Initial Surgical Specimens Research Articles

594. THE IMPACT OF PATIENT CHARACTERISTICS AND NEOADJUVANT TREATMENT ON THE TUMOUR MICRO-ENVIRONMENT OF ESOPHAGEAL CANCER

Abstract Background Esophageal cancer remains associated with poor prognosis, as even with the current standards of multimodal treatment and oncologic surgery many patients show no response to treatment, or suffer early recurrence after surgery. In the current era of precision medicine, a better understanding of the tumor microenvironment (TME) is needed to identify patients with unfavourable biology, but also to illustrate the physiopathology of host reaction to treatment. The aim of this monocentric translational study was to analyse the biomolecular characteristics of esophageal cancer in relation to key clinicopathologic parameters, and in particular to the response to neoadjuvant treatment. Methods A series of patients operated for esophageal cancer with curative intent between 01.2009 and 12.2021 were included in this study. Clinicopathological data were collected, and initial biopsies and surgical specimens were reassessed by a senior GI pathologist. The immune infiltrate markers CD3, CD8, CD163, CD68, PDL1and FOXP3 were recorded as cell counts/high power field. The CPS score was used for PD-L1 quantification, whereas the Mandard regression grade (TRG) assessed pathologic response to neoadjuvant treatment (NAT). Continuous variables were compared with the Mann-Whitney-U and ANOVA tests, and categorical ones with the Chi-2 test. Significance threshold was set at p<0.05. Results Overall, 68 patients (82.4% males, mean age 62.4□9.4 years, 79.4% adenocarcinoma) were included. TME in smokers had lower M2-like (CD163+, p=0.009) and total macrophages (CD68+, p=0.001), but similar CD163/68 ratio and T-cells as non-smokers. Adenocarcinoma histology compared to squamous cell, showed higher M2-like macrophages (p=0.023), mean CPS score (p=0.038) and T-cell infiltration (p=0.006). NAT increased macrophages and cytotoxic T-cells, and decreased Treg/FoxP3 cells in the TME. Chemotherapy, compared to chemoradiation, was associated with higher T-cell TME infiltration. Good responders to NAT (TRG1-2) had similar initial TME characteristics as poor responders, but they displayed lower macrophage count upon final histology (p=0.003). Conclusions In the present series, active smoking was related to attenuated, whereas adenocarcinoma histology to enhanced M2-like macrophage infiltration of esophageal cancer TME. Neoadjuvant treatment, and especially chemotherapy, recruited macrophages and T-cells in the TME. None of the biomarkers derived from the initial biopsies were associated with response to NAT, although an increased macrophage count upon final histology was related to poor response. The present study provides valuable insight to the TME composition of esophageal cancer. However, further studies are needed to assess the exact functional role of TME elements, and specifically macrophages, and their impact on clinical outcomes.

Detection of molecular residual disease in stage II and III melanoma utilizing circulating tumor DNA.

e21564 Background: Overall survival for patients with melanoma has significantly improved with advancements in immunotherapy, especially with immune checkpoint inhibitors and BRAF/MEK inhibitors becoming standard of care for advanced melanoma. However, the decision to proceed with adjuvant therapy should be considered against the risk of adverse side effects, particularly in early-stage melanoma patients. Accurate biomarkers are needed to risk stratify patients, determine who will most likely benefit from adjuvant therapy, and identify when the ideal time is to initiate treatment. This study evaluates the prognostic value of personalized, tumor-informed circulating tumor DNA (ctDNA) testing in patients with stage II and III melanoma. Methods: In this real-world study, plasma samples (n =429) were analyzed from 90 stage IIA-IIID cutaneous melanoma patients treated at Rush University Medical Center between 03/30/2021 and 01/30/2024. A clinically-validated, personalized, tumor-informed 16-plex PCR assay (SignateraTM, Natera, Inc.) was used for detection and quantification of ctDNA in plasma samples. Results: Personalized, tumor-informed ctDNA assays were created using tissue samples from either initial biopsy or surgical excision specimen. Assay design was successful for 100% (90/90) of patients with sufficient tissue; test requests for 4 patients could not proceed due to insufficient tissue. ctDNA was detectable in 28% (25/90) of patients at one or more time points. There was a higher ctDNA-positivity rate in stage III patients (20/50, 40%) compared to stage II patients (5/40, 13%). Of the 25 patients with identifiable ctDNA during surveillance, 13 tested positive on the initial test (2 stage II and 11 stage III). Eighteen of the 25 ctDNA-positive patients received immunotherapy; eight patients achieved sustained ctDNA clearance, 2 had transient clearance, 2 have remained positive on ctDNA testing, and 6 continue to receive adjuvant IO and follow-up ctDNA testing. Clinical or radiographic recurrence occurred in 11/90 patients, 10 of whom tested positive for ctDNA. Conclusions: Personalized, tumor-informed ctDNA offers an adjunct to conventional monitoring for melanoma patients to detect molecular residual disease and was found to be prognostic in our patient cohort. Prospective studies are needed to evaluate the role of ctDNA in clinical decision making for surveillance imaging intervals and appropriate initiation, intensification, or discontinuation of adjuvant therapy.

Retained Biopsy Site Markers After Breast Lesion Surgical Resection: Associations With Residual Malignancy.

BACKGROUND. Biopsy site markers (BSMs) placed during image-guided core needle biopsy (CNB) are typically targeted for surgical excision, along with the breast imaging abnormality. Retained BSMs raise concern of incomplete resection of the breast abnormality. OBJECTIVE. The purpose of our study was to assess the frequency of residual malignancy in patients with retained BSMs identified on the initial mammography performed after breast lesion surgical excision. METHODS. This retrospective study included 30 patients (median age, 59 years) who underwent surgical resection between August 2015 and April 2022 of a borderline, high-risk, or malignant breast lesion after CNB and technically adequate preoperative image-guided localization, in whom the initial postoperative mammography report described a retained nonmigrated BSM. EMR data were extracted. The index pathology from CNB and initial surgical resection was classified as malignant or nonmalignant. The presence of residual malignancy after initial surgical resection required pathologic confirmation from subsequent tissue sampling; the absence of residual malignancy required 2 years of benign imaging follow-up. RESULTS. Thirteen specimen radiographs were interpreted intraoperatively by a surgeon with later radiologist interpretation, and 17 underwent real-time radiologist interpretation. Eighteen patients had malignant index pathology from the initially resected lesion. The frequency of residual malignancy on subsequent follow-up after initial surgical resection was higher in patients with malignant than nonmalignant index pathology (39% [7/18] vs 0% [0/12], respectively; p = .02). Among patients with malignant index pathology, the frequency of residual malignancy was higher in those without, than with, malignancy in the initial surgical specimen (80% [4/5] vs 23% [3/13]; p = .047). Also in these patients, the frequency of a positive interpretation of the initial postoperative mammography (BI-RADS category 4 or 6) was not significantly different between those with and without residual malignancy (57% [4/7] vs 55% [6/11]; p > .99). CONCLUSION. Patients with retained BSMs associated with malignant index lesions are at substantial risk of having residual malignancy. Initial postoperative mammography is not sufficient for excluding residual malignancy. CLINICAL IMPACT. Retained BSMs associated with index malignancy should be considered suspicious for residual malignancy. In this scenario, timely additional tissue sampling targeting the retained BSM is warranted, given the greater-than-2% chance of malignancy. Active surveillance is a reasonable management strategy in patients with retained BSMs from nonmalignant index lesions.

Temporal genomic heterogeneity guiding individualized therapy in recurrent non-small cell lung cancer.

Despite the benefit of adjuvant systemic therapy for patients with resected non-small cell lung cancer (NSCLC), the risk of postoperative recurrence remains high. Our objective was to characterize temporal genetic heterogeneity between primary resected and recurrent tumors, and its impact on treatment outcomes. In this study, next-generation sequencing (NGS) testing was performed on tissue specimens and circulating tumor DNA (ctDNA) collected at postoperative recurrence, and results were compared to the genotypes of initial surgical specimens. Of forty-five patients with matched primary and post-operative recurrent tumors, EGFR status switched in 17 patients (37.8%) at post-operative recurrence and 28 patients (62.2%) had no genotype change (17 mutant, 11 wild-type). Based on the changes of EGFR status, patients were divided into 4 groups. Following subsequent treatment with EGFR TKI o chemotherapy: In group A, with sustained sensitive mutation, the percentage achieving partial response (PR) was the highest, at 72.2%, the median progression-free survival (PFS) was 17 months, and the median overall survival (OS) was 44.0 months respectively; In group B, with genotype changed from wild-type to mutant, 50% achieved PR, PFS was 10 months, and OS was 35 months; In group C, in which mutant status shifted to wild-type or new co-mutation emerged, the percentage achieving PR was 30%, PFS was 9 months, and OS was 35 months. In group D, with sustained wild type, the percentage achieving PR was 27.3%, PFS was 8 months, and OS was 22 months. Genotypic shift between paired primary and post-operative recurrent tumors was not infrequent, and this temporal genomic heterogeneity substantially impacted subsequent treatment outcomes.

Establishment of Mucoepidermoid Carcinoma Cell Lines from Surgical and Recurrence Biopsy Specimens.

Patients with advanced/recurrent mucoepidermoid carcinoma (MEC) have a poor prognosis. This study aimed to establish and characterize human mucoepidermoid carcinoma cell lines from the initial surgical specimen and biopsy specimen upon recurrence from the same patient to provide a resource for MEC research. MEC specimens from the initial surgical procedure and biopsy upon recurrence were used to establish cell lines. The established cell lines were cytogenetically characterized using multi-color fluorescence in situ hybridization and detection, and the sequence of the CRTC1-MAML2 chimeric gene was determined. Furthermore, the susceptibility of head and neck mucoepidermoid carcinoma to standard treatment drugs such as cisplatin, 5-fluorouracil, and cetuximab was investigated. We successfully established unique MEC cell lines, AMU-MEC1, from an initial surgical specimen and AMU-MEC1-R1 and AMU-MEC1-R2 from the recurrent biopsy specimen in the same patient. These cell lines exhibited epithelial morphology and developed in vitro-like cobblestones. They shared eight chromosomal abnormalities, including der(19)ins(19;11)(p13;?), which resulted in a chimeric CRTC1-MAML2 gene, indicating the same origin of the cell lines. The susceptibility of all cell lines to cisplatin and 5-fluorouracil was low. Interestingly, EGFR dependency for cell growth decreased in AMU-MEC-R1 and AMU-MEC-R2 but was retained in AMU-MEC1. These cytogenetic and biochemical findings suggest that the established cell lines can be used to investigate the disease progression mechanisms and develop novel therapeutics for MEC.

Delayed time to surgery with hormonal treatment does not adversely impact outcomes in women with low-grade endometrioid endometrial cancer

<h3>Objectives:</h3> Longer wait times from diagnosis of low grade endometrioid endometrial cancer to treatment is associated with decreased overall survival. LNG-IUD therapy or systemic progesterone therapy can be reasonable options for conservative management of early-grade, uterus confined endometrial cancer in patients who wish to delay definitive surgical management. We sought to determine if delaying surgical treatment with progestin therapy adversely affected grade and stage of cancer at time of surgery. <h3>Methods:</h3> The Tumor Registries at a county and university hospital were used to perform a retrospective chart review of patients diagnosed with endometrial cancer from 2009 to 2017. Those with grade 1 or grade 2 endometrioid endometrial adenocarcinoma on EMB or D&C were included. Exclusion criteria included cervical involvement, imaging suggestive of metastatic disease, or completed surgical treatment prior to presentation for care. Patients were grouped into four cohorts: surgery within 42 days of diagnosis (S, n=65), surgery after 42 days (DS, n=52), delayed surgery after progestin therapy (DS+H, n=20), and progestin therapy alone (H, n=21). A one-way ANOVA test and two-tailed t-test were performed to determine whether cohorts differed demographically or in regard to grades and stages. <h3>Results:</h3> 158 patients met inclusion criteria. In total, average age at diagnosis was 55.30 years, average BMI was 39.22, and average Charlton Comorbidity Index (CCI) was 3.97. There was a difference in average age between the S v DS+H (p=0.002, 58.4 v 46.8) and DS v DS+H (p=0.009, 56.6 vs 46.8) cohorts. There was a difference in average BMI between the S vs DS+H (p=0.005, 35.9 vs 42.7) and S v H (p=0.01, 35.9 vs 46.4) cohorts. There were no differences in CCI scores between groups (p=0.25) (Figure 1). There were no differences between the cohorts in regard to initial grade (p=0.36), grade at surgery (p=0.75), grade change between initial diagnosis and surgical specimen (p=0.47), or surgical stage (p=0.52). <h3>Conclusions:</h3> Delayed time to surgery with progestin treatment does not result in stage progression or change in grade. Patients treated with hormones tended to be younger and with higher BMIs. Temporary progestin therapy should be considered if delaying surgical treatment for women with corpus confined low grade endometrioid endometrial cancer.

Abstract PS2-34: Concordance of breast cancer biomarker testing in core-needle biopsy and surgical specimens: A single institution experience

Abstract Accurate diagnostic biomarker testing, including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her2) expression profile, is crucial to appropriate management decisions in breast cancer. Receptor status testing is typically performed on the initial core needle biopsy (CNB) and surgical specimen (SS). The rate of concordance between CNB and SS is unclear as is the impact this has on clinical decision making. The current guidelines on retesting are vague, which results in individual institutions and providers determining retesting policies. Several studies worldwide have assessed the concordance of receptor testing with mixed conclusions. We aim to determine concordance between CNB and SS, and whether this leads to clinically relevant management changes. A retrospective analysis was performed on patients with invasive breast cancer with available CNB and SS pathology at our institution between January 2010- May 2020. Patients who were treated with primary surgical resection and neoadjuvant chemotherapy with residual disease were included. Concordance rates between CNB and SS were assessed for ER, PR, and Her2 IHC/ FISH amplification. ER and PR status were defined per NCCN guidelines as “positive,” “low-positive (ER)” or “negative.” Major discrepancy was defined as a change in label of “positive” or “negative”. Minor discrepancy was defined as change &amp;gt;10% without a “positive” or “negative” label change. Major discordance in Her2 was defined as change in label of “positive” or “negative” based on IHC or FISH amplification results. A minor discrepancy was a change in Her2 IHC (0-3) or FISH amplification without change in label of “positive” or “negative.” The clinical impact of discordant results was determined by investigator review. 748 patients met the eligibility criteria, and 64 of these patients received neoadjuvant therapy. For ER, there was 90.6% concordance, 2.2% major discordance, and 7.8% minor discordance between CNB and SS. For PR, there was 59.64% concordance, 11.9% major discordance, and 28.46% minor discordance. For Her2, there was 54.7% concordance, 1.6% major discordance, and 43.8% minor discordance. Of major discordance, ER (43.8%) led to the most change in management compared to Her2 and PR (12.5% and 2.2%, respectively). Retesting Her2 on SS did not change management when initial CNB was Her2 positive. For major discrepancies, patient demographics, tumor characteristics, treatment course, recurrence, and survival were reviewed. Although discordance was more common in PR and Her2 than ER biomarker profiles, major discordance leading to treatment changes were more common in ER and Her2. Retesting ER and Her2 on CNB and SS may be more clinically beneficial than retesting PR. Guidelines for retesting receptor profiles on CNB and SS are needed to best guide patient care management decisions that maximize clinical benefits while minimizing healthcare costs. Table: Concordance of ER, PR, and HER2 Expression ProfileConcordanceMajor DiscrepancyMinor Discrepancy# Patients with Change in Treatment with Major DiscrepanciesER90.6%2.2%7.8%7/16 (43.8%)PR59.6%11.9%28.5%2/90 (2.2%)Her254.7%1.6%43.8%5/12 (12.5%) Citation Format: Jessica Anne Slostad, Nicole Yun, Aimee Schad, Surbhi Warrior, Ruta Rao. Concordance of breast cancer biomarker testing in core-needle biopsy and surgical specimens: A single institution experience [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS2-34.

Changes of estrogen receptor, progesterone receptor and HER2 expression in breast cancer with/without neoadjuvant chemotherapy or endocrine therapy.

e14699 Background: Concordance in hormone receptor and Human Epidermal Growth Factor Type 2 (HER2) status in breast cancer was observed between initial biopsy and surgical specimens. This study aimed to analyze the correlation in Estrogen receptor (ER), Progesterone receptor (PR) and HER2 status of the initial biopsy and surgical specimen in non-neoadjuvant therapy (CON), neoadjuvant chemotherapy (NAC) and neoadjuvant endocrine therapy (NAE). Secondary aim is to know the changed expression of ER, PR and HER2 as predictive marker for overall survival. Methods: We retrospectively analyzed 1265 surgical specimens from April 2007 to January 2018 in National Nagasaki Medical Center. Out of 1265 patients, 752 CON, 144 NAC and 28 NAE pairs of samples from initial core biopsy and surgical specimen were compared to the expression of the ER, PR and HER2 by immunohistochemically. Spearman’s rank correlation coefficient is calculated. Results: See table. Conclusions: ER and PR expression percentage is highly correlated between core needle biopsy and surgical specimen. After neoadjuvant chemotherapy, PR lost 8.2% after NAC and 40.8% after NAE. PR loss may become predictive marker after systemic therapy.[Table: see text][Table: see text]

Abstract 6: Role of Notch signaling in bevacizumab-induced vascular normalization in glioblastoma

Abstract Tumor angiogenesis occurs in the setting of a defective vasculature, which is associated with increased vascular permeability and enhanced tumor permeability. Bevacizumab is used to treat malignant glioma and was found to reduce microvascular density and prune abnormal tumor microvessels. Using electron microscopic observation of two autopsy cases, we investigated the effects of blood vessel normalization in glioblastomas treated with bevacizumab. Notch-1 and SMA immunostaining were used to compare initial surgical specimens with postmortem specimens obtained after bevacizumab treatment. Postmortem samples showed marked proliferation of SMA-positive cells (pericytes) in tumor vessels and marked proliferation of Notch-1–positive cells around vessels. Electron microscopic images confirmed the presence of pericytes surrounding the vascular endothelium. These findings suggest that bevacizumab treatment promotes vascular normalization by recruiting mature pericytes. Next, we investigated the effects of bevacizumab on VEGF inhibition in glioma stem cells. Bevacizumab treatment attenuated activation of VEGFR2 and increased Notch signaling expression. VEGF inhibition by bevacizumab treatment attenuated proliferation and self-renewal of glioma stem cells and induced endothelial and pericyte differentiation. In tumor angiogenesis, vascular endothelial growth factor induces sprouting angiogenesis and recruitment of vascular endothelial cells such as tip cells, stalk cells, and phalanx cells. Fully mature phalanx cells are in close contact with pericytes. Our results suggest that bevacizumab treatment induces glioma stem cells to differentiate to endothelium and pericytes. These mechanisms might be important in normalizing tumor vasculature after bevacizumab treatment and could be useful in improving the effectiveness of current glioma therapy. Citation Format: Norihiko Saito, Kazuya Aoki, Nozomi Hirai, Satoshi Fujita, Haruo Nakayama, Morito Hayashi, Takatoshi Sakurai, Satoshi Iwabuchi. Role of Notch signaling in bevacizumab-induced vascular normalization in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 6.

Prognostic Prediction of Oral Squamous Cell Carcinoma by E-Cadherin and N-Cadherin Expression in Overall Cells in Tumor Nests or Tumor Cells at the Invasive Front.

Epithelial-mesenchymal transition (EMT) is a significant process in the invasion and metastasis of cancers including oral squamous cell carcinoma (OSCC), and the cadherin switch has been identified as one of the hallmarks of EMT. The aim of the present study was to evaluate the significance of the cadherin switch in the prognosis of OSCC and generate a model for prognostic predictions. Seventy-six biopsy and/or initial surgical specimens from OSCC patients were immunohistochemically analyzed for the expression of E-cadherin and N-cadherin in either overall OSCC cells in tumor nests or in OSCC cells at the invasive front. Among 76 OSCC cases, overall OSCC cells in tumor nests were negative for the expression of E-cadherin in 10 cases and positive for that of N-cadherin in 53 cases. Among 10 cases negative for the expression of E-cadherin, 4 cases were positive for that of N-cadherin. In OSCC cells at the invasive front, the expression of E-cadherin was negative in 62 cases, while that of N-cadherin was positive in 39 cases. Among 62 cases negative for the expression of E-cadherin, 33 cases were positive for that of N-cadherin. A logistic regression analysis showed that a model using the evaluation of N-cadherin expression in overall OSCC cells in tumor nests with a cut-off point of 70years old was the best fit model. These results suggest that N-cadherin has significant value in prognostic predictions for OSCC patients.

Spontaneous Synchronous Bilateral Ectopic Pregnancy

Background: The occurrence of simultaneous ectopic pregnancies in two extrauterine locations is rare, particularly in spontaneous pregnancies. Case: This article describes the case of a 32-year-old woman who presented with persistently elevated β-hCG levels after a salpingectomy for a left ectopic tubal pregnancy. Results: Follow-up elevated β-hCG levels led to the discovery of a simultaneous right tubal ectopic pregnancy. Conclusions: Bilateral ectopic pregnancy is rare but must be suspected when β-hCG is elevated after treatment of an ectopic pregnancy. β-hCG follow-up can be helpful, even if chorionic villi are present in the initial surgical specimen. (J GYNECOL SURG 33:202)

High-depth sequencing of paired primary and metastatic tumours: Implications for personalised medicine

BackgroundNext-generation sequencing of large panel of genes had been associated with clinical benefit in a significant proportion of patients with advanced cancer. However, the molecular profile of the primary tumour from the initial surgical specimen might significantly differ from the molecular profile in a tumour sample obtained from a biopsy of a metastatic site. Patients and methodsWe compare the genetic profile of primary tumours and paired metastases by using a large panel of cancer genes. Training and validation set including a total of 152 primary and metastatic tumour pairs were sequenced (up to 429 genes) focussing on variants described in the Catalogue of Somatic Mutations in Cancer (COSMIC). ResultsTraining and validation set including a total of 152 primary and metastatic tumour pairs were sequenced focussing on variants described in COSMIC. Agreement rate between the couples of primary and metastasis on COSMIC variants was 65% (24/37) and 43% (49/115) in the training and validation cohort, respectively. That rose to 74% (20/27) and 58% (42/73) when focussing on targetable mutations. In five cases, the discordance was related to appearance of secondary resistance mutation, giving a targetable refined agreement rate of 67% (67/100). ConclusionUp to 40% of paired primary tumour/metastases have discordant molecular profile. Liquid biopsies may overcome, in the near future, the limits of tumour tissue genotyping.

Association of long-term survival in pancreatic cancer (PDAC) with increased proliferative and anti-apoptotic protein activation.

254 Background: 5 year (yr) overall survival (OS) for resected PDAC is typically 20%. To test the potential for molecular prediction of &gt; 5 yr OS in such patients (pts), we analyzed proteomic activation (phosphorylation) patterns in both cancer and stromal cells from initial surgical specimens prior to adjuvant therapy (Rx). Methods: Formalin-fixed, paraffin-embedded tissue from 40 pts (20 pts each with long-term actual disease-free OS [median 65 mo, range 26-137 mo] [LTS] and with early relapse/death &lt; 2 yrs [STS]) with de novo resected PDAC formed the test cohort. All pts received adjuvant Rx (chemo Rx with/without chemoradiation). Laser Capture Microdissection enabled directed cancer and stromal cell isolation. Retrospective blinded protein activation analysis for both was performed via Reverse Phase Protein Array (RPPA). Differences in baseline protein signaling of LTS vs. STS were evaluated via two-way ANOVA analysis. Results: Analysis of &gt; 50 signal transduction proteins (STPs) for activation (phosphorylation) showed these significant differences for LTS vs. STS in cancer cells: 1) Activation of proliferation markers Sox2/ Ki 67 were higher (p&lt;0.0001). 2) Activation of anti-apoptotic signal transducer and activator of transcription 3 (p-STAT 3) ( p=0.047) and p-SRC kinase (p=0.039) were higher. 3) Activated p-m-TOR expression was higher (p=0.021). 4) Activation of mitotic marker histone H3S10 was lower (p=0.03). In stromal cells, activation of the survival marker Mek S298 was lower (p=0.021). For other STPs, differences for LTS vs. STS (e.g. Livin, PCNA) were not seen. Conclusions: 1) LTS and STS of de novo resected PDAC show clear differences in cancer cell protein activation re key markers of proliferation and apoptosis (Sox2, Ki67, STAT3, SRC kinase, H3S10). 2) For stromal cells, protein activation was largely similar, but a difference in activation of one stromal protein (Mek S298) was seen. 3) For these pts, differences in protein activation prior to adjuvant Rx could enhance current prognostic models and/or identify new pharmacological targets designed to improve OS. 4) These findings require further validation: a second 60 sample validation cohort is now under anaylsis.

Missed Initial Diagnosis of Malignant Struma Ovarii Containing Follicular Thyroid Carcinoma

Distant metastasis of rare malignant struma ovarii (MSO) has been reported for cases associated with papillary thyroid cancer but few with follicular thyroid cancer. A 38-yr-old woman with struma ovarii that was initially diagnosed as "benign" presented with pulmonary metastasis and coughing 17 yr later. The lungs lesions were confirmed to be follicular thyroid cancer by biopsy. Rereview of the initial surgical ovary specimens confirmed the condition to be MSO with follicular thyroid cancer. The patient was treated with total thyroidectomy, which showed no thyroid malignancy, followed by (131)I (iodine-131) treatments. Dramatic reduction was observed in both the stimulated thyroglobulin level and the size of the pulmonary metastases over 1 yr. During the following 3-yr follow-up, the patient remained clinically well, with undetectable thyroglobulin (<1 ng/mL) and small stable pulmonary lesions. This is an exceedingly rare case of MSO with follicular thyroid cancer metastasized to the lungs presenting with a late onset but a fortunate excellent response to multidiscipline treatments. It is advisable that struma ovarii be carefully examined to avoid missing malignancy and patients be clinically followed up even with a benign initial diagnosis.

The clinical significance of a second transurethral resection for T1 high-grade bladder cancer: Results of a prospective study

PurposeThis study was designed to estimate the value of a second transurethral resection of bladder tumor (TURBT) procedure in patients with initially diagnosed T1 high-grade bladder cancer.Materials and MethodsBetween August 2009 and January 2013, a total of 29 patients with T1 high-grade bladder cancer prospectively underwent a second TURBT procedure. Evaluation included the presence of previously undetected residual tumor, changes to histopathological staging or grading, and tumor location. Recurrence-free and progression-free survival curves were generated to compare the prognosis between the groups with and without residual lesions by use of the Kaplan-Meier method.ResultsOf 29 patients, 22 patients (75.9%) had residual disease after the second TURBT. Staging was as follows: no tumor, 7 (24.1%); Ta, 5 (17.2%); T1, 6 (20.7%); Tis, 6 (20.7%); Ta+Tis, 1 (3.4%); T1+Tis, 1 (3.4%); and ≥T2, 3 (10.3%). The muscle layer was included in the surgical specimen after the initial TURBT in 24 patients (82.7%). In three patients whose cancer was upstaged to pT2 after the second TURBT, the initial surgical specimen contained the muscle layer. In the group with residual lesions, the 3-year recurrence-free survival and 3-year progression-free survival rates were 50% and 66.9%, respectively, whereas these rates were 68.6% and 68.6%, respectively, in the group without residual lesions. This difference was not statistically significant.ConclusionsInitial TURBT does not seem to be enough to control T1 high-grade bladder cancer. Therefore, a routine second TURBT procedure should be recommended in patients with T1 high-grade bladder cancer to accomplish adequate tumor resection and to identify patients who may need to undergo prompt cystectomy.

Prognostic value of receptor status change following neoadjuvant chemotherapy in locally advanced breast cancer

Abstract Introduction The effect of neoadjuvant chemotherapy (NAC) on the expression of receptor status in locally advanced breast cancer (LABC) is still under investigation. Aims of this study are to evaluate changes in hormone receptor (HR) and HER-2 status post-NAC and correlation with survival. Materials and methods LABC patients who received NAC between 2001 and 2008 at Istanbul University were analyzed retrospectively. Patients with pathologic complete response (pCR) were excluded in analysis. Immunohistochemical (IHC) analyses was performed on both initial biopsies and surgical specimens. Results The median age of 128 patients was 48 years and 55% of them were premenopausal. Most of the patients had invasive ductal (81%) and histologic grade (HG) III (81%) breast cancer. Partial pathologic response (pPR) rate was 86.7%. HR status changed in 36 patients (28%). The rates of ER, PR and HER-2 receptor positivity at diagnosis and after NAC were 44–32.8%, 43–29.7%, and 24–21%, respectively. Negative-to-positive change in HR status was observed in five patients. The 5-year overall survival (OS) was 76% in patients whose HR status converted to negative, compared with 91% in patients who remained HR-positive ( p p =0.002), whereas as it did not have any impact on OS ( p =0.148). Conclusion NAC induced changes in HR and HER-2 expression, predominantly from positive to negative. These changes were associated with shorter DFS. Postoperative re-evaluation of receptor status may have clinical significance.

Engraftment of resected pancreatic adenocarcinoma in SCID mice and patient survival following surgical resection: Roswell Park's experience.

185 Background: Preclinical models developed by implanting resected pancreatic cancer from human donors into immunocompromised (SCID) mice have been valuable in understanding the disease’s biology and developing therapies. The ability of resected tumors to engraft successfully has previously been reported to be a poor prognostic marker. This study was conducted to investigate the relationship between successful engraftment and clinical outcome by analyzing such a model developed at Roswell Park over the last decade. Methods: A retrospective review of 48 donor patients (27 males and 21 females) whose resected pancreatic adenocarcinoma was xenografted in SCID mice between 1999-2009 was conducted. The clinical outcome and baseline information were correlated with engraftment outcome. The expression of potential biomarkers correlating with engraftment was evaluated by performing immunohistochemistry on the initial donor surgical specimens. The expression was scored, assigned an average index value and categorized into groups (High vs Low expression) based on a median cutoff of values. Results: Resected tumors from 21 of the 48 donors successfully engrafted when implanted subcutaneously in SCID mice (44%). The baseline demographics and disease characteristics were balanced between engrafters versus non-engrafters. All of the engrafters and 26 (of 27) of non-engrafters received adjuvant treatment. The 2-year overall survival (OS) of patients whose tumors successfully engrafted was 17% compared to 39% in those whose tumors failed to engraft (P=0.09; hazard ratio 1.305 [95% CI 0.717-2.375]). Analysis to identify potential biological markers associated with engraftment success is underway. Conclusions: A review of the clinical outcome of patients whose tumors were procured and used for the patient-derived primary pancreatic cancer xenograft program at Roswell Park showed that successful engraftment in SCID mice is potentially a poor prognostic marker in patients with resectable pancreatic cancer. Our analysis did not reach statistical significance which is likely due to a smaller sample size but the potential link is consistent with that reported by others.

CD5-Negative Mantle Cell Lymphoma Resembling Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue : A Case Report

A 71-year-old male underwent an upper gastrointestinal endoscopy ; as a result of a biopsy, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) was suspected. Abdominal computed tomography scan disclosed an approximately 4-cm-large mass in the ileocecal region. After ileocecal resection, the patient was diagnosed with MALT lymphoma (CD79a(+), CD20(+), CD3(-), CD5(-), CD10(-), and cyclin D1(-)). He achieved complete remission after receiving chemotherapy. However, four years after the primary onset, he was diagnosed with recurrence. Although he achieved remission again by salvage therapy, six years after the primary onset, he was referred to our hospital with second recurrence. Colonoscopy revealed the appearance of multiple lymphomatous polyposis and biopsy specimens showed monotonous proliferation of centrocyte-like cells (CD79a(+), CD20(+), CD3(-), CD5(-), CD10(-), and cyclin D1(+)), which were consistent with mantle cell lymphoma (MCL) except for CD5. The result of reactivity to cyclin D1 was different from that at initial diagnosis, so we reexamined the initial surgical specimens, the histological and histochemical features of which were proven to be the same as those of colonic biopsy specimens. Finally, the patient was diagnosed with CD5-negative MCL (marginal zone-like variant). As MALT lymphoma and MCL sometimes show similar histological features, they are difficult to distinguish from each other. It is necessary to take the possibility of this rare phenotype of MCL into consideration and to reexamine the initial diagnosis, especially if the clinical course is unusual for MALT lymphoma. This case is very interesting in view of its indolent clinical feature and phenotype.

P5-11-12: Correlation of Ki67 Expression between Initial Biopsy and Surgical Specimen in Untreated Breast Cancer Patients. Does Menstrual Cycle Matter?

Abstract Background: The measure of proliferative index by Ki67 expression is being increasingly used to identify breast cancer subtype and to guide treatment decisions. Findings on initial tumor biopsy are in some cases, such as for primary systemic treatment, the only data available prior to treatment. In addition, results from window studies to develop novel anti-tumor agents depends on initial breast cancer biopsy findings. This study aims to compare the Ki67 expression on initial biopsy with matched primary breast cancer surgical specimens. In addtion, we aimed to explore the possible effect of hormonal levels — as reflected by menstrual cycle phase — on discordant Ki67 cases. Material and Methods: A total of 50 random cases were analyzed by 2 blinded pathologists. Ki67 expression was collected as a continuous variable. Tumors were then classified as high — or low-proliferative according to a Ki67 value of &amp;gt; or = 15% or &amp;lt; 15%, respectively. Sperman Rank test was used to study the correlation between initial and surgical biopsies. Data on menstrual cycle phase at the time of biopsy and surgery were retrived from medical history of all premenopausal patients. Results: Baseline patients characteristics are as follows: median age 48 (35-56 years), premenopausal 27 (54%), postmenopausal 23 (46%), invasive ductal carcinoma 38 (76%). A differential expression of Ki67 was found in 36 patients (72%), 20 pre- and 16 post-menopausal. Spearman's Rank Order correlation did not show any significant difference between biopsy and matched surgical specimen in terms of Ki67 expression. Indeed, there was a strong positive correlation between initial and surgical biopsy, which was statistically significant across all patients (rs = .556, P &amp;lt; 0.001), and regardless the menopausal status. However, 15% of pre-menopausal patients transformed from Ki67 low to high. Therefore, data on pre-menopausal patients were analyzed according to the phase of menstrual cycle at the timing of initial and surgical biopsies. The Spearman's Rank Order gave no correlation among 14 premenopausal patients with differential menstrual cycle phase at the timing of initial biopsy and surgery (rs = .411, P = 0.145). Conclusions: Initial breast cancer biopsy can be used with high confidence for Ki67 determination. However, it should be noted that menstrual cycle phase could affect Ki67 expression as women with distinct menstrual cycle phase at the time of initial biopsy and final surgery do not show concordant results. Prospective evaluation of Ki67 expression in premenopausal patients is being planned. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-11-12.

Light‐guided lumpectomy: first clinical experience

Despite numerous advances, lumpectomy remains a challenging procedure. We report on the early use of light-guided lumpectomy. Eight patients with non-palpable breast cancer undergoing lumpectomy for biopsy-proven and radiographically identifiable cancer were enrolled in the study. An optical wire was designed that incorporated a standard hook-wire with an optical fiber. The optical wire was placed in the same manner as a standard hook-wire. During light-guided lumpectomy, an eye-safe laser illuminated the optical wire and created a sphere of light surrounding the cancer. The light was visible at the beginning of each surgery and facilitated approaching the cancer without using the wire. Dissection around the sphere of light kept the wire tip within the surgical specimen. Three of eight initial surgical specimens had focally positive margins. Additional cavity shaves were performed during five lumpectomies and resulted in negative margins in seven of eight patients. Light-guided lumpectomy is a minor change to breast conserving surgery that can be easily incorporated into clinical practice. Further investigation into the clinical benefit of light-guided lumpectomy is warranted.