional melanoma in order to facilitate targeted screening. METHODS: Prospectively maintained databases were used to identify patients treated for local or regional melanoma who developed stage IV melanoma with and without brain metastasis at initial recurrence. One hundred twenty patients were identified with brain relapse and compared to 487 patients without brain recurrence. RESULTS: On univariate analysis, patients with brain metastases were younger (55 vs. 59yrs, P = 0.04) but did not differ in primary site (head and neck 23% vs. 21%, P = 0.20). Brain metastasis patients had thinner primaries (mean 3.4 vs. 4.5 mm, P = 0.01). There were no other pathologic differences including ulceration (55% vs. 53%, P = 0.75), mitoses (7 vs.7.5, P = 0.61) or histologic subtype. Younger age and decreased Breslow thickness were independently associated with brain metastases at stage IV recurrence (OR = 1.10 P = 0.01 and OR = 1.02 P = 0.02, respectively). CONCLUSIONS: Our analysis, the largest to date, demonstrates that thinner Breslow depth and younger age were associated with brain recurrence at first presentation with Stage IV disease.

Observation after a positive sentinel lymph node biopsy in patients with melanoma.

BACKGROUND: The benefit of completion lymph node dissection (CLND) in melanoma patients with a positive sentinel lymph node (SLN) remains unknown. METHODS: We identified patients with a positive SLN from 1994 to 2012. Patient and tumor characteristics, reasons for not undergoing CLND, patterns of recurrence, and melanoma-specific survival data were analyzed. RESULTS: Of 4,310 patients undergoing SLN biopsy (SLNB), 495 (11 %) had a positive SLN-167 (34 %) patients underwent nodal observation and 328 (66 %) had immediate CLND. Patients in the no-CLND group were older (66 vs. 56 years; p < 0.001) and more likely to have lower extremity lesions (57 vs. 42 %; p = 0.006). There were no differences in tumor thickness, Clark level of invasion, ulceration, or SLN tumor burden. Median follow-up was 23 and 80 months for the no-CLND and CLND groups, respectively, and median time to recurrence was similar at 9 and 12 months, respectively (p = 0.48). There was no difference in local and in transit recurrence rates between groups (16 %, no CLND, and 18 %, CLND; p = 0.48). Nodal disease as a site of first recurrence occurred in 15 % of patients in the no-CLND group and 6 % of CLND patients (p = 0.002). In contrast, systemic recurrences occurred in 8 % of no-CLND patients compared with 27 % of CLND patients (p < 0.001). While median recurrence-free survival was higher after CLND (34.5 vs. 20.9 months; p = 0.02), melanoma-specific survival was similar (not reached, no CLND vs. 110 months, CLND; p = 0.09). CONCLUSIONS: Immediate CLND after a positive SLNB is associated with fewer initial nodal basin recurrences but similar melanoma-specific survival. These results support ongoing equipoise in the Multicenter Selective Lymphadenectomy Trial II (MSLT-II).

Stage-stratified prognosis of signet ring cell histology in patients undergoing curative resection for gastric adenocarcinoma.

BACKGROUND: The prognosis of signet ring cell (SRC) gastric adenocarcinoma is regarded as poor, although studies addressing outcomes in relation to non-SRC tumors are conflicting. Our objective was to compare the survival of SRC tumors with stage-matched intestinal-type tumors in a cohort of Western patients. METHODS: Review of a prospectively maintained database identified 569 patients undergoing curative resection (R0) from 1990 to 2009. Patients were divided into three histologic groups on the basis of the Lauren classification: SRC (n = 210), intestinal well- or moderately differentiated (WMD, n = 242) disease, and intestinal poorly differentiated (PD, n = 117) disease. Patient demographics, clinicopathologic features, and postoperative outcomes were determined. Stage-stratified disease-specific mortality was calculated and multivariate analysis performed. RESULTS: When compared with WMD and PD tumors, SRC tumors were associated with younger age (63 years SRC vs. 71 years WMD and 72 years PD, p < 0.0001) and with female sex (58 % SRC vs. 40 % WMD and 40 % PD, p = 0.0003). Median follow-up was 115 months. Patients with stage Ia SRC lesions had a better 5-year disease-specific mortality compared with stage-matched intestinal-type tumors (0 % SRC vs. 8 % WMD and 24 % PD, p = 0.001). In contrast, SRC patients with stage III disease fared significantly worse (78 % SRC vs. 54 % WMD and 72 % PD, p = 0.001). On multivariate analysis, the risk of death from gastric cancer comparing all three groups was lowest for SRC in stage I and highest for SRC in stage III disease (stage III hazard ratio: SRC 1 vs. 0.47 WMD and 0.85 PD). CONCLUSIONS: When compared with intestinal-type tumors, SRC tumors at early stages are not necessarily associated with poor outcomes.

Metastasectomy for gastrointestinal stromal tumors.

Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the intestinal tract. Improvements in understanding the molecular pathogenesis of GIST have resulted in novel treatment strategies combining surgery with tyrosine kinase inhibitors (TKIs). Metastasectomy in carefully selected patients who have stable or responsive disease on imatinib should be considered in the multidisciplinary setting. We review existing data on surgical cytoreduction in metastatic GIST while on targeted therapy and compare outcomes with either treatment alone.

Dysplasia at the surgical margin is associated with recurrence after resection of non-invasive intraductal papillary mucinous neoplasms.

BACKGROUND: The significance of a positive margin in resected non-invasive pancreatic intraductal papillary mucinous neoplasms (IPMN) remains controversial. The aim of this study was to determine recurrence rates when dysplasia was present at the final surgical margin. METHODS: A prospectively maintained database identified 192 patients undergoing resection of non-invasive IPMN. Pathological, peri-operative and recurrence data were analysed. RESULTS: Ductal dysplasia was identified at the final surgical margin in 86 patients (45%) and defined as IPMN or Pancreatic Intraepithelial Neoplasia PanIN in 38 (20%) and 54 (28%) patients, respectively. At a median follow-up of 46 months, 40 (21%) patients recurred with 31 developing radiographical evidence of new cysts, 6 re-resected for IPMN and 3 diagnosed with pancreatic cancer within the remnant. Of those with margin dysplasia, 31% developed recurrent disease compared with 13% in those without dysplasia (P = 0.002). On multivariate analysis, margin dysplasia was associated with a three-fold increased risk of recurrence (P = 0.02). No relationship between dysplasia and development of pancreatic cancer was found. DISCUSSION: In this study, dysplasia at the margin after a pancreatectomy for non-invasive IPMN was associated with recurrence in the remnant gland, but not at the resection margin. While this finding may warrant closer follow-up, it does not identify a gland at higher risk for the subsequent development of invasive disease.

Minimally invasive surgery for gastric cancer.

Application of minimally invasive techniques to gastric cancer in the West has been curbed by concerns of feasibility and oncologic adequacy. Growing evidence supports improved short-term and equivalent oncologic outcomes in selected patients undergoing laparoscopic surgery for early-stage disease. Laparoscopic resection for advanced gastric cancer remains controversial due to few reliable studies on long-term outcomes. We focus on important studies from Asia and highlight the Western experience with laparoscopic and robotic surgery for gastric carcinoma.

Regulatory T cell infiltration predicts outcome following resection of colorectal cancer liver metastases.

BACKGROUND: Tumor-infiltrating lymphocyte (TIL) counts in colorectal cancer liver metastases (CRCLM) predict survival following resection. While CD4 and CD8 T cells have been correlated with outcome following CRCLM resection, the role of regulatory T cells (Treg) is not well defined. METHODS: TIL in 188 patients who underwent CRCLM resection between 1998 and 2000 were analyzed by immunohistochemistry using tissue microarrays. Correlation between TIL composition and outcome was determined while controlling for established prognostic factors. Total T cells (CD3), helper T cells (CD4), cytotoxic T cells (CD8), and Treg (FoxP3) were analyzed. RESULTS: Median follow-up time was 40 months for all patients and 95 months for survivors. Overall survival (OS) at 5 and 10 years was 40 and 25%, respectively. The CD4 T cell count correlated with OS (p = .02) and recurrence-free survival (p = .04). A high number of CD8 T cells relative to total T cells (CD8:CD3 ratio) predicted longer OS times (p = .05). Analysis of Treg revealed that high FoxP3:CD4 (p = .03) and FoxP3:CD8 (p = .05) ratios were independent predictors of shorter OS. Patients with a high clinical risk score (CRS) were more likely to have a high number of intratumoral Treg, and patients ≥65 years old had a less robust CRCLM T cell infiltration. CONCLUSIONS: A high number of Treg relative to CD4 or CD8 T cells predicted poor outcome, suggesting an immunosuppressive role for FoxP3 + TIL. The intratumoral immune response was an independent predictor of outcome in patients with colorectal liver metastases.

Short-term outcomes in obese patients after colectomy for adenocarcinoma at a bariatric center.

INTRODUCTION: Obesity (body mass index ≥30) is associated with worse outcomes after colon cancer surgery. Most research, however, has been performed outside bariatric centers of excellence. We sought to determine the relationship between obesity and outcomes after colon cancer resection when performed at a center with bariatric expertise. METHODS: We performed a retrospective review of 245 consecutive patients undergoing elective colectomy for adenocarcinoma at a single institution from 2008 to 2009. Body mass index, major and minor postoperative complications, tumor characteristics, lymph node yield, type of resection, and operating times were determined. RESULTS: Complication rates, operative times, and lymph node counts were all similar between the two weight groups. Obese patients had similar tumor characteristics at all stages when compared with nonobese patients. On multivariate analysis, obesity did not correlate with tumor size, tumor differentiation, or presence of lymphovascular or perineural invasion. CONCLUSION: We conclude that obese patients undergoing colon cancer resection at a bariatric center of excellence have similar tumor characteristics and equivalent short-term outcomes as do nonobese patients.

Nilotinib protects the murine liver from ischemia/reperfusion injury.

BACKGROUND & AIMS: The mitogen-activated protein kinases (MAPKs), c-Jun N-terminal kinase (JNK), and p38, mediate liver ischemia/reperfusion (I/R) injury via cell death and inflammatory cytokine expression, respectively. Nilotinib is an orally available receptor tyrosine kinase inhibitor used for chronic myelogenous leukemia that also has in vitro activity against JNK and p38. In this study, we examine its therapeutic potential against hepatic I/R injury. METHODS: The effects of nilotinib on liver I/R injury were tested using a murine model of warm, segmental liver I/R. Serum ALT was measured and livers were analyzed by histology, RT-PCR, Western blot, and flow cytometry. The in vitro effects of nilotinib on hepatocyte and non-parenchymal cell (NPC) MAPK activation and cytokine production were also tested. RESULTS: Mice receiving nilotinib had markedly lower serum ALT levels and less histologic injury and apoptosis following liver I/R. Nilotinib did not inhibit its known receptor tyrosine kinases. Nilotinib lowered intrahepatic expression of IL-1ß, IL-6, MCP-1, and MIP-2 and systemic levels of IL-6, MCP-1, and TNF. Nilotinib reduced NPC activation of p38 MAPK signaling and decreased the recruitment of inflammatory monocytes and their production of TNF. Nilotinib attenuated JNK phosphorylation and hepatocellular apoptosis. In vitro, nilotinib demonstrated direct inhibition of JNK activation in isolated hepatocytes cultured under hypoxic conditions, and blocked activation of p38 MAPK and cytokine production by stimulated NPCs. CONCLUSIONS: Nilotinib lowers both liver JNK activation and NPC p38 MAPK activation and may be useful for ameliorating liver I/R injury in humans.

Updates on the management of gastrointestinal stromal tumors.

Despite being the most common sarcoma of the gastrointestinal tract, gastrointestinal stromal tumor (GIST) has been widely recognized as a unique entity for just over a decade. The advent of tyrosine kinase inhibitors has revolutionized the diagnosis and treatment of GIST. Although surgery remains the only chance for cure, multimodal treatment that includes molecular therapy continues to develop. Optimal management of GIST requires careful radiographic, pathologic, medical, and surgical care, emphasizing the need for a multidisciplinary approach. This review highlights recent developments in the management of GIST.

Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido.

Imatinib mesylate targets mutated KIT oncoproteins in gastrointestinal stromal tumor (GIST) and produces a clinical response in 80% of patients. The mechanism is believed to depend predominantly on the inhibition of KIT-driven signals for tumor-cell survival and proliferation. Using a mouse model of spontaneous GIST, we found that the immune system contributes substantially to the antitumor effects of imatinib. Imatinib therapy activated CD8(+) T cells and induced regulatory T cell (T(reg) cell) apoptosis within the tumor by reducing tumor-cell expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (Ido). Concurrent immunotherapy augmented the efficacy of imatinib in mouse GIST. In freshly obtained human GIST specimens, the T cell profile correlated with imatinib sensitivity and IDO expression. Thus, T cells are crucial to the antitumor effects of imatinib in GIST, and concomitant immunotherapy may further improve outcomes in human cancers treated with targeted agents.

Factors affecting lymph node yield from patients undergoing colectomy for cancer.

PURPOSE: Lymph node (LN) yield is a critical component of colon cancer staging and is often a surrogate for quality assessment in surgery. We investigated the impact of pathologists' training on LN harvest. METHODS: This is a retrospective review on 137 patients undergoing elective colectomy for adenocarcinoma at a single institution from 2008 to 2009. We studied surgeon-, patient- and pathologist-derived factors, and identified independent variables affecting LN yield using logistic regression. RESULTS: LN yield was similar between open and laparoscopic resections (21 versus 23, p = 0.54). Similarly, nodal counts were independent of tumor location (p = 0.08) and no difference was noted between colorectal and general surgeons (24 versus 21, p = 0.31). Strikingly, the number of LNs reported by PGY-1 pathology residents was significantly higher than those with two or more years of training (24 versus 19, p = 0.02). On logistic regression, only the reporting pathologists' year in training remained a significant predictor of the number of nodes reported (OR = 5.28, p = 0.0001). CONCLUSIONS: LN retrieval in patients with colon cancer is inversely related to the interpreting pathologists' level of training.

Neutrophil IL-10 suppresses peritoneal inflammatory monocytes during polymicrobial sepsis.

Septic peritonitis remains a major cause of death. Neutrophils and inflammatory monocytes are principal components of the innate immune system and are essential for defense against a range of microbial pathogens. Their role and interaction in polymicrobial sepsis have not been defined clearly. Using a murine model of CLP to induce moderate sepsis, we found that neutrophil depletion did not alter survival, whereas depletion of neutrophils and inflammatory monocytes markedly reduced survival. After neutrophil depletion, inflammatory monocytes had greater phagocytic capacity and oxidative burst, and increased expression of costimulatory molecules, TNF, and iNOS. Notably, peritoneal neutrophils produced IL-10 following CLP. Adoptive i.p. transfer of WT but not IL-10(-/-) neutrophils into septic mice reduced monocyte expression of TNF. In vitro experiments confirmed that monocyte suppression was mediated by neutrophil-derived IL-10. Thus, during septic peritonitis, neutrophils suppress peritoneal inflammatory monocytes through IL-10 and are dispensable for survival.

Sclerosing angiomatoid nodular transformation of the spleen in an adolescent with chronic abdominal pain.

Sclerosing angiomatoid nodular transformation (SANT) is a relatively new, benign neoplasm arising within the red pulp of the spleen. The lesion is often identified incidentally on imaging, and the diagnosis is confirmed on pathologic assessment of the resected spleen. Although there have been several reports of SANT in the adult population, data on this lesion in the pediatric population are exceedingly rare. We present a case of SANT in an adolescent male with chronic abdominal pain and discuss the management issues that arise in treating this condition in the pediatric population.