High-risk Carcinoma Research Articles

Retrospective review of capecitabine as adjuvant therapy in high risk or recurrent squamous cell carcinoma of head and neck (SCCHN).

e17043 Background:For patients with recurrent SCCHN there are currently no evidence- based, approved adjuvant treatment options (following surgery and/or chemoradiotherapy for recurrent disease). Roughly 40-75% of these high-risk patients recur after treatment, with median survival rates up to 10 months. Capecitabine, an oral 5FU pro-drug, has documented efficacy in the treatment of metastatic and locally advanced SCCHN. In this retrospective analysis, we hypothesize that prolonged exposure to capecitabine may offer benefit to patients with recurrent/high disease when given adjunctively. Methods: We identified 17 patients with either locally advanced SCCHN with multiple high-risk features or recurrent SCCHN that were treated with adjuvant capecitabine post chemo-radiation or surgery for 1 year. The data was extracted from a database of patients treated for SCCHN at the University of Michigan Comprehensive Cancer Center from 2003 through 2015 and matched with 17 control patients by age, sex, and clinical s...

Implications of intraglandular lymph node metastases in primary carcinomas of the parotid gland.

Assess the diagnostic and prognostic relevance of intraglandular lymph node (IGLN) metastases in primary parotid gland carcinomas (PGCs). Retrospective study at a tertiary referral university hospital. We reviewed the records of 95 patients with primary PGCs, treated at least surgically, between 1997 and 2010. We assessed the clinicopathological associations of IGLN metastases, their prognostic significance, and predictive value in the diagnosis of occult neck lymph node metastases Twenty-four (25.26%) patients had IGLN metastases. This feature was significantly more prevalent in patients with advanced pT status (P = .01), pN status (P < .01), and overall stage (P < .001); high-risk carcinomas (P = .01); as well as in patients with treatment failures (P < .01). IGLN involvement was significantly associated with decreased univariate disease-free survival (P < .001). Positive and negative predictive values and accuracy for IGLN involvement in the detection of occult neck lymph node metastases were 63.64%, 90.48%, and 84.91%, respectively. The diagnostic values were generally higher in patients with low-risk subtype of PGCs. IGLN involvement provides prognostic information and is associated with advanced tumoral stage and higher risk of recurrence. This feature could be used as a potential readout to determine whether a neck dissection in clinically negative neck lymph nodes is needed or not. 4.

Abstract PD1-5: Characterizing the Tumor Immune MicroEnvironment (TIME) in high-risk ductal carcinoma in situ

Abstract Background: Ductal carcinoma in situ (DCIS) of the breast is a premalignant condition. Although DCIS is treated as an obligate precursor of invasive ductal carcinoma, the rate and latency of progression from DCIS to invasive breast cancer (IBC) in the absence of treatment are unknown. DCIS is not one condition, but rather a spectrum of disease and although DCIS itself is not a lethal condition, women with DCIS are at higher risk of developing subsequent IBC over a time period of 1-20 years depending on DCIS subtype. Features of DCIS that are associated with high risk of recurrence include large size (&amp;gt; 5cm), high grade, comedo necrosis, palpable mass, hormone receptor (HR) negativity, and HER2 positivity. The objective of this study was to characterize the tumor immune microenvironment (TIME) of these high-risk DCIS lesions. Methods: Forty-eight cases of high grade DCIS, enriched for large, confluent lesions and history of recurrence were age matched with 64 cases of non-high grade DCIS. IHC analyses were performed as single or two-color stains for the following antigens: CD68, CD8, CD4, CD20, HLA-DR, CD115, FoxP3, PCNA, Mac387, MRC1, ALDH, CD24, CD44, Ki-67, and HER2. HR status was determined from ER and PR staining results in pathology reports. A Nuance multispectral imaging system was used to image and spectrally unmix each stain. Protocols for automated image analysis were developed using CellProfiler software. Associations between immune cell populations and clinical parameters (tumor palpability, recurrence, HR status, HER2 status, and Van Nuys score [12-point scale: margins, age, size, grade]) were identified with non-parametric Spearman correlation tests. Results: We found a high macrophage infiltrate associated with a high Van Nuys score, palpability, and high Ki-67. High CD115 (CSF-1 receptor) was associated with HER2+, high Ki-67, and recurrence. Mac387+ cells and FoxP3+ regulatory T cells (Treg) were associated with high Van Nuys score, comedo necrosis, high Ki-67, HR- and HER2+. Interestingly, both Mac387 and CD115 were expressed on tumor cells as well as macrophages and high CD115 staining on tumor cells was associated with recurrence. The presence of CD8+HLA-DR-negative T cells throughout a section was associated with high Van Nuys score, HR-, HER2+, and recurrence. In contrast, CD8+ T cells within the nests of tumor cells were negatively associated with Van Nuys score, palpability, and comedo necrosis. A tumor immune microenvironment score (TIME score) was developed based on the proportions of various immune cell populations. A high TIME score was significantly associated with high Van Nuys scores as well as with recurrence. Summary: These results demonstrate that high risk DCIS features (palpability, high Van Nuys score, high proliferation, HR-, HER2+, and increased recurrence) are associated with a suppressed tumor immune micro-environment (high FoxP3+ cells, CD68+Mac387+ cells, CD8+HLA-DR-neg T cells, and upregulated CD115). These high risk lesions truly represent an opportunity to prevent cancer. Identifying these high risk lesions with the help of tumor immune microenvironment markers and manipulating the DCIS TIME via local or systemic immunotherapeutic strategies may represent an ideal preventative intervention. Citation Format: Michael J Campbell, Rita Mukhtar, Ekene Obi-Okoye, Booyeon Han, Vickram Tandon, Sarah Zheng, Zelos Zhu, Max Endicott, Max Wicha, Linda Lindstrom, Alfred Au, Frederick Baehner, Joe Gray, Laura Esserman. Characterizing the Tumor Immune MicroEnvironment (TIME) in high-risk ductal carcinoma in situ [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD1-5.

101 Endoscopic Resection of High-Risk T1 Colorectal Carcinoma Prior to Surgical Resection Has No Adverse Effect on Long-Term Outcomes

101 Endoscopic Resection of High-Risk T1 Colorectal Carcinoma Prior to Surgical Resection Has No Adverse Effect on Long-Term Outcomes

Phase I trial of sorafenib following liver transplantation in patients with high-risk hepatocellular carcinoma.

401 Background: Liver transplantation (LT) offers excellent long-term survival for hepatocellular carcinoma (HCC) patients who are within established criteria. For those outside such criteria, or with high risk pathologic features in the explant, HCC recurrence rates after LT are high. No treatment has been shown to decrease risk of recurrence post-LT. We conducted a multicenter phase I trial of sorafenib in LT patients with high-risk HCC. Methods: Subjects had pathologically proven high-risk HCC defined as outside Milan (pre- or post-transplant), poorly differentiated tumors, or tumors with vascular invasion. We used a standard 3+3 phase I design, beginning drug between 4 and 16 weeks after LT, with planned duration of treatment of 24 weeks. Cohort dosages were: 1) 200 mg per day, 2) 200 mg twice a day, 3) 200 mg/400 mg per day 4) 400 mg BID. Correlative studies included circulating endothelial cells (CECs) and plasma biomarkers collected prior to treatment, at 1 month, and at recurrence in a subset of subjects, and tumor expression of p-Erk, p-Akt, and c-Met in tissue microarrays. Results: We enrolled 14 patients. Median age was 63 years, and 93% were men. 71% had underlying HCV and 21% had HBV. Maximum tolerated dose (MTD) was 200 mg BID; only 43% of patients received &gt;80% of planned dose. Grade 3-4 toxicities seen in &gt;10% of subjects included: leukopenia (29%), LFT abnormalities (21%), hypertension (14%), hand-foot syndrome (14%) and diarrhea (14%). Over a median follow-up of 953 days, 1 patient died and 4 recurred, with a median recurrence-free survival of 716 days for the 4 patients who recurred. Mean CEC number at baseline was 21 cells/4 ml for those who recurred, and 80 cells/4 ml for those who did not (p=0.10). Mean sVEGFR2 levels decreased after 1 month on sorafenib (p=0.09), but did not correlate with recurrence. There was a trend for tumor c-Met expression with increased risk of recurrence. Conclusions: Post-transplant sorafenib is feasible and tolerable at 200 mg PO BID. Recurrence-free survival appears longer than expected but needs further validation in a larger study. Clinical trial information: NCT00997022.

Gynecologic Cancer InterGroup (GCIG) consensus review for uterine and ovarian carcinosarcoma.

Carcinosarcomas (also known as malignant mixed müllerian tumors) are rare and highly aggressive epithelial malignancies that contain both malignant sarcomatous and carcinomatous elements. Uterine carcinosarcomas (UCs) are uncommon with approximately more than 35% presenting with extra uterine disease at diagnosis. Up to 90% ovarian carcinosarcomas (OCs) will have disease that has spread beyond the ovary. Prognosis for localized stage disease is poor with a high risk of recurrences, both local and distant, occurring within 1 year. The survival of women with advanced UC or OC is worse than survival of endometrioid or high-grade serous histologies. No improvement in survival rates has been observed in the past few decades with an overall median survival of less than 2 years. Currently, there is no clear evidence to establish consensus guidelines for therapeutic management of carcinosarcomas. Until recently, gynecological carcinosarcomas were considered as a subtype of sarcoma and treated as such. However, carcinosarcomas are now known to be metaplastic carcinomas and so should be treated as endometrial or ovarian high-risk carcinomas, despite the lack of specific data. For UCs, a comprehensive approach to management is recommended with complete surgical staging followed by systemic chemotherapy in patients with both early and advanced stage disease. Active agents include paraplatin, cisplatin, ifosfamide, and paclitaxel. The combination of carboplatin-paclitaxel is the most commonly used regimen in the adjuvant and advanced setting. Adjuvant radiotherapy (external beam irradiation and/or vaginal brachytherapy) has not shown any overall survival benefit but has been reported to decrease local recurrences. For OCs and for other ovarian epithelial cancer, the mainstay of treatment remains cytoreductive surgical effort followed, even in early stage, by platinum-based chemotherapy, usually carboplatin-paclitaxel.

Novel Optical Technology in Bladder Cancer Diagnosis and Treatment

Bladder cancer is diagnosed and followed-up with cystoscopy as the “gold standard”. For many decades white light cystoscopy (WLC) has been used. However, several forms of bladder cancer such as the high-risk carcinoma in situ (CIS) may be misdiagnosed with WLC. As WLC still remains the cornerstone for the diagnosis of bladder cancer progress in endoscopic technology is warranted to improve the diagnostic accuracy of both rigid and flexible cystoscopy. Recently, photodynamic diagnosis (PDD) has been introduced for the diagnosis and transurethral resection of bladder cancer (TURBT), especially in cases of CIS (1). Photo-sensitizing drugs are intravesically administrated and are selectively accumulated in cancer cells, leading to the enhancement of contrast between benign and malignant bladder tissues. Prospective randomized studies have demonstrated that PDD improved bladder cancer detection, reduced residual tumor rates after TURBT, and prolonged the recurrence-free survival (1, 2). These studies have demonstrated the superiority of PDD-guided cystoscopy over WLC in tumor detection, as the sensitivity for PDD was 76-97% compared to 46–80% for WLC (1, 2). Narrow band imaging (NBI) is a novel technique used in endoscopy to enhance tissue contrast between cancerous and normal bladder urothelium, while it does not require the administration of contrast agents (1). This technique is based on the phenomenon that the depth of light penetration into the urothelium increases when the wavelength is increased. In particular, NBI uses a light source that filters white light into two wavelengths (415 and 540 nm) which are strongly absorbed by hemoglobin, enhancing the contrast between subepithelial capillaries and mucosa (3). Prospective studies and meta-analyses have demonstrated that 10-25% cases of bladder cancer missed by WLC were detected by NBI (1, 4). Furthermore, NBI resulted in lower rates of residual bladder tumor during repeat TURBT and in reduced recurrence rates (4, 5). Optical coherence tomography (OCT) measures the backscattering of near-infrared light by tissue, and it yields in 2D and 3D images at micrometer-scale resolution, thus providing optical biopsies, approaching the resolution of histopathological imaging (6). It produces high-resolution, cross-sectional images of the bladder tissue enabling real-time bladder cancer staging (6). The principle of OCT is analogous to the B-mode ultrasound except that light is being used instead of sound. Studies have demonstrated that OCT results in high sensitivity and specificity rates for bladder cancer diagnosis (6, 7). The usage of relevant algorithms (i.e. Lingley-Papadopoulos) contributes to the differentiation of benign and malignant bladder tissue with a sensitivity rate of 92 % and a specificity rate of 62 % (7). Raman spectroscopy (RS) is a novel spectroscopic optical technique based on the phenomenon of proton emission after light and tissue molecules interaction. Studies have demonstrated that it successfully diagnosed bladder cancer with sensitivity and specificity rates of 85% and 79%, respectively (8). Similarly, confocal laser endomicroscopy (CLE) is an emerging technology based on the established principles of confocal microscopy, which enables in vivo real-time imaging of the tissue micro-architecture and cellular morphology with promising results. In vivo probe-based CLE of the bladder demonstrated distinct differences between normal mucosa and neoplastic tissues and by using mosaicing, a post hoc image-processing algorithm, individual image frames were juxtaposed to form wide-angle views to better evaluating tissue microarchitecture (9). Lastly, wireless capsule endoscopy (WCE) has been successfully used in Gastroenterology since the 1990s. Recently, it was successfully evaluated in a pig model where the ability to deploy and manipulate the capsule within the bladder was examined as well as the feasibility of capturing and retrieving images in real time (10). In conclusion, novel optical imaging technologies have emerged showing promising results for the diagnosis, management and follow up of patients with bladder cancer. The results of adequately powered comparative studies are warranted to determine the efficacy of these novel techniques in comparison to the standard WLC.

Multicenter phase I trial of sorafenib (S) in high-risk hepatocellular carcinoma (HCC) patients after liver transplantation (LT).

285 Background: LT offers excellent long-term survival for HCC patients within the Milan criteria. For those outside Milan, recurrence rates are higher. No known treatments have been shown to decrease risk of recurrence post-transplant. Methods: Subjects had pathologically proven HCC that was outside Milan (pre- or post-transplant), was poorly differentiated, or had vascular invasion. We used a standard 3+3 design, beginning drug between 4 and 16 weeks after LT, with planned duration of treatment of 24 weeks. Cohort dosages were: 1) 200 mg q day, 2) 200 mg BID, 3) 200 mg/400 mg q day. Correlative studies included circulating endothelial cells (CECs-Veridex) and plasma biomarkers (VEGF, sVEGFR1, sVEGFR2, IL-6 and HGF) collected prior to treatment, at 1 month, and at recurrence. Results: We enrolled 14 patients; 93% were men. Median age was 63; 71% had underlying HCV, 21% HBV, and 21% ETOH. 57% were outside Milan on preoperative imaging. On explant, 29% had poorly-differentiated tumors, and 36% had vascular invasion. MTD was 200 mg BID; only 43% of patients received &gt;80% of planned dose. DLTs included liver function abnormalities (1), transplant rejection leading to death (1), and grade 3 hypertension (1). Grade 3-4 toxicities seen in &gt;10% of subjects included: leukopenia (29%), LFT abnormalities (21%), hypertension (14%), hand-foot syndrome (14%) and diarrhea (14%). Over a median follow-up of 836 days, 1 patient died and 4 recurred (median time to recurrence=716 days). Two recurrences were in subjects with limited exposure to S. Median CEC number at baseline was 16 cells/4 ml for those who recurred, and 42 cells/4 ml for those who did not (p=0.10). Median sVEGFR2 levels decreased after 1 month on S (p=0.09), but did not predict recurrence. Conclusions: To our knowledge, this is the first multicenter phase I trial of S completed in the post-transplant setting for high-risk HCC. MTD of S was 200 mg PO BID. Post-transplant S was feasible. Exploratory biomarker data suggest that low CECs at baseline were potentially associated with a higher recurrence rate. Time to recurrence was promising compared with historic controls, but needs to be further explored and validated in a larger study. Clinical trial information: NCT00997022.

Oncologic colorectal resection after endoscopic treatment of malignant polyps: Does endoscopy have an adverse effect on oncologic and surgical outcomes?

Early colorectal cancer is increasingly treated by endoscopic removal. In cases of incomplete resection or high-risk carcinoma, additional surgery is necessary. To evaluate the frequency of subsequent oncologic surgery after endoscopic resection of colorectal cancer, the rate of lymph node metastasis, residual cancer, and morbidity and mortality rates of the operation. Any eventual adverse effect of the prior endoscopic therapy on the surgical and oncologic outcome was assessed. Retrospective review of prospectively collected data. University hospital. Sixty-six consecutive patients with incomplete endoscopic treatment and need for additional surgery between 2004 and 2011. The data of these patients were compared with those of a group of patients with surgery for early colorectal cancer during the same period without prior endoscopic resection as the control group. Rate of lymph node metastasis and residual cancer, perioperative morbidity and mortality. The lymph node metastasis rate after oncologic resection was 8.6%, and the residual cancer rate was 41%. Risk factors for residual cancer were macroscopic incomplete resection (P < .0001), positive resection margins (P = .03), and piecemeal resection (P = .004). No mortality was observed. Perioperative morbidity, mortality, and oncologic outcome were not significantly different in the group with prior endoscopic resection compared with the primarily operated group. Retrospective study. Endoscopic treatment of malignant polyps does not worsen surgical and oncologic outcomes in cases of subsequent surgery. Because mortality and morbidity are low, oncologic resection generally should be done in the presence of risk factors for residual cancer.

The Role of &amp;lt;sup&amp;gt;18&amp;lt;/sup&amp;gt;F-FDG-PET/CT in the Management of Patients with High-Risk Breast Cancer: Case Series and Guideline Comparison

Objectives: In grade III-IV breast cancer, dissemination of disease needs to be assessed. Until now this was done by conventional imaging (liver ultrasonography, chest X-ray and bone scintigraphy), but evidence favoring the use of FDG-PET/CT is accumulating. Methods: Patients with high-risk breast cancer, who had received conventional imaging and FDG-PET/CT, were included. Patients were staged and assigned a treatment after 1) conventional imaging and 2) FDG-PET/CT, both by a multidisciplinary oncology team. Equivocal FDG-PET/CT findings were histologically confirmed. Results: 16 patients were included (mean age 59 years). TNM-stage changed in 5 patients (31%) after FDG-PET/CT. In 3 patients (19%) unknown distant metastases were detected by FDG-PET/CT. An adjustment of treatment took place in 4 patients (25%). Conclusions: Our case series emphasizes the role of FDG-PET/CT in the staging of high-risk breast carcinoma, especially in the assessment of distant metastases. We suggest replacing conventional imaging with FDG-PET/CT.

Expression of Cancer/Testis genes in ductal carcinoma in situ and benign lesions of the breast.

Cancer/testis (CT) genes represent a unique class of genes, which are expressed by germ cells, normally silenced in somatic cells, but activated in various cancers. CT proteins can elicit spontaneous immune responses in cancer patients and this feature makes them attractive targets for immunotherapy-based approaches. We have previously reported that CTs are relatively commonly expressed in estrogen receptor (ER) negative, high risk carcinomas. In this study, we examined the expression of selected CT genes in ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS) and benign proliferative lesions of the breast. ER negative DCIS were found to be associated with significant CT gene expression together with HER2 positivity and a marked stromal immune response.

Image Guided Radiotherapy by CBCT based Position Verification in High Risk Carcinoma Prostate - an Indian experience and review of literature

Introduction-External beam radiotherapy is one of the principle treatment options for locally advanced prostate cancer. Over the past several decades, RT techniques have evolved to allow higher doses of radiation to be administered safely. We report our experience of Image guided intensity modulated radiotherapy (IGRT) and CBCT based position verification. Material and methods- In this study we are presenting data of 17 consecutive patients that were treated from august 2009 to october 2010. All patients received 76 -78 Gy Gy to clinical target volume for primary disease. Daily online matching was performed by using KV CBCT scan before treatment. In each patient, soft tissue (prostate) matching was done by the radiation oncologist. Results – Median Follow up of our patients is 16 months with minimum follow up of 13 months. 3(17.6%) patients developed grade 2 acute rectal toxicity and 4 (23.5%) bladder toxicity. Till date none of our patients had late bladder or rectal toxicity. None of our patient developed local recurrence. Conclusion-Our study concludes that we can follow the dose escalation with CBCT based position verification .With CBCT we can consider entire prostate and normal structures volume for localization. DOI: http://dx.doi.org/10.3126/ajms.v5i2.8382 Asian Journal of Medical Science, Volume-5(2014): 14-20

Lobulitis in nonneoplastic breast tissue from breast cancer patients: association with phenotypes that are common in hereditary breast cancer

Lobular inflammation (lobulitis) has been demonstrated in benign breast tissue adjacent to in situ and invasive breast cancers and, more recently, in nonneoplastic tissue from prophylactic mastectomy specimens for hereditary high-risk breast carcinoma. The aim of this study is to investigate the incidence of lobulitis in benign breast tissue of patients with breast cancer and associated clinicopathologic features. We reviewed nonneoplastic breast tissue sections from 334 patients with invasive breast carcinoma to study lobulitis in normal breast tissue and to correlate its presence with clinicopathologic features of the associated tumor. Clinical information (age, menopausal status, and follow-up), tumor characteristics (type, grade, size, lymph node status, stage, estrogen and progesterone receptor, HER2), and survival were recorded. Characteristics of women with and without lobulitis were cross-classified with categories of clinical, pathologic, and histologic characteristics, and differences in distributions were tested in univariate and multivariate analysis. Lobulitis was found in 26 (8%) of 334 patients. The lymphocytic infiltrate was predominantly T-cell type. In a multivariate model, lobulitis in patients with breast cancer was significantly associated with younger age, triple (estrogen receptor, progesterone receptor, HER2)-negative cancers, and medullary phenotypes. Lobulitis in nonneoplastic breast tissue, away from tumor, is associated with clinicopathologic features more commonly seen in hereditary breast cancer.

Phase I trial of sorafenib in high-risk hepatocellular carcinoma (HCC) patients after liver transplantation.

280 Background: LT offers long-term survival for HCC patients within the Milan criteria. For those outside, rates of recurrence are higher. There are no known treatments which decrease risk of recurrence post-transplant. We began a multicenter Phase I study of sorafenib in high-risk HCC patients after LT. Methods: Eligible subjects had pathologically proven HCC that was either (1) outside Milan (pre- or post-transplant), (2) poorly differentiated (Edmondson and Steiner grade 4), or (3) had vascular invasion at explant. We used a standard phase I dose-escalation design, beginning drug between 4 and 16 weeks after LT, with a planned duration of treatment of 6 months. Cohort dosages are as follows: (1) 200 mg q day (6 enrolled), (2) 200 mg BID (3 enrolled), (3) 200 mg/400 mg (3 enrolled), and (4) 400 mg BID. Correlative studies include circulating endothelial cells (CECs) and plasma biomarkers which are being collected prior to treatment, at 1 month, and at recurrence. Results: We have enrolled 12 patients, 11 are reported here. Mean age is 62; 64% had underlying HCV, 27% HBV, and 9% ETOH. 45% were outside Milan based on preoperative imaging. On explant, 36% had high grade pathology, and 18% had vascular invasion. Grade 3-4 toxicities seen in &gt;10% include: cytopenias (27% neutropenia), LFT abnormalities (T. bili 18%), HTN (18%), and diarrhea (18%). We are currently enrolling at the 3rd dose level. We had 1 episode acute rejection at the 3rd dose level. CEC data are available for 8 patients, with a baseline range from 15-91, and 1 month range from 2-254. Mean follow up time is 18.0 months. 3 patients have recurred, one who was on drug for &lt; 1 month. Conclusions: To our knowledge, this is the only ongoing multicenter Phase I trial of sorafenib in the post-transplant setting in the US. Post-transplant sorafenib for high-risk patients is feasible, and toxicity has been manageable for the most part. DLT has not yet been defined. Clinical trial information: NCT00997022.

FDG-PET based dose escalated adjuvant tomotherapy (image-guided intensity-modulated radiotherapy) utilizing 4D-CT planning for high-risk adrenocortical carcinoma (ACC): A case study.

e13522 Background: ACC is a rare endocrine malignancy with an annual incidence of 0.5-2/million/year. Surgery is the mainstay of treatment but relapse rate is high and the prognosis is dismal (20-50% 5 year survival). Adjuvant Radiotherapy improves local control in cases with high risk of local failure and dose escalation may achieve better results. Dose Escalation with 3-Dimensional computed tomography (CT) based radiotherapy is difficult for ACC due to unacceptable toxicity to several adjacent organs at risk (OARs) e.g., the kidneys, stomach bowel, liver, spinal cord. FDG-PET helps delineation of areas of higher metabolic activity and density of clonogenic cells within the target (Biological Target Volume or BTV) where focal dose escalation could be directed safely for improving local control as in other solid tumours. Tomotherapy (IMRT with daily image guidance) delivers precision radiotherapy with integrated boost to the BTV, lower dose to OARs, improved coverage of the targets, and better dose delivery across the targets which are essential for tumour control. 4-Dimensional CT for planning allows adequate Clinical Target Volume(CTV) coverage despite respiratory movements. Methods: A 63 year old lady had left adrenalectomy for an adrenocortical carcinoma measuring 29 x 18 x 25mm (TNM pT1NXMX) thought to be microscopically incompletely excised (R1) with a proliferation index ( Ki-67) of 40% for which adjuvant radiotherapy was advised. PET-CT, 4D-CT and Tomotherapy were used for planning. A total dose of 50.4Gy to PTV with a simultaneous integrated boost to BTV taking it up to 59.40Gy (1.98Gy/ fraction) in 30 daily fractions was prescribed. Results: Target dose and coverage were very satisfactory. The doses to OARs were well within tolerance despite dose escalation; she completed treatment with only grade- fatigue. She had metastatic disease at 11 months follow-up without local relapse. Conclusions: To our knowledge this is the first report of using FDG –PET based dose escalation, 4D CT and Tomotherapy in high risk ACC to improve local control and needs further study.

External validation of somatic copy number alteration (SCNA) at chromosome 1q23.3 in advanced urothelial carcinoma (UC).

4585 Background: Advanced UC is associated with multiple SNCAs. To identify SCNA predictors of poor survival in advanced UC, we evaluated SCNAs in two cohorts of high-risk urothelial carcinoma of the bladder. Methods: We obtained DNA copy number data from bladder cancer patients in two independent cohorts [Spanish cohort (n= 93, Agilent aCGH 180k array) and Brigham and Women’s/Dana-Farber (BW/DF) cohort (n = 48, Affymetrix OncoScan FFPE Express 2.0)]. For the BW/DF cohort, we acquired copy number information from 30 primary tumors and 33 metastases. For 12 patients, both primary and matched metastases were available. The GISTIC method was used on GLAD segmented data to identify driver copy number lesions, and the NBC algorithm to identify recurrent breakpoints. Cox proportional hazards models were used to estimate the effect of the identified SCNAs on overall survival, defined as time from start of chemotherapy for metastatic disease (Spanish) or from metastatic recurrence (BW/DF). Copy numbers were incorporated in the Cox models as continuous measures. Statistical significance of optimal cutpoints was estimated with permutation tests. Copy number profiles of primary tumors and metastases were compared with hierarchical clustering. Results: Amplification of 1q23.3 was independently associated with overall survival in both cohorts (Spanish cohort: HR 3.98; 95% 1.64-9.67; p &lt; 0.03; C-statistic 0.54, 95% 0.45-0.65. BW/DF cohort: HR 6.28; 95% 1.84-21.4; p &lt; 0.042; C-statistic 0.62, 95% 0.48-0.76). Amplifications at 22q12.2 were enriched in patients who developed metastasis (p &lt; 0.05). A breakpoint analysis identified possible truncations of ITPR1 (Spanish: 15%; BW/DF: 25%) and PRIM2 (Spanish: 31% BW/DF: 12.5%) in large numbers of samples. For primary tumors with matched metastases, we observed that metastases clustered together with their primary tumors. Conclusions: External validation of the 1q23.3 amplification demonstrates the association of this SCNA with poor outcomes in advanced UC; the identification of the target of this copy number gain is ongoing. Gene truncations and their biological significance require further experimental investigation.

Treatment outcomes and prognostic factors in mexican patients with endometrial carcinoma with emphasis on patients receiving radiotherapy after surgery: an institutional perspective.

Aim. To analyze the clinical characteristics and treatment outcomes in patients with endometrial carcinoma treated in a Latin American institute with emphasis in patients receiving adjuvant radiotherapy. Methods. A total of 412 patients with endometrial carcinoma admitted to our hospital between 1998 and 2008 were evaluated, retrospectively. The mean age was 55 years (28–87). Two hundred seventy patients received RT following surgery. Stage distribution was as follows: 221 patients (54%) stage I, 86 patients (21%) stage II, and 103 patients (24.5%) stage III and 2 patients (0.5%) stage IVA. Results. Overall survival rate was 95% at 2 years, 84% at 5 years, and 79% at 10 years. By the end of followup, 338 patients (82%) were disease-free, and 13 (3%) were alive with disease. Univariate and multivariate analyses identified age, grade, serosal and adnexial involvement as significant predictors for overall survival. Conclusion. The results of our study suggests that early-stage, low-grade endometrial cancer with no risk factors should not receive external beam radiotherapy, intermediate risk patients should receive only vaginal vault brachytherapy, and the use of chemotherapy with radiotherapy for patients high-risk and advanced-stage carcinoma the addition of radiotherapy is associated with a better survival being an effective therapeutic option.

Frozen section pathology at time of hysterectomy accurately predicts endometrial cancer in patients with preoperative diagnosis of atypical endometrial hyperplasia

ObjectivesA significant number of women diagnosed with atypical endometrial hyperplasia (AEH) on endometrial biopsy will be diagnosed with endometrial cancer (EC) on the hysterectomy specimen at permanent section. Surgical treatment for AEH and EC differ substantially. We have assessed the concordance in EC between frozen and permanent sections on patients undergoing hysterectomy for AEH. Materials and methodsA retrospective review of 66 frozen sections on patients undergoing hysterectomy for AEH was performed. Frozen and permanent section diagnoses were categorized as negative or positive for malignancy. Permanent section carcinomas were classified as low or high risk based on their histopathology, myometrial invasion and differentiation. Correlation between frozen and permanent section and sensitivity, specificity, PPV, NPV and accuracy of frozen section in predicting EC in permanent section were calculated. Likelihood of diagnosing EC on frozen section was compared based on risk stratification at permanent section. ResultsFrozen and permanent sections revealed malignancy in 43.9% and 56% of the patients respectively. 94.1% of high risk carcinomas were identified as EC at frozen section as compared to 55% of low risk EC. Concordance was good (κ=0.75). Sensitivity, specificity, NPV, PPV and accuracy in predicting EC at frozen section were 73%, 93.1%, 73% and 93.1% respectively. Carcinomas were detected at frozen section significantly more often if they were at high risk. ConclusionsThe substantial agreement between frozen and permanent sections allows minimizing under- and overtreatment of women undergoing hysterectomy for AEH. High risk EC are efficiently identified in frozen section.

Dose-Escalated Hypofractionated Intensity-Modulated Radiotherapy in High-Risk Carcinoma of the Prostate: Outcome and Late Toxicity

Background. The benefit of dose-escalated hypofractionated radiotherapy using intensity-modulated radiotherapy (IMRT) in prostate cancer is not established. We report 5-year outcome and long-term toxicity data within a phase II clinical trial. Materials and Methods. 60 men with predominantly high-risk prostate cancer were treated. All patients received neoadjuvant hormone therapy, completing up to 6 months in total. Thirty patients were treated with 57 Gy in 19 fractions and 30 patients with 60 Gy in 20 fractions. Acute and 2-year toxicities were reported and patients followed longitudinally to assess 5 year outcomes and long-term toxicity. Toxicity was measured using RTOG criteria and LENT/SOMA questionnaire. Results. Median followup was 84 months. Five-year overall survival (OS) was 83% and biochemical progression-free survival (bPFS) was 50% for 57 Gy. Five-year OS was 75% and bPFS 58% for 60 Gy. At 7 years, toxicity by RTOG criteria was acceptable with no grade 3 or above toxicity. Compared with baseline, there was no significant change in urinary symptoms at 2 or 7 years. Bowel symptoms were stable between 2 and 7 years. All patients continued to have significant sexual dysfunction. Conclusion. In high-risk prostate cancer, dose-escalated hypofractionated radiotherapy using IMRT results in encouraging outcomes and acceptable late toxicity.

Defining the role retropubic radical prostaectomy (RRP) in high-risk (HR) carcinoma prostate (CaP) and their outcome analysis.

e15135 Background: Role of RRP in high risk (HR ) Prostate cancer is still evolving. There is always a discussion regarding the best therapy for this category of individuals. We present our 10 year...