Rapid cancer cell perineural invasion utilizes amoeboid migration.

The invasion of nerves by cancer cells, or perineural invasion (PNI), is potentiated by the nerve microenvironment and is associated with adverse clinical outcomes. However, the cancer cell characteristics that enable PNI are poorly defined. Here, we generated cell lines enriched for a rapid neuroinvasive phenotype by serially passaging pancreatic cancer cells in a murine sciatic nerve model of PNI. Cancer cells isolated from the leading edge of nerve invasion showed a progressively increasing nerve invasion velocity with higher passage number. Transcriptome analysis revealed an upregulation of proteins involving the plasma membrane, cell leading edge, and cell movement in the leading neuroinvasive cells. Leading cells progressively became round and blebbed, lost focal adhesions and filipodia, and transitioned from a mesenchymal to amoeboid phenotype. Leading cells acquired an increased ability to migrate through microchannel constrictions and associated more with dorsal root ganglia than nonleading cells. ROCK inhibition reverted leading cells from an amoeboid to mesenchymal phenotype, reduced migration through microchannel constrictions, reduced neurite association, and reduced PNI in a murine sciatic nerve model. Cancer cells with rapid PNI exhibit an amoeboid phenotype, highlighting the plasticity of cancer migration mode in enabling rapid nerve invasion.

Relative Survival With Early-Stage Breast Cancer in Screened and Unscreened Populations.

Relative survival and disease-specific survival are two statistics that measure net survival from a cancer diagnosis, excluding other causes of death. In most cases, these two rates are comparable. However, in some cancer types for which cancer screening is performed, relative survival is often greater than disease-specific survival. This divergence has been attributed to mechanisms such as the "healthy user effect" and overdiagnosis of indolent tumors detected by screening. Using relative survival rate as a marker of these mechanisms, we examined the association of breast cancer screening with relative survival rates for women diagnosed with early-stage breast cancer. In population-based data from the National Cancer Institute's Surveillance, Epidemiology and End Results registry, we examined relative survival rates in women diagnosed with stage I breast cancer or ductal carcinoma in situ who were in highly screened vs less-highly screened groups, based on time period, age group, and insurance status. In this analysis, relative survival rates for early-stage breast cancer were higher than disease-specific survival, even exceeding 100% in populations experiencing higher rates of screening (ie, women diagnosed during the era of widespread uptake of mammography, age older than 40 years, and women with health insurance coverage). The favorable outcomes observed in screen-detected breast cancers are at least in part attributable to the healthy user effect and overdiagnosis of indolent tumors. Therefore, survival rates may not accurately reflect the effectiveness of cancer screening. These findings have implications for counseling of patients and future clinical studies of active monitoring approaches in breast cancer.

Reprogrammed Schwann Cells Organize into Dynamic Tracks that Promote Pancreatic Cancer Invasion.

Nerves are a component of the tumor microenvironment contributing to cancer progression, but the role of cells from nerves in facilitating cancer invasion remains poorly understood. Here we show that Schwann cells (SC) activated by cancer cells collectively function as tumor-activated Schwann cell tracks (TAST) that promote cancer cell migration and invasion. Nonmyelinating SCs form TASTs and have cell gene expression signatures that correlate with diminished survival in patients with pancreatic ductal adenocarcinoma. In TASTs, dynamic SCs form tracks that serve as cancer pathways and apply forces on cancer cells to enhance cancer motility. These SCs are activated by c-Jun, analogous to their reprogramming during nerve repair. This study reveals a mechanism of cancer cell invasion that co-opts a wound repair process and exploits the ability of SCs to collectively organize into tracks. These findings establish a novel paradigm of how cancer cells spread and reveal therapeutic opportunities. SIGNIFICANCE: How the tumor microenvironment participates in pancreatic cancer progression is not fully understood. Here, we show that SCs are activated by cancer cells and collectively organize into tracks that dynamically enable cancer invasion in a c-Jun-dependent manner. See related commentary by Amit and Maitra, p. 2240. This article is highlighted in the In This Issue feature, p. 2221.

Initial management of esophageal anastomotic strictures after transhiatal esophagectomy for esophageal cancer with dilations up to 18-20 mm.

INTRODUCTION: Esophageal anastomotic stricture is a well-known complication after transhiatal esophagectomy (THE), but there is limited data regarding the initial management and subsequent outcomes after stricture dilation. There is concern that dilating to larger diameters upon the initial encounter, specifically with high-grade strictures, will lead to increased risk for complications. We therefore reviewed one surgeon's experience with esophageal dilations after THE and provided data and treatment recommendations based upon these findings. METHODS: A retrospective review of patients who underwent esophageal dilations ≥ 18 mm up to 20 mm after THE between 2006 and 2019 at our institution was performed. Patient demographics were n = 97, age = 70, 81 males. RESULTS: For all cases, the mean location, length, diameter of the stricture, and number of days from surgery and initial dilation were 20 cm, 1.9 cm, 6.7 mm, and 106 days, respectively. Most dilations (79%) occurred within 2 weeks to 3 months from surgery. 29.9% were dilated up to 18 mm, 10.3% were dilated up to 19 mm, and 59.8% were dilated up to 20 mm upon initial dilation. Even 1-mm-diameter lesions could be safely dilated upon 18-20 mm. In this study group there were no complications after endoscopic dilation that required hospitalization or further surgical or endoscopic interventions. CONCLUSION: These results suggest that early aggressive endoscopic management of esophageal anastomotic strictures after THE can be safely performed.

Racial Disparities in Cancer Presentation and Outcomes: The Contribution of Overdiagnosis.

BACKGROUND: Racial disparities in cancer have been attributed to population differences in access to care. Differences in cancer overdiagnosis rates are another, less commonly considered cause of disparities. Here, we examine the contribution of overdiagnosis to observed racial disparities in papillary thyroid cancer and estrogen/progesterone receptor positive (ER/PR+) breast cancer. METHODS: We used Surveillance, Epidemiology, End-Results (SEER) 13 for analysis of white and black non-Hispanic persons with papillary thyroid cancer or ER/PR+ breast cancer (1992-2014). Analyses were performed using SeerStat (v8.3.5, March 2018). All statistical tests were two-sided. RESULTS: White persons had higher incidence of papillary thyroid cancer than black persons (14.3 vs 7.7 cases per 100 000 age-adjusted population) and ER/PR+ breast cancer (94.8 vs 70.9 cases per 100 000 age-adjusted population) (P < .001). In papillary thyroid cancer, the entire incidence difference was from more frequent diagnosis of 2-cm or less (10.0 vs 4.9 cases per 100 000 population) and localized or regional (13.8 vs 7.4 cases per 100 000 population) cancers in white persons (P < .001), without corresponding excess of metastatic disease, cancers greater than 4 cm, or incidence-based mortality in black persons. In women with ER/PR+ breast cancer, 95% of the incidence difference was from more 2-cm or less (61.2 vs 38.1 cases per 100 000 population) or 2.1- to 5-cm (25.4 vs 23.4 cases per 100 000 population), localized (65.1 vs 43.0 cases per 100 000 population) cancers diagnosed in white women (P < .001), with slightly higher incidence of tumors greater than 5 cm (10.1 vs 9.3 cases per 100 000 population, P < .001) and incidence-based mortality (8.1 vs 7.2 cases per 100 000 population, P < .001) among black women. Overall, 20-30 additional small or localized ER/PR+ breast cancers were diagnosed in white compared with black women for every large or advanced tumor avoided by early detection. Overdiagnosis was estimated 1.3-2.5 times (papillary thyroid cancer) and 1.7-5.7 times (ER/PR+ breast cancer) higher in white compared with black populations. CONCLUSIONS: Differences in low-risk cancer identification among populations lead to overestimation of racial disparities. Estimates of overdiagnosed cases should be considered to improve care and eliminate disparities while minimizing harms of overdiagnosis.

Airway management, symptom relief and best supportive care in anaplastic thyroid cancer.

PURPOSE OF REVIEW: Anaplastic thyroid cancer (ATC) is a rare but aggressive form of thyroid cancer that is associated with significant morbidity and mortality. Because ATC is locally invasive, airway management is a critical component of treating these patients. Timely decisions regarding airway interventions can contribute to symptom relief and supportive care for patients. Over the last decade, there has been a paradigm shift in our recommendations for airway management. The purpose of this review is to summarize airway management, symptom relief and best supportive care for patients with ATC. RECENT FINDINGS: More recent literature discusses the morbidities associated with tracheostomy and instead focuses on the benefits of supportive care and surgical resection. The multidisciplinary treating team should initiate early discussions for airway management, end-of-life care and palliative goals for patients with ATC. Tracheostomy should be offered to patients with careful thought and preoperative planning. SUMMARY: Our goal in symptom relief and airway management is to improve the quality of life of patients with ATC and avoid the unnecessary morbidity of tracheostomy until clinically indicated.

Case distributions in general surgery residency: Subspecialization occurs before fellowship.

BACKGROUND: In the era of subspecialization and duty-hour restrictions, many General Surgery residents desire additional training in their future subspecialty areas. This study examines the relationship between case distributions performed by General Surgery residents and their chosen future subspecialty. METHODS: A retrospective review of Accreditation Council for Graduate Medical Education case logs of 101 graduated General Surgery residents at a single academic institution (2002-2018) was performed. The total number of operative cases performed during General Surgery residency overall and in Accreditation Council for Graduate Medical Education-defined categories were compared between residents with differing areas of future subspecialization. RESULTS: Residents pursuing surgical fellowships in Endocrine, Cardiothoracic, Vascular, and Trauma/Critical Care Surgery logged respectively more endocrine (63 [11] vs 32 [13]; P < .001), thoracic (61 [15] vs 41 [13]; P < .001), vascular (225 [38] vs 162 [38]; P < .001), and operative trauma (83 [29] vs 71 [25]; P = .045) cases, compared with program average. Residents pursuing General Surgery (no fellowship) performed significantly more endoscopies (131 [47] vs 105 [28]; P = .029) than peers. Residents pursuing Breast, Oncology, Colorectal, and Pediatric Surgery fellowships performed numerically (non-significantly) more breast (94 [16] vs 78 [20]; P = .180), liver/pancreas (39 [3.1] vs 33 [8.0]; P = .173), large intestinal (132 [30] vs 125 [24]; P = .507), and pediatric (173 [27] vs 155 [37]; P = .832) cases, respectively, compared with peers. The majority of these additional cases were performed in postgraduate years 3 to 5. CONCLUSION: In this single-institution study, many General Surgery residents perform more cases than peers in respective areas of future subspecialization. This may reflect residents at the reporting institution, and similar large, university-based programs seeking focused training in preparation for fellowship while still meeting case-volume minimums in all Accreditation Council for Graduate Medical Education-defined categories.

Additional 20-Minute Intraoperative Parathormone Measurement Can Minimize Unnecessary Bilateral Neck Exploration.

BACKGROUND: Parathyroidectomy guided by intraoperative parathormone (ioPTH) monitoring for primary hyperparathyroidism (pHPT) confirms removal of all hyperfunctioning parathyroid glands. This study evaluates the utility of an additional 20-min ioPTH measurement in patients who fail to meet the >50% ioPTH drop criterion. METHODS: A retrospective review of prospectively collected data of 706 patients with pHPT who underwent parathyroidectomy guided by ioPTH monitoring was performed. When a >50% ioPTH decrease from the highest either preincision or preexcision level was achieved after 10 min, parathyroidectomy was completed. If this criterion was not met, further exploration was performed or an additional 20-min ioPTH measurement was obtained. RESULTS: Of 706 patients, 72 (10%) patients did not meet the >50% ioPTH drop criterion at 10 min. Of these patients, 67% (48/72) underwent immediate bilateral neck exploration (BNE). For the other 33% of patients (24/72), a 20-min parathormone (PTH) measurement was drawn. Of patients with an additional 20-min PTH measurement, 46% (11/24) had a >50% ioPTH decrease at 20 min where BNE was avoided and parathyroidectomy completed, whereas 54% (13/24) did not. Compared to patients with insufficient ioPTH drop at 10 min and subsequent BNE, there was a statistically significant 46% reduction of BNE in patients with a 20-min PTH level (P < 0.01). CONCLUSIONS: A 20-min ioPTH measurement is useful in preventing unnecessary BNE in some patients who undergo focused parathyroidectomy with a delayed >50% ioPTH drop.

Interinstitutional variation in predictive value of the ThyroSeq v2 genomic classifier for cytologically indeterminate thyroid nodules.

BACKGROUND: The ThyroSeq v2 next-generation sequencing assay estimates the probability of malignancy in indeterminate thyroid nodules. Its diagnostic accuracy in different practice settings and patient populations is not well understood. METHODS: We analyzed 273 Bethesda III/IV indeterminate thyroid nodules evaluated with ThyroSeq at 4 institutions: 2 comprehensive cancer centers (n = 98 and 102), a multicenter health care system (n = 60), and an academic medical center (n = 13). The positive and negative predictive values of ThyroSeq and distribution of final pathologic diagnoses were analyzed and compared with values predicted by Bayes theorem. RESULTS: Across 4 institutions, the positive predictive value was 35% (22%-43%) and negative predictive value was 93% (88%-100%). Predictive values correlated closely with Bayes theorem estimates (r2 = 0.84), although positive predictive values were lower than expected. RAS mutations were the most common molecular alteration. Among 84 RAS-mutated nodules, malignancy risk was variable (25%, range 10%-37%) and distribution of benign diagnoses differed across institutions (adenoma/hyperplasia 12%-85%, noninvasive follicular thyroid neoplasm with papillary-like nuclear features 5%-46%). CONCLUSION: In a multi-institutional analysis, ThyroSeq positive predictive values were variable and lower than expected. This is attributable to differences in the prevalence of malignancy and variability in pathologist interpretations of noninvasive tumors. It is important that clinicians understand ThyroSeq performance in their practice setting when evaluating these results.

Robotic duodeno-duodenostomy creation in a pediatric patient with idiopathic duodenal stricture.

Duodenal stenosis is one of the leading causes of duodenal obstruction in the pediatric population, usually diagnosed in newborns and in Down syndrome patients. It has historically been treated with duodeno-duodenostomy, an operation that is now commonly performed laparoscopically. We present a case of a 10-year-old child with a rare chromosomal abnormality who was diagnosed with a duodenal stricture after presenting with failure to thrive and inability to tolerate tube feeds. Duodeno-duodenostomy was performed using the da Vinci® robot, allowing for improved intra-operative range of motion and control during anastomosis creation, with the same cosmetic benefits of laparoscopic surgery, and subsequent improvement in symptoms postoperatively. This case highlights the utility of robotic surgery in complex operations in the pediatric population.

Better ABSITE performance with increased operative case load during surgical residency.

BACKGROUND: Common measures of evaluating surgical resident progression include American Board of Surgery In-Training Exam scores and Accreditation Council for Graduate Medical Education operative case logs. This study evaluates the relationship between operative cases performed and American Board of Surgery In-Training Exam scores in general surgery residents. METHODS: A retrospective review of American Board of Surgery In-Training Exam scores and operative case logs was performed for postgraduate year 1-5 general surgery residents at a single academic institution (2008-2017). For each resident, the total number of operative cases logged from the start of their postgraduate year 1 until the end of each academic year was calculated and compared to their American Board of Surgery In-Training Exam scores for that corresponding year. RESULTS: At all postgraduate-year levels, there was a positive linear relationship between the number of cases logged and American Board of Surgery In-Training Exam percentile (slope, m = 0.23-5.2, R2 .01-.17) and scaled (m = 0.29-5.3, R2 .13-.37) scores. At the postgraduate year 1, 2, 3, and 5 levels, and with all residents combined, residents in the top quartile of cases logged performed significantly better on the American Board of Surgery In-Training Exam than those in the bottom quartile (P < .05). CONCLUSION: Surgical residents who perform more operative cases do significantly better on the American Board of Surgery In-Training Exam than their peers. This association may be due to increased clinical experience, exposure to pathology, and/or individual resident motivation.

An In Vivo Murine Sciatic Nerve Model of Perineural Invasion.

Cancer cells invade nerves through a process termed perineural invasion (PNI), in which cancer cells proliferate and migrate in the nerve microenvironment. This type of invasion is exhibited by a variety of cancer types, and very frequently is found in pancreatic cancer. The microscopic size of nerve fibers within mouse pancreas renders the study of PNI difficult in orthotopic murine models. Here, we describe a heterotopic in vivo model of PNI, where we inject syngeneic pancreatic cancer cell line Panc02-H7 into the murine sciatic nerve. In this model, sciatic nerves of anesthetized mice are exposed and injected with cancer cells. The cancer cells invade in the nerves proximally toward the spinal cord from the point of injection. The invaded sciatic nerves are then extracted and processed with OCT for frozen sectioning. H&E and immunofluorescence staining of these sections allow quantification of both the degree of invasion and changes in protein expression. This model can be applied to a variety of studies on PNI given its versatility. Using mice with different genetic modifications and/or different types of cancer cells allows for investigation of the cellular and molecular mechanisms of PNI and for different cancer types. Furthermore, the effects of therapeutic agents on nerve invasion can be studied by applying treatment to these mice.

Successful parathyroidectomy guided by intraoperative parathyroid hormone monitoring for primary hyperparathyroidism is preserved in mild and moderate renal insufficiency.

BACKGROUND: The effect of altered parathyroid hormone metabolism in renal insufficiency on intraoperative parathyroid hormone monitoring during parathyroidectomy is not well known. This study evaluates operative outcomes in patients undergoing parathyroidectomy guided by intraoperative parathyroid hormone monitoring for primary hyperparathyroidism with mild and moderate renal insufficiency. METHODS: A retrospective review of prospectively collected data in 604 patients with sporadic primary hyperparathyroidism undergoing parathyroidectomy guided by intraoperative parathyroid hormone monitoring was performed. Patients were stratified by stage of chronic kidney disease (CKD); those with overt secondary hyperparathyroidism (CKD stages IV and V) were excluded. Rates of bilateral neck exploration, multiglandular disease, and long-term operative outcomes, including success, failure, and recurrence were compared. RESULTS: Of the 604 patients, 38% (230/604) had normal renal function or stage I CKD, 44% (268/604) had stage II CKD, and 18% (106/604) had stage III CKD. Overall, there were no differences in the rates of bilateral neck exploration or multiglandular disease or in rates of operative success, failure, or recurrence in patients with normal renal function and stages I to III CKD. CONCLUSION: Parathyroidectomy guided by intraoperative parathyroid hormone monitoring is performed with high operative success uniformly in primary hyperparathyroidism patients with mild and moderate renal insufficiency with outcomes similar to those with normal renal function.

Intraoperative parathormone spikes during parathyroidectomy may be associated with multiglandular disease.

BACKGROUND: The importance of intraoperative parathormone "spikes" during parathyroidectomy remains unclear. This study compared patients with and without intraoperative parathormone spikes during parathyroidectomy using the criterion of a > 50% parathormone and determined the effect of intraoperative parathormone spikes on operative outcome. METHODS: We performed a retrospective review of prospectively collected data on 683 patients who underwent parathyroidectomy guided by intraoperative parathormone monitoring. An intraoperative parathormone "spike value" was calculated by subtracting the preincision intraoperative parathormone value from the pre-excision intraoperative parathormone value (SV = PE - PI). An intraoperative parathormone spike was defined as having a positive spike value ≥9 pg/mL (≥10th percentile of all spike values). RESULTS: Of 683 patients, 224 (33%) had intraoperative parathormone spikes and a greater rate of multiglandular disease (8% vs. 3%, P < 0.05) and bilateral neck exploration (10% vs. 5%, P < 0.05) compared with patients without intraoperative parathormone spikes. Overall, there were no differences between parathyroidectomy patients with and without intraoperative parathormone spikes in terms of operative success (98.2% vs. 98.0%), failure (1.8% vs. 2.0%), or recurrence rates (0.4% vs. 1.3%). CONCLUSIONS: Although the presence of intraoperative parathormone spikes may increase suspicion for multiglandular disease, the ability of intraoperative parathormone monitoring to predict operative success after parathyroidectomy is not affected by spikes.

High perioperative morbidity and mortality in patients with malignant nonfunctional adrenal tumors.

BACKGROUND: Both functional (hormone hypersecreting) and nonfunctional (nonhypersecreting) adrenal tumors can have benign or malignant pathology. This study compares perioperative in-hospital outcomes after adrenalectomy in patients with benign versus malignant nonfunctional primary adrenal tumors. METHODS: A retrospective cross-sectional analysis was performed using the Nationwide Inpatient Sample database (2006-2011) to identify patients who underwent unilateral open or laparoscopic adrenalectomy for nonfunctional primary adrenal tumors. Patients were subdivided by benign and malignant final pathology. Demographics, comorbidities, and perioperative complications were compared between groups using bivariate and multivariate logistic regression. RESULTS: Of 23,297 patients, 89.7% (n = 20,897) had benign tumors, whereas 10.3% (n = 2400) had malignant tumors. Those with malignant tumors had higher Charlson Comorbidity Index scores and were more likely to undergo adrenalectomy at high volume centers. For both laparoscopic and open approach, patients with malignant nonfunctional tumors had higher rates of intraoperative complications including vascular and splenic injury (P < 0.01), as well as postoperative complications including hematoma, shock, acute kidney injury, venous thromboembolism, and pneumothorax (P < 0.01). In addition, the malignant group had higher rates of blood transfusions, longer hospital stay, and higher in-hospital mortality (P < 0.05) than benign counterparts. On risk-adjusted multivariate analysis, malignant nonfunctional primary adrenal tumors were independently associated with increased risk of complications following adrenalectomy. CONCLUSIONS: Patients with malignant nonfunctional primary adrenal tumors have higher perioperative morbidity and mortality compared to patients with benign nonfunctional adrenal tumors. Such patients should be medically optimized before adrenalectomy, and surgeons must remain vigilant in preventing perioperative complications.

Inflammatory Monocytes Promote Perineural Invasion via CCL2-Mediated Recruitment and Cathepsin B Expression.

Perineural invasion (PNI) is an ominous event strongly linked to poor clinical outcome. Cells residing within peripheral nerves collaborate with cancer cells to enable PNI, but the contributing conditions within the tumor microenvironment are not well understood. Here, we show that CCR2-expressing inflammatory monocytes (IM) are preferentially recruited to sites of PNI, where they differentiate into macrophages and potentiate nerve invasion through a cathepsin B-mediated process. A series of adoptive transfer experiments with genetically engineered donors and recipients demonstrated that IM recruitment to nerves was driven by CCL2 released from Schwann cells at the site of PNI, but not CCL7, an alternate ligand for CCR2. Interruption of either CCL2-CCR2 signaling or cathepsin B function significantly impaired PNI in vivo Correlative studies in human specimens demonstrated that cathepsin B-producing macrophages were enriched in invaded nerves, which was associated with increased local tumor recurrence. These findings deepen our understanding of PNI pathogenesis and illuminate how PNI is driven in part by corruption of a nerve repair program. Further, they support the exploration of inhibiting IM recruitment and function as a targeted therapy for PNI. Cancer Res; 77(22); 6400-14. ©2017 AACR.

Uncovering the truth about covered stents: is there a difference between covered versus uncovered stents with transjugular intrahepatic portosystemic shunts?

INTRODUCTION: Polytetrafluoroethylene (PTFE)-covered transjugular intrahepatic portosystemic shunt (TIPS) stents purportedly provide superior patency. This study was undertaken to determine whether covered stents provide better long-term patency and outcomes after TIPSs. METHODS: Patients with portal hypertension undergoing TIPS at a large teaching hospital from 2001 to 2010 were studied. Median data are presented. RESULTS: Two hundred forty-six patients underwent TIPS; 70 received uncovered stents, and 176 received covered stents. Patients who received uncovered stents had more severely impaired liver function (41% were Child class C cirrhotics). The follow-up was longer with uncovered stents (48 vs 24 months, P < .01). Reinterventions for stenosis were undertaken in 33% with uncovered stents versus 19% with covered stents (P = .01). Shunt dysfunction occurred in 57% with uncovered stents versus 21% covered (P = .05). A deterioration of hepatic function occurred in 31% with uncovered stents versus 30% with covered (P = .32). Survival with uncovered stents was 31 months versus 33 months with covered stents (P = .55, Kaplan-Meier). CONCLUSIONS: Covered stents may improve patency but do not mitigate postshunt hepatic dysfunction and do not improve survival.