Barish H. Edil

Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors

Poorly differentiated neuroendocrine carcinomas (NECs) of the pancreas are rare malignant neoplasms with a poor prognosis. The aim of this study was to determine the clinicopathologic and genetic features of poorly differentiated NECs and compare them with other types of pancreatic neoplasms. We investigated alterations of KRAS, CDKN2A/p16, TP53, SMAD4/DPC4, DAXX, ATRX, PTEN, Bcl2, and RB1 by immunohistochemistry and/or targeted exomic sequencing in surgically resected specimens of 9 small cell NECs, 10 large cell NECs, and 11 well-differentiated neuroendocrine tumors (PanNETs) of the pancreas. Abnormal immunolabeling patterns of p53 and Rb were frequent (p53, 18 of 19, 95%; Rb, 14 of 19, 74%) in both small cell and large cell NECs, whereas Smad4/Dpc4, DAXX, and ATRX labeling was intact in virtually all of these same carcinomas. Abnormal immunolabeling of p53 and Rb proteins correlated with intragenic mutations in the TP53 and RB1 genes. In contrast, DAXX and ATRX labeling was lost in 45% of PanNETs, whereas p53 and Rb immunolabeling was intact in these same cases. Overexpression of Bcl-2 protein was observed in all 9 small cell NECs (100%) and in 5 of 10 (50%) large cell NECs compared with only 2 of 11 (18%) PanNETs. Bcl-2 overexpression was significantly correlated with higher mitotic rate and Ki67 labeling index in neoplasms in which it was present. Small cell NECs are genetically similar to large cell NECs, and these genetic changes are distinct from those reported in PanNETs. The finding of Bcl-2 overexpression in poorly differentiated NECs, particularly small cell NEC, suggests that Bcl-2 antagonists/inhibitors may be a viable treatment option for these patients.

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.

Serotonin expression in pancreatic neuroendocrine tumors correlates with a trabecular histologic pattern and large duct involvement

Pancreatic neuroendocrine tumors with prominent stromal fibrosis are often clinically, radiographically, and grossly indistinguishable from ductal adenocarcinoma. We recently described a small series of fibrotic pancreatic neuroendocrine tumors that express serotonin. To understand better the relationship between histopathologic patterns and serotonin expression, we reviewed 361 pancreatic neuroendocrine tumors to identify those with prominent stromal fibrosis exceeding 30% of total tumor area. We identified 52 cases and immunolabeled these neoplasms with antibodies to serotonin and Ki-67. Two predominant histologic subtypes were identified: 14 (26.9%) of 52 had a trabecular or trabecular-glandular cellular pattern with interspersed fibrosis, whereas 38 (73.1%) of 52 had solid architecture. Of the 52, 14 (26.9%) pancreatic neuroendocrine tumors showed at least focal serotonin immunoreactivity. Tumors with predominantly trabecular architecture were significantly more likely to express serotonin than those with solid architecture (P < .01). Only 2 of 34 pancreatic neuroendocrine tumors with fibrosis less than 30% of total tumor area expressed serotonin. The 14 serotonin-expressing tumors were less likely to have lymph node metastases (P = .016) and more likely to involve large pancreatic ducts (P < .01) than were the 38 serotonin-negative tumors. The serotonin-expressing tumors were also found in a younger patient population (P < .01). There was no significant association of serotonin immunoreactivity with Ki-67 proliferation index, tumor size, or distant metastases. Our data demonstrate a strong correlation between trabecular architecture and serotonin immunoreactivity in pancreatic neuroendocrine tumors with stromal fibrosis. Serotonin-expressing tumors are also less likely to have lymph node metastases and more likely to involve large pancreatic ducts.

Preoperative endoscopic tattooing of pancreatic body and tail lesions decreases operative time for laparoscopic distal pancreatectomy

BACKGROUND Precise and expedient localization of small pancreatic tumors during laparoscopic distal pancreatectomy can be difficult owing to the decreased tactile ability of laparoscopy and the homogenous appearance of the surrounding retroperitoneal fat. Precise localization of the lesion is critical to achieving adequate margins of resection while preserving as much healthy pancreas as possible. The objective in this study was to determine the effect of endoscopic tattooing of the distal pancreas on operative time. METHODS We reviewed retrospectively 36 consecutive patients who had a laparoscopic distal pancreatectomy at our institution over a 4-year period (2006-2009). Ten patients underwent preoperative tattooing via an endoscopic transgastric technique using ultrasound guidance. The tattoo was performed using 2-4 cc of sterile purified carbon particles injected immediately proximal and anterior to the pancreatic lesion. Operative times were compared according to the presence of a tattoo. RESULTS The endoscopically placed tattoo was easily visible upon entering the lesser sac in all 10 patients at laparoscopy. Patients with a tattoo had a shorter operative time (median, 128.5 minutes; range, 53-180) compared with patients without a tattoo (median, 180 minutes; range, 120-240; P < .01). None of the tattoo group required repeat surgery, whereas 1 patient who was not tattooed required re-resection for a lesion missed in the initial specimen. There were no complications associated with the endoscopic ultrasound-guided tattoo. CONCLUSION Endoscopic ultrasound-guided tattooing of pancreas lesions before a laparoscopic distal pancreatectomy is safe and is associated with decreased operative time compared with nontattooed patients. This technique can allow for quick and precise localization of the lesion, allowing for optimal preservation of pancreas parenchyma and demarcating an appropriate line of resection.

Immuno- and gene-therapeutic strategies targeted against cancer (mainly focusing on pancreatic cancer)

Current treatment modalities of surgical resection and chemotherapy against cancers have improved survival. However, mortality from tumor recurrence remains high. Immunotherapy and gene therapy are potential additions to the treatment arsenal in the care of cancer patients. These novel therapeutic approaches need further investigation in in vitro and in vivo models as they are developed for potential use in humans. Here we reviewed immunotherapies and gene therapies that included clinical trials against cancers (mainly focusing on pancreatic cancer) suggesting the strong possibility of using these novel approaches.

Abstract A87: Preliminary results of a phase II study of erlotinib combined with adjuvant chemoradiation and chemotherapy in patients with resectable pancreatic cancer.

Background: Both local and systemic recurrences are common after surgical resection of pancreatic ductal adenocarcinoma (PDA). This pattern of failure suggests that a combination of systemic and local adjuvant therapy may positively impact survival. The epidermal growth factor receptor (EGFR) gene is overexpressed in up to 80% of PDA specimens. Thus, EGFR is an attractive target for improving efficacy of adjuvant therapy for PDA. Purpose: (1) To evaluate the antitumor activity of erlotinib (E) combined with standard adjuvant chemoradiotherapy (CRT) and chemotherapy as measured by progression free survival (PFS) and overall survival (OS). (2) To characterize the toxicity profile of E combined with adjuvant therapy. Methods: 43 patients with resected stage I/II PDA were enrolled in a phase II trial of E (100 mg daily) and capecitabine (800 mg/m2 twice daily Monday-Friday) administered concurrently with IMRT delivered at 1.8 Gy daily in 28 fractions (50.4 Gy total). 4–8 weeks following CRT, patients continued treatment with 4 cycles of gemcitabine (1000 mg/m2 on days 1, 8, and 15 every 28 days) and E (100 mg daily). OS and PFS were calculated as time from surgery to death and to disease progression, respectively. Toxicity was assessed using the NCI CTCAE Version 3.0. Results: Mean age was 61.7 years (SD, 8.7) and 44% were male. 72% had tumors of the pancreatic head, while 28% had tumors of the body/tail. 86% had regional nodal involvement and 33% had positive resection margins. Median follow-up was 16.7 months (interquartile range, 7.4–22.8). Median OS was 24.7 months (95% CI, 18.5–30.9). Median PFS was 15.4 months (95% CI, 9.4–21.3). Survival rate at 1 year was 90.3%. Median CA19–9 prior to CRT was 30.6 U/mL; CRT combined with E resulted in CA19–9 reduction or stabilization in 84.8%. No difference in OS was observed between patients with tumors of the pancreatic head versus body/tail (p=0.64). Of 27 patients who progressed, first recurrence developed distantly in 16 (59.3%) and locally in 11 (40.7%). A trend towards greater OS (25.1 vs. 19.0 months) was observed among patients who first recurred locally (p=0.10). CRT was stopped early due to toxicity in 5 patients (11.6%); 11 (25.6%) required a treatment break; and 3 (6.7%) required discontinuation of chemotherapy before completion of CRT. Acute grade 2 toxicity included weight loss (27.9%), abdominal pain/nausea/vomiting (27.9%), anorexia (25.6%), fatigue (23.3%), dermatitis (20.9%), diarrhea (9.3%), and transaminitis (4.7%), but none of these were dose-limiting. Acute grade 3 toxicity included neutropenia (11.6%), transaminitis (7.0%), dermatitis (4.7%), and weight loss (2.3%). 1 patient experienced grade 4 neutropenia during chemotherapy. 3 patients (7.0%) experienced grade ≥3 late toxicity in the form of small bowel obstruction. Conclusions: Preliminary analysis of this phase II trial provides encouraging evidence that E combined with standard adjuvant therapy may improve PFS in patients with resected PDA. Longer follow-up is needed to establish whether the addition of E provides a survival advantage over current standard of care regimens. Acute grade 2 toxicity is considerable, but does not preclude patients from receiving the full dose of RT. Grade ≥3 acute and late toxicities are uncommon, though longer follow-up may be necessary to adequately assess late toxicity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A87.

Correlation between pancreatic tumor size as measured on 3D CT scan versus pathologic specimen: Impact on radiation treatment volume.

276 Background: Definition of the target volume for irradiation of pancreatic cancer (PCA) must balance coverage of micrometastatic disease with toxicity. To determine differences between radiographically defined tumors and true pathologic tumor specimens, we correlated the maximum tumor diameter (TD) of preoperatively imaged tumors with resected tumor specimens. METHODS With IRB approval, a retrospective chart review of patients who underwent resection of PCA between 2006 and 2010 was conducted. 73 patients were identified with preoperative CT imaging and pathologic analysis of tumors. 70 of 73 patients had a preoperative 3D CT performed. The TD as measured by a radiologist (EF) on contrast CT and 3D CT reconstruction was compared with that measured by pathological analysis of the resected specimen. RESULTS 70 patients underwent resection with preoperative CT imaging; 14.1% of these patients had CT performed >6 weeks prior to surgery. The mean (SD) pathologic maximum TD was 31.3 mm (11.3) with range 3 mm to 60 mm. Whereas TD was underestimated by 1.9 mm (1.7 SE) with CT relative to pathologic analysis, this difference was not statistically significant (paired t-test, p=0.27) with a correlation coefficient of 0.265. 3D CT imaging had a smaller mean difference with a mean 3D CT diameter 0.4 mm (1.76 SE) larger than the pathologic specimen (p=0.82) with correlation coefficient 0.222. However, the max TD on 3D CT imaging was on average 2.3 mm larger than on CT (p=0.016) with correlation coefficient 0.798. Of patients with R0 resections (N=48), CT underestimated path size by 3.1 mm (p=0.020), whereas 3D CT was slightly larger (0.1 mm, p=0.949). For R1 resections (n=22), both CT and 3D CT overestimated size (0.8 mm and 1.1 mm, respectively, p>0.5). CONCLUSIONS PCA TD is generally underestimated on CT imaging, yet better approximated with 3D CT. Improved correlation was seen between CT and pathologic specimens following R0 resection. Alternatively, R1 resection specimens were slightly overestimated by CT/3D CT imaging. As a result, clinical target volumes should be expanded accordingly during radiotherapy planning to properly account for these discrepancies in the gross tumor. No significant financial relationships to disclose.