James S. Allan

Adjuvant radiation therapy for stage II thymoma.

BACKGROUND Thymoma is difficult to study because of its indolent natural history. The criteria for administration of adjuvant radiation therapy remain controversial, and it is unclear whether patients with Masaoka stage II thymoma benefit from adjuvant radiation. The goal of this report was to determine whether or not this group benefits from radiation therapy in terms of disease-specific survival and tumor recurrence. METHODS Case records of the Massachusetts General Hospital were retrospectively reviewed from 1972 to 1999. One hundred fifty-five patients underwent resection for thymoma, of which, 49 had stage II disease. The world literature was reviewed using a Medline search (1966 to 2001), and a secondary review of referenced works was performed. RESULTS Fourteen stage II patients underwent radiation therapy. Thirty-five did not receive radiation therapy. Baseline prognostic factors between radiated and nonradiated groups were similar. All patients underwent complete resection. The addition of adjuvant radiotherapy did not significantly alter local or distant recurrence rates in stage II thymoma. Disease-specific survival at 10 years in stage II patients was 100% with radiotherapy and without radiotherapy (p = 0.87). There was one recurrence in the nonradiated group at 180 months, which was outside the usual radiation portal. CONCLUSIONS Most stage II patients do not require adjuvant radiation therapy and can be observed after complete resection.

Biologic rhythm disorders, depression, and phototherapy. A new hypothesis.

Disturbances of the circadian timing system are implicated in the pathogenesis of numerous clinical syndromes, including sleep and affective disorders. Abnormalities of circadian rhythms can now be directly measured in the clinical laboratory and potentially corrected. Sleep scheduling disorders are most commonly due to phase misalignments between the endogenous circadian pacemaker and the socioenvironmental schedule. Current research is increasing our understanding of the influence of bright light exposure on the circadian timing system and has begun to be used successfully in the management of these conditions. There is substantial evidence that abnormalities of the circadian timing system are associated with depression. However, the application of new biologic rhythm diagnostic techniques would be required to establish whether circadian dysfunction is involved in the pathogenesis of these conditions. We propose a new hypothesis that phototherapy for seasonal depression may act by increasing an abnormally low circadian amplitude in those patients, such as that reported in endogenously depressed patients. The powerful effect of light on the circadian system indicates that phototherapy may become an important tool in the management of disorders of circadian etiology.

Solving the Organ Shortage Crisis: The 7th Annual American Society of Transplant Surgeons' State-of-the-Art Winter Symposium

The 2007 American Society of Transplant Surgeons’ (ASTS) State‐of‐the‐Art Winter Symposium entitled, ‘Solving the Organ Shortage Crisis’ explored ways to increase the supply of donor organs to meet the challenge of increasing waiting lists and deaths while awaiting transplantation. While the increasing use of organs previously considered marginal, such as those from expanded criteria donors (ECD) or donors after cardiac death (DCD) has increased the number of transplants from deceased donors, these transplants are often associated with inferior outcomes and higher costs. The need remains for innovative ways to increase both deceased and living donor transplants. In addition to increasing ECD and DCD utilization, increasing use of deceased donors with certain types of infections such as Hepatitis B and C, and increasing use of living donor liver, lung and intestinal transplants may also augment the organ supply. The extent by which donors may be offered incentives for donation, and the practical, ethical and legal implications of compensating organ donors were also debated. The expanded use of nonstandard organs raises potential ethical considerations about appropriate recipient selection, informed consent and concerns that the current regulatory environment discourages and penalizes these efforts.

A systematic review and meta-analysis of surgical treatments for malignant pleural mesothelioma

BACKGROUND Malignant pleural mesothelioma (MPM) is an aggressive disease of the pleural lining with a dismal prognosis. Surgical treatments of MPM with a curative intent include extrapleural pneumonectomy and extended pleurectomy/decortication (P/D). This meta-analysis aimed to compare the perioperative and long-term outcomes of EPP and extended P/D for selected surgical candidates. METHODS A systematic review of the literature was performed on six electronic databases to identify all relevant data on comparative outcomes of extended P/D and EPP in a multimodality setting. Endpoints included perioperative mortality and morbidity, as well as long-term overall survival. RESULTS Seven relevant studies with comparative data on EPP (n=632) versus extended P/D (n=513) were identified from the current literature. Comparison of these two groups demonstrated significantly lower perioperative mortality (2.9% vs. 6.8%, p=0.02) and morbidity (27.9% vs. 62.0%, p<0.0001) for patients who underwent extended P/D compared to EPP. Median overall survival ranged between 13-29 months for extended P/D and 12-22 months for EPP, with a trend favouring extended P/D. CONCLUSIONS Although it must be emphasized that patient selection and treatment strategies differ between EPP and extended P/D, a number of comparative studies have recently been conducted to compare these two surgical techniques for patients with resectable MPM. The present study indicated that selected patients who underwent extended P/D had lower perioperative morbidity and mortality with similar, if not superior, long-term survival compared to EPP, in the context of multi-modality therapy. This may represent an important paradigm shift in the surgical management of MPM.

Transplantation tolerance prevents cardiac allograft vasculopathy in major histocompatibility complex class I-disparate miniature swine

BACKGROUND The mechanisms and treatment of cardiac allograft vasculopathy (CAV) remain elusive. We have used partially inbred miniature swine to determine the role of class I MHC antigens in the pathogenesis of CAV and to determine whether acquired tolerance to donor antigen can prevent the development of CAV in large animals. METHODS Previous studies demonstrated that miniature swine treated with 12 days of cyclosporine (CsA) after the transplantation of MHC class I-disparate kidney allografts all became tolerant to the donor kidneys and survived indefinitely. In the present study, heart allografts were transplanted across the same MHC class I disparity in CsA-treated swine. RESULTS Unlike kidney allografts, heart allografts were rejected in 33-55 days. By postoperative day 28, all cardiac allografts had developed the intimal proliferation characteristic of CAV. When hearts and kidneys from the same donors were transplanted simultaneously into class I-disparate, CsA-treated recipients, the hosts became tolerant to their cardiac allografts and survived long-term. Furthermore, none of the hearts from the combined heart/kidney recipients developed evidence of CAV. Thus, this report demonstrates that: (1) MHC class I antigens play an important role in the pathogenesis of CAV, (2) the specific unresponsiveness to donor class I antigen induced by a class I-disparate kidney protects a heart transplanted from the same organ donor, and (3) the induction of acquired tolerance prevents the development of CAV. CONCLUSION These findings in a preclinical system establish the significance of antigen-dependent mechanisms in the pathogenesis of CAV and underscore the importance of achieving tolerance in clinical transplantation.

Tracheoinnominate fistula: diagnosis and management

TIF is a rare and often fatal complication of tracheostomy. Bleeding from the trachea after tracheostomy demands urgent investigation. Bronchoscopy is the diagnostic procedure of choice. Bedside control of hemorrhage by cuff overinflation or by digital arterial compression can be lifesaving. Prompt operation with division of the innominate artery and subsequent separation of the trachea from the divided artery by viable tissue is indicated. Neurologic complications are rare.

Host Alloreactive Memory T Cells Influence Tolerance to Kidney Allografts in Nonhuman Primates

Only nonhuman primates with low frequencies of donor-specific memory T cells develop tolerance and accept allogeneic kidney transplants. The Slippery Slope of Transplantation Tolerance Although science is respected as an impartial pursuit, even the most unbiased observer must begin with assumptions to design experiments. But even seemingly reasonable hypotheses don’t always survive experimental scrutiny. Transplantation researchers began with the credible assumption that laboratory mice can serve as a model for human transplantation. Thus, when scientists showed that mice can accept human grafts without life-long immunosuppression, researchers enthusiastically attempted to translate these findings to nonhuman primates and patients—to no avail. Nadazdin et al. now provide a potential explanation for this discrepancy—a pre-existing pool of graft-reactive memory T cells. Memory T cells respond more rapidly and with greater strength than other T cells that have not previously seen a specific antigen. As the name suggests, memory T cells are long-lived in patients and explain in part the success of vaccination in preventing subsequent infections. Laboratory mice lack large numbers of memory T cells because they live in germ-free conditions, unlike people who, despite their best efforts, do not. This lifestyle difference was not thought to be a problem for transplantation studies, because people have not been previously exposed to donor-derived alloantigens and thus were not expected to have a memory response. In an unexpected twist, primates have been shown to have a relatively high frequency of alloreactive memory T cells before transplantation, perhaps as a result of cross-reactivity from previous infections. Nadazdin et al. now investigate the effects of these preexisting alloreactive memory T cells on transplant tolerance in nonhuman primates. The authors found that transplanted organs are rejected from monkeys with high numbers of preexisting alloreactive memory T cells, but survive long-term in monkeys with low numbers of these cells. Indeed, the animals with low numbers of alloreactive memory cells were rendered tolerant to the transplanted kidney, which was not rejected despite a lack of continued immunosuppression. This tolerance was allospecific, because both tolerant and rejecting monkeys had similar levels of homeostatic memory T cell expansion, but only rejecting monkeys displayed expanded levels of donor-reactive memory T cells after transplantation. These findings suggest two approaches to improving tolerance induction in transplant patients: One could either pair grafts with patients who have low numbers of donor-specific memory T cells or devise a way to eliminate these memory T cells from patients before transplantation. In this case, questioning assumptions did not validate the assumption, but instead yielded new information that may help researchers overcome barriers to transplant tolerance. Transplant tolerance, defined as indefinite allograft survival without immunosuppression, has been regularly achieved in laboratory mice but not in nonhuman primates or humans. In contrast to laboratory mice, primates regularly have high frequencies of alloreactive memory T cells (TMEMs) before transplantation. These TMEMs are poorly sensitive to conventional immunosuppression and costimulation blockade, and the presence of donor-reactive TMEMs in primates may account for their resistance to transplant tolerance protocols that have proven consistently effective in mice. We measured the frequencies of anti-donor TMEMs before and after transplantation in a series of rejecting and tolerant monkeys that underwent nonmyeloablative conditioning, short-term immunosuppression, and combined allogeneic kidney/cell transplantation. Transplants were acutely rejected in all the monkeys with high numbers of donor-specific TMEMs before transplantation. In contrast, long-term survival was observed in the recipients harboring lower frequencies of anti-donor TMEMs before transplantation. Similar amounts of TMEM homeostatic expansion were recorded in all transplanted monkeys upon hematopoietic reconstitution; however, only the tolerant monkeys had no expansion or activation of donor-reactive TMEMs after transplantation. These results indicate that the presence of high frequencies of host donor-reactive TMEMs before transplantation impairs tolerance induction to kidney allografts in this nonhuman primate model. Indeed, recipients harboring a low anamnestic reactivity to their donor before transplantation were successfully rendered tolerant via infusion of donor cells and short-term immunosuppression. This suggests that selection of allogeneic donors with low memory responses in recipients may be essential to successful transplant tolerance induction in patients.

Cardiac Allograft Vasculopathy Is Abrogated by Anti-CD8 Monoclonal Antibody Therapy

BACKGROUND Cardiac allograft vasculopathy, a diffuse and accelerated form of arteriosclerosis, is a major cause of graft loss or heart transplant recipient death after the first transplant year. This study examined the effects of depleting host CD8 + T lymphocytes on the development of cardiac allograft vasculopathy in miniature swine. METHODS Cardiac allografts were heterotopically transplanted across a major histocompatibility complex class I barrier in partially inbred miniature swine and monitored for rejection by serial biopsies, electrocardiograms, and echocardiograms. Four control animals received cyclosporine on postoperative days 0 to 11. Another four miniswine were given 14.5 mg/kg of 76-2-11 (a mouse anti-swine CD8 monoclonal antibody) on postoperative day 0, in addition to a 12-day course of cyclosporine. Host CD8+ T cells and circulating 76-2-11 monoclonal antibodies were monitored by flow cytometry. RESULTS As compared with cyclosporine-treated control animals, swine receiving 76-2-11 demonstrated near-complete depletion of peripheral CD8+ T cells by postoperative day 2, which persisted for 14 to 18 days. Mean allograft survival of the antibody-treated group and the control group was not statistically different (33 days versus 39 days, respectively) and both groups demonstrated severe interstitial rejection at necropsy. Control animals demonstrated florid intimal thickening of large and small arteries at necropsy. However, swine treated with 76-2-11 showed no intimal proliferation. CONCLUSIONS Depletion of host CD8+ T cells prevents or delays the development of intimal proliferation in miniature swine. CD8+ lymphocytes play an important role in the early development of cardiac allograft vasculopathy in large animals.

Benign broncho-esophageal fistula in the adult

BACKGROUND Benign broncho-esophageal fistula (BEF) in the adult is rare, and occurs as a complication of inflammatory disorders, foreign body ingestion, or congenital anomalies. Nonspecific symptoms lead to a delay in diagnosis. METHODS The charts of 13 patients from 1960 to 2001 at the Massachusetts General Hospital were retrospectively reviewed. RESULTS Nine patients had chronic cough, which worsened upon ingestion. Four patients developed BEF after prior thoracic surgery, and 3 after histoplasmosis. Silicosis, foreign body ingestion, lye ingestion, bronchogenic cyst, esophageal diverticulum, and a congenital anomaly caused BEF in 1 patient each. Barium swallow was the most useful diagnostic test. Fistulas most often arose from the right bronchial tree and communicated with the distal esophagus. Management involved excision of the tract, primary closure of the bronchus and esophagus, and interposition of vascularized tissue. There was one perioperative failure, but no long-term recurrences after successful surgical closure. CONCLUSIONS The majority of benign BEF in adults are acquired, and result from mediastinal inflammation. Accurate recognition and surgical closure prevents persistent uncontrolled aspiration and pulmonary sepsis.

Comparison of perioperative outcomes following open versus minimally invasive Ivor Lewis oesophagectomy at a single, high-volume centre

OBJECTIVES With the increasing popularity of minimally invasive oesophageal resections, equivalence, if not superiority, to open techniques must be demonstrated. Here we compare our open and minimally invasive Ivor Lewis oesophagectomy (MIE) experience. METHODS A prospective database of all oesophagectomies performed at Massachusetts General Hospital in Boston, MA between November 2007 and January 2011 was analysed. A total of 38 MIE and 76 open Ivor Lewis (OIE) oesophagectomies were performed for oesophageal carcinoma. Sixty-day surgical, oncological and postoperative outcomes were examined between the two groups. RESULTS Groups had similar demographics in terms of age, gender, tumour histology, clinical stage, preoperative comorbidities and neoadjuvant therapy. No difference was found with respect to adequacy of oncological resections. The median number of lymph nodes retrieved (OIE: 21, inter-quartile range (IQR): (16, 27) versus MIE: 19, IQR: (15, 28)), resection margins (OIE: 6.6% positive versus MIE: no positive margins) and 60-day mortality (OIE: 2.6% versus MIE: no deaths) were comparable. However, rates of pulmonary complications were significantly lower in the MIE group (OIE: 43.4 versus MIE: 2.6%, P < 0.001). Additionally, the median length of ICU and hospital stay, intraoperative blood loss and amount of intravenous fluids infused intraoperatively were also significantly decreased with MIE, while median operative times and the requirement for intraoperative blood transfusion were not significantly different between the two groups. Multivariate logistic regression analysis identified MIE as the only variable associated with a significant reduction in the rate of pulmonary complications in our study, while pre-existing pulmonary comborbidity was associated with an increased risk of pulmonary complications. CONCLUSIONS Open and MIE appear equivalent with regard to early oncological outcomes. A minimally invasive approach, however, appears to lead to a significant reduction in the rate of postoperative pulmonary complications. Length of ICU and hospital stay, as well as intraoperative blood loss and intravenous fluid requirements are also reduced in the setting of MIE. Long-term survival data will need to be followed closely. A large, multi-centred, randomized, controlled trial is warranted to confirm these results.