Sustained Supratherapeutic Paclitaxel Delivery Enhances Irreversible Sarcoma Cell Death.

Risk of locoregional recurrence after sarcoma resection is high, increasing both morbidity and mortality. Intraoperative implantation of paclitaxel (PTX)-eluting polymer films locally delivers sustained, supratherapeutic PTX concentrations to the tumor bed that are not clinically feasible with systemic therapy, thereby reducing recurrence and improving survival in a murine model of recurrent sarcoma. However, the biology underlying increased efficacy of PTX-eluting films is unknown and provides the impetus for this work. In vitro PTX efficacy is time and dose dependent with prolonged exposure significantly decreasing PTX IC50 values for human chondrosarcoma (CS-1) cells (153.9 nmol/L at 4 hours vs. 14.2 nmol/L at 30 hours, P = 0.0001). High-dose PTX significantly inhibits proliferation with in vivo PTX films delivering a dose >130 µmol/L directly to the tumor thereby irreversibly arresting cell cycle and inducing apoptosis in CS-1 as well as patient-derived liposarcoma (LP6) and leiomyosarcoma (LMS20). Supratherapeutic PTX upregulates the expression of p21 in G2-M arrested cells, and irreversibly induces apoptosis followed by cell death, within 4 hours of exposure. Microarray analyses corroborate the finding of poor DNA integrity commonly observed as a final step of apoptosis in CS-1 cells and tumor. Unlike low PTX concentrations at the tumor bed during systemic delivery, supratherapeutic concentrations achieved with PTX-eluting films markedly decrease sarcoma lethality in vivo and offer an alternative paradigm to prevent recurrence.

Volume of Pancreas-Adjacent Operations Favorably Influences Pancreaticoduodenectomy Outcomes at Lower Volume Pancreas Centers.

OBJECTIVE: This study assesses how the volume of pancreatic-adjacent operations (PAO) impacts the outcomes of pancreaticoduodenectomy (PD). SUMMARY BACKGROUND DATA: It is well-established that regionalization benefits outcomes after PD. However, due to a multitude of factors, including geographic, financial, and personal, not all patients receive their care at high-volume pancreas surgery centers. METHODS: The National Cancer Database was queried for pancreatic cancer patients who underwent PD. Hospital volume was calculated for PD and PAO (defined as gastric, hepatic, complex biliary, or pancreatic operations other than PD) and dichotomized as low- and high-volume centers based on the median. Three study cohorts were created: low-volume hospitals (LVH) for both PD and PAO, mixed-volume hospital (MVH) with low-volume PD but high-volume PAO, and high-volume PD hospital (HVH). RESULTS: In total, 24,572 patients were identified, with 41.5%, 7.2%, and 51.3% patients treated at LVH, MVH, and HVH, respectively. Thirty-day mortality for PD was 5.6% in LVH, 3.2% in MVH, and 2.5% in HVH. On multivariable analyses, LVH was predictive for higher 30-day mortality compared to HVH [odds ratio (OR) 2.068; 95% confidence interval (CI) 1.770-2.418; P< 0.0001]. However, patients at MVH demonstrated similar 30-day mortality to patients treated at HVH (OR 1.258; 95% CI 0.942-1.680; P = 0.1203). CONCLUSIONS: PD outcomes at low-volume centers that have experience with complex cancer operations near the pancreas are similar to PD outcomes at hospitals with high PD volume. MVH provides a model for PD outcomes to improve quality and access for patients who cannot, or choose not to, receive their care at high-volume centers.

Lymphadenectomy and Survival After Neoadjuvant Chemoradiation for Esophageal Adenocarcinoma: Is More Better?

PURPOSE: The purpose of this study was to assess the impact of number of lymph nodes examined on survival in patients with esophageal adenocarcinoma who underwent neoadjuvant chemoradiation. METHODS: The National Cancer Database was queried for patients who underwent neoadjuvant chemoradiation followed by surgery for esophageal adenocarcinoma. Propensity scores were created predicting the odds of undergoing resection of ≥ 25 nodes. Patients were matched on propensity score. Overall survival analyses were performed using the Kaplan-Meier method. Sensitivity analyses were performed using various nodal cutoffs. RESULTS: In total, 3953 patients who underwent neoadjuvant chemoradiation were identified. The median number of resected nodes was 14 nodes (IQR, 8-20 nodes). Resection of ≥ 15 (vs. < 15 nodes: 32 vs. 26 months; p < 0.001), ≥ 20 (vs. < 20 nodes: 36 vs. 28 months; p = 0.001), and ≥ 25 (vs. < 25 nodes: 37 vs. 29 months; p = 0.015) nodes was associated with higher median survival, but resection of ≥ 30 nodes was not (vs. < 30 nodes: 41 vs. 33 months; p = 0.367). Resection of ≥ 25 lymph nodes remained predictive for improved survival on subset analysis in patients with negative nodes and who underwent treatment at high-volume centers. CONCLUSIONS: After neoadjuvant chemoradiation, resection of 25 or more lymph nodes was associated with longer median survival. Prospective trials are warranted to determine the optimal nodal yield after neoadjuvant chemoradiation.

Caprini Risk Model Decreases Venous Thromboembolism Rates in Thoracic Surgery Cancer Patients.

BACKGROUND: Extended postoperative chemoprophylaxis is effective in reducing venous thromboembolism (VTE) among general surgical patients. We hypothesized that implementation of the Caprini risk assessment model (RAM) would reduce VTE rates among patients undergoing lung and esophageal cancer surgery. METHODS: The Caprini RAM, consisting of patient risk stratification and extended postoperative chemoprophylaxis with low molecular weight heparin, was implemented on the thoracic surgery service at Boston Medical Center in July 2014. Patients undergoing lung and esophageal cancer resections were enrolled in the postintervention group beginning in July 2014. Provider and patient adherence to treatment protocol was audited. Venous thromboembolism and adverse bleeding events were monitored for 60 days postoperatively. A preintervention control group including esophagectomy and lung cancer resection patients (January 2005 to June 2013) was used for VTE rate comparison. Exclusion criteria included chronic anticoagulation and presence of filters. RESULTS: There were 302 lung and esophageal cancer resection patients in the preintervention cohort, and 64 thoracic cancer resections in the postintervention group. The overall VTE rates for preintervention and postintervention cohorts were 7.3% (22 of 302) and 3.1% (2 of 64), respectively (p = 0.28). Provider adherence to Caprini RAM score assignment was 100%, whereas patient adherence to treatment was 97.4%. There were no adverse bleeding events. CONCLUSIONS: This study demonstrates a trend toward decreased symptomatic VTE after Caprini RAM implementation, as demonstrated among high-risk cancer patients. The absence of bleeding complications and high provider and patient adherence to VTE RAM support the safety and feasibility of a VTE prevention protocol in thoracic surgery patients.

Long-term outcomes after near-infrared sentinel lymph node mapping in non-small cell lung cancer.

OBJECTIVE: To report the first analysis of long-term outcomes using near-infrared (NIR) image-guided sentinel lymph node (SLN) mapping in non-small cell lung cancer (NSCLC). METHODS: Retrospective analysis of patients with NSCLC enrolled in 2 prospective phase 1 NIR-guided SLN mapping trials, including an indocyanine green (ICG) dose-escalation trial, was performed. All patients underwent NIR imaging for SLN identification followed by multistation mediastinal lymph node sampling (MLNS) and pathologic assessment. Disease-free (DFS) and overall survival (OS) were compared between patients with NIR+ SLN (SLN group) and those without (non-SLN group). RESULTS: SLN detection, recurrence, DFS, and OS were assessed in 42 patients with NSCLC who underwent intraoperative peritumoral ICG injection, NIR imaging, and MLNS. NIR+ SLNs were identified in 23 patients (SLN group), whereas SLNs were not identified in 19 patients enrolled before ICG dose and camera optimization (non-SLN group). Median follow-up was 44.5 months. Pathology from NIR+ SLNs was concordant with overall nodal status in all 23 patients. Sixteen patients with SLN were deemed pN0 and no recurrences were, whereas 4 of 15 pN0 non-SLN patients developed nodal or distant recurrent disease. Comparing SLN versus non-SLN pN0 patients, the probability of 5-year OS is 100% versus 70.0% (P = .062) and 5-year DFS is statistically significantly improved at 100% versus 66.1% (P = .036), respectively. Among the 11 pN+ patients, 7 were in the SLN group, with >40% showing metastases in the SLN alone. CONCLUSIONS: Patients with pN0 SLNs showed favorable disease-free and overall survival. This preliminary review of NIR SLN mapping in NSCLC suggests that pN0 SLNs may better represent true N0 status. A larger clinical trial is planned to validate these findings.

A novel technique for tumor localization and targeted lymphatic mapping in early-stage lung cancer.

OBJECTIVE: To investigate safety and feasibility of navigational bronchoscopy (NB)-guided near-infrared (NIR) localization of small, ill-defined lung lesions and sentinel lymph nodes (SLN) for accurate staging in patients with non-small cell lung cancer (NSCLC). METHODS: Patients with known or suspected stage I NSCLC were enrolled in a prospective pilot trial for lesion localization and SLN mapping via NB-guided NIR marking. Successful localization, SLN detection rates, histopathologic status of SLN versus overall nodes, and concordance to initial clinical stage were measured. Ex vivo confirmation of NIR+ SLNs and adverse events were recorded. RESULTS: Twelve patients underwent NB-guided marking with indocyanine green of lung lesions ranging in size from 0.4 to 2.2 cm and located 0.1 to 3 cm from the pleural surface. An NIR+ "tattoo" was identified in all cases. Ten patients were diagnosed with NSCLC and 9 SLNs were identified in 8 of the 10 patients, resulting in an 80% SLN detection rate. SLN pathologic status was 100% sensitive and specific for overall nodal status with no false-negative results. Despite previous nodal sampling, one patient was found to have metastatic disease in the SLN alone, a 12.5% rate of disease upstaging with NIR SLN mapping. SLN were detectable for up to 3 hours, allowing time for obtaining a tissue diagnosis and surgical resection. There were no adverse events associated with NB-labeling or indocyanine green dye itself. CONCLUSIONS: NB-guided NIR lesion localization and SLN identification was safe and feasible. This minimally invasive image-guided technique may permit the accurate localization and nodal staging of early stage lung cancers.

Safety and feasibility of near-infrared image-guided lymphatic mapping of regional lymph nodes in esophageal cancer.

OBJECTIVE: To assess safety and feasibility of an intraoperative, minimally invasive near-infrared (NIR) image-guided approach to lymphatic mapping in patients with esophageal cancer. METHODS: Although local lymph nodes (LNs) are removed with the esophageal specimen, no techniques are available to identify the regional LNs (separate from the esophagus) during esophagectomy. We hypothesize that NIR imaging can identify regional LNs with the potential to improve staging and guide the extent of lymphadenectomy. Nine of the 10 patients enrolled had resectable esophageal adenocarcinoma and underwent NIR mapping following peritumoral submucosal injection of indocyanine green (ICG) alone or premixed in human serum albumin (ICG:HSA) before resection. NIR imaging was performed in situ and ex vivo. RESULTS: In 6 of the 10 patients, intraoperative NIR imaging demonstrated an NIR signal at all tumors and in 2 to 6 NIR(+) regional LNs. NIR(+) LNs were not identified in 4 patients: 1 patient with occult stage IV disease, for whom further imaging was not performed and thus was excluded from analysis, and 3 patients in whom ICG was used without HSA. Identification of local LNs on the esophagus was obscured by a peritumoral background. Importantly, the pathological status of NIR(+) regional LNs reflected overall regional nodal status. CONCLUSIONS: NIR lymphatic mapping is safe and feasible in patients with esophageal cancer and can identify regional LNs when ICG:HSA is used. Although more work is needed to improve background signals and local LN identification, intraoperative detection of regional NIR(+) LNs allows an in-depth histological analysis of LN basins not commonly scrutinized as part of the specimen and may improve the detection of occult nodal disease.

Prevention of Postoperative Venous Thromboembolism in Thoracic Surgical Patients: Implementation and Evaluation of a Caprini Risk Assessment Protocol.

BACKGROUND: Venous thromboembolism (VTE) can be a devastating postoperative complication, with about one-third of VTEs occurring post-discharge. We previously retrospectively evaluated the Caprini VTE risk assessment model (RAM) in postoperative lung and esophageal cancer patients, demonstrating that "high risk" patients were more likely to have a postoperative VTE. In this study, we sought to implement the RAM protocol in thoracic surgical patients to evaluate adherence, safety, and VTE outcomes. STUDY DESIGN: This prospective cohort study at a large safety net hospital included all surgically treated patients within the thoracic surgery division beginning in July 2014. Per RAM protocol, patients with high risk scores were prescribed a total of 30 days of postoperative daily enoxaparin prophylaxis, and moderate risk patients received a total of 10 postoperative days. Adherence and outcome audits were conducted. RESULTS: A total of 126 patients were included for analysis. Provider adherence to RAM score calculation was 99.2% (125 of 126), with appropriate post-discharge prophylaxis prescribed in 96.0% of cases. Twenty-four patients scored high risk (19.2%), 60 were moderate risk (48.0%), and 41 scored low risk (32.8%). Patient adherence to post-discharge enoxaparin prophylaxis was 97.2%. The overall VTE rate was 2.3%, with no post-discharge VTEs or adverse bleeding events. CONCLUSIONS: Implementation of a VTE risk assessment protocol with extended course prophylaxis in high risk patients is safe and feasible for providers and thoracic surgical patients at a large safety net institution with a diverse patient population. Follow-up studies are needed to assess efficacy of the RAM in this surgical population.

Caprini venous thromboembolism risk assessment permits selection for postdischarge prophylactic anticoagulation in patients with resectable lung cancer.

OBJECTIVE: Postoperative venous thromboembolism (VTE) creates an 8-fold increase in mortality after lung resection. About one third of postoperative VTEs occur after discharge. The Caprini risk assessment model has been used by other specialties to calculate the risk of a VTE. Patients deemed high risk by the model are candidates for prophylactic anticoagulation after discharge, reducing the VTE risk by 60%. Our primary aims were to determine the frequency of VTE events and evaluate whether the Caprini model could risk-stratify patients. METHODS: Patients undergoing lung cancer resections during 2005 to 2013 were evaluated. Exclusion criteria were preoperative filter and therapeutic anticoagulation. A total of 232 patients were reviewed and Caprini scores calculated. Subjects were risk stratified into groups of low risk (0-4), moderate risk (5-8), and high risk (≥ 9). Occurrence of VTE events (deep vein thrombosis; pulmonary embolism) were identified by imaging. RESULTS: The 60-day VTE incidence was 5.2% (12 of 232); 33.3% occurred postdischarge (n = 4). Half (6 of 12) were pulmonary emboli, 1 of which caused a death, in an inpatient with a score of 16. The VTE incidence increased with Caprini score. Scores in the low, moderate, and high risk groups were associated with a VTE incidence of 0%, 1.7%, and 10.3%, respectively. With a high risk score cutoff of 9, the sensitivity, specificity, and accuracy are 83.3%, 60.5%, and 61.6%, respectively. CONCLUSIONS: One third of VTE events occurred after discharge. Postoperative VTE incidence was correlated with increasing Caprini scores. Patients in the high risk group had an incidence of 10.3%. Elevated scores may warrant extended chemoprophylaxis for patients after discharge.

Evaluation of the Caprini Model for Venothromboembolism in Esophagectomy Patients.

BACKGROUND: Patients undergoing esophagectomy for cancer are in the highest-risk group for venous thromboembolism, with a 7.3% incidence reported by the National Surgical Quality Improvement Program. Venothromboembolism (VTE) doubles esophagectomy mortality. The Caprini risk assessment model (RAM) is a method to stratify postoperative thromboembolism risk for consideration of prolonged preventive anticoagulation in higher-risk patients. Our aim was to examine the potential use of this model for reducing the VTE incidence in esophagectomy patients. METHODS: The records of patients who underwent an esophagectomy by the thoracic surgery service at our institution between June 2005 and June 2013 were reviewed. The inclusion criteria were a diagnosis of esophageal cancer treated with esophagectomy (any approach) and with available 60-day postoperative follow-up. Exclusion criteria were the presence of an inferior vena cava filter or chronic anticoagulation therapy. The Caprini risk score and the number of VTE events were recorded retrospectively for each patient. RESULTS: Seventy patients satisfied eligibility criteria. The VTE incidence was 14.3%. Patients with esophageal thromboembolism had a higher Caprini score distribution than patients without thromboembolism (p < 0.001). Adjusted logistic regression analysis demonstrated increased odds of VTE with increasing score (p < 0.05), with good discrimination. CONCLUSIONS: In this first report examining the Caprini model categories in an esophagectomy population, the VTE incidence in true high-risk patients was high. From this retrospective calculation of risk and events, patients in the highest-risk Caprini group may benefit from an enhanced course of postoperative anticoagulation.

Current innovations in sentinel lymph node mapping for the staging and treatment of resectable lung cancer.

Despite surgical resectability, early-stage lung cancer remains a challenge to cure. Survival outcomes are hindered by variable performance of adequate lymphadenectomy and the limitations of current pathologic nodal staging. Sentinel lymph node (SLN) mapping, a mainstay in the management of breast cancer and melanoma, permits targeted nodal sampling for efficient and accurate staging that can influence both intraoperative and adjuvant treatment decisions. Unfortunately, standard SLN identification techniques with blue dye and radiocolloid tracers have not been shown to be reproducible in lung cancer. In more recent years, intraoperative near-infrared image-guided lung SLN mapping has emerged as promising technology for the identification of the tumor-associated lymph nodes most likely to contain metastatic disease. Additionally, the clinical relevance of SLN mapping for lung cancer remains pressing, as the ability to identify micrometastatic disease in SLNs could facilitate trials to assess chemotherapeutic response and the clinical effect of occult nodal disease. This review outlines the status of lung cancer lymphatic mapping and techniques in development that may help close the gap between translational research in this field and routine clinical practice.

Requiring human papillomavirus vaccine for immigrant women.

The Centers for Disease Control and Prevention Advisory Committee on Immunization Practices recommends human papillomavirus (HPV) vaccination of 11- to 12-year-old girls, with catch-up vaccination for girls and women aged 13 to 26 years. Although compulsory HPV vaccination is not currently mandated for any U.S. population, immigrant women aged 11-26 years are now required to receive the first injection of the vaccine (the full series consists of three doses) as a result of the 1996 Illegal Immigration Reform and Immigrant Responsibility Act. According to this law, immigrants applying for visas to enter the United States or to adjust their immigration status must receive the inoculations that the Advisory Committee on Immunization Practices recommends for U.S. residents. In the case of HPV, this law represents not only an undue burden on immigrant women, but also raises scientific and ethical questions regarding the benefit of vaccination in this population. Given these issues, immigrant women should not be required to provide documentation of HPV vaccination at the time of visa application or adjustment of immigration status.