Kia Homayounfar

Liver Transplantation for Neuroendocrine Tumors in Europe—Results and Trends in Patient Selection A 213-Case European Liver Transplant Registry Study

Objective:The purpose of this study was to assess outcomes and indications in a large cohort of patients who underwent liver transplantation (LT) for liver metastases (LM) from neuroendocrine tumors (NET) over a 27-year period. Background:LT for NET remains controversial due to the absence of clear selection criteria and the scarcity and heterogeneity of reported cases. Methods:This retrospective multicentric study included 213 patients who underwent LT for NET performed in 35 centers in 11 European countries between 1982 and 2009. One hundred seven patients underwent transplantation before 2000 and 106 after 2000. Mean age at the time of LT was 46 years. Half of the patients presented hormone secretion and 55% had hepatomegaly. Before LT, 83% of patients had undergone surgical treatment of the primary tumor and/or LM and 76% had received chemotherapy. The median interval between diagnosis of LM and LT was 25 months (range, 1–149 months). In addition to LT, 24 patients underwent major resection procedures and 30 patients underwent minor resection procedures. Results:Three-month postoperative mortality was 10%. At 5 years after LT, overall survival (OS) was 52% and disease-free survival was 30%. At 5 years from diagnosis of LM, OS was 73%. Multivariate analysis identified 3 predictors of poor outcome, that is, major resection in addition to LT, poor tumor differentiation, and hepatomegaly. Since 2000, 5-year OS has increased to 59% in relation with fewer patients presenting poor prognostic factors. Multivariate analysis of the 106 cases treated since 2000 identified the following predictors of poor outcome: hepatomegaly, age more than 45 years, and any amount of resection concurrent with LT. Conclusions:LT is an effective treatment of unresectable LM from NET. Patient selection based on the aforementioned predictors can achieve a 5-year OS between 60% and 80%. However, use of overly restrictive criteria may deny LT to some patients who could benefit. Optimal timing for LT in patients with stable versus progressive disease remains unclear.

Histopathologic Features and Microsatellite Instability of Cancers of the Papilla of Vater and Their Precursor Lesions

The prevalence and development of microsatellite instability (MSI) and underlying mismatch repair (MMR) deficiency in the carcinogenesis of adenocarcinomas of the papilla of Vater and their precursor lesions are not well established. We analyzed 120 ampullary adenomas (31 pure adenomas and 89 carcinoma-associated adenomas) and 170 pure adenocarcinomas for MSI, immunohistochemical expression of MMR proteins and specific histopathologic features. The most common histologic subtype was intestinal (46.5%), followed by pancreatobiliary (23.5%), poorly differentiated adenocarcinomas (12.9%), intestinal-mucinous (8.2%), and invasive papillary carcinomas (5.3%). Eight of 89 adenomas (9%) and 15/144 carcinomas (10%) showed high microsatellite instability (MSI-H), 10/89 adenomas (11%) and 5/144 carcinomas (4%) showed low microsatellite instability (MSI-L), and 71/89 adenomas (80%) and 124/144 carcinomas (86%) were microsatellite stable (MSS). MSI analysis from carcinomas contiguous with an adenomatous component (n=54) exhibited concordant results in 6/8 (75%) MSI-H and 42/46 (91.3%) MSS tumors. Of 14 carcinomas with MSI-H, 7 showed loss of MLH1 and 5/6 (83%) MLH1 promoter methylation, and 2 carcinomas showed simultaneous loss of MSH2 and MSH6. Two carcinomas and 3 adenomas with MSI-H revealed exclusive loss of MSH6. MSI-H cancers were significantly associated with intestinal mucinous subtype (P<0.001), high tumor grade (P=0.003), expansive growth pattern (P=0.044), and marked lymphoid host response (P=0.004). Patients with MSI-H carcinoma had a significantly longer overall survival (P=0.0082) than those with MSI-L or MSS tumors. Our findings indicate that the MSI-phenotype is an early event, which develops at the stage of adenoma and is reliably detectable in the precursor lesion. The MMR deficient molecular pathway of carcinogenesis is associated with a histopathologic phenotype in ampullary cancer, similar to the one that has been well described in colon cancer.

Pattern of chromosomal aberrations in primary liver cancers identified by comparative genomic hybridization

Little is known about the molecular cytogenetic changes in cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma, and on the prognostic significance of chromosomal imbalances in hepatocellular carcinoma. Seventy-eight cases of primary liver cancer with available median follow-up of 16.5 months, including 49 hepatocellular carcinomas, 22 cholangiocarcinomas, and 7 combined hepatocellular-cholangiocarcinomas, were examined by comparative genomic hybridization. In hepatocellular carcinoma, the most frequent changes were +8q (54%), -8p (54%), and +1q (42%), followed by -6q (35%), -4q (33%), -13q (29%), -14q (25%), -16q (19%), -17p (19%), +17q (17%), and +20q (15%). In comparison, cholangiocarcinoma had more gains, losses, and breakpoints than hepatocellular carcinoma or combined hepatocellular-cholangiocarcinoma, specifically more frequently -6q (91%), -3p (68%), -9p (55%), -14q (55%), -13q (45%), +1q (41%), +7q (36%), +7p (32%), and +8q (32%). Combined losses at 6q and 3p appeared to be highly characteristic for cholangiocarcinoma. In contrast, combined hepatocellular-cholangiocarcinoma shared frequent +1q (71%), +8q (57%), and -8p (57%) with hepatocellular carcinoma, but a tendency for higher numbers of imbalances with cholangiocarcinoma. Overall, higher numbers of changes, breakpoints, or gains appeared to carry unfavorable prognostic value among hepatocellular carcinomas, with higher numbers of gains retaining prognostic value among R0-resected hepatocellular carcinomas. Cholangiocarcinoma is characterized by combined losses at 6q and 3p and a tendency for chromosomal instability. On the other hand, combined hepatocellular-cholangiocarcinoma may share similar chromosomal changes with both hepatocellular carcinoma and cholangiocarcinoma, as reflected by common hepatocellular carcinoma-like +8q, +1q, and -8p and a tendency for cholangiocarcinoma-like chromosomal instability. In hepatocellular carcinoma, higher number of gains may prove an adverse prognostic parameter.

Frequency of HER-2 positivity in rectal cancer and prognosis.

In patients with advanced rectal cancer (cUICC II and III) multimodality therapy resulted in better long-term local tumor control. Ongoing clinical trials are focusing on therapy intensification to improve disease-free (DFS) and cancer-specific survival (CSS), the integration of biomarkers for prediction of individual recurrence risk, and the identification of new targets. In this context, we investigated HER-2, a member of the epidermal growth factor receptor family, whose expression pattern and role was unclear in rectal cancer. A total of 264 patients (192 male, 72 female; median age 64 y) received standardized multidisciplinary treatment according to protocols of phase II/III trials of the German Rectal Cancer Study Group. HER-2 status was determined in pretherapeutic biopsies and resection specimens using immunohistochemistry scoring and detection of silver in situ hybridization amplification. Tumors with an immunohistochemistry score of 3+ or silver in situ hybridization ratios of ≥2.0 were classified HER-2 positive; these results were correlated with clinicopathologic parameters [eg, resection (R) status, nodal status ((y)pN)], DFS, and CSS. Positive HER-2 status was found in 12.4% of biopsies and in 26.7% of resected specimens. With a median follow-up of 46.5 months, patients with HER-2 positivity showed in trend a better DFS (P=0.1) and a benefit in CSS (P=0.03). The 5-year survival rate was 96.0% (HER-2 positive) versus 80.0% (HER-2 negative). In univariate and multivariate analyses, HER-2 was an independent predictor for CSS (0.02) along with the (y)pN status (P<0.00001) and R status (P=0.011). HER-2 amplification is detectable in a relevant proportion (26.7%) of rectal cancer patients. For the development of innovative new therapies, HER-2 may represent a promising target and should be further assessed within prospective clinical trials.

Failure of downregulation of survivin following neoadjuvant radiochemotherapy in rectal cancer is associated with distant metastases and shortened survival.

Purpose: Valid molecular markers need to be implemented in clinical trials to fulfill the demand of a risk-adapted and more individualized multimodal therapy of locally advanced primary rectal cancer. In this study, the expression of the inhibitor-of-apoptosis (IAP) protein survivin was evaluated in pretreatment biopsies and corresponding posttreatment resection specimens, and was correlated to histo-pathological tumor characteristics and clinical follow-up. Patients and Methods: One hundred sixteen patients with stage II/III rectal cancer treated with 5-FU–based neoadjuvant radiochemotherapy (RCT) at a single university medical centre within the German Rectal Cancer Trials were investigated. Survivin expression in pretreatment biopsies and surgical resection specimens were determined by immunohistochemistry by two independent institutions and correlated with histopathologic parameters, tumor recurrences, disease-free (DFS), and overall cancer-specific survival (CSS). Results: In pretreatment biopsies, a higher survivin expression correlated with advanced ypT (P = 0.026) and ypUICC (P = 0.05) stage as well as DFS (P = 0.038) after preoperative RCT. High posttreatment survivin levels were associated with advanced ypT stage (P = 0.03) and residual lymph node metastases (P = 0.04). Moreover, neoadjuvant RCT resulted in a significant downregulation of survivin expression (P < 0.0001). A failure of RCT-induced downregulation was associated with development of distant metastases (P = 0.0056) and cancer-related death (P = 0.026), and correlated significantly with DFS (P = 0.011*/0.02**) and CSS (P = 0.0017*/0.01**) in uni-* and multivariate** analyses. Conclusions: Survivin expression displays a marker with prognostic utility in rectal cancers. These results underline the potential of survivin to monitor individual response to RCT and encourage anti-survivin strategies in multimodal rectal cancer therapy within future randomized clinical trials. Clin Cancer Res; 17(6); 1623–31. ©2010 AACR.

Lymph node metastases in rectal cancer after preoperative radiochemotherapy: impact of intramesorectal distribution and residual micrometastatic involvement.

Introduction:After neoadjuvant chemoradiation (CRT), the pathologic determined lymph node (LN) status is the most important prognostic factor in rectal cancer patients. Here we assessed the prognostic impact of residual LN micrometastases (<0.2 cm) and the intramesorectal distribution of LN metastases. Patients and Methods:Surgical specimens from 81 patients with cUICC II/III rectal cancer undergoing neoadjuvant CRT and total mesorectal excision within the German Rectal Cancer Trial CAO/ARO/AIO-04 were prospectively evaluated. The entire mesorectal compartment was paraffin embedded and screened microscopically. The number and distribution of mesorectal LN macrometastases and micrometastases were correlated with disease-free (DFS) and cancer-specific overall survival (CSS). Results:A total of 2412 LNs were detected (mean 29.8±13.7). Twenty-five patients had residual LN metastases (ypN+). The incidence of metastases in the peritumoral mesorectum was higher (7.7%) than that proximal to the tumor (1.5%), whereas no metastases were identified below the tumor level. Patients with both proximal and peritumoral involvement showed a significantly reduced CSS (hazard ratio=5.4; P<0.05). Fourteen patients with ypN+ status (56%) had micrometastases, 9 patients (36%) had only micrometastatic involvement. Patients with nodal macrometastases had a reduced DFS (P<0.01) and CSS (P<0.005) as compared with ypN0 patients, whereas residual micrometastases had no influence on survival. Conclusions:Despite the high incidence of residual LN micrometastases they did not seem to have a prognostic impact in this series. Micrometastases might indicate responsive tumors to CRT with a more favorable biology. The intramesorectal distribution of LN metastases had a prognostic impact and should be validated in further studies.

Enrichment of CD133-expressing cells in rectal cancers treated with preoperative radiochemotherapy is an independent marker for metastasis and survival

The transmembrane glycoprotein CD133 (cluster of differentiation 133; also known as Prominin or PROM1) has been described as a potential stem cell marker in colorectal cancer and is associated with higher tumorigenic potential and resistance to radiochemotherapy (RCT). In this study, CD133 expression was evaluated in pre‐RCT tumor biopsies and the corresponding post‐RCT surgical specimens from patients with locally advanced rectal adenocarcinoma, and expression levels were correlated with histopathologic features and clinical follow‐up.

Ultrasonic scalpel causes greater depth of soft tissue necrosis compared to monopolar electrocautery at standard power level settings in a pig model

BackgroundUltrasonic scalpel (UC) and monopolar electrocautery (ME) are common tools for soft tissue dissection. However, morphological data on the related tissue alteration are discordant. We developed an automatic device for standardized sample excision and compared quality and depth of morphological changes caused by UC and ME in a pig model.Methods100 tissue samples (5 × 3 cm) of the abdominal wall were excised in 16 pigs. Excisions were randomly performed manually or by using the self-constructed automatic device at standard power levels (60 W cutting in ME, level 5 in UC) for abdominal surgery. Quality of tissue alteration and depth of coagulation necrosis were examined histopathologically. Device (UC vs. ME) and mode (manually vs. automatic) effects were studied by two-way analysis of variance at a significance level of 5%.ResultsAt the investigated power level settings UC and ME induced qualitatively similar coagulation necroses. Mean depth of necrosis was 450.4 ± 457.8 μm for manual UC and 553.5 ± 326.9 μm for automatic UC versus 149.0 ± 74.3 μm for manual ME and 257.6 ± 119.4 μm for automatic ME. Coagulation necrosis was significantly deeper (p < 0.01) when UC was used compared to ME. The mode of excision (manual versus automatic) did not influence the depth of necrosis (p = 0.85). There was no significant interaction between dissection tool and mode of excision (p = 0.93).ConclusionsThermal injury caused by UC and ME results in qualitatively similar coagulation necrosis. The depth of necrosis is significantly greater in UC compared to ME at investigated standard power levels.

Repeated adjuvant anti-CEA radioimmunotherapy after resection of colorectal liver metastases: Safety, feasibility, and long-term efficacy results of a prospective phase 2 study

In previous work, a single administration of anticarcinoembryonic antigen (anti‐CEA) 131I‐labetuzumab radioimmunotherapy (RIT) after complete resection of colorectal liver metastases was well tolerated and significantly improved survival compared with controls. In the current phase 2 trial, the authors studied repeated RIT in the same setting, examining safety, feasibility, and efficacy.

Stage-Dependent Frequency of Lymph Node Metastases in Patients With Rectal Carcinoma After Preoperative Chemoradiation: Results from the CAO/ARO/AIO-94 Trial and From a Comparative Prospective Evaluation With Extensive Pathological Workup.

BACKGROUND: For patients with ycT1/2 rectal carcinomas after neoadjuvant chemoradiotherapy, local excision instead of radical surgery has increasingly been discussed as a way to avoid postoperative morbidity associated with radical surgery. OBJECTIVE: The purpose of this study was to determine the incidence of lymph node metastases in total mesorectal excision specimens with ypT0, ypT1/2, and ypT3/4 rectal cancers. DESIGN: This is a prospective and retrospective cohort study. SETTINGS: This study was conducted in tertiary referral hospitals that are part of the German Rectal Cancer Study Group. PATIENTS: A total of 479 patients with stage II and III rectal cancers treated within phase III trials of the German Rectal Cancer Study Group were evaluated. Specimens from 81 patients treated in the Working Group of Surgical Oncology/Working Group of Radiation Oncology/Working Group of Medical Oncology of the Germany Cancer Society (CAO/ARO/AIO-04) trial were prospectively studied with extensive microscopic screening of the entire mesorectum. The frequency and localization of nodal metastases were specified and compared with those of 398 patients having received neoadjuvant chemoradiation within the CAO/ARO/AIO-94 trial. MAIN OUTCOME MEASURES: Frequency and localization of mesorectal lymph node metastases in patients with ypT0, ypT1/2, or ypT3/4 cancer were measured. RESULTS: A mean number of 28.0 ± 13.7 nodes were detected per specimen within the prospective group. A total of 25% of patients in the ypT1/2 group had nodal metastases compared with 40% in the ypT3/4 group. Patients with node-positive ypT1/2 had a mean number of 2.2 metastases, and 55% of these metastases were located far from the primary lesion in the proximal mesorectum. Within the CAO/ARO/AIO-94 cohort (n = 398), 19% of patients with ypT1/2 (ypT1 = 22%; ypT2 = 18%) had ypN+ status compared with 43% with ypT3/4 cancers (ypT3 = 40%; ypT4 = 73%). LIMITATIONS: Low numbers of patients with ypT0 limited the evaluation of nodal metastases in pathologic complete responders. CONCLUSIONS: Even in good responders (ypT1/2), >20% of rectal carcinomas still harbored residual lymph node metastases. Local excision for patients with ycT1/2 rectal cancers would, thus, miss metastases in a considerable percentage and might involve the risk of significant undertreatment in a number of patients.