High-dose chemotherapy and peripheral blood stem cell transplantation as salvage therapy in primary mediastinal nonseminomatous germ cell tumors: The Indiana University experience.

BACKGROUND: Patients with relapsed primary mediastinal nonseminomatous germ cell tumor have low cure rates with salvage chemotherapy or surgery. The authors report survival outcomes of patients who received high-dose chemotherapy (HDCT) and peripheral blood stem cell transplantation (PBSCT) at Indiana University. METHODS: The prospectively maintained Indiana University germ cell tumor database identified 32 patients with primary mediastinal nonseminomatous germ cell tumor who progressed after first-line cisplatin-based combination chemotherapy and received HDCT and PBSCT between 2006 and 2021. Therapy included two consecutive courses of HDCT consisting of 700 mg/m2 carboplatin and 750 mg/m2 etoposide, each for 3 consecutive days, and each followed by PBSCT. A second course was not given if the patient experienced progressive disease or prohibitive toxicity. Progression-free survival and overall survival were analyzed using the Kaplan-Meier method. Medians with 95% confidence intervals were also calculated along with 2-year probabilities. RESULTS: The median age at HDCT was 30 years (range, 18-61 years). With a median follow-up of 4.7 years (range, 1-14 years), the 2-year progression-free survival rate was 31% (95% confidence interval, 16%-47%), and the 2-year overall survival rate was 35% (95% confidence interval, 19%-52%). At last follow-up, nine patients (28%) remained without evidence of disease, including two platinum-refractory patients and two patients who were receiving HDCT as third-line therapy. There were three treatment-related deaths. CONCLUSIONS: Salvage HDCT and PBSCT is an active combination in patients who have relapsed primary mediastinal nonseminomatous germ cell tumor with curative potential and prolonged survival, including in platinum-refractory and third-line settings. The authors recommend this approach for initial salvage chemotherapy in this patient population.

Safety and usability of an endo staple line reinforcement device for pulmonary resections.

Background: Pulmonary resection can present technical challenges for surgeons due to the dissection and closure of tissues, which vary in thickness and elastic properties, occasionally leading to prolonged air leaks. Staple line reinforcements (SLRs) are widely utilized tools for fortifying the stability and integrity of closures in thoracic surgery, however, materials available and ease of use for both surgeon and scrub nurse have been suboptimal. A novel "click-and-go" device pre-loaded with bioabsorbable buttress material was recently developed, the Echelon Endopath SLR (ESLR, Ethicon, Inc., Cincinnati, OH, USA). This prospective study examines the safety and efficacy of this novel device in lung resections. Methods: Adult surgical candidates undergoing primary pulmonary resection (both open and thoracoscopic) where the ESLR would be used were enrolled. Exclusion included reoperation/revision in same anatomical location, hypersensitivity to polyglactin or related products, and body mass index (BMI) ≥46.0 kg/m2. The primary endpoint assessed the incidence of specific device-related adverse events (AEs): prolonged air leak and empyema. Additional endpoints included number of devices replaced during surgery due to slippage or bunching, and surgeon-reported usability responses. Data was summarized for AEs deemed device-related and usability questionnaire responses. Results: A total of 131 subjects were included in the primary endpoint analysis data set with 120 subjects completing the study (91.6%). The mean age at consent was 62.8±12.0 years and 55.7% were female. The most common primary indication for the procedure was malignancy 61.1%, and primary non-malignant lung disease (non-chronic obstructive pulmonary disease) 12.2%. Common procedures performed were wedge resection (58.0%) and lobectomy (34.4%). There were zero reported device-specific/-related AEs which counted toward the primary endpoint. Responses from a usability questionnaire found all surgeons (100.0%) reported the ease of setup was superior to previous devices utilized. Surgeons expressed greater confidence in the buttress material of the ESLR than that of previous SLR devices (strongly agree 88.9%; slightly agree 11.1%). Most also felt that there was less wastage with the click-and-go ESLR (strongly agree 77.8%, slightly agree 11.1%, neutral 11.1%). Conclusions: The ESLR device demonstrates safe and effective performance in this post-market study of specific thoracic procedures. Furthermore, surgeons found this was easier to use.

Thymic Carcinomas and Second Malignancies: A Single-Center Review.

Thymic carcinomas account for less than 0.01% of new cancer diagnoses annually and are more aggressive than thymomas. Autoimmune disorders have been associated with thymomas and only recently with thymic carcinomas. Second malignancies are well described after thymomas. The aim of this study was to analyze the incidence of second malignancies in patients with thymic carcinomas. All cases of thymic carcinomas were identified from the pathology archives of Indiana University. Histological materials were reviewed and further correlated with clinical data to identify incidence of second cancers in patients with thymic carcinomas. Histological material was available for review in 92 cases of thymic carcinoma. Clinical data were available for 85 patients. Fourteen of these (16.5%) patients had a second malignancy; these included small cell lung carcinoma, "testicular cancer", embryonal carcinoma, seminoma, breast carcinoma (two cases), prostatic adenocarcinoma, Hodgkin's lymphoma, thyroid carcinoma, bladder carcinoma (two cases), renal cell carcinoma, and melanoma. The latter could precede, be concurrent with, or follow the diagnosis thymic carcinoma. The incidence of second cancers in patients with thymic carcinomas is similar to that reported for thymomas. Abnormalities in immunological surveillance may be responsible for this high incidence of second malignancies in thymic tumors.

Outcomes following surgery for primary mediastinal nonseminomatous germ cell tumors in the cisplatin era.

OBJECTIVE: Treatment of primary mediastinal nonseminomatous germ cell tumors involves cisplatin-based chemotherapy followed by surgery to remove residual disease. We undertook a study to determine short and long-term outcomes. METHODS: A retrospective analysis of patients with primary mediastinal nonseminomatous germ cell tumors who underwent surgery at our institution from 1982 to 2017 was performed. RESULTS: A total of 255 patients (mean age, 29.2 years) were identified. Acute respiratory distress syndrome occurred postoperatively in 27 patients (10.9%), which was responsible for all 11 (4.3%) postoperative deaths. Of patients who developed acute respiratory distress syndrome, more patients received bleomycin-containing chemotherapy (25 out of 169; 14.8%) than non-bleomycin regimens (2 out of 77; 2.6%) (P = .004). With respect to variables independently predictive of long-term survival, evidence of choriocarcinoma before chemotherapy (n = 12) was determined to be an adverse factor (P = .006). In contrast, biopsy-proven elements of seminoma (n = 34) were predictive of improved survival (P = .04). The worst pathology identified in the residual mediastinal mass after chemotherapy was necrosis in 61 patients (25.0%), teratoma in 84 patients (34.4%), and malignant (persistent germ cell or non-germ cell cancer) in 97 patients (39.8%), which influenced overall survival (P < .001). Additionally, teratoma with stromal atypia (n = 18) demonstrated decreased survival compared with teratoma without atypia (n = 66; P = .031). Patients with malignancy involving >50% of the residual mass (n = 47) had a 2.3-fold increased risk of death compared with ≤50% malignancy (n = 45; P = .008). Finally, elevated postoperative serum tumor markers (n = 40) was significantly predictive of adverse survival (P < .001). CONCLUSIONS: In the treatment of primary mediastinal nonseminomatous germ cell tumors, avoiding bleomycin-containing chemotherapy is important. Pre- and postchemotherapy pathology and postoperative serum tumor markers are independent predictors of long-term survival.

Vasculogenic Mesenchymal Tumor: A Clinicopathologic and Molecular Study of 55 Cases of a Distinctive Neoplasm Originating From Mediastinal Yolk Sac Tumor and an Occasional Precursor to Angiosarcoma.

We report 55 postchemotherapy resections of primary nonseminomatous mediastinal germ cell tumors with prominent vasculogenic features showing the formation of rudimentary to well-developed neoplastic vessels within primitive mesenchyme. These cases represented 25% of a cohort of 221 such specimens. The patients were 19 to 49 years old (mean, 28 y) and 98% had serological evidence of yolk sac tumor. The vasculogenic lesions, felt to represent a neoplastic reiteration of embryonic vasculogenesis in the splanchnic mesoderm of the yolk sac, were further subdivided into teratoma with vasculogenic stroma (n=9), vasculogenic mesenchymal tumor (VMT) (n=42, further classified into low grade [n=24] and high grade [n=18]), and angiosarcoma (n=4). The distinction of teratoma with vasculogenic stroma from VMT was based solely on the greater extent of VMT (exceeding 1 low power [×4 objective] microscopic field), with both categories showing a spectrum of vessels lined by atypical endothelium in a nonendothelial neoplastic stroma that often also generated vascular walls comprised of atypical smooth muscle. The angiosarcomas showed stratification of highly atypical endothelial cells or anastomosing vessels lined by nonstratified but cytologically similar endothelium. Immunohistochemical studies supported the generation of neoplastic vessels from the tumor stroma, most commonly by the development of stromal clefts showing reactivity for podoplanin, CD34, and occasionally ERG, followed by the gradual development from the clefts of thin-walled vessels that later became encircled by stromal cells showing smooth muscle differentiation by immunohistochemistry. Occasionally, round collections of stromal erythrocytes became surrounded by stromal cells to generate blood vessels. Fluorescence in situ hybridization showed chromosome 12p copy number increase in both the endothelial component and stromal component in 8/9 VMT cases and in 1/1 angiosarcoma. On follow-up, no patient with teratoma with vasculogenic stroma had evidence of a subsequent vascular tumor or sarcoma, whereas 8 of the 35 (23%) patients with VMTs (2 low grade and 6 high grade) and meaningful follow-up developed sarcoma (1 angiosarcoma, 2 rhabdomyosarcomas, and 5 not further characterized). The difference between low-grade and high-grade tumors was of borderline significance (P=0.058). Two of the 4 patients with angiosarcoma died of metastatic angiosarcoma, with the other 2 disease-free at 6.8 and 7 years. Compared with the 165 patients with follow-up and no vasculogenic lesions, there was a highly significant (P=4.3×10-5) association of any vasculogenic lesion with sarcomatoid tumors during the clinical course of VMT patients. In addition, 5/46 patients with follow-up and vasculogenic lesions (11%) died of either leukemia or myelodysplastic syndrome compared with 2 of 166 (1%) lacking them (P=0.0012). Three of the 5 patients had identifiable immature hematopoietic cells within their vasculogenic lesions, but 4 other VMT patients with these did not develop leukemia or myelodysplasia. We conclude: (1) vasculogenic lesions are frequent in postchemotherapy resections of primary mediastinal germ cell tumors with yolk sac tumor components; (2) they mostly consist of neoplastic vessels in a stroma that also generates neoplastic vascular walls of smooth muscle; (3) VMTs are associated with an increased incidence of sarcomas, even though most vasculogenic lesions in this context do not meet criteria for angiosarcoma; (4) the presence of vasculogenic lesions in postchemotherapy resections of primary mediastinal germ cell tumors place patients at increased risk for leukemia or myelodysplasia.

Mediastinal Germ Cell Tumors: Updates in Diagnosis and Management.

Primary mediastinal nonseminomatous germ cell tumors represent a rare but important malignancy that occurs in otherwise young and healthy patients. Treatment is challenging and involves cisplatin-based chemotherapy followed by surgery to remove residual disease. Avoiding bleomycin-containing chemotherapy in the treatment of primary mediastinal nonseminomatous germ cell tumors is important. Prechemotherapy and postchemotherapy pathology as well as postoperative serum tumor markers are independent predictors of long-term survival.

An Ivor Lewis Esophagectomy Designed to Minimize Anastomotic Complications and Optimize Conduit Function.

We describe a novel esophagogastric anastomotic technique ("side-to-side: staple line-on-staple line", STS) for intrathoracic anastomoses designed to create a large diameter anastomosis while simultaneously maintaining conduit blood supply. This technique aims to minimize the incidence of anastomotic leaks and strictures, which is a frequent source of morbidity and occasional mortality after esophagectomy. We analyze the results of this STS technique on 368 patients and compared outcomes to 112 patients who underwent esophagogastric anastomoses using an end-to-end stapler (EEA) over an 8-year time interval at our institution. The STS technique involves aligning the remaining intrathoracic esophagus over the tip of the lesser curve staple line of a stomach tube, created as a replacement conduit for the esophagus. A linear stapling device cuts through and restaples the conduit staple line to the lateral wall of the esophagus in a side-to-side fashion. The open common lumen is then closed in two layers of sutures. There was a total of 12 (3.8%) anastomotic leaks in patients who underwent STS esophagogastric anastomosis. Two of eight patients (25%) had anastomotic leaks after esophagectomy for end-stage achalasia as compared to a 2.8% leak rate (10/336) after esophagectomy for other conditions. Eighteen (5.2%) patients required a median of 2 dilatations for anastomotic stricture after STS anastomosis. Supplemental jejunostomy feedings were required in only 11.1% of patients undergoing STS anastomoses following hospital discharge. In contrast, patients undergoing EEA anastomoses demonstrated anastomotic leak and stricture rates of 16.1% and 14.3% respectively (p<0.01). Time analysis of postoperative contrast studies following the STS technique typically demonstrated a straight/uniform diameter conduit with essentially complete contrast emptying into the small bowel within 3 minutes in 88.4% of patients. The incidence of esophagogastric anastomotic leaks and strictures were extremely low using this novel anastomotic technique. Additionally we believe that based on time and qualitative analyses of postoperative contrast studies, this technique appears to optimize postoperative upper gastrointestinal tract function; however, further comparative studies are needed.

The Influence of Airway Closure Technique for Right Pneumonectomy on Wall Tension During Positive Pressure Ventilation: An Experimental Study.

Bronchopleural fistula (BPF) remains a significant source of morbidity and mortality after right pneumonectomy (RPN). Postoperative mechanical ventilation represents a primary risk factor for BPF. We undertook an experiment to determine the influence of airway diameter on suture line tension during mechanical ventilation after RPN. RPN was performed in 6 fresh human adult cadavers. After initial standard bronchial stump closure (BSC), the airway suture lines were subjected to 5 cm H2O incremental increases in airway pressures beginning at 5-40 cm H2O. To minimize airway diameter, a carinal resection was then performed with trachea to left main bronchial anastomosis and the airway suture lines subjected to similar incremental airway pressures. Wall tension (N/m) at the suture lines was measured using piezoresistive sensors at each pressure point. As delivered airway pressure increased, there was a concomitant increase in wall tension after BSC and carinal resection. At every point of incremental positive pressure, wall tension was however significantly lower after carinal resection when compared to BSC (P < 0.05). Additionally the differences in airway tension became even more significant with higher delivered airway pressure (P < 0.001). Airway diverticulum after BSC leads to significantly increased tension on the bronchial closure with positive airway pressure as compared to a closure which minimize airway diameter after RPN. This supports the role of Laplacian Law where small increases in airway diameter result in significant increases on closure site tension. Techniques which reduce airway diameter at the airway closure will more reliably reduce the incidence of BPF following RPN.

Amiodarone for prevention of atrial fibrillation following esophagectomy.

OBJECTIVES: Atrial fibrillation (AF) is a common complication after esophagectomy and is associated with symptoms, hemodynamic instability, prolonged hospital stay, and an increased incidence of mortality. Our objective was to determine the efficacy and safety of intravenous amiodarone for prophylaxis of postesophagectomy AF. METHODS: In this retrospective cohort study, 309 patients who underwent esophagectomy formed the initial cohort. Following propensity score-matching, 110 patients who received prophylactic amiodarone 43.75 mg/hour via continuous intravenous infusion over 96 hours (total dose, 4200 mg) were matched to a control group of patients who did not undergo amiodarone prophylaxis (n = 110). The propensity score was obtained using a multivariate logistic regression model with amiodarone as the variable and the following covariates: age, sex, surgical approach, history of neoadjuvant chemotherapy and/or radiation, chronic obstructive pulmonary disease, heart failure, cardiovascular disease, alcohol use (>7 drinks/week), preadmission ß-blockers discontinued during hospitalization, preoperative use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, preoperative use of corticosteroids, postoperative use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, postoperative use of corticosteroids, postoperative use of statins, and preoperative Charlson comorbidity index. RESULTS: The incidence of AF requiring treatment due to rapid ventricular rate and symptoms was lower in the amiodarone group (17 out of 110 [15.5%] vs 32 out of 110 [29.1%]; odds ratio, 0.45; 95% confidence interval, 0.23-0.86; P = .015). There were no significant differences between the groups in median postoperative length of hospital stay, incidence of pulmonary complications, or mortality. The incidences of hypotension requiring treatment (42.7% vs 21.8%; P = .001), bradycardia (8.2% vs 0.0%; P = .002), and corrected QT interval prolongation (10.9% vs 0.0%; P ≤ .0001) were significantly higher in the amiodarone group. CONCLUSIONS: Prophylactic intravenous amiodarone is associated with a reduction in the incidence of AF following esophagectomy, but is not associated with shorter postoperative length of hospital stay. Intravenous amiodarone for prophylaxis of postesophagectomy AF is associated with hypotension, bradycardia, and corrected QT interval prolongation.

Perioperative Risk Factors for Postoperative Delirium in Patients Undergoing Esophagectomy.

BACKGROUND: Postoperative delirium affects up to 50% of patients undergoing esophagectomy and is associated with negative outcomes. The perioperative risk factors for delirium in this population are not well understood. We conducted this study to assess perioperative risk factors for postoperative delirium among esophagectomy patients. METHODS: We performed a secondary data analysis of patients enrolled in a randomized controlled trial evaluating the efficacy of haloperidol prophylaxis postoperatively in reducing delirium among esophagectomy patients. Postoperative delirium was assessed twice daily using the Confusion Assessment Method for the ICU. Univariate and logistic regression analyses were performed to examine the association between perioperative variables and development of postoperative delirium. RESULTS: Of 84 consecutive esophagectomy patients, postoperative delirium developed in 27 (32%). These patients had higher Acute Physiology and Chronic Health Evaluation II scores (22.1 [SD, 6.5] vs 17.4 [SD, 6.8]; p = 0.003), longer mechanical ventilation days (1.7 [SD, 1.4] days vs 1.0 [SD, 1.1] days; p = 0.001), and longer intensive care unit (ICU) days (5.1 [SD, 2.6] days vs 2.6 [SD, 1.6] days; p < 0.001). In a logistic regression model, only ICU length of stay had a significant association with postoperative delirium (odds ratio, 1.65; 95% confidence interval, 1.21 to 2.25). CONCLUSIONS: ICU length of stay was significantly associated with postoperative delirium. Other perioperative factors, including duration of procedure, blood loss, and hemoglobin levels, were not significantly associated with postoperative delirium.

Management of broncholithiasis.

Broncholithiasis is a condition in which calcified material has entered the tracheobronchial tree, at times causing airway obstruction and inflammation. Broncholiths generally originate as calcified material in mediastinal lymph nodes that subsequently erode into adjacent airways, often as a result of prior granulomatous infection. Disease manifestations range from asymptomatic stones in the airway to life-threatening complications, including massive hemoptysis and post-obstructive pneumonia. Radiographic imaging, particularly computed tomography scanning of the chest, is integral in the evaluation of suspected broncholithiasis and can be helpful to assess involvement of adjacent structures, including vasculature, prior to any planned intervention. Management strategies largely depend on the severity of disease. Observation is warranted in asymptomatic cases, while therapeutic bronchoscopy and surgical interventions may be necessary for cases involving complications. Bronchoscopic extraction is often feasible in cases in which the broncholith is freely mobile within the airway, whereas partially-embedded broncholiths represent additional challenges. Surgical intervention is indicated for advanced cases deemed not amenable to endoscopic management. Complex cases involving complications such as massive hemoptysis and/or bronchomediastinal fistula formation are best managed with a multidisciplinary approach, utilizing expertise from fields such as pulmonology, radiology, and thoracic surgery.

Impact of the development of an endoscopic eradication program for Barrett's esophagus with high grade dysplasia or early adenocarcinoma on the frequency of surgery.

Background and aims The impact of the advent of an institutional endoscopic eradication therapy (EET) program on surgical practice for Barrett's esophagus (BE)-associated high grade dysplasia (HGD) or suspected T1a esophageal adenocarcinoma (EAC) is unknown. The aims of this study are to evaluate the different endoscopic modalities used during development of our EET program and factors associated with the use of EET or surgery for these patients after its development. Methods Patients who underwent primary endoscopic or surgical treatment for BE-HGD or early EAC at our hospital between January 1992 and December 2014 were retrospectively identified. They were categorized by their initial modality of treatment during the first year, and the impact over time for choice of therapy was assessed by multivariable logistic regression. Results We identified 386 patients and 80 patients who underwent EET and surgery, respectively. EET included single modality therapy in 254 (66 %) patients and multimodal therapy in 132 (34 %) patients. Multivariable logistic regression showed that, for each subsequent study year, EET was more likely to be performed in patients who were older ( P  = 0.0009), with shorter BE lengths ( P  < 0.0001), and with a pretreatment diagnosis of HGD ( P  = 0.0054) compared to surgical patients. The diagnosis of EAC did not increase the utilization of EET compared to surgery as time progressed ( P  = 0.8165). Conclusion The introduction of an EET program at our hospital increased the odds of utilizing EET versus surgery over time for initial treatment of patients who were older, had shorter BE lengths or the diagnosis of BE-HGD, but not in patients with EAC.