Andrew J. Meltzer

Accuracy of Axillary Sentinel Lymph Node Biopsy Following Neoadjuvant (Induction) Chemotherapy for Carcinoma of the Breast

Abstract: Sentinel lymph node biopsy (SLNB) is widely employed to detect axillary lymph node metastases in breast cancer patients with clinically negative (N0) axillae. One of the few reported contraindications to SLNB is prior treatment with systemic chemotherapy (neoadjuvant/induction chemotherapy). Previous investigators reported difficulty identifying the sentinel node and an unacceptable false‐negative rate in this patient cohort. We present one experienced surgeons experience with SLNB following induction chemotherapy (n = 21). Following treatment with Adriamycin and Cytoxan (AC)‐based cyclic chemotherapy, patients underwent SLNB, followed by levels I and II axillary lymph node dissection (ALND). At least one sentinel node was identified in all patients (100%). With respect to metastatic disease, the status of the sentinel node(s) accurately reflected the status of the axilla in 20 of 21 patients (95%). Eleven patients (52%) had axillary metastases identified by ALND. Of this group, SLNB failed to identify metastatic disease in one patient (9%). Previous treatment with induction chemotherapy should not be considered an absolute contraindication to SLNB. An experienced surgeon may utilize the technique in these patients, sparing them the added morbidity of axillary dissection.u2002

Repetitive Gastric Aspiration Leads to Augmented Indirect Allorecognition after Lung Transplantation in Miniature Swine

Introduction. Lung transplant recipients with documented gastroesophageal reflux disease (GERD) are at increased risk for graft dysfunction. Here, we present the first large-animal model of gastric aspiration after allogeneic lung transplantation and some preliminary data demonstrating the effect of chronic aspiration on the direct and indirect pathways of allorecognition. Methods. Left orthotopic lung transplants (n=3) were performed in miniature swine across a major histocompatibility complex class I disparity, followed by 12 days of high-dose cyclosporine A. At the time of transplantation, a transtracheal catheter was placed at the carina, above the bronchial anastomosis. A gastrostomy tube was placed for daily aspiration of gastric contents. Subsequently, graft lungs were instilled with gastric aspirate daily (3 mL/hr×8 hr/day) for 50 days. Recipients were followed up with daily complete blood count, scheduled chest radiographs, and biopsies. In vitro studies, including cell-mediated lympholysis, mixed lymphocyte reactions, and peptide proliferation assays, were performed. Results from these three recipients were compared with those of historical controls (n=6) who were treated identically, except for the tracheal cannulation and simulated gastric aspiration. Results. Two of the experimental animals were euthanized with nonviable lungs soon after the postoperative day 50 biopsy. In both cases the native lung was normal. The third animal survived over 180 days without the evidence of chronic rejection. After immunosuppressive treatment, all animals demonstrated donor-specific hyporesponsiveness by assays of direct alloresponse (cell-mediated lympholysis, mixed lymphocyte reaction). A significant response to synthetic donor-derived class I peptide, however, was seen in all animals. A more pronounced and diffuse response was seen in the animals rejecting their grafts. The historical controls showed medium-term graft survival with evidence of chronic rejection in the majority of animals, as previously reported. Conclusion. In a model of GERD after lung transplantation, a spectrum of clinical outcomes was observed. The in vitro data suggest that acid reflux enhances the indirect alloresponse to processed donor class I antigen, giving mechanistic insight into the manner in which GERD may be deleterious to the transplanted lung.

The Indirect Alloresponse Impairs the Induction but not Maintenance of Tolerance to MHC Class I-Disparate Allografts

We studied the effects of indirect allorecognition on the induction and maintenance phases of tolerance in miniature swine cotransplanted with heart and kidney allografts. MHC class I‐mismatched heart and kidney grafts were cotransplanted in recipients receiving CyA for 12 days. Recipients were unimmunized or immunized with a set of donor‐derived or control third‐party MHC class I peptides either 21 days prior to transplantation or over 100 days after transplantation. T‐cell proliferation, delayed type hypersensitivity reaction (DTH) and antibody production were assessed. All animals injected with donor MHC class I peptides developed potent indirect alloresponses specific to the immunizing peptides. While untreated recipients developed stable tolerance, all animals preimmunized with donor allopeptides rejected kidney–heart transplants acutely. In contrast, when peptide immunization was delayed until over 100 days after kidney–heart transplantation, no effects were observed on graft function or in vitro measures of alloimmunity. Donor peptide immunization prevented tolerance when administered to recipients pre transplantation but did not abrogate tolerance when administered to long‐term survivors post transplantation. This suggests that the presence of T cells activated via indirect allorecognition represent a barrier to the induction but not the maintenance of tolerance.

Autoimmune sensitization to cardiac myosin leads to acute rejection of cardiac allografts in miniature swine

Background. Recent studies in mice and patients suggest that posttransplantation induction of autoimmune responses to tissue-specific antigens contributes to the rejection of major histocompatibility complex mismatched allotransplants. The relevance of this phenomenon to the rejection of major and minor histocompatibility-mismatched allografts performed in large-animal models remains to be established. Methods. Miniature swine were immunized with cardiac myosin (CM) in Freunds adjuvant and received heterotopic, minor antigen-mismatched heart transplants. T-cell (proliferation and delayed type hypersensitivity [DTH]) and B-cell (antibody) responses specific to CM were measured. The rejection of heart transplants was assessed histologically. Results. Three of four swine that were immunized with CM before receiving a minor antigen-mismatched heart transplant exhibited potent DTH, T-cell proliferation and antibody responses to CM and rejected their grafts acutely. The fourth swine, which failed to mount a significant DTH response to CM and displayed low and transient anti-CM antibody titers, demonstrated long-term allograft survival. Conclusions. This large-animal study supports the relevance of autoimmunity to CM in the rejection of minor antigen disparate cardiac allotransplants.

Donor Brain Death Inhibits Tolerance Induction in Miniature Swine Recipients of Fully MHC‐Disparate Pulmonary Allografts

We have previously shown that a short course of high‐dose tacrolimus induces long‐term tolerance to fully mismatched lung allografts procured from healthy MHC‐inbred miniature swine. Here, we investigate whether donor brain death affects tolerance induction. Four recipient swine were transplanted with fully mismatched lung grafts from donors that were rendered brain dead and mechanically ventilated for 4 h before procurement (Group 1). These recipients were compared to two control groups (Group 2: 4 h of donor ventilation without brain death [n = 5]; and Group 3: no donor brain death with <1 h of ventilation [n = 6]). All recipients were treated with a 12‐day course of tacrolimus. In contrast to both groups of control animals, the swine transplanted with lung allografts from brain dead donors all rejected their grafts by postoperative day 45 and showed persistent responsiveness to donor antigen by MLR. Several additional swine underwent brain death induction and/or mechanical ventilation alone to determine the effects of these procedures on the expression of proinflammatory molecules. Significant increases in serum concentrations of IL‐1, TNF‐α and IL‐10 were seen after brain death. Upregulation of IL‐1 and IL‐6 gene expression was also observed.

Surgical residency, class of 2010: the kids are all right.

GERY CLASS OF 2010 has the dubious distinction of being the first class to complete the surgical residency program (‘‘The Program’’) under the Accreditation Council on Graduate Medical Education (ACGME) duty hour restrictions, colloquially known as the ‘‘80-hour work week.’’ It is likely that many among this publication’s readership will consider this class, and all subsequent alumni, to be graduates of a modified and less challenging surgical training program. Some may even suggest that future certificates of completion and curriculum vitae should designate our trifling accomplishment in some special manner---an asterisk, for example, as proposed for the Roger Maris(*) or Barry Bonds(*) records. Alternatively, it would be very much in line with The (MGH) Program’s New England heritage to embellish our short, white jackets with a scarlet ‘‘80’’ to remind all witnesses of our sins. Whichever method is chosen, we alumni of The Program can agree that some distinction must be made. After all, it is abundantly clear that the residents are not what they used to be. (I will ignore, for now, former Program Director Charlie Ferguson’s rejoinder: ‘‘That’s okay; neither is the staff.’’) At present, a medical literature search of ‘‘resident work hours’’ yields over 500 recent publications. Unfortunately, duty hour restrictions prohibited me from spending much time reading about this work-related topic. As a surgeon, however, I cannot let my ignorance of the actual data prevent me from voicing an opinion and adding to the ongoing hullaballoo about restrictions in resident work hours. For better or worse, this topic has been a critical issue throughout the residency of the class of 2010.