Time Of Definitive Surgery Research Articles

The Surgical Correction of Hirschsprung’s Disease in Adults Using the Modified Duhamel Procedure

Background: Hirschsprung’s disease (HD) is rare in adults, since a majority of cases are corrected in childhood. Objectives: The authors describe the profile of patients with HD who reached adulthood without having undergone corrective surgery. Also, they describe the outcomes of a modified Duhamel procedure in these patients, in terms of morbidity and mortality. Methods: This retrospective study, included patients 18 years old and above, diagnosed with HD who reached adulthood without having undergone definitive repair and managed surgically by the Division of Colorectal Surgery, UP-PGH from January 1, 2004 to December 31, 2014. A review from the Department Surgical Database was used and patients’ hospital records were used to fill out a Data Collection Form. Descriptive statistics were used to summarize the data. Results: The 13 patients included in the study were diagnosed at an average age of 16.6 (± 13.16) years. The mean age at the time of definitive surgery was 23.46 (± 6.96) years. The M:F ratio was 5.5:1. The most common presenting symptom was constipation (69.23%). All had a prior proximal bowel diversion, with a transverse loop colostomy (61.54%) being the most common. The transition zone was located in the sigmoid in a third of patients. The mean time from diagnosis to definitive surgery was 6.69 years. Eight (61.54%) have since undergone stoma reversal. There was only one (7.69%) morbidity, a superficial surgical site infection. No mortalities were reported. Conclusion: The modified Duhamel procedure is a safe definitive surgical procedure for the adult patient with HD. Key words: adult Hirschsprung’s disease, colostomy, Modified Duhamel procedure

Upstaging of basal cell and squamous cell carcinomas during definitive surgery: a review of predictive preoperative clinical and histologic features.

The incidence of nonmelanoma skin cancer (NMSC) in the United States is increasing with approximately 3.6 million cases diagnosed per year. The staging and treatment of NMSC is guided by histologic subtype based on skin biopsy, along with other tumor-specific factors. However, a biopsy only represents a portion of the tumor, so there is a risk of upstaging at the time of definitive surgery. We conducted a review of the literature and found that a significant proportion of NMSC were upstaged during surgery. The rate of upstaging of basal cell carcinoma (BCC) was 7-31% and that of squamous cell carcinoma in situ (SCCIS) to squamous cell carcinoma (SCC) was 3-39%. Biopsy sampling error and variability in interpreting and reporting by dermatopathologists contribute to these discrepancies. It is pertinent to consider more comprehensive treatment modalities for tumors at high risk for upstaging. Diligence to identify tumors at higher risk for upstaging will allow clinicians to optimize management.

Clinical outcomes of non-osteogenic, non-Ewing soft-tissue sarcoma of bone--experience of the Toronto Sarcoma Program.

Non‐osteogenic, non‐Ewing soft‐tissue sarcoma (NONE‐STS) of bone is a rare presentation of primary bone cancers. Optimal treatments and outcomes for this heterogenous group are poorly described. We evaluated the factors associated with long‐term outcomes in patients with this disease. Patients with localized NONE‐STS of bone treated at the Toronto Sarcoma Program from 1987 to 2017 were identified. Clinical characteristics, treatment, and survival information were collected. Kaplan‐Meier (log‐rank) survival estimates from the time of definitive surgery, with uni‐/multivariate analyses (Cox) of sarcoma‐specific survival were performed. A total of 106 patients (60.4% male; median age 46 years) with NONE‐STS of bone were identified. Common histologies included undifferentiated pleomorphic sarcoma [UPS]/malignant fibrous histiocytoma [MFH] (UPS/MFH, 41.5%), leiomyosarcoma (LMS, 20.8%), and fibrosarcoma (FS, 11.3%). Tumors were often high grade (59.4%) and involved the extremities (88.7%), with most receiving chemotherapy (67.9%) with cisplatin/doxorubicin‐based regimens (73.6%). In the full cohort, 10‐year DFS (45.7%, [95%CI: 35.7‐55.8%]), OS (53.4%, [95%CI: 41.7‐62.2%]), and SSS (63.9%, [95%CI: 53.9‐72.5%]) were moderate. Histology specific, 10‐year SSS was 70.7% [95%CI: 56.1‐85.5%] for UPS/MFH, 51.8% [95%CI: 29.8‐73.8%] for LMS, and 72.2% [95%CI: 45.1‐99.2%] for FS. Only UPS/MFH (n = 4) showed sarcoma‐related death >10 years. Multivariate analysis identified axial location (HR = 35.5, [95%CI: 3.4‐369.6]), high grade (HR = 16.9, [95%CI: 1.6‐185.1]), and disease relapse (HR = 485.1, [95%CI: 36.3‐6482.6]) as risk factors for death (p < 0.05). Treatment with chemotherapy (HR = 0.1, [95%CI: 0.01‐0.86]) and necrosis ≥85% (HR = 0.2, [95%CI: 0.04‐0.99]) showed improved survival (p < 0.05). NONE‐STS of bone has favorable long‐term survival similar to osteosarcoma. Patients receiving chemotherapy derive benefit in retrospective analyses. UPS/MFH histologies show sarcoma‐related death beyond 10 years. Further data on histologic subgroups are needed.

A phase II trial of nivolumab (NIVO) + palbociclib (PAL) + anastrozole (ANA) in postmenopausal women and men with estrogen receptor (ER)+/human epidermal growth factor 2 (HER2)- primary breast cancer (BC): CheckMate 7A8.

TPS1105 Background: Cyclin-dependent kinase 4/6 (CDK 4/6) inhibition coupled with ER signaling blockade is an efficient treatment approach for patients (pts) with metastatic hormone receptor-positive, HER2− BC. Preclinical data suggest synergistic activity of CDK 4/6 inhibition and PD-1 blockade; in a syngeneic mouse tumor model, improved efficacy and complete tumor regression were observed with phased administration of ABE + PD-L1 therapy. Methods: CheckMate 7A8 (NCT04075604) is a randomized, noncomparative, multicenter, phase 2 study evaluating PAL + ANA +/- NIVO in postmenopausal pts with ER+, HER2− primary BC. After determining safe doses for NIVO combination regimens in the safety run-in phase, pts will be randomized in a 4:4:3 ratio to 1 of 3 treatment arms (Table) stratified by PD-L1 expression, node status and tumor size. Following treatment, all pts will undergo surgery and safety follow-up. Eligible pts are postmenopausal women and men with newly diagnosed, untreated, histologically confirmed ER+, HER2− BC with primary tumor ≥ 2 cm; suitable for neoadjuvant endocrine monotherapy and surgery; ECOG PS of 0–1; have baseline tumor tissue available; willing to undergo on-treatment research biopsy and tissue collection at surgery. Primary endpoints are number of pts with occurrence of dose-limiting toxicity (safety run-in phase) and residual cancer burden 0–I rate by central assessment at time of definitive surgery (randomized phase). Secondary endpoints include safety and tolerability, pathologic complete response, objective response rate and breast-conserving surgery rate. Key exploratory endpoints include biomarkers indicative of pharmacodynamic changes and potentially predicting treatment sensitivity. Interim analyses are planned. The study is currently enrolling. Clinical trial information: NCT04075604 . [Table: see text]

Pembrolizumab for Early Triple-Negative Breast Cancer

BackgroundPrevious trials showed promising antitumor activity and an acceptable safety profile associated with pembrolizumab in patients with early triple-negative breast cancer. Whether the addition of pembrolizumab to neoadjuvant chemotherapy would significantly increase the percentage of patients with early triple-negative breast cancer who have a pathological complete response (defined as no invasive cancer in the breast and negative nodes) at definitive surgery is unclear.MethodsIn this phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with previously untreated stage II or stage III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) every 3 weeks plus paclitaxel and carboplatin (784 patients; the pembrolizumab–chemotherapy group) or placebo every 3 weeks plus paclitaxel and carboplatin (390 patients; the placebo–chemotherapy group); the two groups then received an additional four cycles of pembrolizumab or placebo, and both groups received doxorubicin–cyclophosphamide or epirubicin–cyclophosphamide. After definitive surgery, the patients received adjuvant pembrolizumab or placebo every 3 weeks for up to nine cycles. The primary end points were a pathological complete response at the time of definitive surgery and event-free survival in the intention-to-treat population.ResultsAt the first interim analysis, among the first 602 patients who underwent randomization, the percentage of patients with a pathological complete response was 64.8% (95% confidence interval [CI], 59.9 to 69.5) in the pembrolizumab–chemotherapy group and 51.2% (95% CI, 44.1 to 58.3) in the placebo–chemotherapy group (estimated treatment difference, 13.6 percentage points; 95% CI, 5.4 to 21.8; P<0.001). After a median follow-up of 15.5 months (range, 2.7 to 25.0), 58 of 784 patients (7.4%) in the pembrolizumab–chemotherapy group and 46 of 390 patients (11.8%) in the placebo–chemotherapy group had disease progression that precluded definitive surgery, had local or distant recurrence or a second primary tumor, or died from any cause (hazard ratio, 0.63; 95% CI, 0.43 to 0.93). Across all treatment phases, the incidence of treatment-related adverse events of grade 3 or higher was 78.0% in the pembrolizumab–chemotherapy group and 73.0% in the placebo–chemotherapy group, including death in 0.4% (3 patients) and 0.3% (1 patient), respectively.ConclusionsAmong patients with early triple-negative breast cancer, the percentage with a pathological complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy. (Funded by Merck Sharp & Dohme [a subsidiary of Merck]; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.)

Abstract OT2-04-02: CheckMate 7A8: A phase 2 trial of nivolumab + abemaciclib or palbociclib + anastrozole in postmenopausal women with ER+, HER2−primary breast cancer

Background: Programmed death-1 (PD-1) pathway inhibition has demonstrated clinical activity in breast cancer (BC), with modest response rate in advanced, heavily pretreated, hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2−) BC. Cyclin-dependent kinase 4/6 (CDK 4/6) inhibition coupled with estrogen receptor (ER) signaling blockade is an efficient treatment approach for patients with metastatic HR+/HER2− BC, evaluated in the primary setting. Preclinical data suggest potential synergistic activity of CDK 4/6 inhibition coupled with PD-1 blockade through modulation of the tumor microenvironment by the former modality. In a syngeneic mouse tumor model, improved efficacy and complete tumor regression were observed with abemaciclib priming the immune response in phased administration of abemaciclib + anti-programmed death ligand 1 (PD-L1) therapy. Preliminary clinical data demonstrated activity of pembrolizumab + abemaciclib in a phase 1b study of pretreated patients with metastatic HR+, HER2− BC. Trial Design: CheckMate 7A8 is a randomized, noncomparative, multicenter, phase 2 study evaluating nivolumab + either abemaciclib or palbociclib + anastrozole in postmenopausal patients with ER+, HER2− primary BC. After determining safe doses for the nivolumab combination regimens in the safety run-in phase, patients will be randomized in a 4:4:3:4:4:3 ratio to 1 of 6 treatment arms (Table) stratified by PD-L1 expression (+ or −), node status (+ or −), and tumor size (> 3 cm or ≤ 3 cm). Following treatment, all patients will undergo surgery and safety follow-up. Eligible patients are postmenopausal women with newly diagnosed, untreated, histologically confirmed ER+, HER2− BC with primary tumor ≥ 2 cm; with measurable disease based on RECIST v1.1; suitable for neoadjuvant endocrine monotherapy and surgery; have an ECOG PS of 0 or 1; have tumor tissue available at baseline; and are willing to undergo on-treatment research biopsy and tissue collection at surgery. Women of childbearing potential or who are breastfeeding, have a history of ipsilateral invasive BC regardless of treatment or DCIS treated with radiotherapy, metastatic disease, inflammatory/inoperable, multicentric, or bilateral invasive BC, or those suitable for neoadjuvant chemotherapy are excluded. Primary study endpoints are: i) number of patients with occurrence of dose-limiting toxicity (safety run-in phase), and ii) residual cancer burden (RCB) 0-I rate by central assessment at time of definitive surgery (randomized phase). Secondary endpoints include safety and tolerability, pathologic complete response, and objective response rate. Key exploratory endpoints include biomarkers indicative of pharmacodynamic changes in the tumor microenvironment, biomarkers predicting treatment sensitivity, changes in Ki67 levels, ER status and preoperative endocrine prognostic index score, and efficacy by PD-L1 status. Sample size was calculated assuming a 22% target RCB rate; 40 treated patients will provide 81% power at 10% 2-sided type I error to reject the null hypothesis that the true RCB rate is 8%, below which is not clinically meaningful. For primary and secondary endpoints, estimates of response rates and corresponding 95% confidence intervals will be generated for each arm using the Clopper-Pearson method. No patients have yet been recruited. For information, please contact Xiaochun.Liu@bms.com. Citation Format: Sara Tolaney, Guy Jerusalem, Roberto Salgado, Xiaochun Liu, Tian Chen, Hongxia Zhang, Mustimbo Roberts, Dimitrios Zardavas, Aleix Prat. CheckMate 7A8: A phase 2 trial of nivolumab + abemaciclib or palbociclib + anastrozole in postmenopausal women with ER+, HER2−primary breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-04-02.

Predicting Upstaging of DCIS to Invasive Disease: Radiologists's Predictive Performance

The purpose of this study is to quantify breast radiologists' performance at predicting occult invasive disease when ductal carcinoma in situ (DCIS) presents as calcifications on mammography and to identify imaging and histopathological features that are associated with radiologists' performance. Mammographically detected calcifications that were initially diagnosed as DCIS on core biopsy and underwent definitive surgical excision between 2010 and 2015 were identified. Thirty cases of suspicious calcifications upstaged to invasive ductal carcinoma and 120 cases of DCIS confirmed at the time of definitive surgery were randomly selected. Nuclear grade, estrogen and progesterone receptor status, patient age, calcification long axis length, and breast density were collected. Ten breast radiologists who were blinded to all clinical and pathology data independently reviewed all cases and estimated the likelihood that the DCIS would be upstaged to invasive disease at surgical excision. Subgroup analysis was performed based on nuclear grade, long axis length, breast density and after exclusion of microinvasive disease. Reader performance to predict upstaging ranged from an area under the receiver operating characteristic curve (AUC) of 0.541-0.684 with a mean AUC of 0.620 (95%CI: 0.489-0.751). Performances improved for lesions smaller than 2 cm (AUC: 0.676 vs 0.500; p = 0.002). The exclusion of microinvasive cases also improved performance (AUC: 0.651 vs 0.620; p = 0.005). There was no difference in performance based on breast density (p = 0.850) or nuclear grade (p = 0.270) CONCLUSION: Radiologists were able to predict invasive disease better than chance, particularly for smaller DCIS lesions (<2 cm) and after the exclusion of microinvasive disease.

Ovarian stimulation for oocyte vitrification does not modify disease-free survival and overall survival rates in patients with early breast cancer.

Does ovarian stimulation for oocyte vitrification affect disease-free survival and overall survival rates in women with early breast cancer? This cohort study included 259 patients with early breast cancer; 148 patients underwent ovarian stimulation, whereas 111 patients did not. Patients were treated between January 2008 and December 2016. To calculate the disease-free survival time and overall survival rate, the time of definitive surgery was defined as the starting point. The follow-up was conducted up to 5 years. Exposed and non-exposed groups were comparable in tumour, node and metastases classification, Nottingham grade, hormonal receptor status, tumour molecular phenotype, histology and pathology stage. The exposed group was younger than the non-exposed. Recurrences occurred in 9/148 women (6.1%) in the exposed group and 15/111 women (13.5%) in the non-exposed group, with no significant difference. The mean disease-free survival time was 63.9 months (95% confidence interval [CI]: 61.5-66.4) in the exposed group and 60.6 months (95% CI: 56.9-64.2) in the non-exposed, with no significant difference (log-rank [Mantel-Cox] test). Overall survival rates were comparable; 2/148 (1.4%) and 4/111 (3.6%) patients died, in exposed and non-exposed groups, respectively, during the period analysed. Mean overall survival times were 67.2 months (95% CI: 66.2-68.2) in the exposed group and 65.9 months (95% CI: 64.0-67.9) in the unexposed, with no significant difference (log-rank [Mantel-Cox] test). This study suggests that ovarian stimulation in patients with early-stage breast cancer is safe in the long term.

DOZ047.102: Previously undescribed association of esophageal atresia, congenital microgastria, and pyloric atresia: a difficult case of ‘pure’ atresia.

Abstract This study reports the case of a male infant born at full term with antenatal suspicion for esophageal atresia (EA). At birth inability to pass a feeding tube and a gasless abdomen on plain film X-ray led to the diagnosis of pure EA according to international guidelines. In the first week of life a stomach could not be identified at surgery for open gastrostomy and a feeding jejunostomy was formed. Subsequent investigations including CT scan did not detect the presence of a stomach. Cervical esophagostomy was performed at 8 weeks old as there was no expectation of achieving an esophageal anastomosis and a deviated septum had complicated the placement of nasal tubes for management of the proximal esophageal pouch. At 6 months of age esophageal replacement with a jejunal pull-up graft was undertaken as staged surgery. At mobilization of a large midline liver to expose the hiatus, a microstomach was revealed, in association with a type 2 pyloric atresia (PA) and a distal tracheoesophageal fistula (TEF). Following ligation of the TEF by lateral thoracotomy, the TEF and microstomach were resected and the jejunal pull-up graft was completed. Discharge home was achieved 1 month post-op. Oral intake was established for solids by 1 year of age. The patient is thriving at 4 years of age with additional overnight jejunal feeds. A unifying genetic diagnosis has not been made to date. Congenital microgastria or PA has been described to co-exist with EA but never previously have all these anomalies been reported occurring together. This unique scenario permitted the distal TEF to be clinically silent and present as a pure atresia. In turn congenital microgastria together with a diagnosis of pure EA obscured the presence of PA, which classically presents with vomiting of feeds and massive gastric distension. Investigations, and in particular cross-sectional imaging, were on the whole unhelpful. This case illustrates that correct diagnosis in this complex case ultimately could only be made at the time of definitive surgery.

Abstract P3-01-02: Detection of circulating tumor cells (CTC) in blood and disseminated tumor cells (DTC) in bone marrow at surgery identifies breast cancer patients (pts) with long-term risk of distant recurrence and breast cancer-specific death

Abstract We examined the prognostic impact of CTCs and DTCs detected at the time of definitive surgery in pts diagnosed with early breast cancer (EBC). Methods: Blood and bone marrow samples from 742 treatment-naïve EBC pts, not eligible for neoadjuvant therapy, were collected immediately prior to surgery. 87% were hormone receptor (HR)-positive, and 71% were node-negative. DTCs (n=584) were enumerated using an EPCAM-based method involving immunomagnetic enrichment and flow cytometry (IE/FC). CTCs were enumerated either by IE/FC (n=288) or CellSearch (n=380). Optimal cutoffs for CTC-/DTC-positivity were selected using Monte-Carlo cross validation. Multivariate Cox regression analysis was performed to determine correlation between levels of CTCs/DTCs vs. distant recurrence-free survival (DRFS) and breast cancer-specific survival (BCSS). The overall median follow-up was 7.1 years for DRFS and and 9.1 years for BCSS, but extended up to 13.3 years in subset analyses (Table 1). Results: CTC-positivity by CellSearch was associated with HER2-positivity (Fisher p=0.01). Using optimized cutoffs in multivariate analyses, we found that CTC-positive pts by CellSearch had a statistically significant increased risk of distant recurrence (HR 4.93, p=0.0067). Moreover, pts who were CTC-positive by IE/FC had a statistically significant increased risk of breast cancer-specific death (HR=3.54, p=0.0138). DTC status, by itself, was not prognostic; however, when combined with CTC status by IE/FC (n=273), positive detection for both (CTC+DTC+) was significantly associated with increased risk of distant recurrence (HR=3.09, p=0.0270) and breast cancer-specific death (HR=4.55, p=0.0205). Table 1.Multivariate analysis to determine the prognostic significance of CTCs and DTCs detected at the time of surgery in treatment naive early breast cancer patients. Adjusted for age at diagnosis, tumor size, pathologic stage, HR and HER2 status, node status and grade. DRFS BCSS Variable and Method% positiveHR [95% CI]Wald p-valueMedian f/u [range] Years*HR [95% CI]Wald p-valueMedian f/u [range] Years*CTC+ vs. CTC- by CellSearch94.93[1.56-15.6]0.00676.4 [0.16-13.8]4.50[0.76-26.5]0.09627.5 [0.71-15.0]CTC+ vs. CTC- by IE/FC401.92[0.93-3.95]0.07599.8 [0.09-18.5]3.54[1.29-9.72]0.013813.3 [1.93-18.5]DTC+ vs. DTC- by IE/FC181.46[0.75-2.81]0.26317.5 [0.09-18.5]1.48[0.64-3.42]0.35429.8 [1.55-18.5]CTC+DTC+ vs. CTC-DTC- by IE/FC8**3.09[1.14-8.40]0.02709.8 [0.09-18.5]4.55[1.26-16.39]0.020513.3 [1.93-18.5]*f/u - follow-up; **double positive Conclusions: We demonstrate the impact of quantitative evaluation of CTCs and DTCs by IE/FC. Our large single institution dataset, in which CTCs and DTCs have been contemporaneously quantitated, has the longest patient follow-up. Simultaneous detection of CTCs and DTCs at the time of definitive surgery in treatment naïve EBC pts is an independent prognostic factor associated with increased long-term risk of distant recurrence and death due to breast cancer. Given the lack of early endpoints for low-risk patients, liquid biopsy may be an important consideration for future studies. Citation Format: Magbanua MJM, Yau C, Wolf D, Lee JS, Chattopadhyay A, Scott JH, Yoder E, Hwang S, Alvarado M, Ewing CA, Delson AL, van't Veer L, Esserman L, Park JW. Detection of circulating tumor cells (CTC) in blood and disseminated tumor cells (DTC) in bone marrow at surgery identifies breast cancer patients (pts) with long-term risk of distant recurrence and breast cancer-specific death [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-01-02.

Questioning the Value of Evaluating Estrogen and Progesterone Receptors on Core Biopsy Specimens of Patients with Ductal Carcinoma in Situ (DCIS)

Purpose: To evaluate the value of estrogen and progesterone receptors on core biopsy specimens of patients with ductal carcinoma in situ.&#x0D; &#x0D; Introduction: The immunohistochemical determination of the estrogen receptor (ER) and progesterone receptor (PR) status is predictive of the response of patients with invasive cancer to hormonal therapy. The value of the receptor status prior to definitive surgery with either breast conservation or mastectomy for patients with ductal carcinoma in situ (DCIS) and no invasive component is less clear.&#x0D; &#x0D; Methods: We identified through the tumor registry 344 patients with breast cancer diagnosed from 2014 through 2015. Two hundred seventy-seven patients had invasive cancer at diagnosis.&#x0D; &#x0D; Results: Of the remaining 67 patients with DCIS or atypical hyperplasia alone on core biopsy, 15 (22%) patients were found to have invasive cancer at the time of definitive surgery.&#x0D; &#x0D; Forty-six patients without an invasive component had definitive surgery at the study institution, of which three had a component of higher grade DCIS than on the core biopsy. Fourteen patients (30%) underwent a mastectomy.&#x0D; &#x0D; Conclusion: A significant proportion (29%) of patients with DCIS alone on core biopsy had either an invasive component at the time of definitive surgery or a higher grade DCIS component. An additional 14/46 (30%) of patients chose mastectomy, for whom consideration of adjuvant endocrine therapy for contralateral risk reduction did not depend on the receptor status of the index DCIS.&#x0D; &#x0D; Cost savings could be realized if the determination of ER is deferred until after definitive surgery. Determination of PR on DCIS specimens can be omitted entirely.

Abstract P3-01-18: Determining the need for axillar lymph node dissection based on pre-neoadjuvant chemotherapy sentinel lymph node biopsy results

Abstract An open-label single institution study of sentinel lymph node biopsy prior to neoadjuvant chemotherapy is conducted in the N.N. Petrov research institute of oncology. So far 30 patients with locally advanced breast carcinoma (T2-4N0) were included. Mammography, breast US and SPECT are performed prior to hospitalization so as core biopsy with subsequent IHC staining to determine the levels of ER, PR, KI67 and HER2. Sentinel lymph node biopsy with the use of radiocompound is performed prior to the first cycle of neoadjuvant chemotherapy. Patients receive 4 to 6 cycles with response evaluation after cycles 2, 4 and 6 (same evaluations as at the baseline). Axillary lymph node dissection is later performed along with the definitive surgery of the primary. Interim analysis showed: 3 of 30 patients with cN0 were node positive after sentinel lymph node biopsy, 27 were node-negative (sn)pN0. All patients with (sn)pN0 completed neoadjuvant chemotherapy with clinical response. No cases of upfront progression were detected. All patients (sn)pN0 underwent axillary dissection upon completion of the neoadjuvant therapy. No cases of nodal involvement were detected (ypN0). All of the patients considered node-positive after sentinel biopsy also underwent lymph node dissection after completion of the neoadjuvant therapy. 2 of them were pN1 and one was pN2. Conclusion: sentinel lymph node biopsy in cN0 patients prior to neoadjuvant chemotherapy allows to determine a category of patients ((sn)pN0) in whom axillary dissection can be avoided, provided they remain clinically node-negative at the time of definitive surgery. Citation Format: Semiglazov VF, Krivorotko PV, Zhiltsova EK, Dashayan GA, Zernov KU, Bessonov AA, Trufanova ES, Tabagua TT, Ivanova OA, Kanaev SV, Novikov SN, Krzivickiyi PI, Brayanceva ZV, Komayachov AV, Nikolaev KS, Gigolaeva LP. Determining the need for axillar lymph node dissection based on pre-neoadjuvant chemotherapy sentinel lymph node biopsy results [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-01-18.

Abstract P2-02-09: Breast cancer subtype distribution and circulating tumor DNA in response to neoadjuvant chemotherapy: Experiences from a preoperative cohort within SCAN-B

Abstract Introduction: Preoperative chemotherapy in early breast cancer increases the rate of breast preservation and provides prognostic information. In the case of residual disease, a change in subtypes may be observed. Sensitive and reproducible biomarkers predicting treatment response early during the treatment course are needed in order to better exploit the potential benefit of an individualized preoperative treatment. Material and Methods: In an ongoing prospective study within the population-based SCAN-B project (NCT02306096), patients undergoing preoperative chemotherapy for early or locally recurrent breast cancer have been treated with iv Epirubicin and Cyclophosphamide q3w x 3 in sequence with either Docetaxel q3w x 3 or Paclitaxel q1w x 9 with a preoperative intent. HER2-positive cases also received HER2-directed treatment. At baseline, patients were staged using sentinel node biopsy for clinically node-negative patients and CT scan for cytologically confirmed node-positive cases. A clinical core needle biopsy as well as tissue from the surgical specimen was collected for determination of conventional biomarkers including ER, PgR, HER2 and Ki67. Tumor biopsies for biomolecule-extraction and RNA-sequencing were taken using ultrasound guidance and collected fresh in RNAlater at baseline, after 2 treatment cycles, as well as at surgery. Blood plasma samples were collected at baseline, after one-, three-, and six- 3w treatment cycles, and post-surgery. Using RNA-sequencing data, somatic mutations were identified in the tumor biopsies and personalized analyses for circulating tumor DNA (ctDNA) were performed. A pathological complete remission (pCR) was defined as the complete disappearance of invasive breast cancer in the breast and axilla at time of definitive surgery. Subtyping was performed using modified St Gallen criteria (2013). Results: Thus far, 45 patients aged 24-74 years have been included, of which 34 (76 %) were clinical stage 2 and 11 (24%) were stage 3. The subtype distribution at baseline was five Luminal A-like (11 %), 21 Luminal B-like (HER2 negative) (47 %), 8 HER2-positive (18 %) and 11 Triple-negative (ductal) (24 %). The rates of pCR in 38 operated cases to date were 0/3 Luminal A-like, 3/19 Luminal B-like (HER2 negative), 2/8 HER2-positive, and 4/7 Triple-negative (overall 24 % pCR rate). One patient did not undergo surgery due to clinically progressive disease. In 25 cases with evaluable residual disease at surgery, there was a shift in the subtype in 13 (52 %), the majority of which represented a transition from Luminal B to Luminal A. No Triple-negative cases underwent a change in subtype during treatment. Results of the ctDNA analyses will be presented at the meeting. Discussion: We have established an infrastructure allowing for an extensive evaluation of preoperative chemotherapy in early breast cancer. The goal is to develop methods to refine response-guided treatment in early breast cancer using molecular responses in the tumor as well as in the blood circulation. The patients continue to be prospectively monitored with iterative ctDNA analyses during follow-up. Citation Format: Loman N, Chen Y, Aaltonen K, Brueffer C, George AM, Zander L, Vallon-Christersson J, Häkkinen J, Förnvik D, Rigo R, Ehinger A, Malmberg M, Larsson C, Hegardt C, Borg Å, Rydén L, Saal LH. Breast cancer subtype distribution and circulating tumor DNA in response to neoadjuvant chemotherapy: Experiences from a preoperative cohort within SCAN-B [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-02-09.

Abstract P2-03-12: Incidence and implications for hormone receptor status change pre- and post- neoadjuvant chemotherapy for locally advanced breast cancer: A retrospective single-center cohort study

Abstract Background: Hormone receptors (HR) and Human Epidermal Growth Factor Receptor 2 (HER2) status are variables that significantly influence the treatment regimens chosen for each patient (pt). The main objective of this study present was to determine the incidence of HR status change pre- and post- neoadjuvant chemotherapy (NAC) in patients with locally advanced breast cancer (LABC). Methods: A single-centre study was retrospectively conducted at The Ottawa Hospital Cancer Centre looking at a group of 546 pts diagnosed with LABC from 2006-2015. A number of variables were observed including HR and HER2 status, tumor size and grade, regional lymph nodes involvement, presence of DCIS, treatment regimens. 'Positive to Negative' considered pts who were HR and/or HER2 positive pre-NAC and negative post-NAC, 'No Change' represented the pts whose pathology did not change before and after NAC, and 'Negative to Positive' characterized those pts whose HR and/or HER2 pathology was initially negative and became positive post-NAC. Wilcoxon signed-rank test for paired dichotomous variables has been performed in order to estimate statistical significance of changes in status of HR and HER2. To explore possible relationship between HR and HER2 status change and other factors we used Logistic regression method. Results: Of the 386 pts who were examined for Estrogen Receptor (ER) twice, 285 had positive status before surgery, after surgery there were 12 pts (3.11%*) with a 'Positive to Negative' change, 362 pts (93.78%) with no change, and 12 pts who represented a 'Negative to Positive' change. 254 of 378 pts, who had two tests for Progesterone Receptor (PR), had positive results at first time, and 29 (7.67%*) of those represented a 'Positive to Negative' change, there were 337 (89.15%) with no change, and 12 (3.17%) with a 'Negative to Positive' change. From 387 pts who were tested for HER2 before and after surgery, 105 had initially positive status. Of those, 12 (3.10%*) represented a 'Positive to Negative' change, there were 364 (94.06%) with 'No Change' and 11 (2.84%*) with a 'Negative to Positive' change. Logistic regression analysis did not reveal any significant factors that can predict changes in receptors` status. *-Statistically significant changes (p&amp;lt;0.001). The results are comparable with previously published works, which demonstrated changes in IHC status during treatment in metastatic disease (E.Amir, 2011) and a in patients with LABC (Y.Yang, 2013; R.Gahlaut, 2016). Results of comparative meta-analysis will be presented also. Conclusions: Our study shows that a change in HR and HER2 status is common in this population, indicating that close monitoring of biopsy results should be closely compared to surgical pathology specimens to determine a change in biomarkers, and therefore, a potential change in treatment regimen. None of analyzed factors can predict change in status of ER, PR, and HER2 after neoadjuvant treatment. Even though the incidence of change in status is small, the implications for accurate and personalized treatment are important and HR and HER2 testing should be performed as a routine practice on the biopsy and at the time of definitive surgery. Citation Format: Aseyev O, Simmonds L, Gertler M, Verma S. Incidence and implications for hormone receptor status change pre- and post- neoadjuvant chemotherapy for locally advanced breast cancer: A retrospective single-center cohort study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-03-12.

Abstract P3-05-01: Immune and transcriptional signatures of dendritic dell (DC) vaccination combined with chemotherapy in locally advanced, triple-negative breast cancer (TNBC) patients

Abstract BACKGROUND: Women with TNBC who do not achieve a pathologic complete response (pCR) with preoperative (preop) chemotherapy have a high risk of recurrence and death from BC. Immunotherapy is an attractive strategy as human BCs can be immunogenic, and enhancing the immune effector function may augment the cytotoxic effects of standard therapies. CLINICAL TRIAL: Following IRB-approved informed consent, 10 pts with locally advanced TNBC received preop dose-dense doxorubicin/cyclophosphamide (AC) followed by paclitaxel and carboplatin (TCb) chemotherapy, combined with antigen-loaded (TNBC antigens: Cyclin B1, WT1, and control viral antigens: CEF) autologous monocyte-derived DC vaccinations administered intratumorally and subcutaneously. DCs were generated with GM-CSF and type I interferon, loaded with antigen in the form of long peptides and activated with innate ligands (LPS and Clo75) and CD40 ligand. Vaccines were given at 4 time points prior to definitive surgery, and 3 times post-surgery, pre- and post-radiation therapy (RT). Safety was the primary study endpoint, and pCR rate in breast and axilla was a secondary endpoint. Correlative studies included assessment of immune response via ELISpot and transcriptional profiling of blood samples collected over time. RESULTS: All pts received the 4 vaccines during preop chemotherapy, and 7/10 received all 7 vaccines. At the time of definitive surgery, 4 pts achieved a pCR, 3 pts had macroscopic residual disease in the breast and axillary lymph nodes, and 3 pts had residual cancer burden scores of 1. As of June 1, 2017, all pts have been in follow-up for at least 1 year s/p completion of all vaccines, and 7/10 patients have no evidence of disease. To assess immune signatures with IFN-γ-ELISpot, PBMCs from baseline (BL) and several time points during vaccine treatment were cultured with control peptides or with peptide libraries covering vaccine antigens. Using a linear mixed model to account for repeated and missing observations we found statistically significant (α = 0.05) increases in Cyclin B1, WT1, and CEF ELISpots in at least 1 time point post-DC vaccination and in follow-up. Compared to BL, Cyclin B1 and WT1 increased at 3 day pre-RT in 8/10 and 7/10 pts, respectively. To assess transcriptional signatures, a linear mixed model was utilized to determine statistically significant differences in fold-change over time compared to the BL and healthy controls. Modular analysis of differentially expressed transcripts at BL revealed downregulation of transcripts related to the monocyte lineage in 7/10 pts. Longitudinal analysis revealed profound transcriptional changes during AC with downregulation of lymphocyte modules and upregulation of innate and inflammation modules. While the latter ones have normalized during TCb and follow-up, T cell module remained substantially downregulated throughout treatment and follow-up. CONCLUSIONS: Combination of preop chemotherapy and intratumoral and subcutaneous autologous DC vaccination is safe in locally advanced TNBC pts and is linked with profound changes in immune transcription signatures and with expansion of antigen-specific immune responses that can be detected in IFN-γ ELISpot. Citation Format: Palucka AK, Roberts LK, Zurawski SM, Tarnowski J, Turner J, Wang X, Blankenship D, Smith JL, Levin MK, Finholt JP, Burkeholder SB, Timis R, Muniz LS, Dao T, Grant M, Banchereau J, Zurawski G, Pascual V, O'Shaughnessy JA. Immune and transcriptional signatures of dendritic dell (DC) vaccination combined with chemotherapy in locally advanced, triple-negative breast cancer (TNBC) patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-05-01.

The Role of Postmastectomy Radiation Therapy for Clinical Stage II-III Breast Cancer Patients With Pathological Complete Remission of Axillary Lymph Nodes After Neoadjuvant Chemotherapy

With the increasing use of neoadjuvant chemotherapy (NAC), patients with pathologically involved nodes had a great chance to be found as pathologically node negative at the time of definitive surgery. Several retrospective studies addressed that there were no survival benefits in those patient with pathologically complete remission (pCR) of axillary lymph node who treated with postmastectomy radiotherapy (PMRT) after NAC. We aim to retrospectively evaluate the role of PMRT in clinical stage II-III breast cancer patients with pathological nodes negative (ypN0) after NAC. We retrospectively identified 946 breast cancer patients with clinical stage II-III who underwent NAC in our center between 2003 and 2013. There were 290 patients achieved ypN0 after mastectomy and the clinical outcomes of the patients had been elucidated. The effects of PMRT on locoregional recurrence-free survival (LRRFS), disease-free survival (DFS) and overall survival (OS) were evaluated by Kaplan-Meier method and compared using the log-rank test. Prognostic factors associated with survival were evaluated by univariate and multivariate analysis. The median age was 50 years old (range, 25-80 years). All patients received 2-8 cycles (median, 4 cycles) of preoperative chemotherapy contained with anthracycling and paclitaxel and mastectomy. Of the 290 patients, 217 (74.8%) underwent PMRT and 73 (25.2%) did not. With a median follow-up time of 63 month, 12 patients developed LRR and 39 developed distant metastasis. The 5-year LRRFS, DFS and OS was 94.2%, 79.3% and 91.8% in no-PMRT group and 95.9%, 84.3% and 92.4% in PMRT group, respectively (p=NS). There was no significant difference between the patients with PMRT and without PMRT in terms of survival outcome, even for the subgroup of patients with clinical stage III disease or with residual disease in breast after NAC. On univariate and multivariate analysis, there were no benefits of PMRT on LRRFS (hazard ratio [HR], 0.714; 95% confidence interval [CI], 0.193-2,634; p =0.612), DFS (HR 0.908; 95%[CI], 0.477-1.734; p = 0.773) or OS (HR, 0.829; 95% [CI], 0.291-2.359; p =0.725). Age at diagnosis，ER and LVI status, adjuvant chemotherapy were independent prognostic factors for LRRFS （p＜0.01）, primary tumor response to NAC was marginally significant with poor LRRFS (hazard ratio [HR] 0.109; 95% CI, 0.011-1.098; p=0.06). Advanced Clinical T stage (T3-T4) was independently associated with decreased DFS and OS. Patients who achieved ypN0 after NAC without PMRT had similar outcomes compared with patients treated with PMRT, regardless of clinical stage and primary tumor response. PMRT might not be necessary for ypN0 patients. Prospective randomized study is needed to identify whether it is safe to omit PMRT in patients with clinical stage II-III disease and achieved ypN0 after NAC and mastectomy

A Validated Nomogram to Predict Upstaging of Ductal Carcinoma in Situ to Invasive Disease.

Approximately 8-56% of patients with a core needle biopsy (CNB) diagnosis of ductal carcinoma in situ (DCIS) will be upstaged to invasive disease at the time of excision. Patients with invasive disease are recommended to undergo axillary nodal staging, most often requiring a second operation. We developed and validated a nomogram to preoperatively predict percentage of risk for upstaging to invasive cancer. We reviewed 834 cases of DCIS on CNB between January 2004 and October 2014. Multivariable analysis was used to evaluate CNB and imaging factors to develop a nomogram to predict the risk of upstaging from DCIS to invasive cancer. This nomogram was validated with an external dataset of 579 similar patients between November 1998 and September 2016. An area under the receiver operating characteristic curve was constructed to evaluate nomogram discrimination. The rate of upstaging to invasive disease was 118/834 (14.1%). On multivariable analysis, grade on CNB and imaging factors, including mass lesion, multicentric disease, and largest linear dimension, were associated with upstage to invasive disease, and was used to develop a nomogram (c-statistic 0.71). In the external validation dataset, 62/579 (10.7%) patients were upstaged to invasive disease. Our nomogram was validated in this dataset with a c-statistic of 0.71. For patients with a CNB diagnosis of DCIS, our validated nomogram using DCIS grade on biopsy, and imaging factors of mass lesion, multicentric disease, and largest linear dimension, may be used for preoperative assessment of risk of upstaging to invasive disease, allowing patient counseling regarding axillary staging at the time of definitive surgery.

Incidence of sinonasal anatomical variations associated with chronic sinusitis by CT scan in Karaikal, South India

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; Variations in sinonasal anatomy of adults&lt;strong&gt; &lt;/strong&gt;are common and vary among different populations. Their role in development of pathological conditions such as sinusitis, epistaxis, etc is debated. Having clear picture of sinonasal anatomy of a person is essential in avoidance of complications during surgery. This study was done&lt;strong&gt; &lt;/strong&gt;to&lt;strong&gt; &lt;/strong&gt;analyze&lt;strong&gt; &lt;/strong&gt;sinonasal anatomy in adults from Karaikal region having chronic sinusitis by nasal endoscopy and CT scan imaging.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; A total of 50 patients undergoing endoscopic sinus surgery were studied by preoperative nasal endoscopy, CT scanning and endoscopy at the time of definitive surgery and variations recorded and analyzed. &lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Results:&lt;/strong&gt; The incidence of the sinonasal anatomical variations in CT scan study were – discharge in the frontal sinus (100%), agger nasi cells (96%), deviated nasal septum (70%), anterior ethmoidal cells (86%), posterior ethmoidal cells (58%), sinus lateralis (52%), frontal cells (50%), discharge in sphenoid sinus (50%), pneumatised superior turbinate (46%), INSA (34%), prominent bulla ethmoidalis (30%), supra orbital cells (26%), pneumatised septum(16%), medialised uncinate process (16%), paradoxical middle turbinate (16%), Haller cells (14%), supreme turbinate (14%), pneumatised inferior turbinate (12%), frontal recess obliteration (12%), absent pneumatisation of frontal sinus (12%), pneumatised middle turbinate (10%), Onodi cells (6%), pneumatised uncinate process (2%), maxillary sinus septation (2%).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; The high incidence of variations emphasises the need for proper preoperative assessment for safe and effective endoscopic sinus surgery. &lt;/p&gt;

Can Occult Invasive Disease in Ductal Carcinoma In Situ Be Predicted Using Computer-extracted Mammographic Features?

This study aimed to determine whether mammographic features assessed by radiologists and using computer algorithms are prognostic of occult invasive disease for patients showing ductal carcinoma in situ (DCIS) only in core biopsy. In this retrospective study, we analyzed data from 99 subjects with DCIS (74 pure DCIS, 25 DCIS with occult invasion). We developed a computer-vision algorithm capable of extracting 113 features from magnification views in mammograms and combining these features to predict whether a DCIS case will be upstaged to invasive cancer at the time of definitive surgery. In comparison, we also built predictive models based on physician-interpreted features, which included histologic features extracted from biopsy reports and Breast Imaging Reporting and Data System-related mammographic features assessed by two radiologists. The generalization performance was assessed using leave-one-out cross validation with the receiver operating characteristic curve analysis. Using the computer-extracted mammographic features, the multivariate classifier was able to distinguish DCIS with occult invasion from pure DCIS, with an area under the curve for receiver operating characteristic equal to 0.70 (95% confidence interval: 0.59-0.81). The physician-interpreted features including histologic features and Breast Imaging Reporting and Data System-related mammographic features assessed by two radiologists showed mixed results, and only one radiologist's subjective assessment was predictive, with an area under the curve for receiver operating characteristic equal to 0.68 (95% confidence interval: 0.57-0.81). Predicting upstaging for DCIS based upon mammograms is challenging, and there exists significant interobserver variability among radiologists. However, the proposed computer-extracted mammographic features are promising for the prediction of occult invasion in DCIS.

A Retrospective Cohort Study of Total Colonic Aganglionosis: Is the Appendix a Reliable Diagnostic Tool?

Background: Hirschsprung's disease (HD) is characterized by a lack of ganglion cells in the myenteric and submucosal plexus, associated with increased numbers of acetyl cholinesterase (AChE) positive nerve fibres. In approximately 10% of patients with HD the entire colon will be affected; a condition known as Total Colonic Aganglionosis (TCA). Aganglionosis of the appendix has long been considered to be an important finding in a patient in whom TCA is suspected, but its reliability for diagnosis has seldom been discussed. The aim of our study was to assess the reliability of the appendix as a histological specimen for the diagnosis of TCA, and to evaluate the long-term outcome of TCA. Methods: A retrospective cohort study was performed of all pathological specimens of patients with confirmed HD in our institution between March 2006 and April 2016. Results: Out of a total of 91 patients identified, 15 patients also had histopathological analysis of the appendix. Nine of these cases were confirmed as having TCA. The remaining 6 patients had HD involving the rest of the bowel up to the ascending colon, with normal ganglion present in the caecum. The appendix was removed in all the 15 cases. All 9 patients with confirmed TCA had aganglionosis of the appendix as well. The remaining 6 cases of short and long segment HD not involving the caecum, demonstrated normal ganglion cells within the appendix. Conclusion: Aganglionosis of the appendix is a reliable tool in the diagnosis of TCA. The authors recommend that at the time of levelling biopsies, if aganglionosis extends to the mid-transverse colon, an ileostomy be performed and appendix sent for definitive confirmation of TCA. However, at the time of definitive surgery, a frozen section of pull-through segment of bowel is recommended to confirm the presence of ganglion cells.