TDP2 is a regulator of estrogen-responsive oncogene expression.

With its ligand estrogen, the estrogen receptor (ER) initiates a global transcriptional program, promoting cell growth. This process involves topoisomerase 2 (TOP2), a key protein in resolving topological issues during transcription by cleaving a DNA duplex, passing another duplex through the break, and repairing the break. Recent studies revealed the involvement of various DNA repair proteins in the repair of TOP2-induced breaks, suggesting potential alternative repair pathways in cases where TOP2 is halted after cleavage. However, the contribution of these proteins in ER-induced transcriptional regulation remains unclear. We investigated the role of tyrosyl-DNA phosphodiesterase 2 (TDP2), an enzyme for the removal of halted TOP2 from the DNA ends, in the estrogen-induced transcriptome using both targeted and global transcription analyses. MYC activation by estrogen, a TOP2-dependent and transient event, became prolonged in the absence of TDP2 in both TDP2-deficient cells and mice. Bulk and single-cell RNA-seq analyses defined MYC and CCND1 as oncogenes whose estrogen response is tightly regulated by TDP2. These results suggest that TDP2 may inherently participate in the repair of estrogen-induced breaks at specific genomic loci, exerting precise control over oncogenic gene expression.

Socioeconomic disparities in patients with small bowel neuroendocrine tumors.

BACKGROUND AND OBJECTIVES: Demographic and socioeconomic disparities affect cancer specific outcomes in numerous malignancies, but the impact of these for patients with small bowel neuroendocrine tumors (SBNETs) is not well understood. The primary objective was to investigate the impact of demographic and socioeconomic factors on overall survival (OS) for patients with SBNETs. METHODS: We performed a retrospective cohort study utilizing the National Cancer Database to assess patients diagnosed with SBNET between 2004 and 2015. Patients were stratified by demographics, socioeconomic factors, insurance status, and place of living. RESULTS: The 5-year OS for the entire cohort was 78.5%. The 5-year survival was worse in patients with lower income (p < 0.0001), lower education (p < 0.0001), not in proximity to a metro area (p = 0.0004), and treatment at a community cancer center (p < 0.0001). Adjusting for age and sex, factors associated with worse OS were lower income (<$38 000) (hazard ratio [HR]: 1.16, 95% confidence interval [CI]: 1.04-1.28), lower education (>20% no HSD) (HR: 1.14, 95% CI: 1.02-1.26), no insurance (HR: 1.66, 95% CI: 1.33-2.06), and not living in proximity to a metro area (HR: 1.27, 95% CI: 1.10-1.47). CONCLUSIONS: Patient demographics and socioeconomic factors play an important role in survival of patients with SBNETs, specifically proximity to a metro area, median income, education level, and type of treatment center. Strategies to improve access to care must be considered in this at-risk population.

Neoadjuvant rectal score is prognostic for survival: A population-based propensity-matched analysis.

INTRODUCTION: Neoadjuvant rectal (NAR) score may serve as a surrogate short-term endpoint for overall survival (OS) in clinical trials. This study aims to test the NAR score using a large, national cancer registry. METHODS: National Cancer Database patients with clinical stage II/III rectal adenocarcinoma (RAC) treated with neoadjuvant chemoradiation (CRT) followed by surgery were selected and divided into low-, intermediate-, and high-NAR subgroups. OS outcomes were analyzed using Kaplan-Meier and logistic regression models. RESULTS: A total of 12 452 patients were selected, of which 5071 (40.7%) were in clinical stage II and 7381 (59.3%) were in clinical stage III; 15.2% had pathologic complete response. The mean NAR score was 10.01 ± 10.61. Six thousand nine hundred and forty-one (55.7%) did not receive adjuvant chemotherapy (AC) and were propensity-matched across NAR subgroups (966 in each group). A significant difference in 5-year OS between low-, intermediate-, and high-NAR groups was observed (85% vs. 76% vs. 68%; p < 0.001). Five thousand five hundred and eleven (44.3%) received AC and 1045 triplets were propensity-matched per NAR groups. A significant difference was again observed for 5-year OS (93% vs. 88% vs. 75%; p < 0.001). Logistic regression confirmed NAR strata as a significant predictor of 5-year OS. CONCLUSION: NAR score, as a neoadjuvant response measure, is a strong predictor of 5-year OS, regardless of AC receipt in a heterogenous population of locally advanced RAC patients.

The fragility of a structurally diverse duplication block triggers recurrent genomic amplification.

The human genome contains hundreds of large, structurally diverse blocks that are insufficiently represented in the reference genome and are thus not amenable to genomic analyses. Structural diversity in the human population suggests that these blocks are unstable in the germline; however, whether or not these blocks are also unstable in the cancer genome remains elusive. Here we report that the 500 kb block called KRTAP_region_1 (KRTAP-1) on 17q12-21 recurrently demarcates the amplicon of the ERBB2 (HER2) oncogene in breast tumors. KRTAP-1 carries numerous tandemly-duplicated segments that exhibit diversity within the human population. We evaluated the fragility of the block by cytogenetically measuring the distances between the flanking regions and found that spontaneous distance outliers (i.e DNA breaks) appear more frequently at KRTAP-1 than at the representative common fragile site (CFS) FRA16D. Unlike CFSs, KRTAP-1 is not sensitive to aphidicolin. The exonuclease activity of DNA repair protein Mre11 protects KRTAP-1 from breaks, whereas CtIP does not. Breaks at KRTAP-1 lead to the palindromic duplication of the ERBB2 locus and trigger Breakage-Fusion-Bridge cycles. Our results indicate that an insufficiently investigated area of the human genome is fragile and could play a crucial role in cancer genome evolution.

New cars on the highways: Trends in injuries and outcomes following ejection.

BACKGROUND: Although ejections from motor vehicles are considered a marker of a significant mechanism and a predictor of severe injuries and mortality, scant recent data exist to validate these outcomes. This study investigates whether ejections increase the mortality risk following a motor vehicle crash using data that reflect the introduction of new vehicles to the streets of a large city in the United States. METHODS: The Trauma and Emergency Medicine Information System of Los Angeles County was queried for patients ≥ 16 years old admitted following a motor vehicle crash between 2002 and 2012. Ejected patients were compared to nonejected. Primary outcome was mortality. A logistic regression model was used to identify predictors of mortality and severe trauma. RESULTS: A total of 9,742 (6.8%) met inclusion criteria. Of these, 449 (4.6%) were ejected; 368 (82.0%) were passengers and 81 (18.0%) were drivers. The rate of ejection decreased linearly (6.1% in 2002 to 3.4% in 2012). Compared to nonejected patients, ejected patients were more likely to require intensive care unit admission (43.7% vs 22.1%, P < .01), have critical injuries (Injury Severity Score > 25) (24.2% vs 7.3%, P <.01), require emergent surgery (16.3% vs 8.0%, P <.01), and expire in the emergency department (3.6% vs 1.2%, P <.01). Overall mortality was 3.6%: 9.6% for ejected and 3.3% for nonejected patients (P <.01). In a logistic regression model, ejection and extrication both predicted mortality (adjusted odds ratio: 1.83, P <.01 and 1.87, P <.01, respectively). Ejection also predicted critical injuries (Injury Severity Score > 25) with adjusted odds ratio of 2.48 (P <.01). CONCLUSION: Ejections following motor vehicle crash have decreased throughout the years; however, they remain a marker of critical injuries and predictive of mortality.

Midgut Neuroendocrine Tumors with Liver-only Metastases: Benefit of Primary Tumor Resection.

BACKGROUND: Management of metastatic midgut neuroendocrine tumors (MNET) remains controversial. The benefits of resecting the primary tumor are not clear and advocated only for select patients. This study aimed to determine whether resection of the primary MNET in patients with untreated liver-only metastases has an impact on survival. METHODS: This retrospective study reviewed data of the National Cancer Database from 2004 to 2015 for patients with liver-only metastatic MNETs and compared those who received resection of their primary MNET with those who did not. Patient demographics, tumor characteristics, and clinical outcomes were compared between the groups. The primary outcome was overall survival (OS) after adjustment for patient, demographic, and tumor-related factors. RESULTS: The study identified 1952 patients with a median age of 63 years (range, 18-90 years). The median primary tumor size was 2.4 cm (range, 0.1-20 cm). Of these patients, 1295 (66%) underwent resection of the primary tumor and 667 (34%) did not. The patients who underwent resection were younger (median age, 63 vs 65 years; p < 0.001) and had smaller primary tumors (median, 2.3 vs 3.0 cm; p < 0.001). The patients with clinical T1 or T2 tumors were significantly less likely to undergo resection than those with stage T3 or T4 tumors (58.5% vs 89.7%; p < 0.001). The median follow-up period was 43 months (range, 1-83 months). In the entire cohort, 483 deaths occurred, with a 5-year OS of 61%. The 5-year OS rate was 49% for the patients who underwent resection and 66% for those who did not (p < 0.001). When the patients were grouped according to T stage, no OS difference between resection and no resection for stages T1 (p = 0.07) and T2 (p = 0.40) was identified. However, the 5-year OS rate was significantly better for the resected patient cohort with T3 (67.5% vs 37.2%; p < 0.001) or T4 (59.8% vs 21.5%; p < 0.001) tumors. CONCLUSIONS: The patients with treatment-naïve liver-only metastatic MNET had improved OS when the primary tumor was resected, particularly those with clinical stage T3 or T4 tumors. These patients may benefit from surgical resection of their primary tumor.

Impact of Resident and Fellow Participation on Surgical Outcomes in Breast Conserving Surgery for Invasive Breast Cancer.

OBJECTIVE: Few studies examine the impact of surgical trainee involvement on tumor-free margins in breast conserving surgery (BCS). Our objective was to investigate the impact of resident and fellow involvement on positive margins rates following BCS for invasive breast cancer (BC). DESIGN: We identified female patients who had BCS for BC between January 2005 to December 2015. SETTING: Tertiary care hospital. PARTICIPANTS: Around 1089 patients were identified from a prospectively maintained database. RESULTS: Of 1089 patients, mean age was 63 (range 43-99) years. Around 768 patients (70.1%) required preoperative localization, and 328 patients (29.9%) had a palpable cancer. Nonpalpable cancers had a smaller volume of specimen tissue excised (p = 0.0005) compared to palpable cancers, and no significant difference was observed in the positive margin rate between the nonpalpable group compared to the palpable group (24.7% nonpalpable vs. 25.3% palpable, p = 0.88). Nonpalpable cancer positive margin rates were 23.9% (n = 102/427) for cases performed by an attending surgeon, 25.0% (n = 15/60) with a junior resident (PGY 2-3), 28.6% (n = 8/28) with a senior resident (PGY 4-5), and 25.7% (n = 65/253) with a fellow, which were not statistically significant (p = 0.89). Palpable cancer positive margin rates were 27.6% (n = 47/170) for cases performed by an attending, 13.9% (n = 5/36) with an intern (PGY-1), 40.9% (n = 9/22) with a junior resident, 0% (n = 0/8) with a senior resident, and 23.9% (n = 22/92) with a fellow, which were also not significantly different (p = 0.07). CONCLUSION: Resident and fellow participation in BCS for BC does not appear to impact the rate of positive margins.

Prognostic factors influencing survival in small bowel neuroendocrine tumor with liver metastases.

BACKGROUND: Resection of liver metastasis in small bowel neuroendocrine tumors (SBNET) may improve survival, however, factors influencing prognosis are unclear. We evaluated how the extent of resection influences outcomes. METHODS: Patients with SBNET with liver metastasis from 1990 to 2013 who underwent resection of the primary tumor were identified. Outcomes among patients undergoing complete resection (CR), partial resection (PR), or no resection (NR) of liver metastases with resection of the primary tumor only were compared. RESULTS: One hundred eleven patients met the criteria. The median number of liver lesions was seven and median lesions resected was one. Fifty (45%) patients had NR, 41 (36.9%) underwent CR, and 20 (18.1%) underwent PR. The 5-year overall survival (OS) was 79.4% for NR, 84.7% for PR, and 100% for CR, demonstrating a trend that CR was best, followed by PR then NR (P = .02). 10-year OS showed no significant differences (72.7% NR; 84.7% PR; 82.5% CR; P = .10). Greater than 10 liver lesions (hazard ratio [HR] 3.6; P = 0.04) or receiving chemotherapy (HR 3.7; P = .03) were negative predictors of survival. CONCLUSION: The extent of resection of liver disease in SBNET influenced survival at 5 years but not at 10 years. In addition, more than 10 liver lesions and chemotherapy were predictors of mortality.

Association of Emotional Intelligence With Malpractice Claims: A Review.

IMPORTANCE: Approximately 8% of physicians experience a malpractice claim annually. Most malpractice claims are a result of adverse events, which may or may not be a result of medical errors. However, not all medicolegal cases are the result of medical errors or negligence, but rather, may be associated with the individual nature of the patient-physician relationship. The strength of this relationship may be partially determined by a physician's emotional intelligence (EI), or his or her ability to monitor and regulate his or her emotions as well as the emotions of others. This review evaluates the role of EI in developing the patient-physician relationship and how EI may influence patient decisions to pursue medicolegal action. OBSERVATIONS: Several physician characteristics are associated with increased medicolegal risk. Some of these traits, such as sex, age, level of experience, and specialty, are inherent. Other characteristics, such as patient interaction, patient satisfaction, and prior legal history, appear to be related to physicians themselves, yet they are modifiable if such physicians can be identified. Numerous tools exist that provide general measures of different aspects of EI. Furthermore, identification of those with lower EI and intervention with specific training has been shown to improve both EI and patient satisfaction. CONCLUSIONS AND RELEVANCE: The study and effect of EI within medicine offers great opportunity to investigate how physician characteristics may influence one's EI, as well as medicolegal risk. This review suggests an indirect negative correlation between a physician's level of EI and his or her risk of litigation. Studies directly linking physicians with low EI to a higher risk of litigation are lacking and may provide valuable insight. Demonstrating such a correlation should prompt the development of interventions that may enhance a physician's level of EI early in his or her career and may limit future legal action.

The Impact of Epidural Analgesia on the Rate of Thromboembolism without Chemical Thromboprophylaxis in Major Oncologic Surgery.

Patients with abdominopelvic cancers are at increased risk of venous thromboembolism (VTE) due to their malignancy. We evaluated outcomes and the rate of VTE in patients undergoing abdominopelvic surgery for malignancy with preoperative epidural analgesia without postoperative chemical VTE prophylaxis. A retrospective review between 2009 and 2015 identified 285 patients with malignancy who underwent abdominopelvic surgery by a single surgeon (AWS). Lower extremity venous duplex scans (VDS) were performed preoperatively and before discharge. Demographics, procedures, and VTE outcomes were reviewed. The median age was 66 years. The average operative time was 315 minutes. All patients ambulated on postoperative day (POD) one or two. Epidural catheters (ECs) were removed on postoperative day four or five. No patient received VTE prophylaxis while an epidural catheter was in place. Preoperative lower extremity VDS revealed above-knee deep vein thrombosis (DVT) in seven patients (2.5%). Postoperative lower extremity VDS revealed acute DVT in 24 patients (8.4%): nine (3.2%) above-knee and 15 (5.2%) below-knee. The nine patients with above-knee DVT were anticoagulated after epidural removal. No patient developed a pulmonary embolism. Our data suggest that patients undergoing major open operations with epidural analgesia have low rates of DVT and may obviate the need for chemical prophylaxis. However, larger studies are required to determine the overall effects of epidural analgesia on the development of DVTs postoperatively.

Prevalence and Predictors of Preoperative Venous Thromboembolism in Asymptomatic Patients Undergoing Major Oncologic Surgery.

BACKGROUND: Postoperative venous thromboembolism (VTE) is a leading cause of in-hospital mortality for cancer patients; however, the prevalence of preoperative VTE remains unclear. OBJECTIVE: The aim of this study was to evaluate the prevalence and risk factors associated with preoperative VTE in asymptomatic patients undergoing major oncologic surgery. METHODS: Retrospective analysis of 346 patients identified from our prospectively maintained database of patients undergoing abdominopelvic oncologic surgery from 2009 to 2016. RESULTS: The prevalence of preoperative VTE found on screening venous duplex scan was 10.1%. Patients with a history of prior VTE were more likely to have a preoperative deep vein thrombosis (DVT) versus those with no prior VTE (42.9% vs. 4.5%, p < 0.01). Relative risk for prior VTE was 8.2 [95% confidence interval (CI) 4.7-14.3]. Older age was also associated with preoperative VTE. Regression modeling determined that patients were 1.24-fold as likely to have a preoperative DVT for every 5-year increase in age (relative risk 1.24, 95% CI 1.09-1.42). Patients with preoperative DVT were more likely to have been diagnosed with sepsis 1 month prior to surgery (8.6% vs. 1.6%, p = 0.04). There were no postoperative pulmonary emboli. The overall postoperative complication rate was higher in those with a preoperative DVT (25.7% vs. 13.2%, p = 0.071). CONCLUSION: Asymptomatic patients undergoing major oncologic surgery have a 10.1% prevalence of preoperative DVT. Increasing age, recent diagnosis of sepsis, and a history of prior VTE are significantly associated with preoperative DVTs. This suggests high-risk oncologic patients may benefit from screening lower extremity venous duplex ultrasound prior to Surgery.

The role of pre-operative imaging and double balloon enteroscopy in the surgical management of small bowel neuroendocrine tumors: Is it necessary?

BACKGROUND AND OBJECTIVES: Pre-operative localization of small bowel neuroendocrine tumors (SBNET) is important for operative planning. The aim was to determine the effectiveness of pre-operative imaging and double-balloon enteroscopy (DBE) in identifying extent of disease. METHODS: Database review identified 85 patients with primary SBNET between 2006 and 2013. Analysis included patients who underwent imaging, endoscopy, and surgery at our institution. RESULTS: Average age was 60.7 years. Sixty-six (77.1%) patients had a primary NET in the ileum. Seventy-two patients (67.3%) underwent CT, 47 (46.7%) had MRI, 44 (46.7%) had somatostatin receptor imaging (SRI), and 41 (39.3%) underwent DBE. The sensitivity of each in identifying the NET was 59.7% for CT, 54% for MRI, 56% for SRI, and 88.1% for DBE. Eighteen (21.2%) patients had primary tumors not identified on imaging. Of these 18, 13 underwent DBE, and 12 of 13 (92.3%) DBEs identified the primary lesion. DBE was significantly better at identifying the primary NET than CT, MRI or SRI (P = 0.004, 0.007, and 0.012). CONCLUSIONS: Most SBNETs are identified with a combination of imaging modalities. In those with unidentified primary tumors after imaging, DBE should be considered as it may provide valuable information as to the location of the primary tumor.

Long-Term Outcomes after Elective versus Emergency Surgery for Small Bowel Neuroendocrine Tumors.

Small bowel neuroendocrine tumors (SBNETs) are often indolent, but occasionally, patients present with acute symptoms requiring emergent operative intervention. Our aim was to determine whether emergency surgery for SBNETs affects long-term outcomes. An institutional database was reviewed to identify patients with SBNET diagnosed between 1990 and 2015. Need for emergency resection (ER) was compared with elective resection (ELR). One hundred and thirty-four patients met inclusion criteria. Median age was 59 years (range, 21-91), and median tumor size was 1.5 cm (range, 0.1-5). Median follow-up time was 5.5 years. One hundred (74.6%) patients had ELR, whereas 34 (25.4%) required ER. ELR had a higher number of lymph nodes resected (median 12.5 vs 8 ER, P = 0.04); however, there was no difference in the number of positive nodes (median 3 vs 2, P = 0.85). There were 45 (33.6%) recurrences (31 [31.0%] ELR vs 14 [41.7%] ER, P = 0.29) and 13 (9.7%) deaths (7 [7.0%] ELR; 6 [17.6%] ER). There was no significant difference in 5-year disease-free survival (ELR 72.6% vs ER 77.9%, P = 0.71) or overall survival (ELR 97.2% vs ER 96.6%, P = 0.81). Although patients undergoing ER have significantly fewer lymph nodes resected, they have comparable recurrence rates and long-term outcomes with those patients undergoing ER.

Prognostic Factors Associated with Outcomes in Small Bowel Neuroendocrine Tumors.

Small bowel neuroendocrine tumors (SBNET) account for most gastrointestinal neuroendocrine tumors. Patients often present with late-stage disease; however, there is little information regarding factors that contribute to recurrence. Database review identified 301 patients diagnosed with SBNET between 1990 and 2013. Univariate analysis included patients who underwent complete resection. Survival was estimated by the Kaplan-Meier method. A total of 147 patients met study criteria. Average age was 60 years (range 21-91); 49 per cent were male. Thirty-seven (25.3%) patients had laparoscopic resection, and 29 (19.9%) patients had only small bowel disease, whereas 108 (72.6%) had nodal metastasis. Five-year overall and disease-free survival were 97.5 and 73.5 per cent. Forty-seven (32%) patients had recurrence. The recurrence group was more likely to have an open operation (59.6 vs 32%, P < 0.01), mesenteric invasion, or lymphatic metastasis (87.2 vs 67%, P < 0.01) compared with the no-recurrence group. Cox regression analysis showed that variables associated with recurrence included nodal disease (HR 9.06, P = 0.03), lymphovascular invasion (LVI) (3.95, P < 0.01), perineural invasion (PNI) (3.48, P < 0.01), and mesenteric involvement (3.77, P = 0.03). Patients with SBNET presenting with nodal metastasis, mesenteric involvement, LVI, or PNI have a higher risk of recurrence. Closer surveillance should be considered after operative resection.

Neoadjuvant Chemotherapy and Surgical Management of the Axilla in Breast Cancer: A Review of Current Data.

Neoadjuvant chemotherapy has become the standard of care for patients with locally advanced breast cancer, large tumors, certain biologic subtypes of breast cancer, or locally inoperable disease, and for patients who desire breast conservation. It has the advantage of downstaging the tumor, thereby allowing for conversion from mastectomy to breast conservation, and perhaps decreasing the need for axillary lymph node dissection (ALND). In the past, axillary management involved complete ALND for all patients presenting with breast cancer and involved nodes. With neoadjuvant chemotherapy, some patients exhibit a complete clinical axillary response, which may make them candidates for sentinel lymph node biopsy (SNLB) rather than ALND, with its associated morbidities. While there is widespread use of SLNB in the treatment of breast cancer, its use following neoadjuvant chemotherapy remains widely debated.