Consolidation Therapy in Esophageal Cancer.

Consolidation therapy describes dose intensification strategies or additional treatment performed following completion of the primary regimen. In the case of esophageal cancer, this applies to cases of potentially persistent disease after definitive multi-modality therapy, including surgery. Consolidation should also be considered for patients initially planned to undergo surgery after neoadjuvant therapy, but for any reason elected a nonoperative strategy during treatment. With the advent of targeted therapy and immunotherapy, additional options may be available for consolidation in the future.

Surgeons' Role in Local Palliation of Esophageal Cancer.

Esophageal cancer commonly presents in advanced stage, and many patients will require palliative intervention. Endoscopic stenting remains an excellent first-line therapy; however, this should be discussed in a multidisciplinary setting, considering expectations for long-term survival.

S100A4 alters metabolism and promotes invasion of lung cancer cells by up-regulating mitochondrial complex I protein NDUFS2.

It is generally accepted that alterations in metabolism are critical for the metastatic process; however, the mechanisms by which these metabolic changes are controlled by the major drivers of the metastatic process remain elusive. Here, we found that S100 calcium-binding protein A4 (S100A4), a major metastasis-promoting protein, confers metabolic plasticity to drive tumor invasion and metastasis of non-small cell lung cancer cells. Investigating how S100A4 regulates metabolism, we found that S100A4 depletion decreases oxygen consumption rates, mitochondrial activity, and ATP production and also shifts cell metabolism to higher glycolytic activity. We further identified that the 49-kDa mitochondrial complex I subunit NADH dehydrogenase (ubiquinone) Fe-S protein 2 (NDUFS2) is regulated in an S100A4-dependent manner and that S100A4 and NDUFS2 exhibit co-occurrence at significant levels in various cancer types as determined by database-driven analysis of genomes in clinical samples using cBioPortal for Cancer Genomics. Importantly, we noted that S100A4 or NDUFS2 silencing inhibits mitochondrial complex I activity, reduces cellular ATP level, decreases invasive capacity in three-dimensional growth, and dramatically decreases metastasis rates as well as tumor growth in vivo Finally, we provide evidence that cells depleted in S100A4 or NDUFS2 shift their metabolism toward glycolysis by up-regulating hexokinase expression and that suppressing S100A4 signaling sensitizes lung cancer cells to glycolysis inhibition. Our findings uncover a novel S100A4 function and highlight its importance in controlling NDUFS2 expression to regulate the plasticity of mitochondrial metabolism and thereby promote the invasive and metastatic capacity in lung cancer.

National Analysis of Unplanned Readmissions After Thoracoscopic Versus Open Lung Cancer Resection.

BACKGROUND: Hospital readmissions are viewed as a mark of inferior health care quality and are penalized. Unplanned postoperative readmission reason and timing after lung resection are not well understood. We examine related, unplanned readmissions after thoracoscopic versus open anatomic lung resections to identify opportunities to improve patient care. METHODS: We analyzed the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) data set, 2012 to 2015, characterizing 30-day related, unplanned postoperative readmissions after anatomic lung resections for primary lung cancer. Risk-adjusted comparison of readmission after thoracoscopic and open resection was performed using propensity matching. RESULTS: Patients (n = 9,510) underwent anatomic lung resections; 4,935 (51.9%) were thoracoscopic resections and 4,575 (48.1%) were open resections. Of the thoracoscopic patients, 10.9% experienced one or more complications, versus 19.4% of patients with open resection (p < 0.0001). Of the thoracoscopic patients 5.5% experienced related, unplanned readmissions versus 7.2% of the patients with open resection (p < 0.001). 24.8% of complications after thoracoscopic approach occurred after discharge, versus 15.5% after open approach (p < 0.0001). Timing of unplanned readmission was similar for both groups. The propensity-matched odds ratio of risk of readmission after thoracoscopic versus open resection was 1.16 (95% confidence interval, 0.949 to 1.411, p = 0.15). CONCLUSIONS: Open anatomic lung resections for primary lung cancer had nearly twice the complication rate but only a slightly higher readmission rate than thoracoscopic resection. More complications occurred after discharge after thoracoscopic than open resections. Most readmissions occurred within 2 weeks after both thoracoscopic and open resections. Risk-adjusted comparison identified no statistically significant difference in risk of related, unplanned readmission after thoracoscopic versus open resections. Future studies should focus on identification of processes of care to decrease complications and unplanned readmissions after lung cancer resection.

Failure to operate on resectable gastric cancer: implications for policy changes and regionalization.

BACKGROUND: A significant proportion of patients never receive curative-intent surgery for resectable gastric cancer (GC). The primary aims of this study were to identify disparities and targetable risk factors associated with failure to operate in the context of national trends in surgical rates for resectable GC. METHODS: The National Cancer Database was used to identify patients with resectable GC (adenocarcinoma, clinical stage IA-IIIC, 2004-2013). Multivariate modeling was used to identify predictors of resection and to analyze the impact of surgery on overall survival (OS). RESULTS: Of 46,970 patients with resectable GC, 18,085 (39%) did not receive an appropriate operation. Among unresected patients, 69% had no comorbidities. Failure to resect was associated with reduced median OS (44.4 versus 11.8 mo, hazard ratio [HR]: 2.09, P < 0.001). In the multivariate analysis, the most critical factors affecting OS were resection (HR: 2.09) and stage (reference IA; HR range: 1.16-3.50, stage IB-IIIC). Variables independently associated with no surgery included insurance other than private or Medicare (odds ratio [OR]: 1.60/1.54), nonacademic/nonresearch hospital (OR: 1.16), non-Asian race (OR: 1.72), male (OR: 1.19), older age (OR: 1.04), Charlson-Deyo score >1 (OR: 1.17), residing in areas with median income <$48,000 (OR: 1.23), small urban populations <20,000 (OR: 1.41), and stage (reference IA; OR range: 1.36-3.79, stage IB-IIIC, P < 0.001). CONCLUSIONS: Over one-third of patients with resectable GC fail to receive surgery. Suitable insurance coverage and treatment facility are the most salient (and only modifiable) risk factors for omitting surgery. To mitigate national disparities in surgical care, policymakers should consider improving insurance coverage in underserved areas and regionalization of gastric cancer care.

Emergent Minimally Invasive Esophagogastrectomy.

Introduction. Esophageal perforation in the setting of a malignancy carries a high morbidity and mortality. We describe our management of such a patient using minimally invasive approach. Methods. An 83-year-old female presented with an iatrogenic esophageal perforation during the workup of dysphagia. She was referred for surgical evaluation immediately after the event which occurred in the endoscopy suite. Minimally invasive esophagectomy was chosen to provide definitive treatment for both her malignancy and esophageal perforation. Results. Following an uncomplicated operative course, she was eventually discharged to extended care for rehabilitation and remains alive four years after her resection. Conclusion. Although traditional open techniques are the accepted gold standard of treatment for esophageal perforation, minimally invasive esophagectomy plays an important role in experienced hands and may be offered to such patients.

Video-Assisted Thoracoscopic versus Open Lobectomy: Costs and Outcomes.

OBJECTIVES: Video-assisted thoracoscopic (VATS) lobectomy is considered a promising surgical therapy for the diagnosis and treatment of non-small-cell lung carcinoma. The issue of whether VATS is superior to open thoracotomy remains controversial, however. We sought to determine whether the use of VATS lobectomy for diagnosing and treating non-small-cell lung carcinoma would improve patient outcomes at our institution. METHODS: A retrospective review of electronic and paper medical charts identified 109 consecutive operations for all patients undergoing thoracotomy or VATS lobectomy performed at the University of Kentucky Chandler Medical Center for fiscal years 2013 and 2014. Variables of interest included operative procedure (thoracotomy vs VATS) and operative findings (pathologic stage, operative time, postoperative length of stay [LOS], time spent in the intensive care unit, postoperative complications, direct cost). RESULTS: The demographic characteristics of the patients of both groups were similar in terms of sex (64.6% vs 44.3% male) and age (62.4 vs 61.6 years), but not stage, which was higher in the thoracotomy group. The overall operative procedure time (170.6 vs 196.3 minutes), postoperative LOS (5.7 vs 5.5 days), number of lymph nodes sampled (6.2 vs 7.0), and time spent in the intensive care unit (2.1 vs 2.4 days) did not vary between both groups. The average cost per procedure did not vary significantly-$14,003.61 compared with $15,588.11 for thoracotomy and VATS, respectively. CONCLUSIONS: In our study, the VATS group was associated with no reduction in postoperative LOS and a nonsignificant reduction in the amount of time spent in the intensive care unit. Postoperative perception of pain did not vary between either group. Pain perception did, however, correlate strongly with time from operation. Cost did not vary significantly between both groups, with VATS being equivalent to thoracotomy in terms of cost at our institution. In our experience, VATS is an effective, minimally invasive, and safe approach for the resection of lung nodules.

Distinctly perturbed metabolic networks underlie differential tumor tissue damages induced by immune modulator ß-glucan in a two-case ex vivo non-small-cell lung cancer study.

Cancer and stromal cell metabolism is important for understanding tumor development, which highly depends on the tumor microenvironment (TME). Cell or animal models cannot recapitulate the human TME. We have developed an ex vivo paired cancerous (CA) and noncancerous (NC) human lung tissue approach to explore cancer and stromal cell metabolism in the native human TME. This approach enabled full control of experimental parameters and acquisition of individual patient's target tissue response to therapeutic agents while eliminating interferences from genetic and physiological variations. In this two-case study of non-small-cell lung cancer, we performed stable isotope-resolved metabolomic (SIRM) experiments on paired CA and NC lung tissues treated with a macrophage activator ß-glucan and (13)C6-glucose, followed by ion chromatography-Fourier transform mass spectrometry (IC-FTMS) and nuclear magnetic resonance (NMR) analyses of (13)C-labeling patterns of metabolites. We demonstrated that CA lung tissue slices were metabolically more active than their NC counterparts, which recapitulated the metabolic reprogramming in CA lung tissues observed in vivo. We showed ß-glucan-enhanced glycolysis, Krebs cycle, pentose phosphate pathway, antioxidant production, and itaconate buildup in patient UK021 with chronic obstructive pulmonary disease (COPD) and an abundance of tumor-associated macrophages (TAMs) but not in UK049 with no COPD and much less macrophage infiltration. This metabolic response of UK021 tissues was accompanied by reduced mitotic index, increased necrosis, and enhaced inducible nitric oxide synthase (iNOS) expression. We surmise that the reprogrammed networks could reflect ß-glucan M1 polarization of human macrophages. This case study presents a unique opportunity for investigating metabolic responses of human macrophages to immune modulators in their native microenvironment on an individual patient basis.

Impact of Residents on Surgical Outcomes in High-Complexity Procedures.

BACKGROUND: There are different views on the effects of resident involvement on surgical outcomes. We hypothesized that resident participation in surgical care does not appreciably alter outcomes. STUDY DESIGN: We analyzed an American College of Surgeons NSQIP subset of inpatients having procedures with high complexity, including 4 surgical specialties (general surgery, cardiothoracic surgery, neurosurgery, and vascular surgery) with the highest mean work relative value units. We evaluated surgical outcomes in patients having procedures performed by the attending surgeon alone, or by the attending surgeon with assistance from at least one surgical resident (PGY1 to PGY≥6). Outcomes measures included operative mortality, composite morbidity, and failure to rescue (FTR). Propensity-score matching minimized the effects of nonrandom assignment of residents to procedures. RESULTS: In 266,411 patients, unmatched comparisons showed significantly higher operative mortality and composite morbidity rates, but decreased FTR, in operations performed with resident involvement. After propensity-score matching, there were small but significant resident-related increases in composite morbidity, but significant improvement in FTR. Senior-level resident involvement translated into improved outcomes, especially in cardiothoracic surgery procedures where >63.6% of procedures had PGY≥6 resident involvement. Resident involvement attenuated the significant worsening of operative mortality and FTR associated with multiple serious complications in individual patients. Measures of resource use increased modestly with resident involvement. CONCLUSIONS: We found substantial improvement in FTR with resident involvement, both in unmatched and propensity-matched comparisons. Senior-level resident participation seemed to attenuate, and even improve, surgical outcomes, despite slightly increased resource use. These results provide some reassurance about teaching paradigms.

Venous Thromboembolism Prophylaxis For Esophagectomy: A Survey of Practice Patterns Among Thoracic Surgeons.

BACKGROUND: Current guidelines for gastrointestinal cancer surgical intervention in high-risk patients recommend postoperative venous thromboembolism (VTE) chemical prophylaxis for 4 weeks with low-dose unfractionated heparin or low-molecular-weight heparin, but specific guidelines for esophagectomy are lacking. This survey identified the clinical patterns affecting postesophagectomy VTE chemoprophylaxis use among general thoracic surgeons. METHODS: General Thoracic Surgery Club members were invited to complete an online survey on VTE prophylaxis to analyze clinical factors affecting their choices. RESULTS: Seventy-seven surgeons (37% membership) responded; of these, 94% (72 of 77) completed fellowships, and 76% (58 of 77) worked at universities. VTE chemoprophylaxis administration varied widely in drug, dosing, and duration, with 30% using suboptimal dosing of unfractionated heparin (every 12 hours). Participants agreed that esophagectomy patients are at high VTE risk, yet 29% (22 of 76) of surgeons delay VTE chemoprophylaxis until postoperative day 1. Only 13% (10 of 77) prescribe postdischarge chemoprophylaxis. Minimally invasive surgeons (>90% of cases) were more likely to prescribe postdischarge prophylaxis (p = 0.007). Epidurals, routinely used by 65% (51 of 78), led to less compliance with recommended dosing. Only 53% (27 of 51) of pain teams allow unfractionated heparin every 8 hours, yet 73% (37 of 51) allow suboptimal dosing (every 12 h). Postoperative major complications were identified as a VTE risk factor by only 21% (15 of 72) of surgeons. Most (92% [68 of 74]) would follow esophagectomy-specific guidelines, if developed. CONCLUSIONS: Thoracic surgeons agree that VTE chemoprophylaxis is necessary for esophagectomy, yet substantial variability exists in current practice. A noteworthy proportion use suboptimal dosing, and very few choose postdischarge prophylaxis. To improve postesophagectomy morbidity and mortality outcomes, thoracic surgeons are willing to follow evidence-based guidelines for VTE chemoprophylaxis.

Laparoscopic Robot-Assisted Diaphragm Plication.

Minimally invasive approaches to diaphragm plication for eventration include thoracoscopic and laparoscopic techniques. The elevated hemidiaphragm and ribs limit thoracoscopic techniques. We report our modification of the laparoscopic approach using robotic assistance with the da Vinci Surgical System, (Intuitive Surgical Inc, Sunnyvale, CA) to avoid single-lung ventilation, facilitate exposure, and allow more precise placement of plication sutures to achieve an even tension and maximum plication. Critical steps include creation of a small defect in the diaphragm to equalize pressures between cavities and placement of multiple, pledgeted interrupted horizontal mattresses.

Nodal Upstaging During Lung Cancer Resection Is Associated With Surgical Approach.

BACKGROUND: Recent reports indicate that thoracoscopic lobectomy for lung cancer may be associated with lower rates of surgical upstaging. We queried a statewide cancer registry for differences in upstaging rates and survival by surgical approach. METHODS: The Kentucky Cancer Registry (KCR) collects data, including centralized pathology reporting, on cancer patients treated statewide. We performed a retrospective review from 2010 to 2012 to examine clinical and pathologic stage. We assessed rates of upstaging and whether the surgical approach, thoracotomy (THOR) versus minimally invasive techniques (video-assisted thoracic surgery; VATS), had an impact on final pathologic stage and survival. RESULTS: The KCR database from 2010 to 2012 contained information on 2830 lung cancer cases, 1964 having THOR procedure and 500 having VATS resections. Preoperatively, 36.4% of THOR were clinically stage 1a versus 47.4% VATS (p = 0.0002). Of these, final pathologic stage remained stage 1a in 30.5% of THOR procedures and 38.0% of VATS (p = 0.0002). The overall nodal upstaging rate for THOR was 9.9% and 4.8% for VATS (p = 0.002). Decreased nodal upstaging was found with VATS, independent of tumor size and extent of resection (odds ratio 0.6, 95% confidence interval [CI]: 0.387 to 0.985, p = 0.04). However, improved survival was found with VATS compared with THOR (hazard ratio 0.733, 95% CI: 0.592 to 0.907, p = 0.0042). CONCLUSIONS: Consistent with other reports, we report a lower upstaging rate with VATS. Nevertheless, there is a survival advantage in VATS patients. Although selection bias may play a role in these observed differences, the improved quality of life measures associated with VATS may explain survival improvement despite lower surgical upstaging.

Blood Conservation.

Patient blood management requires multi-modality and multidisciplinary collaboration to identify patients who are at increased risk of requiring blood transfusion and therefore decrease exposure to blood products. Transfusion is associated with poor postoperative outcomes, and guidelines exist to minimize transfusion requirements. This review highlights recent studies and efforts to apply patient blood management across disease processes and health care systems.

Endobronchial Valves in the Treatment of Persistent Air Leaks.

BACKGROUND: Endobronchial valves (EBVs) are a useful adjunct in the management algorithm of patients with persistent pulmonary air leaks. They are increasingly used in the management of postsurgical parenchymal air leaks and carry a humanitarian use device exemption for this purpose. We report our experience with EBVs in the management of patients with bronchopleural fistula secondary to postsurgical intervention and spontaneous pneumothorax from medical comorbidities. METHODS: An institutional review board-approved retrospective review was conducted of our single-center EBV experience. Patients were categorized as postsurgical versus medical. Data collected included demographic characteristics, indication for and number of valves placed, and chest tube duration before and after valve placement to evaluate overall resolution of air leak. Success was defined as resolution of air leak. RESULTS: A total of 14 valve placement procedures were performed. Mean age was 60 years and 10 patients were men. Eight represented prolonged leaks secondary to postsurgical complications and six were secondary to medical comorbidities. Indications for placement of valves in medical patients included persistent leak secondary to lung biopsy, ruptured bleb disease, and pneumothorax after cardiopulmonary resuscitation. Postsurgical indications included leaks secondary to lung biopsy, lobectomy, and ruptured bleb disease. A median of two valves were placed per procedure. A postprocedure median length of stay of 14.5 days was observed in the surgical group compared with 15 days in the medical group. Overall success rate was 57% (surgical group, 62.5%; medical group, 50%). CONCLUSIONS: EBVs are a useful adjunct in the management of persistent pulmonary air leaks, particularly when conventional interventions are contraindicated or not ideal. EBVs are well tolerated in the critically ill, have few known complications, are removable, and do not preclude future surgical intervention. Future studies should evaluate EBV efficacy versus the natural course of persistent pulmonary air leaks and their impact on cost and length of stay.

Increased morbidity and mortality of a concomitant colectomy during a pancreaticoduodenectomy: an NSQIP propensity-score matched analysis.

BACKGROUND: Select patients with peri-ampullary cancers require concomitant colon resection (CR) during a pancreaticoduodenectomy (PD) for margin-negative resections. This study analysed the impact of concomitant CR on major morbidity (MM) and mortality. METHODS: National Surgical Quality Improvement Program (NSQIP) patients undergoing PD for peri-ampullary cancers were identified from 2005 to 2012. A 4 : 1 propensity-score matched analysis isolated the impact of CR upon PD. Risk factors for 30-day MM and mortality were analysed to determine post-operative sequelae of PD+CR. RESULTS: From 10 965 PD and 159 PD+CR patients, 624 and 156, respectively, were selected for 4 : 1 matched analysis. PD+CR resulted in a higher MM and mortality (50.0% and 9.0%) versus PD alone (28.8% and 2.9%, respectively, P < 0.001). Multivariate analysis identified risk factors for MM after PD: concomitant CR [odds ratio (OR)-3.19, P < 0.001], smoking (OR-1.92, P = 0.005), a lack of functional independence (OR-3.29, P = 0.018), cardiac disease (OR-2.39, P = 0.011), decreased albumin (per g/dl, OR-1.38, P = 0.033) and a longer operative time (versus median time, OR-1.56, P = 0.029). Independent predictors of mortality included concomitant CR (OR-3.16, P = 0.010), ventilator dependence (OR-13.87, P < 0.001) and septic shock (OR-6.02, P < 0.001). CONCLUSIONS: CR was an independent predictor of MM and mortality after a PD. Patients requiring PD+CR should be identified pre-operatively, maximally optimized and referred to experienced surgeons at expert centres.

Identifying Esophagectomy Patients at Risk for Predischarge Versus Postdischarge Venous Thromboembolism.

BACKGROUND: Current guidelines recommend postoperative venous thromboembolism (VTE) chemoprophylaxis for moderate-risk patients (3% rate or greater) and extended-duration chemoprophylaxis for high-risk patients (6% or greater). Large-scale studies of and recommendations for esophagectomy patients are lacking. This study was designed to evaluate the timing, rates, and predictors of postesophagectomy VTE. METHODS: Patients undergoing esophagectomies for cancer were identified from the 2005 to 2012 American College of Surgeons National Surgical Quality Improvement database. Timing and rates of VTE (deep venous thrombosis or pulmonary embolism, or both) were calculated. Events were stratified as predischarge or postdischarge. Perioperative factors associated with 30-day rates of predischarge and postdischarge VTE were analyzed. RESULTS: Of 3,208 patients analyzed, the surgical approach was Ivor-Lewis (n = 1,131, 35.3%), transhiatal (n = 945, 29.5%), three-field (n = 587, 18.3%), thoracoabdominal (n = 364, 11.3%), and nongastric conduit reconstruction (n = 181, 5.6%). Rates were 2.0% pulmonary embolism, 3.7% deep venous thrombosis, and 5.1% VTE. Overall median length of stay was 11 days (versus 19 days, p < 0.001, if predischarge VTE). Predischarge VTE occurred on median day 9, whereas postdischarge VTE occurred on day 19 (p < 0.001). Only 17% of VTE occurred after discharge. Multivariate analysis identified being male (odds ratio [OR] 2.09, p = 0.018), white race (OR 1.93, p = 0.004), prolonged ventilation (OR 3.24, p < 0.001), and other major complications (OR 1.90, p = 0.005) as independent predictors of predischarge VTE. Older age (OR 1.06 per year, p = 0.006) and major complications (OR 3.14, p = 0.004) were independently associated with postdischarge VTE. CONCLUSIONS: Postesophagectomy VTE occurs in a clinically significant proportion of esophageal cancer patients with identifiable risk factors for predischarge and postdischarge events. Elderly patients and patients with major complications are most likely to benefit from extended-duration chemoprophylaxis.