Unknown Margins Research Articles

Endoscopic papillectomy could be rewarding to patients with early stage duodenal ampullary carcinoma?

There is currently no consensus on the use of endoscopic papillectomy (EP) for early stage duodenal ampullary adenocarcinoma. This study aimed to evaluate the feasibility of EP for patients with early stage duodenal ampullary adenocarcinoma. Patients who underwent EP for ampullary adenocarcinomas were investigated. Complete and clinical complete resection rates were evaluated. Clinical complete resection was defined as either complete resection or resection with positive or unknown margins but no cancer in the surgically resected specimen, or no recurrence on endoscopy after at least a 1-year follow-up. Adenocarcinoma developed in 30 patients (carcinoma insitu [Tis]: 21, mucosal tumors [T1a(M)]: 4, tumors in the sphincter of Oddi [T1a(OD)]: 5). The complete resection rate was 60.0% (18/30) (Tis: 66.7% [14/21], T1a[M]: 50.0% [2/4], and T1a[OD]: 40.0% [2/5]). The mean follow-up period was 46.8 months. The recurrence rate for all patients was 6.7% (2/30). The clinical complete resection rates of adenocarcinoma were 89.2% (25/28); rates for Tis, T1a(M), and T1a(OD) were 89.4% (17/19), 100% (4/4), and 80% (4/5), respectively. EP may potentially achieve clinical complete resection of early stage (Tis and T1a) duodenal ampullary adenocarcinomas.

The impact of surgical resection margins on outcomes for adults with head and neck osteosarcomas: A Canadian sarcoma research and Clinical Collaboration (CanSaRCC) study

ObjectiveThe aim of the study is to describe the factors that influence outcome in adults with head and neck osteosarcoma (HNO) with a specific focus on the margin status. MethodsPatients with a diagnosis of HNO between the years 1996–2021 were reviewed from the Canadian Sarcoma Research and Clinical Collaboration (CanSaRCC) Database. Baseline characteristics, pathology, treatment, and outcomes were analyzed. Univariable (UVA) and multivariable (MVA) Cox regression models were performed. 5-year locoregional control rate and overall survival (OS) were estimated using Kaplan-Meier method and Log-Rank test. ResultsOf 50 patients with a median age of 40 years (range 16–80), 27 (54%) were male. HNO commonly involved the mandible (n = 21, 42%) followed by maxilla (n = 15, 30%). Thirteen (33.3%) had low-intermediate grade and 26 (66.6%) had high grade tumors. Three patients (6%) had negative resection margins (>5 mm), 24 (48%) had close margins (1–5 mm), 15 (30%) had positive margins (<1mm) and 7 (16%) had unknown margin status. In total, 39 (78%) received chemotherapy – 22 (44%) received neoadjuvant chemotherapy while 17 (34%) received adjuvant chemotherapy. A total of 12 (24%) patients received radiotherapy, of whom 8 (16%) had adjuvant and 3 (6%) had neo-adjuvant. Median follow-up time was 6.3 years (range 0.26–24.9). Disease recurred in 21 patients (42%), of whom 15 (30%) had local recurrence only, 4 (8%) had distant metastasis, and 2 (4%) had both local and distant recurrence. 5-year locoregional control rate and OS was 62% and 79.2% respectively. Resection margins <3 mm was associated with lower 5 years OS and locoregional control rate (Log-Rank p = 0.02, p = 0.01 respectively). ConclusionOsteosarcomas of the head and neck are rare and local recurrence remains a concern. Surgical resection with negative resection margins may improve survival, and a 3 mm resection margin threshold may optimize survival. Radiotherapy and/or chemotherapy should be considered in a multidisciplinary setting based on risk-features.

Recurring Pancreatic Neuroendocrine Tumor: Timing and Pattern of Recurrence and Current Treatment.

The objective of this study was to describe the pattern of recurrence, treatments received, as well the oncological outcomes, of pancreatic neuroendocrine tumors (PanNETs) following curative surgery. PanNETs recur in 10% to 15% of cases following surgery. Information on the natural history and management of recurring disease is lacking. Patients with PanNET that underwent curative surgery at 4 institutions between 2000 and 2019 were identified. Patients with poorly differentiated tumors, unknown tumor grade and differentiation, hereditary syndromes, unknown margin or R2 status, metastatic, and those that had neoadjuvant treatment or perioperative mortality were excluded. Clinical variables were assessed including first site of recurrence, treatment received, and survival outcomes. A total of 1402 patients were included: 957 (74%) had grade 1, 322 (25%) had grade 2, and 13 (1%) had grade 3 tumors. Median follow-up was 4.8 years (interquartile range: 2-8.2 years). Cumulative incidence of recurrence at 5 years was 13% (95% CI: 11%-15.2%) for distant disease, 1.4% (95% CI: 0.8%-2.3%) for locoregional recurrence, and 0.8% (95% CI: 0.4%-1.5%) for abdominal nodal recurrence. Patients who recurred had 2.89 increased risk of death (95% CI: 2-4.1) as compared with patients who did not recur. Therapy postrecurrence included: somatostatin analogs in 111 (61.0%), targeted therapies in 48 (26.4%), liver-directed therapies in 61 (33.5%), peptide receptor radionuclide therapy in 30 (16.5%), and surgery in 46 (25.3%) patients. Multiple treatments were used in 103 (57%) cases. After the first recurrence, 5-year overall survival was 74.6% (95% CI: 67.4%-82.5%). Recurrence following surgery is infrequent but reduces survival. Most recurrences are distant and managed with multiple therapies. Prospective studies are needed to establish strategies for surveillance and the sequence of treatment to control the disease and prolong survival.

Impact of salvage surgery for recurrent sinonasal cancers with skull base and intracranial involvement.

Patients with recurrent sinonasal cancers (RSNCs) often present with extensive involvement of the skull base and exhibit high rates of subsequent recurrence and death after therapy. The impact of salvage surgery and margin status on progression-free survival (PFS) and overall survival (OS) has yet to be demonstrated. The goal of this study was to determine whether skull base resection with negative margins has an impact on outcomes in the recurrent setting. A retrospective chart review of 47 patients who underwent surgery for RSNC with skull base invasion between November 1993 and June 2020 was conducted. The following variables were extracted from the clinical records: patient demographic characteristics (age and sex), tumor pathology, dural and orbital invasion, and prior radiation exposure and induction chemotherapy. Metastatic disease status, surgical approach, margin status, and history of postoperative chemotherapy and/or postoperative radiation therapy were noted. The primary and secondary outcomes were PFS and OS, respectively. The cohort included 30 males (63.8%) and 17 females (36.2%), with a mean ± SD age of 54.8 ± 14.4 years. Thirty-five (74.5%) patients showed disease progression, and 29 (61.7%) patients died during the study period. The mean ± SD patient follow-up period was 61.8 ± 64.4 months. Dural invasion was associated with increased risk of death (HR 2.62, 95% CI 1.13-6.08). High-risk histopathology (HR 3.14, 95% CI 1.10-8.95) and induction chemotherapy (HR 2.32, 95% CI 1.07-5.06) were associated with increased odds of disease progression. When compared to patients with positive margins or gross-total resection with unknown margin status, those with negative margins had decreased odds of disease progression (HR 0.30, 95% CI 0.14-0.63) and death (HR 0.38, 95% CI 0.17-0.85). RSNCs show high rates of subsequent disease progression and mortality. This study demonstrated that negative margins may be associated with improved PFS and OS in carefully selected patients who have undergone salvage surgery for RSNC.

Impact of Treatment Modalities upon Survival Outcomes in Skull Base and Clival Chordoma: An NCDB Analysis.

Objectives Skull base chordomas are locally aggressive malignant tumors derived from the notochord remnant. There are limited large-scale studies examining the role and extent of surgery and radiation therapy. Design Analysis of the National Cancer Database (NCDB) was performed to evaluate the survival outcomes of various treatments, and to assess for predictors of overall survival (OS). Participants This is a retrospective, population-based cohort study of patients diagnosed with a clival/skull base chordoma between 2004 and 2015 in the NCDB. Main Outcome Measures The primary outcome was overall survival (OS). Results In all, 468 cases were identified. Forty-nine percent of patients received surgery and 20.7% had positive margins. Mean age at diagnosis was 48.4 years in the surgical cohort, and 55% were males. Of the surgical cohort, 33.8% had negative margins, 20.7% had positive margins, and 45.5% had unknown margin status. Age ≥ 65 (hazard ratio [HR]: 3.07; 95% confidence interval [CI]: 1.63-5.76; p < 0.001), diagnosis between 2010 and 2015 (HR: 0.49; 95% CI: 0.26-0.90; p = 0.022), tumor size >5 cm (HR: 2.29; 95% CI: 1.26-4.15; p = 0.007), and government insurance (HR: 2.28; 95% CI: 1.24-4.2; p = 0.008) were independent predictors of OS. When comparing surgery with or without adjuvant radiation, no survival differences were found, regardless of margin status ( p = 0.66). Conclusion Surgery remains the mainstay of therapy. Advanced age (>65 years), large tumor size, and government insurance were predictors of worse OS. Whereas negative margins and the use of adjuvant radiation did not appear to impact OS, these may very well reduce local recurrences. A multidisciplinary approach is critical in achieving optimal outcomes in this challenging disease.

A Farewell to the Encephalization Quotient: A New Brain Size Measure for Comparative Primate Cognition

Both absolute and relative brain sizes vary greatly among and within the major vertebrate lineages. Scientists have long debated how larger brains in primates and hominins translate into greater cognitive performance, and in particular how to control for the relationship between the noncognitive functions of the brain and body size. One solution to this problem is to establish the slope of cognitive equivalence, i.e., the line connecting organisms with an identical bauplan but different body sizes. The original approach to estimate this slope through intraspecific regressions was abandoned after it became clear that it generated slopes that were too low by an unknown margin due to estimation error. Here, we revisit this method. We control for the error problem by focusing on highly dimorphic primate species with large sample sizes and fitting a line through the mean values for adult females and males. We obtain the best estimate for the slope of circa 0.27, a value much lower than those constructed using all mammal species and close to the value expected based on the genetic correlation between brain size and body size. We also find that the estimate of cognitive brain size based on cognitive equivalence fits empirical cognitive studies better than the encephalization quotient, which should therefore be avoided in future studies on primates and presumably mammals and birds in general. The use of residuals from the line of cognitive equivalence may change conclusions concerning the cognitive abilities of extant and extinct primate species, including hominins.

Risk Factors Associated to Residual Tumor in Re-excision for Positive Margins in Breast Conservative Surgery.

Breast conservative surgery (BCS) is an adequate treatment for patients with early breast cancer. Local recurrence is associated with diverse factors. Our objective was to evaluate risk factors associated with finding residual tumor in patients with positive margins in BCS. Observational retrospective study, including patients diagnosed with breast cancer undergoing BCS between 2000 and 2016. Clinicopathological and treatment variables were collected. Main outcome was the finding of residual tumor on re-excision. Positive margins were defined as tumor present on ink. Three hundred and six patients underwent BCS. Mean age was 57 ± 12.2years. Positive margins were found in 84 (27.4%) patients, 15 (4.9%) had unknown margin status, and 207 (67.6%) had negative margins. Seventy-eight patients from the positive margin group and 23 patients from the unknown/negative margin group were reintervened. Residual tumor was present in 41% of patients with positive margins and in 45% of patients with negative margins (P = .192). In univariate analysis, overweight (P = .04) and positive axillary lymph nodes (P = .02) were associated with residual tumor on re-excision. In multivariate analysis, postmenopausal status was a protective factor (HR .047, P = .30). Mean follow-up was 58.4months and mean local recurrence-free survival (LRFS) was 56.4months (.1-203.2), with no difference regarding margin status or residual tumor. Postmenopausal status was associated with a decreased rate of residual tumor in patients with positive margins. The presence of residual tumor on re-excision was not associated with a lower LRFS. These factors must be considered when positive margins are present in BCS.

Total laryngectomy and permanent tracheostomy in six dogs.

The objective of this report is to describe the surgical technique for total laryngectomy and outcome in six dogs. Laryngeal cancer is an uncommon and challenging clinical problem. Total laryngectomy can provide local disease control but is uncommonly performed. Detailed procedural descriptions are limited and similarly limited information is available regarding patient outcome. Institutional medical records were searched for dogs treated with total laryngectomy. Six dogs were identified. The procedure resulted in postoperative quality of life similar to permanent tracheostomy alone. Surgical margin status was evaluated in five of six cases and was complete in those five. All dogs survived to discharge from the hospital. Complications were mostly related to tracheostomy occlusion or collapse which is recognized as a complication associated with permanent tracheostomy. Patient quality of life was acceptable. Local recurrence was suspected in one dog. Recurrence was not observed in the case with unknown margin status.

Regret lower bound and optimal algorithm for high-dimensional contextual linear bandit

In this paper, we consider the multi-armed bandit problem with high-dimensional features. First, we prove a minimax lower bound, $\mathcal{O}\big((\log d)^{\frac{\alpha+1}{2}}T^{\frac{1-\alpha}{2}}+\log T\big)$, for the cumulative regret, in terms of horizon $T$, dimension $d$ and a margin parameter $\alpha\in[0,1]$, which controls the separation between the optimal and the sub-optimal arms. This new lower bound unifies existing regret bound results that have different dependencies on T due to the use of different values of margin parameter $\alpha$ explicitly implied by their assumptions. Second, we propose a simple and computationally efficient algorithm inspired by the general Upper Confidence Bound (UCB) strategy that achieves a regret upper bound matching the lower bound. The proposed algorithm uses a properly centered $\ell_1$-ball as the confidence set in contrast to the commonly used ellipsoid confidence set. In addition, the algorithm does not require any forced sampling step and is thereby adaptive to the practically unknown margin parameter. Simulations and a real data analysis are conducted to compare the proposed method with existing ones in the literature.

Acute and chronic toxicity of nickel on freshwater and marine tropical aquatic organisms

Water quality guidelines and ecological risk assessment of chemical substances like nickel (Ni) in tropical regions such as South East Asia and Melanesia are often based on temperate information as a result of fewer Ni ecotoxicity data available for tropical species. This leaves an unknown margin of uncertainty in the risk assessment in the tropics. In order to fill this data gap, this study was designed to conduct standard toxicity tests on Ni with two freshwater species (acute tests) and three marine species (acute and chronic tests) originated from tropical Hong Kong. All tests were carried out using measured concentrations of Ni with control mortality below 15%. The median lethal concentrations (LC50s) were determined as 2520 (95% confidence interval: 2210, 2860) and 426 (351, 515) μg Ni L−1 for the freshwater gastropods Pomacea lineata (48 h) and Sulcospira hainanensis (96 h), respectively, while 96 h LC50s of 4300 (3610, 5090), 18,200 (6470, 51,200), 62,400 (56,800, 68,500), and 71,700 (68,200, 75,400) μg Ni L−1 were derived for the marine copepod Tigriopus japonicus, the gastropod Monodonta labio, juvenile and adult of the marine fish Oryzias melastigma, respectively. The chronic effect concentration of 10% (EC10) based on the intrinsic rate of increase of the population of T. japonicus was 29 (12, 69) μg Ni L−1. In terms of growth inhibition, the chronic EC10 for M. labio was 34 (17, 67) μg Ni L−1. The results also indicated that T. japonicus in maturation stage (LC10: 484 (349, 919) μg Ni L−1) was less sensitive than its nauplii stage (LC10: 44 (27, 72) μg Ni L−1). This study represents an important addition of high-quality toxicity data to the tropical Ni toxicity database which can be used for future ecological risk assessment of Ni and derivation of its water quality guidelines in tropical regions.

Impact of Surgical Margins in Breast Cancer After Preoperative Systemic Chemotherapy on Local Recurrence and Survival

BackgroundWhile “no tumour on ink” is an accepted margin width for R0 resection in primary surgery, it’s unclear if it’s oncologically safe after neoadjuvant chemotherapy (NAC). Only limited data demonstrate that surgery within new margins in cases of a pathological complete response (pCR) is safe. We therefore investigated the influence of different margins and pCR on local recurrence and survival rates after NAC.MethodsWe retrospectively analysed data of 406 women with invasive breast cancer, treated with NAC and breast-conserving therapy between 1994 and 2014 in two certified Austrian breast health centres. We compared R ≤ 1 mm, R > 1 mm and RX (pCR) for local recurrence-free survival (LRFS), disease-free survival (DFS) and overall survival (OS).ResultsAfter a median follow-up of 84.3 months, the 5-year LRFS (R ≤ 1 mm: 94.2%, R > 1 mm: 90.6%, RX: 95.0%; p = 0.940), the 5-year DFS (R ≤ 1 mm: 71.9%, R > 1 mm: 74.1%, RX: 87.2%; p = 0.245) and the 5-year OS (R ≤ 1 mm: 85.1%, R > 1 mm: 88.0%, RX: 96.4%; p = 0.236) did not differ significantly between narrow, wide, nor RX resections. Regarding DFS and OS, a negative nodal status reduced the hazard ratio significantly.ConclusionThere is no significant difference in LRFS, DFS and OS comparing close, wide or unknown margins after pCR. We suggest that resection in new margins after NAC is safe according to “no tumour on ink”. Resection of the clipped area in cases of pCR is emphasized.

P2.04-039 Long-Term Risk of Recurrence in Benign Pleural Solitary Fibrous Tumors: A Single Institution Review: Topic: Esophageal Cancer and Other Malignancies

Solitary fibrous tumor (SFT) is a rare tumor of submesothelial origin that can occur in the abdomen, extremities, trunk, head, neck and pleura. Pleural SFTs are defined as benign or malignant based on the number of mitoses and the presence of pleomorphism, hemorrhage, or necrosis. There is limited data in the literature regarding the recurrence risk of benign pleural SFT and the need for long-term follow up in these patients. A single institution retrospective chart review was performed on all surgically resected primary pleural SFTs between 1992 and 2015. Preoperative clinical information, pathologic tumor characteristics, and long-term recurrence and survival data were collected. There were 29 primary pleural SFTs resected between 1992 and 2015. Patients had a mean age of 60 years and there were 16 men (55%) and 13 women (45%). Fourteen (48%) presented with symptoms, including two patients with paraneoplastic syndromes, and the other 15 tumors (52%) were found incidentally on imaging. There were six giant SFTs defined as size greater than 15 cm, with two of six giant SFTs undergoing preoperative embolization to aid surgical resection. Otherwise, there were no neoadjuvant or adjuvant treatments in any patient. There was no perioperative 30-day mortality (0%). Mean follow up time was 77 months, during which 4 (14%) patients recurred and 21 of 29 patients (72%) were alive at last follow up. Three of the 8 deaths occurred in patients with recurrent disease. Among the 19 benign pleural SFTs, 2 (11%) recurred at 5 and 9 years postoperatively and 2 of the 6 malignant SFTs (33%) recurred at 4 and 15 years postoperatively. Margin status was known in 25 cases, of which 21 (84%) were negative and 4 (16%) were positive. There were no recurrences in patients with known negative margins. This study represents one of the largest contemporary single institution reviews of outcomes of pleural SFT. While benign pleural SFTs were less likely to recur than malignant pleural SFTs, benign pleural SFTs with positive or unknown margin status remain at risk for recurrence up to a decade following resection and require ongoing long-term follow up and surveillance imaging.

Usefulness of two-point fixed endoscopic submucosal dissection for superficial esophageal neoplasms

Endoscopic submucosal dissection (ESD) is becoming widely regarded as a highly complicated but useful treatment for superficial esophageal neoplasms. However, the technique tends to be associated with adverse events. To evaluate the safety and utility of two-point fixed ESD for superficial esophageal neoplasms, and to discuss future directions. Between December 2006 and December 2013, we performed two types of ESD procedures, the two-point fixed ESD that uses continuous countertraction to ensure a sufficient operative field was performed in 107 patients and conventional ESD was performed in 80 patients. Short-term outcomes and adverse events were evaluated. This study was retrospective study from a single institution. Significant differences were observed between conventional ESD and the two-point fixed ESD with regard to the operation time, tumor positive and unknown vertical margins of the resected specimen, perforation as an adverse event, mediastinal emphysema, and postoperative stenosis. The two-point fixed ESD is a very useful method compared with the conventional procedure.

Abstract P2-13-04: The role of preoperative MRI in negative margins after breast conserving surgery in patients with invasive breast cancer or purely DCIS

Abstract Introduction Clinical benefit of preoperative MRI in invasive breast cancer (IBC) patients and patients with purely ductal carcinoma-in-situ (DCIS) remains controversial. We aimed to study the role of preoperative MRI in negative margins after breast conserving surgery (BCS) and reexcision rate in a large population-based cohort. Methods Retrospective analyses were performed in women diagnosed with IBC and purely DCIS and surgically treated between 2011-2013 extracted from the Eindhoven Cancer Registry. Patients were excluded in case of: neo-adjuvant systemic therapy, (clinical or pathological) tumor stadium T4, distant metastasis, and unknown resection margin status. According to preoperative MRI use, the study population was divided into a non-MRI and MRI group. All multivariable analyses were adjusted for baseline differences between non-MRI and MRI group with P&amp;lt;0.1. No information was available on the exact reason to perform MRI preoperatively in these patients. Results A total of 3,116 patients were eligible of which 2,238 (71.8%) patients were treated by breast conserving surgery (BCS) and included for analyses. Preoperative MRI was performed in 592 (30.6%) IBC patients and 55 (18.3%) DCIS patients. In IBC patients, differences in non-MRI and MRI group were: median age (62 vs 58), histology (lobular type in 5.7% vs 24.5%), median tumor size (13 mm vs 15 mm), her2neu receptor status and specific tumor locations. Median (interquartile range) time between diagnosis and surgery in the non-MRI and MRI group were 21 (16-28) and 31 (22-40) days respectively (univariable and multivariable P&amp;lt;0.001). Negative margin was attained in 1,135 (84.4%) and 489 (82.6%) patients respectively (OR 0.88 95%CI 0.68-1.14 P=0.326). After adjustment for baseline differences and for factors associated with negative margin with P&amp;lt;0.1 (i.e. histology, tumor size, differentiation grade, progesterone receptor %, her2neu receptor status, regional lymph node stadium, and tumor location) MRI use was not associated with negative margin (OR 1.09 95%CI 0.81-1.45 P=0.587). Reexcision was performed in 96 (7.1%) and 62 (10.5%) patients (P=0.013). In case reexcision was needed, conversion to mastectomy occurred in 32 (2.4%) vs 20 (3.4%) patients (P=0.210). In patients with purely DCIS, only median age differed in non-MRI and MRI group (61 vs 57). Median (interquartile range) time between diagnosis and surgery in the non-MRI and MRI group were 22 (16-31) and 35 (23-49) days respectively (univariable P&amp;lt;0.001 and multivariable P=0.024). Negative margin was attained in 197 (80.1%) and 42 (76.4%) patients respectively (OR 0.80 95%CI 0.40-1.61 P=0.538). After adjustment for baseline differences and for factors associated with negative margin with P&amp;lt;0.1 (i.e. differentiation grade and tumor location) MRI use was not associated with negative margin (OR 1.51 95%CI 0.72-3.16 P=0.280). Reexcision was performed in 39 (15.9) and 10 (18.2) (P=0.672). In case reexcision was needed, conversion to mastectomy occurred in 12 (4.9%) vs 3 (5.5%) patients (P=0.859). Conclusion In both IBC and DCIS patients, preoperative MRI delayed time between diagnosis and surgery, but was not associated with a higher percentage of negative margins after BCS. Citation Format: Elvira L Vos, Adri C Voogd, Cornelis Verhoef, Inge-Marie Obdeijn, Linetta B Koppert. The role of preoperative MRI in negative margins after breast conserving surgery in patients with invasive breast cancer or purely DCIS [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 P2-13-04.

Are the Randomized Trials of Radiation Therapy for Ductal Carcinoma in Situ Still Relevant?

The article by Warnberg et al that accompanies this editorial completes a recent series of updates of four randomized trials begun between 1985 and 1990 comparing outcome with or without radiation therapy (RT) after breast-conserving surgery for patients with ductal carcinoma in situ (DCIS; Table 1). Rates of local failure (sometimes referred to as ipsilateral breast events [IBE]) at median follow-up intervals of approximately 13 to 17 years were 25% to 35% in the unirradiated arms compared with 10% to 20% in the irradiated arms. But are these findings still relevant today? So many aspects of patient evaluation and selection for breast-conserving therapy were different then than they are now. There was much less use of magnification mammography resulting in underestimation of lesion extent. Pathologic evaluation was not standardized, and only limited sampling was performed even with large specimens. For example, in the National Surgical Adjuvant Breast and Bowel B-17 trial, a median of nine slides were sent for central pathology review with a range of one to 70 slides. Interestingly, that review also reclassified 18% of patients as having involved or inevaluable margins. The trials had broad selection criteria with regard to patient age at diagnosis, the means of presentation (mammographically detected or symptomatic), lesion size, and histologic features. Finally, they required only negative resection margins, which was defined as the absence of tumor at the inked specimen edges. The Swedish trial also accepted patients with positive or unknown margins, who constituted approximately 20% of the study population. Clues appeared in the late 1980s, and after that, the minimum tumor-free margin width was a critical variable for the risk of IBE for unirradiated patients. Other studies found that larger size and the presence of high nuclear grade and comedo-type necrosis increased local recurrence rates. An influential study assigned points for histology, tumor size, and margin width and combined them into a single number, which predicted the risk of relapse after lumpectomy with or without RT. This index was later revised to include patient age. With a median follow-up of 75 months, unirradiated patients with a University of Southern California-Van Nuys Prognostic Index score of 4 to 6 had a 10-year IBE rate of 6%—only slightly higher than those who were irradiated. A study from the S. Orsola Malpighi Hospital in Bologna, Italy, found a 10-year disease-free survival rate of 5% among 144 such low-score patients with mean follow-up of 130 months. Other groups have also proposed prognostic indices, although these have not always been reliable. The first prospective trial in the United States testing whether a group could be chosen that would do well with excision alone was conducted from 1995 to 2002 in Boston. Patients were eligible if they had DCIS of predominant nuclear grade 1 or 2 that was 25 mm or smaller, a minimum tumor-free margin width of 10 mm or no tumor on reexcision, and no calcifications on postoperative mammography.

Semiparametric Gaussian copula models: Geometry and efficient rank-based estimation

We propose, for multivariate Gaussian copula models with unknown margins and structured correlation matrices, a rank-based, semiparametrically efficient estimator for the Euclidean copula parameter. This estimator is defined as a one-step update of a rank-based pilot estimator in the direction of the efficient influence function, which is calculated explicitly. Moreover, finite-dimensional algebraic conditions are given that completely characterize efficiency of the pseudo-likelihood estimator and adaptivity of the model with respect to the unknown marginal distributions. For correlation matrices structured according to a factor model, the pseudo-likelihood estimator turns out to be semiparametrically efficient. On the other hand, for Toeplitz correlation matrices, the asymptotic relative efficiency of the pseudo-likelihood estimator can be as low as 20%. These findings are confirmed by Monte Carlo simulations. We indicate how our results can be extended to joint regression models.

The effect of margin status and molecular subtype on women with invasive breast cancer treated with breast-conservation therapy.

83 Background: A consensus statement was recently published by SSO/ASTRO on margins for stage I and II invasive breast cancer treated with breast conserving surgery (BCS). We examined patients with invasive breast cancer who underwent BCS to determine if margin status and molecular subtype influence outcomes. Methods: We the reviewed charts of 754 Stage I-III breast cancer patients treated with BCS from 2003-2010. Margin status was defined as negative ≥ 2mm, close &lt; 2mm and positive as tumor on ink. Conventional receptor analyses were used as markers for molecular subtype classification (luminal A, luminal B, Her2 positive, and basal). Clinicopathologic variables were tested using the Fisher’s exact, Chi-square, ANOVA F-test, and Kruskal-Wallis tests. A Cox proportional - Hazards model was used to measure the impact of these variables on locoregional recurrence (LRR), breast cancer-specific (BCSS) and overall survival (OS). Results: The median age of the cohort was 58 (range 27-89 years). Most were white (88%), had T1 tumors (76%), luminal A tumors (66%), invasive ductal histology (80%), and were node negative (76%). Of the 754 patients, 26% had close margins, 2% positive margins, and 9% unknown margins. With a median follow-up of 5.2 years, OS was 92%. Twenty eight patients had a LRR with a median time to recurrence of 5.1 years. On multivariate analysis, molecular subtype, pathologic grade (p=0.01), and use of radiation (p&lt;0.0001) were the only significant predictors of LRR. Unknown subtype, compared to Luminal A, was less likely to have a LRR (p=0.04). Basal (p=0.0002), Her2+ (p=0.03), Luminal B (p=0.002) and unknown subtype (p=0.04) had worse BCSS compared to Luminal A tumors. Margins had no impact on LRR or BCSS but those with close margins and unknown margins had worse OS compared to negative margins (p=0.01, p=0.007). Variables predictive of OS were margins, age, race, node status, chemotherapy, anti-endocrine therapy, and radiation. Conclusions: In this cohort treated with BCS, molecular subtype was a predictor of LRR and BCSS but not OS. Margin status did not impact LRR and BCSS. Although margin status was a predictor of OS, tumor biology remains the significant determinant of outcome.

The significance of margin status in patients with DCIS undergoing breast-conserving surgery.

98 Background: Recently, SSO/ASTRO published a consensus statement on margins for stage I and II invasive breast cancer treated with breast conserving surgery (BCS). We examined patients with ductal carcinoma in situ (DCIS) who underwent BCS to determine the effect of clinicopathologic and treatment factors including margin status, on locoregional recurrence (LRR), breast cancer-specific (BCSS) and overall survival (OS). Methods: From 2003-2010, we conducted a retrospective chart review of 253 consecutively diagnosed patients who underwent BCS for DCIS. Clincopathologic and treatment data were extracted. Margin status was defined by pathology reports with a negative margin as ≥ 2mm, close margin &lt; 2mm and positive margin as tumor on ink. Clinicopathologic variables were tested using the Fisher’s exact test, Chi-square test, ANOVA F-test, and Kruskal-Wallis test. A Cox proportional - Hazards model was used to calculate the impact of these factors on LRR, BCSS and OS. Results: The median age of the cohort was 57 (range 21-89) and the majority were white (79%), ER+ (78%) and underwent radiation therapy (67%). Forty six percent took anti-endocrine therapy. Of 252 patients, 29% had close margins, 63% had negative margins and 7% had unknown margins. One patient had a positive margin and was alive without disease at last follow-up. At a median follow-up of 5 years, OS was 96%. Thirteen patients experienced a LRR with a median time to recurrence of 4.9 years (5 with close margins, 7 with negative, 1 unknown). On multivariate analysis, age and PR status were significant predictors of LRR. Patients with age &gt;70 were more likely to recur than those age 50-69 (HR 6.7 95% CI (1.7-25.4) p= 0.005) as were patients with PR negative tumors (HR 5.7 95% CI (1.7-19.5) p= 0.005). Those patients who did not receive radiation therapy had a worse OS than those who did (HR 4.3 95%CI (1.5-12.6) p = 0.007). No variables were significant for BCSS. Conclusions: In this cohort of patients with DCIS treated with BCS, age and PR status were the only predictors of LRR. OS was only impacted by receipt of radiotherapy. Margin status was not predictive of LRR, BCSS or OS. This data suggests that routine re-excision for close margins may not be warranted.

Efficacy and Safety of Accelerated Partial Breast Irradiation after Breast-conserving Surgery: A Meta-analysis of Published Comparative Studies

To compare the treatment outcomes between accelerated partial breast irradiation (APBI) and conventional whole-breast irradiation (WBI) and to explore the efficacy and safety of APBI as an adjuvant treatment for early-stage breast cancer who received breast-conserving therapy. Eligible studies were identified on Medline, Embase, and the Cochrane Library updated to July 10, 2012. Comparative studies were considered for inclusion. Analyses were carried out using Stata software. Eleven comparative studies with a total of 7,097 patients were included. The meta-analysis showed that there were no statistically significant differences between group APBI and group WBI associated with the supraclavicular failure, distant metastasis, overall survival, and disease-free survival, while local recurrence (LR) and axillary failure (AF) increased in group APBI. The sensitivity analysis indicated that both the LR and AF were not statistically significant difference between the two groups. In the subgroup analysis, LR was statistically significantly higher in group APBI for patients with the age <60, large tumor size, and unknown margin status. APBI is a safe treatment modality and could become a potential option for the delivery of adjuvant radiation therapy in patients receiving breast-conserving therapy, especially for the suitable group that was classified by the American Society of Radiation Oncology Consensus Panel.

Semiparametric Gaussian Copula Models: Geometry and Efficient Rank-Based Estimation

For multivariate Gaussian copula models with unknown margins and structured correlation matrices, a rank-based, semiparametrically efficient estimator is proposed for the Euclidean copula parameter. This estimator is defined as a one-step update of a rank-based pilot estimator in the direction of the efficient influence function, which is calculated explicitly. Moreover, finite-dimensional algebraic conditions are given that completely characterize adaptivity of the model with respect to the unknown marginal distributions and of efficiency of the pseudo-likelihood estimator. For correlation matrices structured according to a factor model, the pseudo-likelihood estimator turns out to be semiparametrically efficient. On the other hand, for Toeplitz correlation matrices, the asymptotic relative efficiency of the pseudo-likelihood estimator with respect to our one-step estimator can be as low as 20%. These findings are confirmed by Monte Carlo simulations.