Amy G. Fiedler

Targeting the MAGE A3 antigen in pancreatic cancer

Pancreatic cancer is the fourth-leading cause of death in the United States and one of the most aggressive known malignancies. New and innovative advances in treatment are desperately needed. One promising area of investigational treatment for pancreatic cancer involves the use of immunotherapy. The development of immunotherapy for pancreatic cancer has been hampered by difficulty in generating tumor-reactive lymphocytes from resected specimens and by a lack of appropriate target antigens expressed on tumor cells. Innovative strategies have been developed with the use of peripheral blood lymphocytes that are genetically engineered to express T-cell receptors targeting common tumor antigens, including cancer-testis antigens, such as the MAGE-A3 antigen. Cancer-testis antigens pose excellent targets for immunotherapy because they are expressed in cancer and in the testis, an immune-privileged site, but have limited expression in normal tissue. An additional advantage in targeting cancer-testis antigens for immunotherapy is that their expression can be selectively up-regulated in tumor cells via epigenetic regulation with chromatin remodeling agents. Current interest in targeting cancer-testis antigens in pancreatic cancer is well-founded because cancer-testis antigens have been shown to be expressed in pancreatic cancer as potential targets for therapy. In our studies, we validated the expression pattern of cancer-testis antigens in resected specimens of pancreatic cancer and tested the hypothesis that treatment of pancreatic cancer cells with chromatin remodeling agents would render them more sensitive to antigen-specific T lymphocytes. We focused predominately on the MAGE-A3 antigen because it is highly expressed in pancreatic cancer, and several immunotherapeutic strategies are in clinical trials targeting this specific antigen. The results of these studies have important translational implications and provide the rationale for combined treatment with chromatin remodeling agents and immunotherapeutic approaches for pancreatic cancer.

Parathyroid carcinoma in a child: an unusual case of an ectopically located malignant parathyroid gland with tumor invading the thymus

Parathyroid carcinoma is exceptionally rare in children. Parathyroid carcinoma in the pediatric population most typically presents with significant hypercalcemia and a palpable neck mass. The authors report the seventh case of parathyroid carcinoma diagnosed in a child younger than 16 years. To our knowledge, this case is the first documented case, in the pediatric population, of parathyroid carcinoma in an ectopically located parathyroid gland with tumor invading the thymus.

Variability in Integrated Cardiothoracic Training Program Curriculum

BACKGROUND Development of curricula that appropriately progress a resident from medical school graduate to fully trained cardiothoracic surgeon is a key challenge for integrated cardiothoracic training programs. This study examined variability and perceived challenges in integrated curricula. METHODS Responses to the 2016 TSDA/TSRA survey that accompanies the annual in-training exam taken by current cardiothoracic surgery residents were analyzed. Standard statistical methods were utilized to examine trends in participant responses. RESULTS General surgery experience decreased with post-graduate year, whereas cardiac operative experience increased. Rotations in a wide variety of adjunct fields were common. The majority (87%) of respondents reported had dedicated cardiothoracic intensive care unit (ICU) rotations, and surgical ICU and cardiac care unit rotations were less common (68% and 42%, respectively). The most common surgical subspecialty rotations were vascular (94%) and acute care surgery (88%), with a wide range of clinical exposure (ie, 3-44 weeks for vascular). Importantly, 52% felt competition with general surgery residents for experience and 22.5% of general surgery rotations were at hospitals without general surgery residents. Perceived challenges included optimization of rotations (78%), faculty allowing residents to perform case components (60%), faculty teaching in the operating room (29%), and improving surgical experience on general surgery rotations (19%). CONCLUSIONS Significant variation exists in integrated cardiothoracic surgery curricula. Optimization of rotations, access to surgical experience, and integration with general surgery appear to be the most significant perceived challenges. These data suggest that optimization of early clinical and surgical experience within institutions could improve trainee preparedness for senior cardiothoracic surgery training.

Right Heart Failure: An Ischemic Model and Restraint Therapy for Treatment

BACKGROUND Right heart failure is poorly understood and treated. In left heart failure, ventricular restraint can reverse pathologic left ventricular remodeling. The effect of restraint in right heart failure, however, is not known. We hypothesize that ventricular restraint can be applied selectively to the right ventricle (RV) to promote RV reverse remodeling. METHODS Right heart failure was induced by right coronary artery ligation in a sheep model. Eight weeks later, a saline-filled epicardial balloon was placed around the RV surface for restraint. Restraint level was defined by measuring balloon luminal pressure at end-diastole. Maximum balloon pressure was determined by the amount of balloon pressure required to decrease systemic mean arterial pressure by 10 mm Hg. We determined end-diastolic transmural myocardial pressure, indices of myocardial oxygen consumption, and RV diastolic compliance at 4 different restraint levels. RESULTS After coronary ligation, RV ejection fraction (EF) decreased from 0.574±0.04 to 0.362±0.03 (p<0.05). End-diastolic RV volume increased from 70.8 mL/m2±9 to 82.2 mL/m2±7 (p<0.05) by magnetic resonance imaging. After application of restraint to the RV only, RV transmural pressure decreased significantly by 27%. Greater levels of restraint also improved RV EF (0.347±0.06 to 0.473±0.05) but did not change RV end-diastolic volume. CONCLUSIONS A model of ischemic right heart failure was successfully created. Selective RV restraint results in improved mechanical efficiency, decreased wall stress, and improved EF. The benefits of restraint in right heart failure warrant further investigation.

Aortic valve replacement associated with survival in severe regurgitation and low ejection fraction

Objectives Although guidelines support aortic valve replacement (AVR) in patients with severe aortic regurgitation (AR) and left ventricular ejection fraction (LVEF) <50%, severe left ventricular dysfunction (LVEF <35%) is thought to confer high surgical risk. We sought to determine if a survival benefit exists with AVR compared with medical management in this high-risk, relatively rare population. Methods A large institutional echocardiography database was queried to identify patients with severe AR and LVEF <35%. Manual chart review was performed. Due to small sample size and population heterogeneity, corrected group prognosis method was applied, which calculates the adjusted survival curve for each individual using fitted Cox proportional hazard model. Average survival adjusted for comorbidities and age was then calculated using the weighted average of the individual survival curves. Results Initially, 2 54 614 echocardiograms were considered, representing 1 45 785 unique patients, of which 40 patients met inclusion criteria. Of those, 18 (45.0%) underwent AVR and 22 (55.0%) were managed medically. Absolute mortality was 27.8% in the AVR group and 91.2% in the medical management group. After multivariate adjustment, end-stage renal disease (HR=17.633, p=0.0335) and peripheral arterial disease (HR=6.050, p=0.0180) were associated with higher mortality. AVR was associated with lower mortality (HR=0.143, p=0.0490). Mean follow-up time of the study cohort was 6.58 years, and mean survival for patients undergoing AVR was 6.31 years. Conclusions Even after adjustment for clinical characteristics and patient age, AVR is associated with higher survival for patients with low LVEF and severe AR. Although treatment selection bias cannot be completely eliminated by this analysis, these results provide some evidence that surgery may be associated with prolonged survival in this high-risk patient group.

Redesigning Care for Patients With Acute Myocardial Infarction Complicated by Cardiogenic Shock: The "Shock Team".

Redesigning Care for Patients With Acute Myocardial Infarction Complicated by Cardiogenic Shock: The “Shock Team” To the Editor The Viewpoint by Tchantchaleishvili et al1 calling for organized statewide networks for the management of acute myocardial infarction–related cardiogenic shock brings to attention the critical need for multidisciplinary, multicenter, coordinated efforts to treat and manage patients presenting with cardiogenic shock. This is a timely message because the mortality rate for these patients remains nearly 50%, despite improving technologies and access to mechanical circulatory support. Recognizing the complexity and time-sensitive nature of treating a patient with cardiogenic shock, our center, the Massachusetts General Hospital, created the “Shock Team” in 2011. This team, formally composed of the Departments of Cardiothoracic Surgery, Cardiology, Pulmonology, Interventional Cardiology, Critical Care, and Nursing; Perfusion Services; and Respiratory Therapists is available not only within the confines of our hospital but also to regional centers 24 hours a day, 7 days a week. In the acute setting, the mode of mechanical circulatory support most commonly used is extracorporeal membrane oxygenation. When a patient is considered for extracorporeal membrane oxygenation, a Shock Team activation page is delivered, and a multidisciplinary meeting is held to determine the best management strategy. Candidacy is evaluated based on predetermined indications and contraindications. If a patient receives extracorporeal membrane oxygenation, the entirety of the Shock Team is dedicated to daily rounds and optimizing care throughout the patient’s hospitalization. One of the major barriers to maximal utilization of mechanical circulatory support for the treatment of patients with cardiogenic shock is the lack of education and outreach programs to disseminate this information. Our center has created a Shock Team pocket card that succinctly defines patient criteria, contraindications, general guidelines, and absolute trigger notifications for a Shock Team consultation or referral. These informational cards have been distributed throughout Massachusetts General Hospital, as well as throughout our surrounding regional centers, via outreach education, to increase awareness of the Shock Team’s availability and the crucial importance of early activation and rapidity of care. In addition, through a collaborative effort by the members of the Shock Team, a comprehensive training program has been developed and is being offered to other centers. It is our hope that this will assist other programs in developing Shock Teams and avoiding “learning curve” catastrophes. As discussed by Tchantchaleishvili et al,1 formalized networks for the treatment of patients presenting with cardiogenic shock and for the streamlining of their care are of utmost importance. The education and outreach programs used to facilitate program development and expedite time to mechanical circulatory support can only improve outcomes. We applaud the authors’ efforts in bringing this important concept to our attention.

Appraisal of mentorship in cardiothoracic surgery training

Objectives: Although the importance of mentorship in training the next generation of cardiothoracic surgeons is widely recognized, the current state of mentorship remains undefined. Methods: Trainee responses to questions in the 2017 In‐Training Examination regarding aspects of mentorship were analyzed. Response rate was 78% (288/370). Mentor‐related and trainee‐related characteristics were assessed. Results: The majority (84%) of residents had mentors, with a high impact on specialty choice (80%), and 91% of respondents viewed mentorship as critical to success. Nearly half (42%) had program‐assigned mentors; 53% found them as productive, and 13% reported more consistent/frequent meetings than personally selected mentors, with 22% reporting less ideal personality match compared with personally selected mentors. Among residents with mentors, 36% lacked mentorship in work‐life balance, 23% lacked mentorship in job assistance, and 22% lacked mentorship in career advice. Junior residents more often valued mentors as role models, whereas mentors chosen by senior residents were more impactful in technical training, job counseling, and societal involvement. Compared with men, women more often valued mentors as role models and assisting in networking. Men reported their mentors were more impactful in teaching technical skills and clinical ability than women. Conclusions: The majority of current cardiothoracic surgery trainees had mentorship; however, gaps remain: Many residents lacked career path guidance, assistance obtaining a job, and advice regarding life‐work balance. The role of mentorship varied with program type, seniority, and gender, emphasizing the need to tailor mentorship to the individual and changing needs of the resident.

Perforation of a mesenteric Meckel’s diverticulum

Abstract Meckel’s diverticulum is a remnant of the embryologic omphalomeseteric duct and is a common congenital anomaly found in ~2% of the population. The clinical significance of this anomaly is that the persistent diverticulum can lead to intestinal obstruction or diverticulitis and may contain ectopic tissue which can lead to bleeding, ulceration or perforation. The classic location of a Meckel’s diverticulum has been described ~40 cm from the ileocecal valve on the antimesenteric side of the distal ileum. There have only been a few documented cases of a Meckel’s diverticulum found on the mesenteric border of the ileum. In this report, we describe a patient who presented with a perforated Meckel’s diverticulum which was found on the mesenteric border and performed a review to determine the significance of this finding.

Delayed Presentation of Traumatic Pericardial Rupture: Diagnostic and Surgical Considerations for Treatment

Traumatic pericardial rupture is a rare event with high mortality. We present the case of a 15-year-old boy who sustained thoracic and abdominal trauma secondary to motor vehicle collision, with a delayed diagnosis of traumatic pericardial rupture with cardiac herniation. Out of concern for torsion and hemodynamic collapse, surgical repair was advised. We have developed a novel surgical approach to this rare condition, utilizing a combination of thoracoscopic and open surgical techniques. The guiding principles of our repair include the utilization of fenestrated pieces of bovine pericardium to create a tension free repair, minimizing the likelihood of pericardial effusion, and returning the cardiac mass to normal anatomic position.

The effect of donor age on posttransplant mortality in a cohort of adult cardiac transplant recipients aged 18-45

Hearts from older donors are increasingly utilized for transplantation due to unmet demand. Conflicting evidence exists regarding the prognosis of recipients of advanced age donor hearts, especially in young recipients. A retrospective analysis was performed on 11 433 patients aged 18 to 45 who received a cardiac transplant from 2000 to 2017. Overall, 10 279 patients received hearts from donors less than 45 and 1145 from donors greater than 45. Recipients of older donors were older (37 vs. 34 years, P < .01) and had higher rates of inotropic dependence (48% vs. 42%, P < .01). However, groups were similar in terms of comorbidities and dependence on mechanical circulatory support. Median survival for recipients of older donors was reduced by 2.6 years (12.6 vs. 15.2, P < .01). Multivariable analysis demonstrated donor age greater than 45 to be a predictor of mortality (HR 1.18 [1.05‐1.33], P = .01). However, when restricting the analysis to patients who received a donor with a negative preprocurement angiogram, donor age only had a borderline association with mortality (HR 1.20 [0.98‐1.46], P = .06). Older donor hearts in young recipients are associated with decreased long‐term survival, however this risk is reduced in donors without atherosclerosis. The long‐term hazard of this practice should be carefully weighed against the risk of waitlist mortality.