Time Of Primary Tumor Resection Research Articles

Progression of Papillary Thyroid Carcinoma to Anaplastic Carcinoma in Metastatic Lymph Nodes: Solid/Insular Growth and Hobnail Cell Change in Lymph Nodes Are Predictors of Subsequent Anaplastic Transformation

Most anaplastic thyroid carcinomas (ATCs) arise from papillary thyroid carcinoma (PTC). This process is also called anaplastic transformation, and the morphological harbingers of this phenomenon in nodal recurrence have not been assessed systematically. For this reason, the current study focused on features of 10 PTCs with regional lymph node recurrence that was accompanied with disease progression due to anaplastic transformation in at least one of the nodal recurrences. The findings of additional 19 PTCs which recurred without anaplastic transformation after ≥ 10 years of follow-up served as the control group. There were no clinicopathological differences between the two groups at initial surgery including age, gender, tumor size, lymph node metastasis, distant metastasis, extrathyroidal extension, histologic subtype, and treatment. The median time from the initial thyroid surgery to anaplastic transformation in the nodal recurrence was 106 months (range 6 to 437 months). Mutational analyses showed recurrent PTCs with anaplastic transformation had a high prevalence of BRAFV600E mutation (8/9) and TERT promoter mutation (9/9), both of which were detected in primary tumors. PIK3CAH1047R mutation was detected in one case. No case had RAS mutation. Nineteen recurrent PTCs without anaplastic transformation harbored BRAFV600E mutation and seventeen of these had TERT promoter mutation. Unlike primary tumors with subsequent nodal anaplastic transformation, TERT promoter mutation was only present in the metastatic nodal recurrence from 4 patients without transformation. No patients had neither high-grade features (necrosis and increased mitotic activity) nor solid/insular growth or hobnail cell features in their primary tumors. In the group of patients with transformation, 3 had solid/insular growth in the lymph node metastasis at the time of primary tumor resection (one displaying nuclear features of PTC and solid growth with increased mitotic activity, one with insular component consistent with poorly differentiated carcinoma component, and one displaying nuclear features of PTC and solid growth), and additional 2 patients had solid/insular growth with no high-grade features or poorly differentiated carcinoma component at the time of subsequent nodal recurrence prior to anaplastic transformation. Hobnail cell features were exclusively seen in subsequent metastatic lymph nodes prior to anaplastic transformation. The control group lacked solid/insular growth and hobnail cell features in the metastatic nodal disease. Aberrant p53 expression and loss of TTF-1 featured tumor components with anaplastic transformation. This series identified a subset of recurrent PTCs with TERT promoter mutation was prone to undergo anaplastic transformation, and that solid/insular growth and hobnail cell features were morphological predictors of anaplastic transformation in the nodal recurrence.

Abstract 6519: Patient, primary colorectal tumor and liver metastases factors which influence survival after liver metastasectomy and therefore should be considered at the preoperative tumor board

Abstract Aim of the study: Patients with colorectal liver metastases (CRLM) should be considered for liver surgery and this study illuminate important factors to be considered at the preoperative multidisciplinary tumor board. Background: Survival after surgical resection or ablation of colorectal liver metastases is increasingly favorable but only a minority of patients undergo curatively intended treatment. Several studies have shown the importance of assessing resectability by liver surgeons. Which prognostic factors to consider before liver surgery is not fully understood. Methods: The Swedish colorectal cancer registry (SCRCR) and the Swedish registry for liver tumors (SweLiv) were linked to identify radically resected primary colorectal cancer patients during the years 2009-2013 also surgically treated for liver metastases, synchronously or metachronously. CRLM characteristics and treatment strategies as well as primary tumor and patient factors were analyzed for prognostic impact. 5-year age-standardized relative survival (RS) and 5-year excess mortality rate ratio (EMRR) were calculated. Treatment with ablation only for tumors with maximum size of 30 mm was analyzed in a propensity score weighted cox regression. Results: 1325 patients were included in the study cohort, whereof 300 were 75 years or older. 1200 were treated with resection and 125 were treated with ablation only. Age-standardized relative five-year survival after open resection of colorectal liver metastases was 54.8 % (95 % CI: 50.6-58.7) and after ablation 32.4 % (95 % CI: 23.3-41.9). Multivariate analysis identified age ≥75 years, tumor size >20 mm, location in segment 4, 6, 7 or 8, multiple metastatic sites and progress after chemotherapy as important risk factors with more than 25 % higher EMRR. Only when analyzed without segments included in the multivariate model was the number of metastases a significant risk factor. Vascular invasion, lymph node ratio and complications at time of primary tumor resection were also important negative prognostic factors. Ablation of small metastases compared to resection was a significant risk factor (HR 2.25 (95 % CI 1.61-3.15)). Conclusion: Tumor size over 20 mm and location of metastases as well as lymph node status and complications after resection of the primary tumor are important risk factors for survival outcome after liver surgery of CRLM. Progress after preoperative chemotherapy and ablation compared to resection more than doubled the risk of death within 5 years. Citation Format: Peter Scherman, Peter Naredi, Ingvar Syk, Erik Holmberg, Magnus Rizell. Patient, primary colorectal tumor and liver metastases factors which influence survival after liver metastasectomy and therefore should be considered at the preoperative tumor board [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6519.

Impact of patient, primary tumor and metastatic pattern including tumor location on survival in patients undergoing ablation or resection for colorectal liver metastases: A population-based national cohort study

IntroductionSelecting the optimal treatment strategy for patients with colorectal liver metastases (CRLM) aim to improve survival for the total cohort. Following the introduction of laparoscopic resections and ablation, localization may direct choice of method. The aim with this study was to re-evaluate prognostic factors that should be considered at the preoperative multidisciplinary tumor board, based on a national population cohort. Materials and methodsA national cohort with radically operated colorectal cancer in 2009-2013, also treated for CRLM was identified in Swedish national registries. Prognostic factors were identified and evaluated in multivariable analyses. Results1200 patients treated with resection and 125 with ablation only were included in the study cohort. Relative five-year survival was 54.7% (50.9%-58.4%) and 32.0% (22.4%-41.9%), respectively). High age, acute surgery and complications at time of primary tumor resection remained important risk factors at liver surgery, as well as the primary tumor characteristics; vascular invasion and high lymph node ratio. As for metastatic pattern; tumor size, location in segment 4, 6, 7 or 8, multiple metastatic sites and progress after preoperative chemotherapy were significant risk factors. In multivariate analyses, ablation therapy doubled the risk of death within 5 years. This strong negative impact was confirmed in a weighted propensity score analysis (HR = 2.1 (95 % CI 1.5 -3.0)). ConclusionSegmental localization and tumor size were prognostic factors but also patient and primary tumor factors significantly impacted survival after intervention for CRLM. Long-term survival was significantly lower after ablation therapy compared to surgical resection.

Abstract P5-08-10: Surveillance for BRCA1/2 mutation carriers - Is "early detection" really early enough?

Abstract Background: Annual MRI screening is associated with a significant reduction in the incidence of advanced-stage breast cancer (BC) in BRCA1/2 mutation carriers. The purpose of our study was to assess stage at diagnosis and therapeutic approaches in BRCA1/2 carriers and compare these parameters in women who developed BC while adhering to the recommended surveillance scheme ("known carriers"), with BC cases who became aware of their BRCA carreirship after BC diagnosis ("latent carriers"). Methods: Retrospective data were collected on BRCA1/2 mutation carriers treated for BC at the Sheba medical center, both at the oncology institute and the high-risk clinic. The main variables evaluated were tumor characteristics, stage at diagnosis, and treatment decisions. Results: Overall, 529 BRCA1/2 carriers were identified. At the time of data summary, relevant clinical information was available for 297 patients. Median follow-up time was 77.4 months (range, 2.5-519). The group of known carriers included 95 women (median age at diagnosis 41.9 [range 27.8-80.3 years]), 70 (74%) were BRCA1 carriers, 23 (24%) BRCA2 carriers, and 2 (2.1%) carried mutations in both genes. The median age at diagnosis of 202 latent carriers was 43.7 (range 23.8-75 years), p=0.8284. Of latent carriers 117 (58%) were BRCA1 mutation carriers and 85 (42%) harbored a BRCA2 mutation. In the group of known carriers, 19% were diagnosed with carcinoma in situ (DCIS) vs. 5% in the group of latent carriers (p=00012). Stage T1N0 disease was diagnosed in 54/95 (56.8%) of known carriers vs. 59/202 (29.2%) of latent carriers (p<0.00001). Node-positive disease was diagnosed in 11/95 (11.6%) of known carriers vs. 98/202 (48.5%) of latent carriers (p<0.00001). Metastatic disease was diagnosed at presentation in none of the known carriers vs. 4/202 (2%) of latent carriers (p=0.16758). Overall, in the group of known carriers (including all stages) 46/95 (48.4%) received neoadjuvant (n=12) or adjuvant (n=34) chemotherapy (71.7% of them for triple-negative disease), and 41/95 (43.2%) received radiotherapy. In the group of latent carriers, 162/202 (80.2%) received neoadjuvant (n=74) or adjuvant (n=88) chemotherapy (p<0.00001), 59.3% of them for triple-negative disease, and 173/202 (85.6%) underwent radiotherapy. Contralateral risk-reducing mastectomy (CRRM) was performed by 59/95 (62%) of the known carriers, 73% of them at the time of primary tumor resection and the rest – at a later stage. Among latent carriers, 82/202 (40.6%) underwent CRRM, 44% at the time of primary tumor resection (p=0.00054). Conclusions: As expected, diagnosis of early stage disease (DCIS or T1N0) was significantly higher in the group of known BRCA1/2 carriers - disease that was diagnosed in the course of tight surveillance. Yet, despite this early stage diagnosis, chemotherapy and radiotherapy treatments were employed in a substantial proportion of these cases. Healthy BRCA1/2 mutation carriers should be informed about these chemotherapy and radiotherapy rates while discussing risk-reducing surgical options. There is an urgent need for a more accurate ability to predict individual mutation carrier cancer risk, as well as tools for selection of patients with stage I triple-negative disease who will do well without chemotherapy. Citation Format: Rinat Bernstein Molho, Bella Kaufman, Merav A Ben David, Miri Sklair-Levy, Yael Laitman, Eitan Friedman. Surveillance for BRCA1/2 mutation carriers - Is "early detection" really early enough? [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-08-10.

The natural history of renal cell carcinoma with pulmonary metastases illuminated through mathematical modeling

The goal of this study is to uncover some unobservable aspects of the individual-patient natural history of metastatic renal cell carcinoma (RCC) through mathematical modeling. We analyzed four clear cell RCC patients who at the time of primary tumor resection already had pulmonary metastases. Our description of the natural history of cancer in these patients was based on a parameterized version of a previously proposed very general mathematical model adjusted to these clinical cases. For each patient, identifiable model parameters were estimated by the method of maximum likelihood from the volumes of lung metastases computed from CT scans taken at or around the time of surgery. The model-based distribution of the volumes of lung metastases with likelihood maximizing parameters provided an excellent fit to the data for all patients analyzed. We found that, according to the model, the most likely scenario in all four patients had the following clinically important features: (1) duration of metastatic latency was very small compared to the growth period; (2) seeding of the first lung metastasis occurred before primary tumor reached detectable size, which implies that early cancer detection would not have prevented metastasis; (3) primary tumor contained a relatively fast growing subpopulation of metastasis-producing cells, which is consistent with the observed aggressive course of the disease; and (4) the volume of the primary tumor at the time of metastasis survey does not seem to be correlated with such characteristics of the metastatic burden as the number of detected lung metastases, their total volume, and the volume of the largest detected lung metastasis.

Non-invasive expandable prosthesis in musculoskeletal oncology paediatric patients for the distal and proximal femur. First results.

The non-invasive expandable prosthesis for skeletally immature patients is used after limb salvage surgery following tumor resection. The aim of the study was to assess the effectiveness of this treatment. Seven paediatric patients with femoral tumors had resection and limb salvage with an uncemented non-invasive growing prosthesis. Mean age at the time of surgery was 9.8 (range 8-12) years. There were six distal femur osteosarcomas and one proximal femur Ewing sarcoma. Six total knee prosthesis were implanted at the time of primary tumor resection and one bipolar hip prosthesis was a revision from a failed osteoarticular hip allograft. Functional outcomes and emotional acceptance were assessed using the MSTS score. The mean follow-up was 65.3months (range 29-91) months. Two patients died of pulmonary metastasis and there was no local recurrence. The mean femoral resection was 18 cm (range 17-19) on the knee, and 24cm on the hip. Mean total expansion was 36.4mm (range 12.3-63.5). The mean MSTS score after rehabilitation was 26.3 (range 21-29). There was one lengthening device failure, one late infection and one patient who required iliofemoral bypass grafting surgery for a pelvic metastasis. No local recurrence occurred. The non-invasive expandable prosthesis reduces the final limb-length discrepancy in growing patients with an acceptable function and appears to have an advantage as compared to invasive expandable prostheses which require multiple surgical procedures, but the complications rate is still high.

Renal cell carcinoma with vena caval involvement: a contemporary clinicopathologic analysis of 53 cases

A clinicopathologic analysis of patients with renal cell carcinoma (RCC) and vena caval involvement diagnosed at our institution was performed. Multiple clinicopathologic parameters were examined. Fifty-three cases were identified. Mean patient age was 62 years (range, 40-82 years). The cohort comprised 36 of 53 (68%) men and 17 of 53 (32%) women. Mean primary tumor size was 10.4 cm (range, 3.1-21.0 cm). The breakdown of tumor stage was as follows: 37 of 53 (70%) were pT3b, 14 of 53 (26%) were pT3c, and 2 of 53 (4%) were pT4. Most of the tumors were clear cell RCC (45/53, 84.6%), although other variants were also represented. All cases were Fuhrman nuclear grade 3 (34/53, 64%) or 4 (19/53, 36%). Tumor necrosis was present in 41 of 53 (77%) cases. At the time of the initial tumor resection, 11 of 53 (21%) cases were staged pM1. Of the 42 patients staged as pMX at the time of primary tumor resection, 12 of 42 (29%) later developed metastasis, most commonly to the lungs. Of all 53 cases with these very advanced tumors, only 6 of 53 (11.3%) had positive surgical margins: 4 of 53 (7.5%) had positive vascular resection margins, and 2 of 53 (3.8%) had focally positive perinephric fat margins. The mean 5-year survival in our cohort was 50%. Our findings suggest that a select group of patients with RCC with vena caval involvement may benefit from radical nephrectomy, although some tumors may have positive vascular and/or nonvascular surgical resection margins even in the best surgical hands. Multi-institutional studies are needed to further characterize these advanced tumors from the molecular standpoint.

Detection of liver micrometastases from colorectal origin by perfusion CT in a rat model

Some patients with colorectal carcinoma have liver metastases (LMs) which cannot be detected by conventional imaging. This study aimed to assess whether hepatic perfusion changes induced by micrometastases can be detected by perfusion computed tomography (CT). LMs were produced in rats by injecting carcinoma cells into the portal vein. Perfusion CT was performed at microscopic (day 10), interval (day 17), and macroscopic stage (day 34). Perfusion parameters were computed using a dual-input one-compartmental model. Micro and macro LMs presented a mean diameter of 0.5 and 2.6 mm, respectively. Compared to controls, LMs at interval (1.1 mm) and macroscopic stage induced significant perfusion changes: a decrease of 42% (P=0.004) and 41% (P=0.029) in hepatic transit time and an increase of 292% (P=0.073) and 240% (P=0.001) in portal delay, respectively. LMs with a mean diameter between 1.1 and 2.6 mm induced significant hepatic perfusion changes, detected by CT. Such detection may help to select patients and propose chemotherapy at the time of primary tumor resection.

Is elective neck dissection needed in clinically N0 neck in maxillary cancer?

Maxillary cancer can be classified according to its primary site. In the literature, many authors divide maxillary cancer into carcinomas of the oral mucosa (gingiva, alveolus and hard palate), and carcinomas of the maxillary sinus and nasal cavity malignancies1,2,3,4. The incidence of neck node metastasis was reported to be 3% to 26% and 12% to 29% in the maxillary sinus and oral mucosa, respectively1,4,5,6,7,8,9,10,11. Recent studies have demonstrated that the incidence of regional metastasis of squamous cell carcinoma (SCC) of the upper gingiva, alveolus and hard palate is similar to that of the tongue and mouth floor5,6,7,8. The traditional management of clinically N0 neck in maxillary cancer has been to wait and see, and this strategy has been widely accepted. Elective neck dissection in clinically N0 neck in maxillary cancer remains controversial. There have been no prospective studies on this topic because of the rarity of maxillary cancer. It is widely accepted that neck dissection is the best course of treatment for maxillary cancer if the possibility of neck metastasis is greater than 15% to 20%12,13,14. In SCC of the hard palate, maxillary gingiva and alveolus, Montes and Schmidt6 demonstrated a 27% regional failure rate in clinically N0 neck after primary resection. Simental et al.5 reported the occult metastasis rate of SCC to be 29% in the maxillary gingiva, alveolus, and hard palate. Yorozu et al.8 found the occult metastasis rate of SCC in the hard palate to be 21%. In patients with maxillary sinus cancer, Kim et al.15 reported 13.5% occult metastasis in those who did not receive elective neck dissection at the time of primary resection. Le et al.4 described a 5-year nodal relapse rate of 20% in N0 neck of maxillary sinus carcinoma without elective neck control at the time of or after surgery, while this rate was reduced to 0% with elective neck irradiation after surgery. Many studies have reported that occult metastasis of cancers of the oral mucosa of the maxilla is more common than it is in cancers of the maxillary sinus. However, there have been no randomized prospective studies regarding occult metastasis of these cancers. Traditionally, elective neck dissection of clinically N0 neck is delayed after primary resection of maxillary cancer. Recently, many authors have agreed that regional metastasis of maxillary cancer is aggressive and comparable to cancers of tongue and mouth floor1,5,6,7. Consequently, they recommend elective neck dissection at the time of primary tumor resection. Simental et al.5 noted that maxillary cancer of the hard palate and alveolus behave like lower gingival cancer, not like sinonasal cancer, and drained level I, II, and III. Also, the rate of occult metastasis of maxillary oral mucosa cancer is very high, and most recent reports have recommended elective neck dissection in N0 neck2,3,5,7,8,10,12,13. Salvage surgery may be unsuccessful in cases of regional failure after primary resection. Elective neck dissection is highly recommended in cancers of the maxillary gingiva, alveolus, and hard palate for regional control. Elective neck dissection is also recommended in cases of locally-advanced maxillary sinus cancer. For regional control, many authors suggest that elective neck dissection is better than radiation therapy, because salvage surgery after radiation therapy can be very difficult2,3,5,7,12,13,14.

Negative trial results are important to understand the mechanisms of multimodality therapy in gastric cancer

Several factors influence the outcome of gastric cancer patients with invasive growth beyond the submucosa, which includes lymphatic and concomitant occult, intraperitoneal tumor cell spread. Organ metastasis or tumor dissemination outside the abdominal cavity is a late finding in gastric cancer compared to other tumor entities. Therapy of gastric cancer thus has to address this fact not only by the complete removal of the primary lesion (R0 resection), but at the same time by the adequate treatment of the routes of tumor cell dissemination. The dissection of the gastric lymph node basins at the time of primary tumor resection constitutes the surgical, and probably most important, part of this treatment. However, invisible tumor spread outside the resectable plane, whether it be peritoneal or within the abdominal organs and tissue, needs additional consideration. Before evaluating additional modalities to tackle this disease-inherent problem, the importance of the experience of the treating surgeon should be stressed. Surgical quality seems to be the most important factor influencing longterm patient survival and sets the benchmark against which all additional (neo) adjuvant treatments must be compared. Historically, postoperative application of chemotherapy has been used first to address the poor outcome of gastric cancer patients (i.e., adjuvant chemotherapy if given after an R0 resection). This approach aims to eliminate any minimal residual tumor, which, at the time of initial treatment, is not detectable by diagnostic means. After two decades of clinical trials and two meta-analyses with inconsistent results, the concept of the preoperative application of chemotherapy was introduced (neoadjuvant chemotherapy). In contrast to adjuvant treatment, neoadjuvant chemotherapy aims primarily at downsizing the primary lesion in order to increase the chance of a complete tumor resection. In the initial trial to test this hypothesis, polychemotherapy–based on cisplatinum–was used, comparable to those known from many previous adjuvant trials. In addition to cytostatic medication, radio-chemotherapy has been evaluated, to improve the local tumor control and thus prolong survival. Three European studies (MAGIC, ACCORD, EORTC 40954), one American trial (SWOG INT 0116), and one Japanese trial (ACTS GC) have addressed these options in the past decade, all with the highest level of methodological evidence. None of the regimens used targeted the intraperitoneal cavity, however, a clinical fact of great importance, which has now been addressed by the Japan Clinical Oncology Group trial (JCOG) 9206-2 reported in this issue of Gastric Cancer. The neoadjuvant application of chemotherapy in all the above-mentioned trials improved the resectability of the primary lesion compared to the surgery-alone arm. Also, all the above-mentioned trials, with the exception of the EORTC 40954 study, showed a statistically significant improvement in survival in the multimodality-treatment arm. In addition, in the United States, radiotherapy, and in Japan, adjuvant chemotherapy, did result in a better outcome if compared to surgery alone. With this short overview in mind, how should we interpret the final results of the JCOG trial 9206-2? This editorial refers to the article doi:10.1007/s10120-011-0027-3.

Abstract 5215: Detection of circulating tumor cells in peripheral blood of patients with renal cell carcinoma

Abstract Detection of circulating tumor cells in peripheral blood of patients with renal cell carcinoma The aim of this study was to evaluate the clinical relevance of the presence of disseminated tumor cells in peripheral blood, so called circulating tumor cells (CTCs), for renal cell carcinoma (RCC) patients. 233 peripheral blood samples from 154 RCC patients were investigated for the presence of disseminated tumor cells (DTCs) by autoMACS technique and immunocytochemical (ICC) staining of cytokeratin. The frequency of CTCs was analyzed statistically for correlation with relevant clinical data. Two kinds of tumor cells were detected: those with expression of cytokeratin 8/18 (CK+), but also cells without a detectable CK+ expression, which we called large blue stained (Bl+) cells with a tumor-like morphology. After following the CD45 autoMACS depletion protocol, we identified CTCs in 96 out of 233 peripheral blood samples (41%), which originated from 81 out of 154 (53%) RCC patients. A significant correlation between the detection of CTCs and positive lymph node status (p < 0.001; Chi-square test) and the presence of synchronous metastases at the time of primary tumor resection (p < 0.02; Chi-square test) was found. In a multivariate Cox's regression hazard model, presence of CK+ CTCs was significantly correlated with poor overall survival for RCC patients (RR=2.3; p < 0.05). The presence of CTCs correlated to lymph node status and presence of synchronous metastases in RCC. It is important to evaluate CK+ and Bl+ tumor cells together to determine the role of CTCs in tumor behavior and disease progression. Detection of CK+ CTCs in peripheral blood is a significant and independent prognostic factor for RCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5215. doi:10.1158/1538-7445.AM2011-5215

Abstract 2231: Detection of circulating tumor cells in peripheral blood of patients with renal cell carcinoma correlates with prognosis

Abstract Purpose. The aim of this study was to evaluate the clinical relevance of the presence of disseminated tumor cells in peripheral blood [so called circulating tumor cells (CTCs)] for renal cell carcinoma (RCC) patients. Methods. 233 peripheral blood samples from 154 RCC patients were investigated for the presence of disseminated tumor cells (DTCs) by autoMACS technique and immunocytochemical (ICC) staining of cytokeratin. The frequency of CTCs was analyzed statistically for correlation with relevant clinical data. Results. Two kinds of tumor cells were detected: those with expression of cytokeratin 8/18 (CK+), but also cells without a detectable CK+ expression, which we called large blue stained (Bl+) cells with a tumor-like morphology. After following the CD45 autoMACS depletion protocol, we identified CTCs in 96 out of 233 peripheral blood samples (41%), which originated from 81 out of 154 (53%) RCC patients. A significant correlation between the detection of CTCs and positive lymph node status (p<0.001; chi2-test) and the presence of synchronous metastases at the time of primary tumor resection (p=0.014; chi2-test) was found. In a multivariate Cox's regression hazard model, presence of CK+ CTCs was significantly correlated with poor overall survival for RCC patients (RR=2.3; P=0.048). Conclusions. The presence of CTCs correlated to lymph node status and presence of synchronous metastases in RCC. It is important to evaluate CK+ and Bl+ tumor cells together to determine the role of CTCs in tumor behavior and disease progression. Detection of CK+ CTCs in peripheral blood is a significant and independent prognostic factor for RCC. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2231.

Detection of Circulating Tumor Cells in Peripheral Blood of Patients with Renal Cell Carcinoma Correlates with Prognosis

The aim of this study was to evaluate the clinical relevance of the presence of disseminated tumor cells in peripheral blood (so-called circulating tumor cells) for renal cell carcinoma patients. Two hundred thirty-three peripheral blood samples from 154 renal cell carcinoma patients were investigated for the presence of disseminated tumor cells by autoMACS technique and immunocytochemical staining of cytokeratin. The frequency of circulating tumor cells was analyzed statistically for correlation with relevant clinical data. Two kinds of tumor cells were detected: those with expression of cytokeratin 8/18 (CK+) and cells without a detectable cytokeratin expression, which we called large blue-stained cells with a tumorlike morphology. After following the CD45 autoMACS depletion protocol, we identified circulating tumor cells in 96 (41%) of 233 peripheral blood samples, which originated from 81 (53%) of 154 renal cell carcinoma patients. A significant correlation between the detection of circulating tumor cells and positive lymph node status (P < 0.001; chi(2) test) and the presence of synchronous metastases at the time of primary tumor resection (P = 0.014; chi(2) test) was found. In a multivariate Cox's regression hazard model, presence of CK+ circulating tumor cells was significantly correlated with poor overall survival for renal cell carcinoma patients (relative risk, 2.3; P = 0.048). The presence of circulating tumor cells correlated to lymph node status and presence of synchronous metastases in renal cell carcinoma. It is important to evaluate CK+ and blue-stained tumor cells together to determine the role of circulating tumor cells in tumor behavior and disease progression. Detection of CK+ circulating tumor cells in peripheral blood is a significant and independent prognostic factor for renal cell carcinoma.

INTRAOPERATIVE ARACHNOID AND CEREBROSPINAL FLUID SAMPLING IN CHILDREN WITH POSTERIOR FOSSA BRAIN TUMORS

This study was conducted to determine whether arachnoid tissue or cerebrospinal fluid (CSF) sampling is valuable for risk stratification in children with posterior fossa brain tumors. Arachnoid tissue and CSF from the cisterna magna (CSFCM) was sampled at the time of primary tumor resection. Results were compared with conventional staging methods (M stage) and correlated with patient outcome. Eighty-three patients were enrolled in the study. Arachnoid infiltration was identified in 11 of 80 (13.8%) and CSFCM was positive in 20 of 77 (26.0%) specimens. Arachnoid infiltration and CSF cytology were found in 20.0% and 44.8%, respectively, for medulloblastoma/pineoblastoma (primitive neuroectodermal tumor), 6.9% and 3.6% for pilocytic astrocytoma, and 0.0% and 33.3% for ependymoma. The 3-year event-free survival (EFS) was negatively influenced by either arachnoid infiltration (40.9% arachnoid positive versus 65.4% arachnoid negative; P = 0.23) or CSFCM positivity (52.6% CSFCM positive versus 67.1% CSFCM negative; P = 0.03). The 3-year EFS for patients with primitive neuroectodermal tumor who had positive arachnoid sampling was 33.3%, compared with 67.3% in patients who had no evidence of arachnoid infiltration (P = 0.26). The 3-year EFS for patients with primitive neuroectodermal tumor who had positive CSFCM was 50.0% compared with 67.5% in patients who had negative cytological analysis of CSFCM (P = 0.07). Arachnoid infiltration and CSF sampling were congruous with M stage in 73.3% and 86.2% of patients, respectively. Intraoperative evidence of arachnoid infiltration or CSFCM dissemination in patients with posterior fossa brain tumors occurs at a variable frequency that is dependent on tumor type, correlates with conventional M stage, and may be predictive of outcome.

Use of angiopoietin-2 serum levels as a clinical surrogate for vascular normalization under bevacizumab treatment

4133 Background: The combination of chemotherapy and the anti-VEGF antibody bevacizumab (BV) is the current standard treatment for advanced colorectal cancer (CRC). Previous efforts to identify biomarkers that predict outcome after BV treatment have failed. Experimental data suggest that the clinical benefit of BV treatment is related to vascular normalization, i.e. the shift of chaotic and immature tumor vessels to a more mature organized state. Angiopoietin-1 (Ang-1) and -2 (Ang-2) are key regulators of vascular maturation. In this pilot study, we examined angiopoietin serum levels in CRC patients before and during BV treatment. Methods: A cohort of n=82 CRC patients was analysed for VEGF, Ang-1 and Ang-2 serum concentrations at the time of primary tumor resection (n=63) or prior to treatment with chemotherapy and BV (n=19). In 15 of these patients, serum levels of Ang-1 and Ang-2 were measured every 4 weeks during therapy for three months. Results: Ang-2 but not Ang-1 serum concentrations were significantly higher in CRC patients compared to 15 healthy volunteers (Ang-2 2,465±1,312 pg/ml vs. 1,813±844 pg/ml, p<0.021, Ang-1 29,226±12,527 pg/ml vs. 35,447±13,553 pg/ml, p=0.108). No significant differences were observed between CRC stages. Pretherapeutic Ang-1 and Ang-2 serum levels were not predictive for response to therapy. However in the course of treatment, in patients responding to therapy (n=10) decreasing Ang-2 levels (mean Δ -622 pg/ml) were observed whereas increasing Ang-2 levels were found in non-responders (n=5) (mean Δ +429 pg/ml, p=0.042). Compared to healthy controls, VEGF serum concentrations tended to be higher in CRC patients (330±299 pg/ml vs. 214±180 pg/ml, p=0.115). Although not significant, VEGF serum levels showed a trend towards increased values in more advanced stages. In accordance with published results, pretherapeutic serum VEGF levels did not correlate with treatment response. Conclusion: Ang-2 serum levels are significantly increased in CRC patients. Furthermore, during treatment with chemotherapy and BV Ang-2 levels fall in responders and rise in non-responders. We suggest that these changes in Ang-2 levels could serve as a clinical surrogate for vascular normalization under BV treatment. No significant financial relationships to disclose.

What Is the Best Treatment for Stage IV Colorectal Cancer?

For decades, clinicians have seen patients who present with extensive stage IV colorectal cancer, frequently with hepatomegaly, weight loss, and poor performance status. Such patients receive supportive care or, if performance status allows, a trial of systemic chemotherapy. With the increased use of preoperative imaging, clinicians are now seeing many patients who present with asymptomatic or minimally symptomatic stage IV colorectal cancer. Management of such patients lacks a significant evidence base. Cook et al. have used the Surveillance, Epidemiology, and End Results (SEER) database from 1988 to 2000 to analyze the patterns of care of such patients. The authors have thoughtfully analyzed these population-based data and have carefully couched their conclusions with appropriate caveats. The data are quite clear in demonstrating that most patients undergo surgical resection of their primary tumors despite the presence of unresectable distant disease—hence, palliative surgery. The SEER data are incomplete in pivotal areas, and this invalidates comparisons of up-front operation versus systemic chemotherapy followed by surgical resection only for subsequent obstruction, perforation, or hemorrhage. The median survival for initial-resection patients was 11 months, compared with 2 months for those who did not undergo resection. These differences suggest that the groups were vastly different with regard to the extent of disease and comorbidities; these elements are not captured in the SEER database. In addition, many patients who present with stage IV disease have the diagnosis made at the time of primary tumor resection, at which time the decision for resection has already been made. The authors clearly define the key arguments: elective operations have a much lower morbidity and mortality than emergency operations, so we should remove the primary tumor and then proceed with chemotherapy with hopes for a good response. However, additional issues relevant to this paradigm are that (1) initial operative intervention (with or without laparoscopic-assisted resection) delays systemic chemotherapy; (2) with recent advances in systemic therapies, median survival with metastatic disease approaches 2 years; (3) it is likely that response at metastatic sites will also be associated with tumor regression at the primary tumor site; and (4) obstruction is uncommon with proximal cancers. We do not know the natural history of unresected primary tumors in patients receiving state-of-the-art chemotherapy who survive 2 to 3 years with initial stage IV cancer. In the absence of prospective clinical data (either randomized or a broad cohort of well-defined clinical and tumor data), stage IV colorectal cancer patients may be treated on the basis of the extent of metastatic disease, comorbidities, location of the primary tumor, symptoms related to the primary tumor, age, and the desire for and likelihood of tolerating systemic chemotherapy. My personal management algorithm is summarized in Table 1. Rectosigmoid and rectal cancer patients are more problematic than those with colon cancer. Abdominoperineal resection is not an attractive palliative operation. Six weeks of radiotherapy may stop or prevent bleeding, but it is time-consuming and uncomfortable. The main clinical challenge is the large cohort of patients with stage IV disease and asymptomatic or minimally symptomatic distant Received March 15, 2005; accepted April 17, 2005; published online June 16, 2005. Address correspondence and reprint requests to: Alfred M. Cohen, MD, FACS, FASCRS; E-mail: acohen@email.uky.edu.

Evaluation of Intracavitary Chemotherapy Delivery for the Treatment of Mammary Carcinoma

Introduction: The purpose of this study was to evaluate tolerability and efficacy of local (intracavitary) delivery of paclitaxel from a gel polymer (poloxamer 407) following marginal (histologically incomplete) resection of mammary carcinoma in a mouse modelMethods: In vitro sensitivity to paclitaxel as well as poloxamer‐taxol mixture (polotax) was determined for 4 human breast tumor cell lines using the MTS‐assay (Promega). Nude mice were then injected with MCF‐7/ADR (AdriamycinR resistant) cells. Tumor growth was monitored by imaging of luciferase activity with a CCD camera (IVIS system, Xenogen). Primary tumors were allowed to grow to 3 different size ranges. At the time of primary tumor resection, animals were randomly assigned to treatment groups comparing intracavitary (in the wound) polotax to intravenous paclitaxel. Mice were imaged weekly to evaluate tumor regrowth and metastasis.Results: All cells lines demonstrated sensitivity to paclitaxel and three of the four cell lines demonstrated improved cytotoxicity with polotax compared to drug delivered alone. One of 9 mice treated with polotax had local regrowth (by 60 days) compared to 6 of 9 mice treated with intravenous paclitaxel. One of 9 mice treated with polotax had distant metastasis at 60 days compared to 5 of 8 mice treated with intravenous paclitaxel. These effects were seen with tumors of all sizes.Discussion/Conclusions: Poloxamer delivery of paclitaxel appears to result in improved efficacy compared to paclitaxel alone. Improved local and systemic control of mammary carcinoma is seen following intracavitary poloxamer delivery of paclitaxel compared to paclitaxel alone in this mouse model.

Detection of disseminated tumor cells in peripheral blood of patients with breast cancer: correlation to nodal status and occurrence of metastases

Objective. Soon after breast cancer becomes invasive, it sheds cancer cells into the blood stream or the cancer cells are spread via lymphatic vessels. The early and unambiguous detection of these disseminated tumor cells (DTC) is of importance for the evaluation of the tumor process and for monitoring therapy response. The detection of disseminated tumor cells by immunocytochemistry (ICC) without previously performing tumor cell enrichment is time consuming and may miss a considerable part of these cells. Therefore, we have applied a negative immunomagnetic enrichment of disseminated tumor cells from the peripheral blood of patients with breast cancer by the depletion of CD45 + leukocytes using automated magnetic activated cell separation (autoMACS). Methods. One hundred twenty-five blood samples from 83 breast cancer patients were investigated for occurrence of disseminated tumor cells by autoMACS technique and immunocytochemical cytokeratin staining. Frequency of disseminated tumor cells was analyzed statistically for correlation to clinical data. Results. Thirty-three of the 125 blood samples (26%) originating from 29 of 83 breast cancer patients (35%) carried cytokeratin positive (CK +) tumor cells. The occurrence of CK + tumor cells correlated significantly with the nodal status ( P = 0.009) and with the occurrence of metastases at the time of primary tumor resection ( P = 0.003). Conclusions. The finding that occurrence DTC detected in peripheral blood of breast cancer patients correlated with nodal stage and metastases is described for the first time. It suggests that disseminated tumor cells identified in peripheral blood by autoMACS are associated with tumor characteristics of breast cancer.

Early multicenter experience with a noninvasive expandable prosthesis.

A noninvasive expandable prosthesis for skeletally immature children after limb salvage surgery has been developed. Between 1998 and 2001, 18 Phenix prostheses were implanted in 15 pediatric patients who had been diagnosed and treated for osteosarcoma about the knee. Of the 15 original prostheses, 10 were implanted at the time of primary tumor resection and five were revisions from an endoprosthetic modular knee system. Sixty expansions of the 18 prostheses were done, with all but two done as outpatient procedures. An average 8.5 mm was obtained per lengthening (range, 1-30 mm). The average followup was 21.5 months (range, 12-33 months) and the latest Musculoskeletal Tumor Society functional scores averaged 90%. Eight revisions were required for stem fracture or loosening. There was one amputation because of a postoperative arterial thrombosis. The principle of the Phenix prosthesis involves storage of energy in a spring compressed by a locking system. Lengthening is achieved via exposure to an electromagnetic field that allows controlled release of the spring. This is a unique expandable custom prosthesis that offers many benefits in maintaining limb length equality in growing patients. Although the early experience is promising, additional data are required regarding the long-term structural integrity of the prosthesis. We are optimistic that this technology will prove beneficial, not only for patients with malignant bone tumors but in applications requiring serial limb length equalizations or for spinal deformities.

Timing of percutaneous endoscopic gastrostomy tube placement in head and neck cancer patients

Percutaneous endoscopic gastrostomy (PEG) is an effective method for providing alimentation in patients with upper aerodigestive tract carcinoma. Multiple complications of this procedure have been reported, ranging from leakage around the tube to tumor seeding of the abdominal cavity. This study was undertaken to determine whether the timing of PEG tube placement with respect to primary tumor extirpation led to a difference in the number and severity of observed complications. The medical records of 43 patients with head and neck carcinoma who had PEG tubes placed from 1995 to 1996 were retrospectively reviewed. Comparisons of timing of PEG tube placement, complication, location, and stage of the primary tumor were performed. In addition, the use of adjuvant therapy with respect to the time of PEG tube placement and complications was evaluated. Of these, 23% were done before and 30% during surgery at the time of primary tumor resection (9 of 13 were after primary removal). One patient had an intraabdominal abscess. Minor complications occurred in 15 of 43 patients (35%) and included granulation tissue at the PEG site, leakage, and tube displacement. Eight of the 9 patients who underwent intraoperative PEG after tumor resection had no complications. Patients who underwent PEG during or after surgery had significantly fewer complications than those who underwent preoperative PEG or had unresectable tumors (P = 0.038). The largest number of complications occurred in patients who underwent preoperative PEG (57%) followed by patients whose tumors were unresectable (31%). There was no statistical difference with regard to tumor location or postoperative x-ray therapy in PEG complications. This study demonstrates that PEG tube placement after tumor resection has the lowest incidence of postoperative complications. Performing PEGs intraoperatively after tumor resection can prevent the need for additional anesthesia to provide alimentation in patients with upper aerodigestive tract carcinoma. (Otolaryngol Head Neck Surg 1999;120:479-82.)