Jonathan D’Cunha

Esophageal stents for anastomotic leaks and perforations

OBJECTIVE Intrathoracic esophageal anastomotic leaks and perforations are very morbid and challenging problems. Esophageal stents are increasingly playing an integral role in the management of these patients. Our objective was to report our experience with esophageal stent placement for anastomotic leaks and perforations and to provide a treatment algorithm. METHODS We performed a review of patients with stent placement for esophagogastric anastomotic leaks or esophageal perforation from March 2005 to August 2009. A prospective database was used to collect data. Success was defined as endoscopic defect closure, negative esophagram, and resumption of oral intake. Failure was defined as no change in leak size or clinical signs of ongoing infection. We collected and analyzed patient demographics, diagnosis, clinical history, and poststent outcomes using descriptive statistics. RESULTS Thirty-seven patients underwent esophageal stent placement for anastomotic leaks (n = 22) and perforations (n = 15). The median time from original procedure to diagnosis of leak or perforation was 6 days (0-420 days). Nineteen patients (51%) had 21 associated procedures for source control. We placed 94 stents (mean = 2.7 stents/patient); 16 patients (43%) required more than 1 stenting procedure (mean = 1.8 procedures/patient). The median time to restoration of esophageal integrity was 33 days (7-120 days). There were 22 successes (59%); 2 failures were secondary to undrained abscess. Only 2 failures occurred in the last 15 patients (88% success). Strictures did not develop in any patients. Serious complications occurred in 3 patients (stent erosion, leak enlargement, fatal gastroaortic fistula). CONCLUSIONS Esophageal stents can potentially play an integral role in the management of anastomotic leaks and perforations. Success depends on appropriate procedures for source control and surgeon experience.

De novo donor-specific HLA antibodies are associated with early and high-grade bronchiolitis obliterans syndrome and death after lung transplantation

BACKGROUND The development of human leukocyte antigen (HLA) antibody responses has been associated with worse clinical outcomes, such as bronchiolitis obliterans syndrome (BOS) and death, in lung transplant recipients (LTRs). However, the role of donor-specific HLA antibody (DSA) responses as a risk factor for poor outcomes remains controversial. METHODS We prospectively screened 445 LTRs for DSA at our institution at the time of surveillance bronchoscopies for the first 2 years after transplantation between 2003 and 2008, and evaluated clinical outcomes. For this purpose, we used the combination of panel-reactive antibodies (PRA) by enzyme-linked immunosorbent assay (ELISA) and the Luminex single-antigen bead (SAB) assay (One Lambda, Canoga Park, CA). RESULTS We detected de novo DSA (dnDSA) in 58 of 445 (13%) LTRs in our cohort. Freedom from BOS was significantly reduced in LTRs with dnDSA versus those without dnDSA (p < 0.001). Using a Cox proportional hazards model, the development of dnDSA was associated with a significantly increased hazard ratio (HR = 6.59 [4.53 to 9.59]; p < 0.001) for BOS and high-grade BOS (Stage ≥ 2) (HR = 5.76 [3.48 to 9.52]; p < 0.001). Freedom from death was significantly reduced in LTRs with dnDSA (p < 0.001), including mortality attributable to BOS (HR = 9.86 [4.91 to 19.78]; p < 0.001). CONCLUSIONS Taken together, our findings provide evidence that dnDSA is associated with accelerated BOS kinetics and severity, as well as death due to BOS after lung transplantation. In addition, these data support regular monitoring for the development of dnDSA in LTRs and underscore the need for novel strategies to mitigate the increased risk of poor outcomes associated with dnDSA.

VATS Lobectomy Has Better Perioperative Outcomes Than Open Lobectomy: CALGB 31001, an Ancillary Analysis of CALGB 140202 (Alliance)

BACKGROUND The short-term superiority of video-assisted thoracoscopic surgery lobectomy compared with open lobectomy for early-stage lung cancer has been suggested by single-institution studies. Lack of equipoise limits the feasibility of a randomized study to confirm this. The hypothesis of this study (CALGB 31001) was that VATS lobectomy results in shorter length of hospital stay and fewer complications compared with open lobectomy in stages I and II non-small cell lung cancer in a multi-institutional setting. METHODS Five hundred nineteen patients whose tumors had been collected as part of CALGB 140202 (lung cancer tissue bank) were eligible. Propensity-scoring using age, race, sex, performance status, comorbidities, histology, tumor stage, and size as independent variables was used to create a 1:1 matched group of 175 pairs of patients. McNemars test for binary variables and Wilcoxon signed-rank test for continuous variables were used to assess differences in length of hospital stay, complications, and discharge dispositions between the groups. Comparison of disease-free and overall survival between the two approaches was done using the log-rank test. Probability values of less than 0.05 were considered significant. RESULTS The matched data on length of hospital stay, complications, and discharge dispositions significantly favored the video-assisted thoracoscopic surgery group. There was no statistically significant difference in survival between the two approaches. CONCLUSIONS This multi-institutional study supports the assertion that thoracoscopic lobectomy results in shorter hospital length of stay, fewer perioperative complications, and greater likelihood of independent home discharge compared with open lobectomy for early-stage lung cancer. Survival was comparable between the two groups.

Minnelide: A Novel Therapeutic That Promotes Apoptosis in Non-Small Cell Lung Carcinoma In Vivo

Background Minnelide, a pro-drug of triptolide, has recently emerged as a potent anticancer agent. The precise mechanisms of its cytotoxic effects remain unclear. Methods Cell viability was studied using CCK8 assay. Cell proliferation was measured real-time on cultured cells using Electric Cell Substrate Impedence Sensing (ECIS). Apoptosis was assayed by Caspase activity on cultured lung cancer cells and TUNEL staining on tissue sections. Expression of pro-survival and anti-apoptotic genes (HSP70, BIRC5, BIRC4, BIRC2, UACA, APAF-1) was estimated by qRTPCR. Effect of Minnelide on proliferative cells in the tissue was estimated by Ki-67 staining of animal tissue sections. Results In this study, we investigated in vitro and in vivo antitumor effects of triptolide/Minnelide in non-small cell lung carcinoma (NSCLC). Triptolide/Minnelide exhibited anti-proliferative effects and induced apoptosis in NSCLC cell lines and NSCLC mouse models. Triptolide/Minnelide significantly down-regulated the expression of pro-survival and anti-apoptotic genes (HSP70, BIRC5, BIRC4, BIRC2, UACA) and up-regulated pro-apoptotic APAF-1 gene, in part, via attenuating the NF-κB signaling activity. Conclusion In conclusion, our results provide supporting mechanistic evidence for Minnelide as a potential in NSCLC.

Delayed chest closure after lung transplantation: Techniques, outcomes, and strategies

BACKGROUND Delayed chest closure (DCC) after lung transplantation is a viable option to be taken in the cases of prolonged cardiopulmonary bypass time, prolonged ischemic time, coagulopathic problems or oversized donor lung grafts. Decision-making for DCC in the operating room remains challenging to surgeons, because the impact of DCC on outcomes after lung transplantation has not yet been fully elucidated. METHODS We performed a retrospective review of 90 lung transplantations with DCC and 783 cases with primary chest closure to clarify the reasons for DCC, complications of DCC, and the risk factors for adverse outcomes. RESULTS The 30- and 90-day mortality in the DCC group was 7.8% and 9.9%, respectively. Early post-operative bleeding and severe primary graft dysfunction (PGD) were higher in the DCC group (p<0.05). In multivariate analysis, prolonged cardiopulmonary bypass use (>4 hours), post-operative extracorporeal oxygen requirement and use of a DCC technique with open skin and retracted ribs were significantly associated with mortality (p<0.05), whereas prolonged duration of DCC was not. In a matched cohort study to compare the results of a DCC technique with skin closure to similarly matched controls with primary closure, DCC contributed to significantly decreased incidence of severe PGD (9.6% vs. 26%, p<0.05), leading to an improved post-transplant survival and functional status as compared with primary closure. CONCLUSIONS Our technical approaches to prevent possible problems in DCC cases are described. DCC can be safely performed with acceptable procedure-related risks. DCC should not be considered a sub-optimal option after lung transplantation.

Detection of Occult Micrometastases in Patients With Clinical Stage I Non–Small-Cell Lung Cancer: A Prospective Analysis of Mature Results of CALGB 9761 (Alliance)

PURPOSE Outcomes after resection of stage I non-small-cell lung cancer (NSCLC) are variable, potentially due to undetected occult micrometastases (OM). Cancer and Leukemia Group B 9761 was a prospectively designed study aimed at determining the prognostic significance of OM. MATERIALS AND METHODS Between 1997 and 2002, 502 patients with suspected clinical stage I (T1-2N0M0) NSCLC were prospectively enrolled at 11 institutions. Primary tumor and lymph nodes (LNs) were collected and sent to a central site for molecular analysis. Both were assayed for OM using immunohistochemistry (IHC) for cytokeratin (AE1/AE3) and real-time reverse transcriptase polymerase chain reaction (RT-PCR) for carcinoembryonic antigen. RESULTS Four hundred eighty-nine of the 502 enrolled patients underwent complete surgical staging. Three hundred four patients (61%) had pathologic stage I NSCLC (T1, 58%; T2, 42%) and were included in the final analysis. Fifty-six percent had adenocarcinomas, 34% had squamous cell carcinomas, and 10% had another histology. LNs from 298 patients were analyzed by IHC; 41 (14%) were IHC-positive (42% in N1 position, 58% in N2 position). Neither overall survival (OS) nor disease-free survival was associated with IHC positivity; however, patients who had IHC-positive N2 LNs had statistically significantly worse survival rates (hazard ratio, 2.04, P = .017). LNs from 256 patients were analyzed by RT-PCR; 176 (69%) were PCR-positive (52% in N1 position, 48% in N2 position). Neither OS nor disease-free survival was associated with PCR positivity. CONCLUSION NSCLC tumor markers can be detected in histologically negative LNs by AE1/AE3 IHC and carcinoembryonic antigen RT-PCR. In this prospective, multi-institutional trial, the presence of OM by IHC staining in N2 LNs of patients with NSCLC correlated with decreased OS. The clinical significance of this warrants further investigation.

The surgical technique of bilateral sequential lung transplantation

Since the first successful lung transplant performed three decades ago, the technique of lung transplantation has evolved with acceptable short- and long-term outcomes such that it has become the standard for those with end stage pulmonary disease. Herein, we describe our current favored approach and discuss some of the current areas in need of further investigation as they relate to the technical aspects of the operation.

Diaphragmatic hernias after sequential left ventricular assist device explantation and orthotopic heart transplant: early results of laparoscopic repair with polytetrafluoroethylene.

OBJECTIVE Patients who undergo an orthotopic heart transplant after explantation of an intraperitoneal left ventricular assist device are at an increased risk of developing diaphragmatic hernias. The aim of this study was to determine the incidence of these hernias and to evaluate the morbidity and short-term efficacy of laparoscopic repair. METHODS Using our prospectively maintained database, we performed a single-institution, retrospective review of all patients who underwent laparoscopic repair of a diaphragmatic hernia resulting from defects created by left ventricular assist device explantation. RESULTS From January 1, 1995 to March 1, 2007, 5 men at our institution (median age, 56 years) out of 97 patients at risk developed a diaphragmatic hernia after left ventricular assist device explantation (5.2% incidence). The median time to presentation was 25.4 months (range, 9-62 months). The median size of the hernia defect was 8 cm (range, 6-15 cm). We performed all repairs completely laparoscopically. None of the defects were repaired primarily because doing so would have resulted in significant tension. Instead, we secured a polytetrafluoroethylene patch over the defect with pledget-reinforced, braided, nonabsorbable, handsewn mattress sutures, followed by reinforcement with laparoscopic tacking screws. We noted no perioperative complications. The median length of stay was 2 days (range, 1-4 days). At a median follow-up period of 12.2 months (range, 1-31 months), no recurrences had occurred. CONCLUSION Laparoscopic repair of diaphragmatic hernias with polytetrafluoroethylene can be performed with minimal morbidity and excellent short-term results.

Minnelide/Triptolide Impairs Mitochondrial Function by Regulating SIRT3 in P53-Dependent Manner in Non-Small Cell Lung Cancer.

Minnelide/Triptolide (TL) has recently emerged as a potent anticancer drug in non-small cell lung cancer (NSCLC). However, the precise mechanism of its action remains ambiguous. In this study, we elucidated the molecular basis for TL-induced cell death in context to p53 status. Cell death was attributed to dysfunction of mitochondrial bioenergetics in p53-deficient cells, which was characterized by decreased mitochondrial respiration, steady-state ATP level and membrane potential, but augmented reactive oxygen species (ROS). Increased ROS production resulted in oxidative stress in TL-treated cells. This was exhibited by elevated nuclear levels of a redox-sensitive transcriptional factor, NF-E2-related factor-2 (NRF2), along with diminished cellular glutathione (GSH) content. We further demonstrated that in the absence of p53, TL blunted the expression of mitochondrial SIRT3 triggering increased acetylation of NDUAF9 and succinate dehydrogenase, components of complexes I and II of the electron transport chain (ETC). TL-mediated hyperacetylation of complexes I and II proteins and these complexes displayed decreased enzymatic activities. We also provide the evidence that P53 regulate steady-state level of SIRT3 through Proteasome-Pathway. Finally, forced overexpression of Sirt3, but not deacetylase-deficient mutant of Sirt3 (H243Y), restored the deleterious effect of TL on p53-deficient cells by rescuing mitochondrial bioenergetics. On contrary, Sirt3 deficiency in the background of wild-type p53 triggered TL-induced mitochondrial impairment that echoed TL effect in p53-deficeint cells. These findings illustrate a novel mechanism by which TL exerts its potent effects on mitochondrial function and ultimately the viability of NSCLC tumor.

Lung transplantation after hematopoietic stem cell transplantation

Whitson BA, Shelstad RC, Hertz MI, Kelly RF, D’Cunha J, Shumway SJ. Lung transplantation after hematopoietic stem cell transplantation. 
Clin Transplant 2011 DOI: 10.1111/j.1399‐0012.2011.01482.x. 
© 2011 John Wiley & Sons A/S.