Matthew G. Hartwig

Neoadjuvant chemoradiation for rectal cancer: analysis of clinical outcomes from a 13-year institutional experience.

ObjectiveTo examine clinical outcomes in patients receiving neoadjuvant chemoradiation for locally advanced rectal adenocarcinoma. Summary Background DataPreoperative radiation therapy, either alone or in combination with 5-fluorouracil-based chemotherapy, has proven both safe and effective in the treatment of rectal cancer. However, data are lacking regarding which subgroups of patients benefit from the therapy in terms of decreased local recurrence and increased survival rates. MethodsA retrospective chart review was performed on 141 consecutive patients who received neoadjuvant chemoradiation (5-fluorouracil ± cisplatin and 4,500–5,040 cGy) for biopsy-proven locally advanced adenocarcinoma of the rectum. Surgery was performed 4 to 8 weeks after completion of chemoradiation. Standard statistical methods were used to analyze recurrence and survival. ResultsMedian follow-up was 27 months, and mean age was 59 years (range 28–81). Mean tumor distance from the anal verge was 6 cm (range 1–15). Of those staged before surgery with endorectal ultrasound or magnetic resonance imaging, 57% of stage II patients and 82% of stage III patients were downstaged. The chemotherapeutic regimens were well tolerated, and resections were performed on 140 patients. The percentage of sphincter-sparing procedures increased from 20% before 1996 to 76% after 1996. On pathologic analysis, 24% of specimens were T0. However, postoperative pathologic T stage had no effect on either recurrence or survival. Positive lymph node status predicted increased local recurrence and decreased survival. ConclusionsNeoadjuvant chemoradiation is safe, effective, and well tolerated. Postoperative lymph node status is the only independent predictor of recurrence and survival.

Active Rehabilitation During Extracorporeal Membrane Oxygenation as a Bridge to Lung Transplantation

BACKGROUND: Patients with end-stage lung disease often progress to critical illness, which dramatically reduces their chance of survival following lung transplantation. Pre-transplant deconditioning has a significant impact on outcomes for all lung transplant patients, and is likely a major contributor to increased mortality in critically ill lung transplant recipients. The aim of this report is to describe a series of patients bridged to lung transplant with extracorporeal membrane oxygenation (ECMO) and to examine the potential impact of active rehabilitation and ambulation during pre-transplant ECMO. METHODS: This retrospective case series reviews all patients bridged to lung transplantation with ECMO at a single tertiary care lung transplant center. Pre-transplant ECMO patients receiving active rehabilitation and ambulation were compared to those patients who were bridged with ECMO but did not receive pre-transplant rehabilitation. RESULTS: Nine consecutive subjects between April 2007 and May 2012 were identified for inclusion. One-year survival for all subjects was 100%, with one subject alive at 4 months post-transplant. The 5 subjects participating in pre-transplant rehabilitation had shorter mean post-transplant mechanical ventilation (4 d vs 34 d, P = .01), ICU stay (11 d vs 45 d, P = .01), and hospital stay (26 d vs 80 d, P = .01). No subject who participated in active rehabilitation had post-transplant myopathy, compared to 3 of 4 subjects who did not participate in pre-transplant rehabilitation on ECMO. CONCLUSIONS: Bridging selected critically ill patients to transplant with ECMO is a viable treatment option, and active participation in physical therapy, including ambulation, may provide a more rapid post-transplantation recovery. This innovative strategy requires further study to fully evaluate potential benefits and risks.

Role of flow cytometry to define unacceptable HLA antigens in lung transplant recipients with HLA-specific antibodies

Background. Antidonor HLA-specific antibodies have been associated with hyperacute rejection and primary graft failure in lung transplant recipients. Thus, transplant candidates with HLA-specific antibodies generally undergo prospective crossmatching to exclude donors with unacceptable HLA antigens. However, the need to perform a prospective crossmatch limits the donor pool and is associated with increased waiting list times and mortality. A virtual crossmatch strategy using flow cytometry, which enables precise determination of HLA-specific antibody specificity, was compared to prospective crossmatching in sensitized lung transplant candidates. Methods. In all, 341 lung transplant recipients were analyzed retrospectively (April 1992 to July 2003). Sixteen patients with HLA-specific antibodies underwent transplantation based on flow cytometric determination of antibody specificity and 10 underwent prospective crossmatching. Results. Freedom from bronchiolitis obliterans syndrome (BOS) at three years was similar in those undergoing a virtual crossmatch, those undergoing prospective crossmatching, and those without HLA-specific antibodies (80.4%±13.4, 85.7%±13.2, and 73.8%±2.8, respectively, P=0.88). Three-year survival was also comparable (87.5%±8.3, 70.0%±14.5, and 78.5%±2.4, respectively, P=0.31). Elimination of prospective crossmatching for sensitized patients was associated with a significant decrease in time on the waiting list (P<0.01) and in waiting list mortality (P<0.05). All 16 patients undergoing a virtual crossmatch had negative retrospective crossmatches. Conclusions. By carefully determining the specificity of HLA-specific antibodies, flow cytometry methodologies enable the prediction of negative crossmatch results with up to 100% accuracy, enabling the determination of appropriateness of donors. Using this virtual crossmatch strategy, crossmatching can be safely omitted prior to lung transplantation, thereby decreasing waiting list time and mortality rates for candidates with HLA-specific antibodies.

Fundoplication After Lung Transplantation Prevents the Allograft Dysfunction Associated With Reflux

BACKGROUND Gastroesophageal reflux disease (GERD) in lung recipients is associated with decreased survival and attenuated allograft function. This study evaluates fundoplication in preventing GERD-related allograft dysfunction. METHODS Prospectively collected data on patients who underwent transplantation between January 2001 and August 2009 were included. Lung transplant candidates underwent esophageal pH probe testing before transplantation and surveillance spirometry evaluation after transplantation. Bilateral lung transplant recipients who had pretransplant pH probe testing and posttransplant 1-year forced expiratory volume in the first second of expiration (FEV1) data were included for analysis. RESULTS Of 297 patients who met study criteria, 222 (75%) had an abnormal pH probe study before or early after transplantation and 157 (53%) had a fundoplication performed within the first year after transplantation. Patients with total proximal acid contact times greater than 1.2% or total distal acid contact times greater than 7.0% demonstrated an absolute decrease of 9.4% (±4.6) or 12.0% (±5.4) in their respective mean 1-year FEV1 values. Patients with abnormal acid contact times who did not undergo fundoplication had considerably worse predicted peak and 1-year FEV1 results compared with recipients receiving fundoplication (peak percent predicted=75% vs. 84%; p=0.004 and 1-year percent predicted=68% vs. 77%; p=0.003, respectively). CONCLUSIONS Lung transplant recipients with abnormal esophageal pH studies attain a lower peak allograft function as well as a diminished 1-year FEV1 after transplantation. However a strategy of early fundoplication in these recipients appears to preserve lung allograft function.

Improved Survival but Marginal Allograft Function in Patients Treated With Extracorporeal Membrane Oxygenation After Lung Transplantation

BACKGROUND Previous reports demonstrate that 1-year survival is severely compromised in patients with severe primary graft dysfunction (PGD) after lung transplantation. We examined if advances in extracorporeal membrane oxygenation (ECMO) support, including polymethylpentene oxygenators and reliance on venovenous (VV) ECMO have improved outcomes in patients with severe PGD after lung transplantation. METHODS The analysis included data prospectively collected on all single-lung or double-lung transplants between November 2001 and December 2009. Heart-lung transplants were excluded. Comparisons were made between recipients who did and did not require ECMO for PGD after transplant. RESULTS Since November 2001, when VV ECMO became the routine treatment for severe PGD after transplant at our center, 28 of 498 patients (6%) have required VV ECMO support. Successful weaning occurred in 27 of 28 (96%). Support was withdrawn for 1 patient with irreversible neurologic injury. Survival was substantially better than in previous reports: 30 days, 82%; 1 year, 64%; and 5 years, 49%. Freedom from bronchiolitis obliterans syndrome was 88% in the ECMO survivors at 3 years, but maximum allograft function was considerably worse than in transplant recipients not requiring ECMO (peak forced expiratory volume in 1 second: 58% in ECMO vs 83% in non-ECMO, p=0.001). CONCLUSIONS Advances in ECMO technology, particularly VV ECMO, have greatly improved the ability to support patients with severe PGD after lung transplantation. VV ECMO is an important tool in the armamentarium of any lung transplant program to optimize patient outcomes; however, strategies to improve lung allograft function in patients experiencing severe PGD are still needed.

Characterization of the innate immune response to chronic aspiration in a novel rodent model

BackgroundAlthough chronic aspiration has been associated with several pulmonary diseases, the inflammatory response has not been characterized. A novel rodent model of chronic aspiration was therefore developed in order to investigate the resulting innate immune response in the lung.MethodsGastric fluid or normal saline was instilled into the left lung of rats (n = 48) weekly for 4, 8, 12, or 16 weeks (n = 6 each group). Thereafter, bronchoalveolar lavage specimens were collected and cellular phenotypes and cytokine concentrations of IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, GM-CSF, IFN-gamma, TNF-alpha, and TGF-beta were determined.ResultsFollowing the administration of gastric fluid but not normal saline, histologic specimens exhibited prominent evidence of giant cells, fibrosis, lymphocytic bronchiolitis, and obliterative bronchiolitis. Bronchoalveolar lavage specimens from the left (treated) lungs exhibited consistently higher macrophages and T cells with an increased CD4:CD8 T cell ratio after treatment with gastric fluid compared to normal saline. The concentrations of IL-1alpha, IL-1beta, IL-2, TNF-alpha and TGF-beta were increased in bronchoalveolar lavage specimens following gastric fluid aspiration compared to normal saline.ConclusionThis represents the first description of the pulmonary inflammatory response that results from chronic aspiration. Repetitive aspiration events can initiate an inflammatory response consisting of macrophages and T cells that is associated with increased TGF-beta, TNF-alpha, IL-1alpha, IL-1beta, IL-2 and fibrosis in the lung. Combined with the observation of gastric fluid-induced lymphocyitic bronchiolitis and obliterative bronchiolitis, these findings further support an association between chronic aspiration and pulmonary diseases, such as obliterative bronchiolitis, pulmonary fibrosis, and asthma.

Chronic Aspiration of Gastric Fluid Induces the Development of Obliterative Bronchiolitis in Rat Lung Transplants

Long‐term survival of a pulmonary allograft is currently hampered by obliterative bronchiolitis (OB), a form of chronic rejection that is unique to lung transplantation. While tracheobronchial aspiration from gastroesophageal reflux disease (GERD) has clinically been associated with OB, no experimental model exists to investigate this problem. Using a WKY‐to‐F344 rat orthotopic left lung transplant model, the effects of chronic aspiration on pulmonary allograft were evaluated. Recipients received cyclosporine with or without 8 weekly aspirations of gastric fluid into the allograft. Six (66.7%) of 9 allografts with aspiration demonstrated bronchioles with surrounding monocytic infiltrates, fibrosis and loss of normal lumen anatomy, consistent with the development of OB. In contrast, none of the allografts without aspiration (n = 10) demonstrated these findings (p = 0.002). Of the grafts examined grossly, 83% of the allografts with chronic aspiration but only 20% without aspiration appeared consolidated (p = 0.013). Aspiration was associated with increased levels of IL‐1α, IL‐1β, IL‐6, IL‐10, TNF‐α and TGF‐β in BAL and of IL‐1α, IL‐4 and GM‐CSF in serum. This study provides experimental evidence linking chronic aspiration to the development of OB and suggests that strategies aimed at preventing aspiration‐related injuries might improve outcomes in clinical lung transplantation.

Role of Adjuvant Therapy in a Population-Based Cohort of Patients With Early-Stage Small-Cell Lung Cancer

PURPOSE Data on optimal adjuvant therapy after complete resection of small-cell lung cancer (SCLC) are limited, and in particular, there have been no studies evaluating the role of adjuvant chemotherapy, with or without prophylactic cranial irradiation, relative to no adjuvant therapy for stage T1-2N0M0 SCLC. This National Cancer Data Base analysis was performed to determine the potential benefits of adjuvant chemotherapy with and without prophylactic cranial irradiation in patients who undergo complete resection for early-stage small-cell lung cancer. PATIENTS AND METHODS Overall survival of patients with pathologic T1-2N0M0 SCLC who underwent complete resection in the National Cancer Data Base from 2003 to 2011, stratified by adjuvant therapy regimen, was evaluated using Kaplan-Meier and Cox proportional hazards analysis. Patients treated with induction therapy and those who died within 30 days of surgery were excluded from analysis. RESULTS Of 1,574 patients who had pT1-2N0M0 SCLC during the study period, 954 patients (61%) underwent complete R0 resection with a 5-year survival of 47%. Adjuvant therapy was administered to 59% of patients (n = 566), including chemotherapy alone (n = 354), chemoradiation (n = 190, including 99 patients who underwent cranial irradiation), and radiation alone (n = 22). Compared with surgery alone, adjuvant chemotherapy with or without radiation was associated with significantly improved survival. In addition, multivariable Cox modeling demonstrated that treatment with adjuvant chemotherapy (hazard ratio [HR], 0.78; 95% CI, 0.63 to 0.95) or chemotherapy with radiation directed at the brain (HR, 0.52; 95% CI, 0.36 to 0.75) was associated with improved survival when compared with no adjuvant therapy. CONCLUSION Patients with pT1-2N0M0 SCLC treated with surgical resection alone have worse outcomes than those who undergo resection with adjuvant chemotherapy alone or chemotherapy with cranial irradiation.

Antibody Desensitization Therapy in Highly Sensitized Lung Transplant Candidates

As HLAs antibody detection technology has evolved, there is now detailed HLA antibody information available on prospective transplant recipients. Determining single antigen antibody specificity allows for a calculated panel reactive antibodies (cPRA) value, providing an estimate of the effective donor pool. For broadly sensitized lung transplant candidates (cPRA ≥ 80%), our center adopted a pretransplant multi‐modal desensitization protocol in an effort to decrease the cPRA and expand the donor pool. This desensitization protocol included plasmapheresis, solumedrol, bortezomib and rituximab given in combination over 19 days followed by intravenous immunoglobulin. Eight of 18 candidates completed therapy with the primary reasons for early discontinuation being transplant (by avoiding unacceptable antigens) or thrombocytopenia. In a mixed‐model analysis, there were no significant changes in PRA or cPRA changes over time with the protocol. A sub‐analysis of the median fluorescence intensity (MFI) change indicated a small decline that was significant in antibodies with MFI 5000–10 000. Nine of 18 candidates subsequently had a transplant. Posttransplant survival in these nine recipients was comparable to other pretransplant‐sensitized recipients who did not receive therapy. In summary, an aggressive multi‐modal desensitization protocol does not significantly reduce pretransplant HLA antibodies in a broadly sensitized lung transplant candidate cohort.

Rabbit Anti-thymocyte Globulin Induction Therapy Does Not Prolong Survival After Lung Transplantation

BACKGROUND Lung transplant survival is limited by the development of bronchiolitis obliterans syndrome (BOS). The strongest risk factor for BOS is acute rejection (AR). We have previously shown that rabbit anti-thymocyte globulin (RATG) induction therapy is associated with a decrease in early AR. Thus, we hypothesized that RATG induction would translate to reduced BOS and improved long-term graft survival. METHODS Forty-four lung recipients were prospectively randomized to receive conventional immunosuppression with RATG induction (RATG group) or conventional immunosuppression alone (control group). End-points included graft survival, early and total acute rejection, BOS and treatment complications. RESULTS There was no difference in graft survival between the groups at 8 years (RATG: 36%; control: 23%; p = 0.48). The RATG group had fewer early rejections compared with the control group (5% vs 41%; p = 0.01). However, the overall rejection incidence did not differ (RATG: 62%; control: 68%; p = 0.52). There was a trend toward a delay in BOS onset among RATG subjects compared with control subjects (2,376 days vs 1,108 days; log rank, p = 0.15). There was no difference in the incidence of infections, but the RATG group had a higher rate of malignancies. CONCLUSIONS Our results suggest that alternative approaches to anti-thymocyte induction should be pursued to reduce BOS and prolong allograft survival.