Abraham Lebenthal

Primary high-grade neuroendocrine carcinoma of the esophagus: a clinicopathologic and immunohistochemical study of 42 resection cases.

Primary high-grade neuroendocrine carcinoma of the esophagus (HNCE) is rare and poorly understood. In this study, we aimed at delineating the clinicopathologic and immunohistochemical characteristics of HNCE diagnosed on the basis of the World Health Organization criteria for pulmonary neuroendocrine carcinomas. We identified 42 (3.8%) consecutive resection cases of HNCE among 1105 esophageal cancers over a 7-year period. Patients’ mean age was 62 years (range, 47 to 79 y) with a male to female ratio of 3.7. Dysphagia was present in 79% of patients and tobacco abuse in 50%. Most tumors were centered in the middle (52%) or lower (36%) esophagus; 48% were ulcerated and 31% exophytic. All tumors were sharply demarcated with a pushing border in either solid sheet (83%) or nodular (17%) growth patterns. Pure HNCE was found in 57%, and the remainder also exhibited small components of squamous cell carcinoma (SqCC) or glandular, signet ring cell differentiations. SqCC in situ was present in 50%. Most tumors (88%) were the small cell type with pure oat-like cells in 52%, and the larger spindled, anaplastic, and giant cells were common. Tumor crush artifact (98%) and the Azzopardi effect (88%) were widespread. Extensive lymphovascular (50%) and perineural (33%) invasion and metastasis to regional (48%) and abdominal celiac lymph nodes (29%) were observed. Neoplastic cells were immunoreactive to synaptophysin (100%), CD56 (93%), chromogranin A (67%), p63 (55%), TTF-1 (71%), CK8/18 (90%), CD117 (86%), HER2 (16%), and p16 (84%) antibodies. The 5-year survival rate was 25%, similar to that of SqCC. Lymphovascular and perineural invasion was associated with a worse prognosis.

Benign Metastasizing Leiomyomas to the Lungs: An Institutional Case Series and a Review of the Recent Literature

BACKGROUND Benign metastasizing leiomyomas (BMLs) represent the extrauterine spread of a benign uterine process. Pulmonary BMLs are the most common example of distant spread of uterine leiomyomas and are usually found incidentally in premenopausal women. The rarity of BMLs accounts for the limited literature that currently exists regarding their underlying pathophysiology, disease course, and management. METHODS A retrospective analysis was performed of all BML cases diagnosed and managed at Brigham and Womens Hospital during a 22-year period. The demographic and clinical characteristics of these patients were compared with a PubMed-derived cohort of BML cases reported since 2006. RESULTS Benign metastasizing leiomyoma tumors were identified in 10 Brigham and Womens Hospital patients, whereas 57 cases were reported in the literature. The average age at diagnosis was 54.1 and 46.7 years, respectively. Mean interval time from a pertinent gynecologic procedure to BML diagnosis was 23 years at Brigham and Womens Hospital. All patients demonstrated positivity for actin, desmin, and estrogen/progesterone receptors, confirming the diagnosis of uterine leiomyomas. Management primarily consisted of diagnostic resection with subsequent observation with or without hormonal suppression for residual pulmonary nodules. Progression of residual BMLs was noticed in 30% and 8.3% of Brigham and Womens Hospital and literature patients, respectively, when follow-up was reported. One patient in our series required further surgical management. CONCLUSIONS Benign metastasizing leiomyomas are a rare cause of pulmonary nodules. They likely represent a clonal spread of uterine leiomyomas to the lungs. Management includes pathologic diagnosis with long-term surveillance with or without hormonal manipulation.

Treatment and controversies in paraesophageal hernia repair.

Background Historically all paraesophageal hernias were repaired surgically, today intervention is reserved for symptomatic paraesophageal hernias. In this review, we describe the indications for repair and explore the controversies in paraesophageal hernia repair, which include a comparison of open to laparoscopic paraesophageal hernia repair, the necessity of complete sac excision, the routine performance of fundoplication, and the use of mesh for hernia repair. Methods We searched Pubmed for papers published between 1980 and 2015 using the following keywords: hiatal hernias, paraesophageal hernias, regurgitation, dysphagia, gastroesophageal reflux disease, aspiration, GERD, endoscopy, manometry, pH monitoring, proton pump inhibitors, anemia, iron-deficiency anemia, Nissen fundoplication, sac excision, mesh, and mesh repair. Results Indications for paraesophageal hernia repair have changed, and currently symptomatic paraesophageal hernias are recommended for repair. In addition, it is important not to overlook iron-deficiency anemia and pulmonary complaints, which tend to improve with repair. Current practice favors a laparoscopic approach, complete sac excision, primary crural repair with or without use of mesh, and a routine fundoplication.

Malabsorption of modified food starch (acetylated distarch phosphate) in normal infants and in 8-24-month-old toddlers with non-specific diarrhea, as influenced by sorbitol and fructose.

Acetylated distarch phosphate (ADiSP) is a modified starch used in some baby foods. The bioavailability of ADiSP and a native (unmodified) starch was evaluated in 20 normal infants and 21 toddlers aged 8–24 mo with chronic non‐specific diarrhea. Formulae contained 8% native or 8% modified waxy maize starch. No infant or toddler consuming Formula N (native starch) had elevated peak breath hydrogen levels (20 ppm or greater), stools clinically positive for reducing substances (0.75% or greater) or loose stools. Fourteen infants received formula M (modified starch): 2 had elevated breath hydrogen, 1 had positive stools and another had loose stools. Of the 21 toddlers fed formula M, 2 had elevated breath hydrogen, but none had positive stools or loose stools. Formula NS (native starch with 2% sorbitol) had little effect on breath hydrogen in the infants but significantly increased it in the toddlers. Formula NS produced loose stools in 2 toddlers but no clinically positive stools in any infant or toddler. Formula MS (modified starch with 2% sorbitol) elevated breath hydrogen in 3 infants and 8 toddlers, and produced positive stools in 2 infants and 2 toddlers, and loose stools in 4 infants and 7 toddlers. Formula MSF (modified starch with 2% sorbitol and 5% fructose) elevated breath hydrogen in 7 infants and 10 toddlers, positive stools in 7 infants and 6 toddlers, and loose stools or diarrhea in 7 infants and 11 toddlers.

The 3-Hole Minimally Invasive Esophagectomy: A Safe Procedure Following Neoadjuvant Chemotherapy and Radiation

Induction therapy followed by esophagectomy has become standard for treatment of intermediate-stage esophageal cancer in many centers. Herein we evaluate the feasibility and safety of the 3-hole minimally invasive esophagectomy (3HMIE) approach in patients who received induction radiation and chemotherapy. Between 2003 and 2012, the records of 119 consecutive patients with esophageal cancer who underwent 3HMIE were reviewed for perioperative complications and long-term outcomes. Comparison was made between procedures performed for patients receiving neoadjuvant chemoradiation and patients who were treated with only surgery. Of them, 78 patients received neoadjuvant chemoradiation and 41 patients were treated with only surgery. Tumor locations were upper (2), middle (16), distal (64), and gastroesophageal junction (37). In all, 76 patients were at clinical stage IIA or above at presentation. Increased requirement for blood replacement in the induction therapy group was significant compared with the surgery-only group. Operative time, estimated blood loss, proximal and distal margin lengths, and length of stay were not significantly different between the cohorts. There was a 30-day perioperative death (0.8%), and this patient was from the surgery-only group. No conduit necrosis or need for diversion was recorded. Overall, 5-year survival was 62% among the 107 patients with early-stage esophageal cancer. 3HMIE is feasible with low mortality and acceptable morbidity even in patients with locally advanced esophageal cancer who received neoadjuvant radiochemotherapy. Overall perioperative and survival outcomes are similar to or better than those reported in the published literature on esophagectomy after induction therapy.

Diagnostic Evaluation of Achalasia: From the Whalebone to the Chicago Classification

From the earliest description of dysphagia relieved by dilatation with a whalebone in 1674 we have witnessed the evolution of esophageal function testing from the conventional manometry to the high-resolution manometry (HRM) and esophageal topography pressure plotting that have led to the revised Chicago classification for esophageal motility disorders in 2014. The goals of this paper are, therefore, (1) to highlight the historical milestones that have led to the diagnostic definition of achalasia, as we know it today; (2) to describe the evaluation process of patients with suspected achalasia; (3) to describe the diagnostic value of the HRM and the usefulness of the Chicago classification in predicting treatment outcomes. The value of Chicago classification is linked to the ability of the clinician to perform a thorough clinical evaluation to identify and correlate specific clinical phenotypes to specific manometric subtypes and predict treatment outcomes. Chicago classification, however, cannot predict which treatment, pneumatic dilatation, or Heller myotomy, should be selected for those with a specific subtype of achalasia.

Early Surgical Outcomes of En Bloc Resection Requiring Vertebrectomy for Malignancy Invading the Thoracic Spine.

BACKGROUND En bloc vertebral resection of locally invasive T4 lung cancers led to the development of a surgical sequence for resection; posterior stabilization, reposition, thoracotomy, lobectomy, vertebrectomy, and anterior spine stabilization in 1 procedure. This technique expanded indications for vertebrectomy to selected patients with sarcoma and metastatic disease. We review our experience to identify areas for clinical improvement. METHODS Operative case logs were cross-checked with billing data from 2003 to 2014 with Current Procedural Terminology (CPT, American Medical Association) codes for vertebrectomy. Thirty-two cases involving en bloc resection of malignancy invading at least 1 thoracic vertebra were selected. Outcomes data were analyzed using summary statistics. RESULTS Series includes 14 men and 18 women, median age 50 years. Twenty-five patients (78%) received preoperative chemoradiation. Nineteen total and 13 partial vertebrectomy were performed. Average number of vertebrae resected was 1.6 (range, 1 to 4). Median operative length was 8.5 hours (range, 2.8 to 14.5), mean blood loss 923 mL (SD ± 477 mL), and median length of stay 8 days (range, 3 to 56). Major morbidity followed 56% of cases. Thirty-day mortality was 3%. Overall median survival was 43.6 months, 1-year survival was 73.6%, and 5-year survival was 40.3%. CONCLUSIONS En bloc vertebrectomy for malignant disease is feasible. Our 1 stage and 2 team approach allows completion of the operation within a standard day, but is associated with long operative time. Complication rates may improve with decreased operative times. Review of available data warrants future prospective studies.

Trauma education in a state of emergency: a curriculum-based analysis

BACKGROUND Trauma is the leading cause of death from ages 1-44-y in the United States and the fifth leading cause of death overall, but there are few studies quantifying trauma education in medical school. This study reviews curriculum hours devoted to trauma education at a northeastern medical school. MATERIALS AND METHODS We reviewed the preclinical curriculum at a northeastern medical school affiliated with three adult and two pediatric level I trauma centers verified by the American College of Surgeons. We reviewed curricular hours and we categorized them according to the leading ten causes of death in the United States. We also compared the number of educational hours devoted to trauma to other leading causes of death. RESULTS The total amount of time devoted to trauma education in the first 2 y of medical school was 6.5 h. No lectures were given on the fundamentals of trauma management, traumatic brain injury, or chest or abdominal trauma. The most covered topic was heart disease (128 h), followed by chronic lower respiratory disease (80 h). Curricular time for heart disease, chronic lower respiratory disease, cancer, diabetes, renal disease, and influenza and pneumonia far exceeded that devoted to trauma, after adjusting for the mortality burden of these diseases (P < 0.05 for all). CONCLUSIONS Our study demonstrates that trauma education at a northeastern medical school is nearly absent. With the large burden of trauma and rise in mass casualty incidence, the preclinical curriculum might not be sufficient to expose students to the fundamentals of trauma management. A broader multi-institutional study may shed more insight on these curricular deficiencies in trauma education and detect if these deficiencies are widespread nationally.

Transdiaphragmatic minimally invasive lobectomy is feasible in a pig.

Video-assisted thoracoscopic surgery lobectomy has gained acceptance as a safe and oncologically sound alternative to the open procedure. Intercostal incisions alter chest wall mechanics and lead to postoperative pain. We postulated that performing the procedure without disruption of the intercostal spaces may lead to better outcomes because of the decreased effect on chest wall mechanics and postoperative pain. This initial experiment attempts to test the feasibility and possible changes in technique during transdiaphragmatic lobectomy and lymphadenectomy based on currently available instrumentation. Three access ports were placed beneath the costal margin of an anesthetized adult pig, and the thoracic cavity was accessed through the diaphragm. A transdiaphragmatic minimally invasive right lower lobectomy with complete lymph node dissection was performed. We report the first transdiaphragmatic minimally invasive right lower lobectomy and lymphadenectomy in a pig. The procedure is feasible using current commercially available standard instrumentation in a pig. Further, study is warranted to further refine the surgical technique.

Induction Therapy for Locally Advanced, Resectable Esophagogastric Cancer: A Phase I Trial of Vandetanib (zd6474), Paclitaxel, Carboplatin, 5-fluorouracil, and Radiotherapy Followed by Resection

Objectives: Preoperative chemotherapy and radiation for localized esophageal cancer produces cure rates near 30% when combined with surgical resection. Vandetanib, a small molecule receptor tyrosine kinase inhibitor of VEGFR-2, VEGFR-3, RET, and EGFR, demonstrated synergy with radiation and chemotherapy in preclinical models. We conducted a phase I study to assess the safety and tolerability of vandetanib when combined with preoperative chemoradiation in patients with localized esophageal carcinoma who were surgical candidates. Methods: Patients with stage II-III esophageal and gastroesophageal junction carcinoma without prior therapy were enrolled in a 3+3 phase I design. Patients received once-daily vandetanib (planned dosing levels of 100, 200, and 300 mg) with concomitant daily radiotherapy (1.8 Gy/d, 45 Gy total) and chemotherapy, consisting of infusional 5-FU (225 mg/m2/d over 96 h, weekly), paclitaxel (50 mg/m2, days 1, 8, 15, 22, 29) and carboplatin (AUC of 5, days 1, 29). Results: A total 9 patients were enrolled with 8 having either distal esophageal or gastroesophageal junction carcinomas. All patients completed the planned preoperative chemoradiation and underwent esophagectomy. Nausea (44%) and anorexia (44%) were the most common acute toxicities of any grade. One grade 4 nonhematologic toxicity was observed (gastrobronchial fistula). One additional patient suffered a late complication, a fatal aortoenteric hemorrhage, not definitively related to the investigational regimen. Five (56%) patients achieved a pathologic complete response. Three (33%) additional patients had only microscopic residual disease. Five (56%) patients remain alive and disease free with a median follow-up of 3.7 years and median overall survival of 3.2 years. The maximum tolerated dose was vandetanib 100 mg/d. Conclusions: Vandetanib at 100 mg daily is tolerable in combination with preoperative chemotherapy (5-FU, paclitaxel, carboplatin) and radiation therapy with encouraging efficacy worthy of future study.