Microscopic Tumor Foci Research Articles

Mirk kinase inhibition blocks the in vivo growth of pancreatic cancer cells.

The Mirk/dyrk1B gene is upregulated and sometimes amplified in pancreatic ductal carcinomas. In poor microenvironmental conditions Mirk mediates cell survival by maintaining cancer cells in a largely quiescent, noncycling state and by decreasing toxic ROS levels through maintaining expression of a series of antioxidant genes. Premature entry into cycle, increased ROS levels, DNA damage, and apoptosis follow Mirk kinase depletion or inhibition. Mirk kinase inhibitor EHT5372 treated Panc1 spheroids lost quiescence markers coincident with an increase in cyclin A showing entry into cycle, and exhibited DNA damage, apoptosis and smaller size. EHT5372 treatment in vivo led to an increased fraction of Ki67 positive, cycling cells in Panc1 xenografts whose size was reduced. Pdx-1-cre LSL/KrasG12D/Ink4a/Arf null B6 mice always develop pancreatic cancer, allowing only 30% survival by 8 weeks, while each of the Mirk kinase inhibitor treated mice survived 8 weeks. Mirk inhibition led to a roughly four-fold increase in tumor αSMA-positive fibroblasts and large stromal collagen-rich infiltrates in the pancreas that can restrain tumor growth. The mTOR inhibitor RAD001 alone, or together with EHT5372, reduced pancreatic cancer size 30-fold, while the drug combination reduced the number of microscopic tumor foci 2-fold compared to RAD001 alone.

Prognostic role and predictors of complete pathologic response to neoadjuvant chemotherapy in primary unresectable ovarian cancer

The objective of the study was to analyze in a large series of unresectable advanced ovarian cancer (AOC) patients the prognostic role of pathological response to neoadjuvant chemotherapy (NACT). We retrospectively evaluated 322 unresectable AOC patients treated with NACT followed by interval debulking surgery (IDS). Pathological response was classified as follows: complete (cPR) in the absence of residual disease, microscopic (microPR) in the presence of microscopic tumor foci (maximum diameter ≤3 mm), and macroscopic (macroPR) when macroscopic residual disease was detected. cPR was observed in 21 (6.5%), microPR in 104 (32.3%), and macroPR in 197 (61.2%) patients. No differences were observed in the distribution of baseline clinicopathological characteristics between the groups. Median progression-free survival was 36 months in cPR, 16 in microPR, and 13 in macroPR (P = .001). Median overall survival was 72 months in cPR, 38 in microPR, and 29 in macroPR (P = .018). The survival differences between microPR and macroPR patients were not confirmed when the analysis included only cases resected to no gross residual disease at IDS. cPR retained the independent prognostic role in the multivariate analysis. International Federation of Gynecology and Obstetrics stage IV was the only negative independent predictor of cPR (χ(2) = 5.362, P = .021). cPR is an uncommon event in AOC patients receiving NACT and is associated with a longer progression-free survival and overall survival compared with women showing no cPR, even in patients receiving IDS with no gross residual disease. The proposed classification of pathological response may serve in the next future as an easily assessable and highly valuable prognostic tool in this clinical setting.

Identification of microscopic ovarian tumor foci utilizing a novel imaging device in a murine ovarian cancer model: An opportunity to improve optimal cytoreduction

Objectives: In patients with advanced ovarian cancer, resection of all gross residual disease is associated with a significant improvement in survival. Disease remaining either as infiltrative or microscopic tumor deposits is a challenge to identify. Detection of this disease during cytoreductive surgery may lead to a more thorough reduction of cancer burden. We evaluated the performance of a fluorescent molecular imaging agent, LUM015 (Lumicell, Wellesley, MA), which is activated by cathepsin enzymes in the tumor, and a wide field-of-view imaging device (Lumicell) to detect sub-millimeter residual cancer clusters in an mouse model for ovarian cancer.

Lack of Matrilin-2 favors liver tumor development via Erk1/2 and GSK-3β pathways in vivo.

Matrilin-2 (Matn2) is a multidomain adaptor protein which plays a role in the assembly of extracellular matrix (ECM). It is produced by oval cells during stem cell-driven liver regeneration. In our study, the impact of Matn2 on hepatocarcinogenesis was investigated in Matn2-/- mice comparing them with wild-type (WT) mice in a diethylnitrosamine (DEN) model. The liver tissue was analyzed macroscopically, histologically and immunohistochemically, at protein level by Proteome Profiler Arrays and Western blot analysis. Matn2-/- mice exhibited higher susceptibility to hepatocarcinogenesis compared to wild-type mice. In the liver of Matn2-/- mice, spontaneous microscopic tumor foci were detected without DEN treatment. After 15 μg/g body weight DEN treatment, the liver of Matn2-/- mice contained macroscopic tumors of both larger number and size than the WT liver. In contrast with the WT liver, spontaneous phosphorylation of EGFR, Erk1/2 GSK-3α/β and retinoblastoma protein (p-Rb), decrease in p21/CIP1 level, and increase in β-Catenin protein expression were detected in Matn2-/- livers. Focal Ki-67 positivity of these samples provided additional support to our presumption that the lack of Matn2 drives the liver into a pro-proliferatory state, making it prone to tumor development. This enhanced proliferative capacity was further increased in the tumor nodules of DEN-treated Matn2-/- livers. Our study suggests that Matn2 functions as a tumor suppressor in hepatocarcinogenesis, and in this process activation of EGFR together with that of Erk1/2, as well as inactivation of GSK-3β, play strategic roles.

Close/positive margins after breast-conserving therapy: Additional resection or no resection?

The primary goal of breast conserving surgery or mastectomy is the prevention of recurrent breast cancer. The distinguishing goal of breast conserving surgery is preservation of a breast as normal in appearance as possible. If the margins of the excised breast cancer extend to the border of the excised specimen one cannot determine the amount of gross tumor that was not excised. Retrospective analyses of surgical series show a 2–3 fold increase in local recurrence of the breast tumor if the margin is positive under the microscope, even when the surgeon believed it to be clear on gross examination [1]. This fact has led to a variety of techniques attempting to ensure that the margins of the excised specimen are free of obvious tumor including pre-operative and specimen imaging and mapping, neo-adjuvant therapy to shrink the primary tumor, touch-prep and frozen section of the specimen margins during the procedure, shaving additional margins about the specimen at the closest aspects grossly or on all six surfaces, and examinations of the in situ walls of the remaining breast with new instrumentation. An obvious approach to diminishing the likelihood of positive specimen margins is taking a wider margin of normal tissue. As the volume of resected breast increases by the cube of the radius of excised tissue, this tracks all too well with diminishing cosmetic results and patient approval of the conserved breast.The question posed regards the finding of a positive or close margin after the surgical procedure. The finding of a positive margin can be parsed to a microscopic focus of tumor at the margin vs. the margin inking on a tumor surface. The latter demands re-excision despite the morbidity involved barring an extraordinary contra-indication or patient refusal. It represents the very real possibility of sufficient residual gross tumor in the breast that even with systemic therapy and breast irradiation the tumor will be un-controlled. A microscopic focus separated from the bulk of the primary tumor and adjacent to a margin has not been shown to carry such risk.The margin of normal tissue beyond the primary tumor that significantly reduces the risk of local recurrence remains undefined. Sufficient data are available to say that in the era of systemic therapy, excellent radiation therapy techniques, and boost doses when indicated, no margin of normal breast tissue beyond the tumor has been shown to be clearly superior to a layer of cells between the ink and the tumor. The larger the tumor and the more aggressive its biology is judged to be the lower the confidence that a single layer of cells at the point of histologic study accurately represents a clear margin. As in all medical decisions wise judgment must integrate all of the known factors to reach the best recommendation. There are few circumstances that would warrant a second surgical procedure for a close but clear margin today.

Pre-hysterectomy cone biopsy is able to predict response in locally advanced cervical cancer patients submitted to neo-adjuvant chemoradiation

To evaluate the feasibility and the predictive value of cone biopsy before performing radical hysterectomy in locally advanced cervical cancer patients showing complete clinical response to neo-adjuvant chemoradiation. Between March 2010 to March 2012 74 consecutive FIGO stage IIA2-IIB patients were submitted to neo-adjuvant chemoradiation. All complete clinical responder patients were enrolled in this pilot trial. Fifty-seven out of 74 patients (77%) showed complete clinical response and were enrolled in the study. Forty-two out of 57 patients (74%) underwent successful pre-completion surgery cone biopsy with a median cone's tissue diameter of 24mm (range 18-35). In 33 out of 42 patients (58%) a complete pathological response was found. In the remaining 5 (9%) and 4 (7%) a microscopic partial and partial response was found, respectively. All 33 cases (58%) with negative cone showed complete pathological response in the radical hysterectomy specimens. Patients with microscopic residual tumor foci in the cone showed negative residual cervical and paracervical tissue at definitive diagnosis, whereas in patients with partial response macroscopic residual disease in the surgical specimens was found. The negative predictive value of cone biopsy, MRI and PET/CT in the prediction of pathological status of the cervical and paracervical tissue was 100%, 79% and 79%, respectively (Table 2). In this study we observed that, in locally advanced cervical patients showing complete clinical response to neo-adjuvant chemoradiation, the cone biopsy feasibility was almost 75%, and that there is a complete pathological correspondence between cone and definitive pathology.

CTV Boost Margin for Adjuvant Breast Radiation Therapy — Results of a Study Comparing US Versus CT Imaging

A clinical target volume (CTV) boost margin of 10 mm is recommended around the seroma based upon the data from the anatomical distribution of microscopic tumor foci surrounding the primary breast tumor reported in mastectomy and re-lumpectomy specimen studies. For boost delivery and partial breast irradiation, the seroma is defined on Computed Tomography (CT) scan images. On CT, the high-density seroma can include the fluid-filled cavity, but may also include postoperative architectural distortion, breast tissue stranding, fibrosis, adjacent retroareolar tissue, and normal dense breast parenchyma.

Adjuvant therapy in breast cancer and venous thromboembolism

Breast cancer patients are considered to be at relatively low risk of developing a TEE. The highest incidence of VTE events occurs in metastatic breast cancer patients likely due to extension of disease, immobility for pathologic bone fractures, cancer cachexia and venous compression by the tumour mass. Although thrombosis is less common in patients with early stage cancer compared to those with more advanced disease, it does occur and is clinically challenging.The adjuvant setting is of particular interest in order to assess the specific thrombogenic potential of systemic chemotherapy, because of the low tumor burden with only microscopic tumor foci at the time of treatment administration.This review summarizes risk factors, incidence and strategies to avoid VTE in breast cancer patients receiving adjuvant therapy.

Hereditary diffuse gastric cancer: strategies to reduce tumoral risk

The main goal at a High-Risk Gastrointestinal Cancer Clinic is to identify individuals at increased risk of developing tumors for diagnosis them in presymptomatic stages, when they are potentially curable. We report an asymptomatic patient belonging to a family with hereditary diffuse gastric cancer syndrome with a novel pathogenic mutation in the E-cadherin gene. In the absence of any proven diagnostic tool in surveillance tumor of this syndrome, the recommendation accepted today for an asymptomatic individual with known mutation is to perform prophylactic surgery. This patient underwent total laparoscopic gastrectomy. A microscopic focus of tumor was detected in the surgical specimen. Strategies to reduce the tumor risk in the hereditary diffuse gastric cancer syndrome are limited, but it is necessary to recognize them in order to treat these patients accordingly to the available evidence.

Role of portal vein embolization in hepatocellular carcinoma management and its effect on recurrence: a case-control study.

BackgroundLiver regeneration that occurs after portal vein embolization (PVE) may have adverse effects on the microscopic tumor foci in the residual liver mass in patients with hepatocellular carcinoma (HCC).MethodsFifty-four HCC patients with inadequate functional residual liver volume were offered PVE during a seven-year period. Among them, 34 (63%) patients underwent curative resection. They were compared with a matched control group (n = 102) who underwent surgery without PVE. Postoperative complications, pattern of recurrence, and survival were compared between groups.ResultsIn the PVE group, a pre-embolization functional residual liver volume of 23% (12–33.5%) improved to 34% (20–54%) (p = 0.005) at the time of surgery. When the two groups were compared, minor (PVE, 24%; control, 29%; p = 0.651) and major (PVE, 18%; control, 15%; p = 0.784) complications were similar. After a follow-up period of 35 months (standard deviation 25 months), extrahepatic recurrences were detected in 10 PVE patients (29%) and 41 control patients (40%) (p = 0.310). Intrahepatic recurrences were seen in 10 (29%) and 47 (46%) cases (p = 0.109) in the PVE and control groups, respectively. In the PVE group, 41% (n = 14) of the recurrences were detected before one year, compared with 42% (n = 43) in the control group (p = 1). Disease-free survival rates at 1, 3, and 5 years were 57, 29, and 26% in the control group and 60, 42, and 42% in the PVE group (log-rank, p = 0.335). On multivariate analysis, PVE was not a factor affecting survival (p = 0.821).ConclusionsPortal vein embolization increases the resectability of initially unresectable HCC due to inadequate functional residual liver volume, and it has no deleterious oncological effect after major resection of HCC.

Concomitant boost radiotherapy and multidrug chemotherapy in the neoadjuvant treatment of locally advanced rectal cancer: Results of a phase II study

Background. An intensified multidrug chemotherapy regimen (raltitrexed plus oxaliplatin, Tom-Ox) plus concomitant boost radiotherapy, in the neoadjuvant treatment of locally advanced rectal cancer patients, was shown feasible in our previous study. The aim of this study was to evaluate the efficacy in terms of pathologic complete response to pre-operative therapy. Material and methods: A Phase II study was designed and clinical stage T3-T4 and/ or N ≥ 1 patients were treated with concomitant boost radiotherapy (55 Gy/5 weeks) plus concurrent chemotherapy (Tom-Ox). The primary endpoint was the assessment of efficacy in terms of clinical and pathologic response to pre-operative therapy. According to the Gehan's design study, 25 patients were enrolled. Toxicity was assessed according to the RTOG-EORTC and CTCAE v.3.0 criteria. Results: Twenty-five consecutive patients were treated. Twenty-two of the 25 (88%) patients had a partial clinical response at the time of pre-operative magnetic resonance imaging (MRI). Only one patient showed progressive systemic disease at pre-surgical revaluation and was subjected only to biopsy to evaluate pathological response. Twenty-four patients (96%) underwent surgery. Overall, pathologic complete response was observed in eight patients (32%; CI 0.95:12–55%) and only microscopic tumor foci (pTmic) in two patients (pT0-mic: 40%; CI 0.95:18–63%). Nineteen patients (76%) showed tumor down-staging. Proctitis and/or diarrhea were the most frequent acute side effects experienced. Eighteen patients had grade 1–2 toxicity (77%); whereas two patients experienced grade 3 toxicity (8%). Two-year Local control and actuarial Disease Free Survival were 100% and 91%, respectively. Conclusion. An intensified regimen of concomitant boost radiotherapy plus concurrent raltitrexed and oxaliplatin, can be safely administered in patients with locally advanced rectal cancer. This regimen produces high rates of pathological complete response. Based on available data, this type of treatment could be offered to patients with more advanced tumors (T4 or local recurrence).

Abstract 797: Characterization of endogenous antibodies to tumor

Abstract Early detection of malignancy is crucial for long-term survival in patients with various types of cancer; however, this remains a challenge in a wide variety of tumors. This study tests whether a patient's own antibodies can be used diagnostically for early detection. It has been proposed that the body is undergoing continuous surveillance by the immune system, with elimination of newly transformed cells. Cancer becomes a clinical problem when the immune system fails to eliminate these cells. Many studies have looked at the immune system, particularly antibodies, as a therapeutic tool against tumor-associated antigens. However, single antigens are rarely sensitive or specific for a certain tumor type. The use of panels of antigens and antibodies has increased the sensitivity of tumor detection, however not sufficiently. We tested if the polyclonal spectra of antibodies that an individual creates can still detect tumors even if the immune system cannot eliminate the tumor. These antibodies will vary considerably in affinity and specificity. The goal was to determine if they could serve as a dependable and reliable means to detect microscopic foci of tumor, and distinguish transformed from normal tissue. We therefore tested for the presence of endogenous antibodies in tissue from multiple mouse models of cancer, including models consisting of over expression of an oncogene in addition to deletion of a tumor suppressor gene. We obtained tissue from four mouse models of tumor: liver tissue from transgenic alb-myc mice, breast tissue from transgenic MMTV-neu mice, and prostate tissue from two prostate models (a transgenic Pb-myc model and a knock-out PTEN model). These were compared to matched tissue samples from wild-type mice. Paraffin embedded and frozen section slides of test and matched wild-type tissue were tested for the presence of endogenous antibody with immunofluorescence, using a rabbit secondary anti-mouse IgG. Immunofluorescence with a goat anti-rabbit IgG served as a negative control. There was a significantly higher intensity of immunofluorescence in tissue from mice genetically engineered to have tumors compared to the wild-type mice. Adjacent sections stained with H&E were evaluated by a veterinary histo-pathologist in a double-blind study. Areas marked as altered by H&E were significantly enhanced in antibody binding. Similar results were observed in the liver, prostate and breast cancer models. No signal was observed with the goat anti-rabbit negative control. The results indicate that the spectra of endogenous antibodies have the potential to detect these genetically engineered tumors at early stages of transformation. The success of this approach opens the possibility of using these antibodies both diagnostically and therapeutically. 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 797. doi:10.1158/1538-7445.AM2011-797

Coactivation of AKT and β-catenin in mice rapidly induces formation of lipogenic liver tumors.

Obesity is a risk factor for development of certain cancers but the basis for this risk is unclear. In this study, we developed a novel mouse model that demonstrates directly how lipogenic phenotypes commonly associated with diet-induced metabolic syndromes can influence hepatic cancer development. Activated AKT and β-catenin (AKT/CAT) genes were hydrodynamically codelivered using the Sleeping Beauty transposon to initiate liver tumorigenesis. AKT/CAT and MET/CAT combination induced microscopic tumor foci by 4 weeks, whereas no tumorigenesis resulted from delivery of AKT, MET, or CAT alone. Primary AKT/CAT tumor cells were steatotic (fatty) hepatocellular adenomas which progressed to hepatocellular carcinomas (HCC) upon in vivo passage, whereas primary MET/CAT tumors emerged directly as frank HCC. Conversion of AKT/CAT tumor cells to frank HCC during passage was associated with induction of the human HCC marker α-fetoprotein and the stem cell marker CD133. Using hierarchical clustering and gene set enrichment analysis, we compared the primary murine AKT/CAT and MET/CAT tumors to a panel of 53 human HCCs and determined that these two mouse models could be stratified as distinct subtypes associated in humans with poor clinical prognosis. The chief molecular networks identified in primary and passaged AKT/CAT tumors were steatosis and lipid metabolic pathways, respectively. Our findings show how coactivation of the AKT and CAT pathways in hepatocytes can efficiently model development of a lipogenic tumor phenotype. Furthermore, we believe that our approach could speed the dissection of microenvironmental factors responsible for driving steatotic-neoplastic transformation to frank carcinoma, through genetic modification of existing immunodefined transgenic models.

Abstract P4-10-10: The Gammapod TM: A Novel Breast Specific Stereotactic Body Radiation Therapy (SBRT) for Small Breast Cancers

Abstract Introduction: SBRT is a novel approach to precisely deliver high doses of radiation therapy to a define target, while normal tissues immediately surrounding the tumor receives a significantly lower (i.e. tolerable) dose. This technique has revolutionized the management of small medically inoperable lung cancer with local control rates recently reported in the co-operative setting of 98% now setting the stage for challenging surgery as the standard of care for select patients with lung cancer. SBRT has not been used in the breast, since the breast is a pliable organ without a suitable immobilization device and the lack of an SBRT system that can create the rapid fall off in dose necessary to deliver ablative doses of radiation safely in the breast. The purpose of this NIH funded project is to develop a dedicated SBRT system for early breast cancer which could eventually lead paradigm shift in the management of breast cancer similar to lung cancer. Materials and Methods: The SBRT system was developed such that dose distributions produced would be similar to stereotactic radiosurgery in the brain where the the drop off of the prescription isodose to 50% of the prescription dose was less than 5 mm. The device uses 36 non-coplanar Co-60 sources which rotate around a focal point to produce 36 non-coplanar arcs. The system incorporates the use of a floating/dynamic table which together with the rotatable sources enables differential dosing of target volumes similar to intensity modulated RT allowing higher ablative doses to the gross tumor and a lower sub clinical dose to treat microscopic tumor foci. In addition the SBRT system, a breast specific immobilization device was developed. This system consists of 2 layers with an air tight seal in between. Once placed on the breast a small negative pressure secures it to the breast. A prospective trial tested the reproducibility of the breast cup using the centroid of the post-operative clips on 2 consecutive CT simulations separated by 10 to 60 minutes simulating the treatment planning scenerio in the prone position. During this time, patients were also asked to fill out a questionaire regarding the comfort of this approach. Results: The issues within the specific aims of the grant have been effectively solved and have led to a breast specific immobilization device and a breast specific SBRT system — The Gammapod TM. The immobilization device demonstrated a set up error of less than 3 mm a significant decrease from the 10 mm planning target volume expansion as recommended in NSABP B39 for patients undergoing 3 dimensional conformal partial breast radiotherapy. All patients described this experience as more comfortable in comparison to a biopsy and similar to the experience of a mammogram.Dosimetric studies using Monte Carlo simulation demonstrate that tumors up to 5 cm in diameter, and 5 mm from the chest wall, lung/heart receive < 10% of the maximum dose. Conclusions: A breast specific immobilization device and SBRT system has been developed produces dose distributions similar to stereotactic radiosurgery in the brain. The first prospective studies testing this device clinically through a multi-institutional consortium are expected to open in early 2011. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-10-10.

Planar scintimammography and SPECT in neoadjuvant chemo or hormonotherapy response evaluation in locally advanced primary breast cancer

Conventional imaging procedures have proved of limited value in assessing tumor response to neoadjuvant chemotherapy in locally advanced primary breast cancer (LAPBC). We evaluated the usefulness of radioisotopic procedures comparing planar scintimammography (SM) to SPECT, monitoring pre-surgery neoadjuvant chemo- or hormonotherapy response in 32 LAPBC patients. In all cases, 99mTc-tetrofosmin conventional planar SM and SPECT were acquired by dual-head gamma camera with HR parallel hole collimators. In 15 cases, planar SM with small field of view high resolution dedicated breast camera (DBC) was also acquired. Scintigraphic data always correlated with histopathological findings. At surgery, 4/32 patients had pathological complete remission (pCR), while 28/32 patients had residual tumors. Both conventional planar SM and SPECT were true negative in 4/4 (100%) pCR patients, as was DBC in the only studied case. Conventional planar SM and SPECT detected residual tumors in 23/28 (82%) and in 25/28 (89.2%) cases, respectively. Both procedures missed 2 multifocal, scattered microscopic residues, only evidenced at DBC. Conventional planar SM also missed 3 further macroscopic residues (15-20 mm), while SPECT only one of these, a mucinous BC, in which DBC was not performed. DBC correctly classified all other 12 patients in whom the procedure was performed. Both conventional planar SM and SPECT proved useful diagnostic tools in monitoring neoadjuvant chemo/hormono therapy response in LAPBC with SPECT appearing more sensitive; however, our data, although in a limited number of cases, suggest that sensitivity can further be increased using high resolution DBC, especially in detecting microscopic residual tumor foci.

Preoperative treatment of potentially-resectable pancreatic adenocarcinoma with fixed-dose rate gemcitabine (GEM), bevacizumab (BEV), and 30 Gy radiotherapy (RT)

4631 Background: Nearly 80% of patients with resected pancreatic cancer develop local or distant failure within two years. We hypothesized that short-course neoadjuvant treatment with systemically-active doses of combination chemotherapy and RT to the surgical margin may improve outcomes. Methods: This is a single center, two stage phase II trial of induction fixed-dose rate (FDR) GEM (1,500 mg/m2) plus BEV (10 mg/kg) q 2 weeks for three cycles, followed by BEV (10 mg/kg) with accelerated RT (30 Gy in 10 fractions) directed at the gross tumor volume and a 1–2 cm vascular margin. Eligible pts had FNA-proven pancreatic adenocarcinoma and were potentially-resectable on screening pancreas protocol CT scan. Stage I required six pts; 48 resected pts are required to evaluate dual primary endpoints: a 25% improvement in the margin-negative resection rate (65% to 80%) and a 10% pathological response rate (≥80% power; combined type I error 0.14). Results: This is an exploratory analysis of stage I data. Fourteen pts completed treatment: 10 males; median Karnofsky score 90; and median age 57 (37–75). Lesions measured 1.6–4.5 cm with CT criteria for portal venous invasion (n=5) and malignant adenopathy (nodes ≥ 1 cm; n=6). Median treatment duration was 56 days (55–71 days) with three delays. Only one of six pts experienced treatment-related grade 3 toxicity, while two pts required dose reduction due to grade 2 events. Median Ca 19–9 decreased from 128 to 32 U/ml. Radiographic responses included 1 CR, 2 PR, and 10 SD upon completion. Ten pts underwent pancreatoduodenectomy with two portal vein resections. Eight of ten pts had negative surgical margins (80%) with three (30%) near-complete pathological responses (microscopic foci of residual tumor only). Four pts (4/14) had metastatic disease; all had nodes ≥ 1 cm on pretreatment CT (p<0.02). Median length of stay was 10 days (2–17). Four pts had grade 3 wound complications (29%) with one grade 2 pancreatic leak (10%). Conclusions: Induction therapy with FDR GEM and BEV, followed by concurrent BEV/RT to 30 Gy, is safe neoadjuvant treatment for patients with resectable pancreatic cancer. The resectability rate and evidence for pathologic downstaging meet criteria for accrual to stage II. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech Genentech

Prevention of local tumor growth with paclitaxel-loaded microspheres

Lung cancer is associated with a significant rate of locoregional recurrence after surgical resection, particularly when nonanatomic wedge resections are performed. The primary aim of this study was to assess the feasibility of a microsphere drug delivery system to locally deliver chemotherapy and prevent the establishment and growth of lung cancer cells and establish proof of concept for a potential future approach to target occult microscopic disease remaining at the surgical resection margin. Poly-(D,L-lactic-co-glycolic acid) (PLGA) microspheres loaded with the antineoplastic agent paclitaxel were prepared and tested for antitumor efficacy in an in vitro cell proliferation assay for tumor inhibition and induction of apoptosis. The in vivo prevention of Lewis lung carcinoma cell establishment and growth in subcutaneous tissues of mice was also assessed by comparing 4 treatment groups: Lewis lung carcinoma cells alone, Lewis lung carcinoma cells combined with 100 x 10(6) unloaded (carrier alone) PLGA microspheres, and Lewis lung carcinoma cells combined with 50 x 10(6) or 100 x 10(6) paclitaxel-loaded PLGA microspheres. After the coinjection of Lewis lung carcinoma cells with or without microspheres, in vivo tumor growth was monitored, and tumor weight was recorded on death. Paclitaxel-loaded PLGA microspheres were found to effectively prevent growth of tumor cells in culture through the induction of apoptosis. Similarly, paclitaxel-loaded PLGA microspheres significantly inhibited tumor growth in vivo at both the 50 x 10(6) and 100 x 10(6) microsphere dose (0.497 +/- 0.183 and 0.187 +/- 0.083 g total tumor weight, respectively) compared with 2.91 +/- 0.411 g for Lewis lung carcinoma cells with unloaded microspheres and 3.37 +/- 0.433 g for untreated tumor (P < .001). Toxicity was not clinically apparent in any animal treated with paclitaxel-loaded PLGA microspheres. Paclitaxel-loaded PLGA microspheres induce tumor apoptosis and inhibit the establishment and growth of lung cancer cells both in vitro and in vivo without obvious systemic toxicity. By using models consistent with localized microscopic tumor burdens, these results suggest that local delivery of paclitaxel through a microsphere system might lead to an effective future method of decreasing local tumor recurrence in non-small cell lung cancer when applied to the surgical margins at risk for microscopic tumor foci. Such an approach might be particularly efficacious after wedge resection in the setting of poor pulmonary reserve or significant comorbidity, where local recurrence rates are increased and acceptable alternative treatment options are limited.

Clinicopathologic and prognostic study of pediatric immature teratoma

To study the clinicopathologic features and biologic behavior of pediatric immature teratoma. The clinical data, pathologic features, immunohistochemical findings (for cyclin D1, P27 and Ki-67) and follow-up information of 39 cases of pediatric immature teratoma were analyzed. Amongst the 39 cases studied, 12 arose in the sacrococcygeal region, 12 in testis, 5 in retroperitoneum, 4 in ovary, 4 in abdomen and 2 in mediastinum. Histologically, 16 cases were of grade 1, 8 cases of grade 2 and 15 cases of grade 3. Seven of the cases contained foci of yolk sac tumor. Immature neuroepithelial features used in histologic grading included the presence of primitive neural tubules, immature rosettes, undifferentiated neuroblastoma cells and primitive neuroectodermal structures. Immunohistochemical study showed that cyclin D1 was positive in 3 cases of grade 1 tumors, 4 cases of grade 2 tumors and 9 cases of grade 3 tumors. The positivity rates for p27 were 8, 3 and 6 cases respectively, while those for Ki-67 were 3, 4 and 13 cases respectively. Follow-up data were available in 30 cases. Three of them, including 2 cases with histologic grade 3 (with or without yolk sac tumor component), recurred after operation. The expression of cyclin D1 and Ki-67 is a useful adjunct in histologic grading. On the other hand, p27 overexpression shows little correlation with tumor grade. The prognosis of immature teratoma in children is different from that in adults. Sacrococcygeal immature teratoma occurring in patients younger than 1 year old and with low histologic grade do not require postoperative chemotherapy if the tumor is completely excised. Similarly, for testicular immature teratoma occurring in patients below 1 year of age, regardless of tumor grading, need no adjunctive therapy. On the other hand, ovarian immature teratoma with high histologic grade requires postoperative chemotherapy, regardless of age of the patients. The presence of microscopic foci of yolk sac tumor is a useful predictor of recurrence in pediatric immature teratoma.

Pathology and Molecular Biology of Teratomas in Childhood and Adolescence

The biologic behaviour of teratomas depends on various interdependent clinical and epidemiologic variables such as the age at diagnosis, sex, tumor site, histology which all correlate to different cytogenetic and molecular biologic aberrations. Thus, testicular teratomas of infancy are generally benign. Accordingly, prepubertal teratomas show no cytogenetic or molecular genetic aberrations. In contrast, postpubertal testicular teratomas can present as clinically malignant tumors and may show complex cytogenetic aberrations such as the isochromosome 12p, which is pathognomonic of malignant germ cell tumors. Notably, teratomas of both age groups show an at least partial erasure of the genomic imprinting, correlating with their origin from primordial germ cells. The Kiel Pediatric Tumor Registry includes 541 teratoma specimens, and among these, the most frequent tumor sites (in descending order) are: the sacrococcygeal region (33.8 %), the ovaries (31.2 %) and the testes (10.5 %). Rare localizations include the mediastinum, the retroperitoneum, the head and neck region as well as the central nervous system. The WHO classification of germ cell tumors distinguishes mature and immature teratomas as well as teratomas with malignant transformation. In immature teratomas, primitive neuroectodermal structures predominate. According to the grading system (Gonzalez-Crussi, 1982), mature teratomas (G0) are more frequent (54.5 %) than immature teratomas (G1-G3, 45.5 %). Only 7.8 % of all teratomas show the highest grade of immaturity (G3). The frequency of additional microscopic foci of malignant yolk sac tumor correlates with the grade of immaturity. In sacrococcygeal teratomas, the yolk sac tumor microfoci may give rise to a malignant relapse after incomplete resection. The rare teratomas with malignant transformation contain components with "conventional" somatic type malignancy such as leukaemia, carcinoma or sarcoma. Here, molecular genetic analysis has demonstrated the origin of the somatic malignancy from a malignant transformation within the germ cell tumor with retention of the cytogenetic changes characteristic of malignant germ cell tumors.

Induction chemotherapy (ICT) followed by pre-operative chemoradiotherapy in locally advanced rectal cancer

13531 Background: Preoperative radiotherapy (RT)with or without chemotherapy (CRT) for patients (ptns) with T3,4 rectal carcinoma is increasingly accepted.We presented, 3 yrs ago, our experience with Cisplatin-5FU-Folonic(FA)regimen (FOLFC) in patns with metastatic CR carcinoma.We proved it is comparable to other regimens with lower cost. Methods: Between 10/99 &amp; 8/04, 104 ptns between 18 and 65 year old (PS 0–1) were assessed retrospectively (24 T3 &amp; 80 T4). Ptns received 2 months of ICT Cis(40mg/m2 D1)+FA(200mg/m2 2hrs infusion D1,2)followed by 5FU bolus(400 mg/m2 D1,2)+5FU cont inf(1200 mg/m2 D1–2)this cycle repeated q 2 wks for 8 wks. Starting on wk 9, 5 FU-FA was given as in Mayo-clinic regimen (D1–5, D21–25) with concomitant RT 45Gy in 25 fractions followed by 9 Gy boost to primary tumor. TME was planned at 4–6 wks from completion of ICT. 2 more cycles of FOLFC was given post-operatively. Results: All ptns (104) undergoing CRT completed therapy as planned, with no treatment-related interruptions. No GIII-IV toxicity. The radiological RR (after ICT) was 75% and (4 wks after CRT) was 89% (20CRs, 73PRs). 92% of ptns had subjective R in a median of 24 days from start of ICT in terms of improvement of diarrhea/constipation (90.4%), in obstructive symptoms (40/ 50 ptns)&amp;weight gain in 100% of ptns.Reduced rectal bleeding (100%) &amp; pelvic pain (100%). 17 of 20 ptns who were considered to be inoperable prior to the treatment underwent TME with negative radial margins. Anastomotic leakage occurred in 8 ptns (7.7%). Wound infection occurred in 4 ptns (3.8%). Delayed complications occurred in 3 ptns one required surgery for a stomal stricture. All ptns underwent R0 resection with clear CRM. Pathological CR was found in 32 ptns and in an additional 41 ptns, only microscopic tumor foci were found on surgical specimens. After a median follow-up of 16 months, two ptns had developed LR. Conclusions: ICT followed by synchronous CRT and TME results in marked tumor regression, rapid symptomatic response and achievement of R0 resection. The majority of ptns considered inoperable prior to receiving this treatment underwent successful excision. Given the low toxicity and promising activity, this regimen is being compared to standard synchronous 5FU- pelvic chemoradiation in a randomized study. No significant financial relationships to disclose.