The value of disease-free survival (DFS) and osimertinib in adjuvant non-small-cell lung cancer (NSCLC): an international Delphi consensus report.

BACKGROUND: Rates of disease recurrence and death following surgery remain high in early-stage non-small-cell lung cancer (NSCLC), despite adjuvant treatment and curative intent. Recently, osimertinib showed overwhelming evidence for disease-free survival (DFS), as demonstrated by an overall reduction in the risk of disease recurrence or death in the adjuvant setting of 80% versus control in the ADAURA study (stage IB-IIIA; hazard ratio 0.20; 99.12% confidence interval 0.14-0.30; P < 0.001). However, due to the early unblinding of ADAURA and lack of mature overall survival data, there is a need to qualitatively confirm consensus on the clinical and patient relevance of DFS. MATERIALS AND METHODS: We conducted a modified Delphi panel study consisting of two rounds of surveys, followed by a consensus meeting. An international panel of experts in the field of NSCLC and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) (n = 13) was asked to rate agreement and comment on a list of pre-defined statements covering key consensus gaps. Statements were eliminated or updated between surveys, depending on the level of agreement. A final list of agreed-upon statements was drafted in the consensus meeting. RESULTS: Consensus was reached on 32 qualitative statements, with topics including unmet needs in early-stage NSCLC, the value of DFS, and the value of osimertinib. Crucially, DFS was agreed to be a clinically and patient-relevant endpoint in adjuvant NSCLC. The relevance of DFS was found to relate to the ability of an adjuvant therapy, such as osimertinib, to keep patients in the clinically valuable curative intent setting, while preventing the burden associated with distant and locoregional recurrence, and progressive disease. CONCLUSIONS: Addressing the need for measures that reflect clinical benefit is essential to continue improving outcomes for NSCLC patients. To that end, this work provides a qualitative framework for clinicians to consider the clinical and patient relevance of DFS in adjuvant NSCLC and the benefit demonstrated in ADAURA thus far.

Surgical management of chylothorax.

BACKGROUND: Chylothorax remains an uncommon but challenging clinical problem. Thoracic duct ligation is the treatment of choice for postsurgical patients. However, the optimal treatment for traumatic patients is unclear. We wanted to examine the outcomes of patients with high output or recurrent chylothorax who were treated by surgical means. METHODS: From December 1992 to April 2008, 29 patients underwent surgical procedures for high output (> 1 L/day) (16) or recurrent chylothorax (13). We analyzed these patients to determine the surgical approach, perioperative complications, and outcomes of the treatment approach. RESULTS: Of the 29 patients, 12 patients developed chylothorax following esophagectomy, in 5 patients it resulted from lymphoproliferative disorders, in 2 patients following ascending aneurysm repair, in 2 after trauma, in 3 following lung resection, and in 1 patient respectively from coronary artery bypass grafting (CABG), thymectomy for thymoma, vasculitis, and metastatic lung cancer, while 1 patient had no clear etiology. The median age of patients was 61 (range 20-79) years. 22 patients initially underwent thoracic duct ligation, 6 had talc pleurodesis, and one underwent bilateral pleuroperitoneal shunt placement. Approaches for thoracic duct ligation included: right thoracotomy (16), left thoracotomy (3), VATS (2), and right thoracotomy together with laparotomy (1). There were no intraoperative complications or deaths within 30 days or during postoperative hospitalization. The success rate after initial thoracic duct ligation was 95 % (21/22). One patient needed re-exploration after ligation with resolution of chylothorax after the second operation. The success rate after pleurodesis was 83 % (5/6). One patient after pleurodesis needed subsequent thoracic duct ligation for resolution of bilateral chylothoraces. All patients in this series had resolution of chylothorax. CONCLUSIONS: Thoracic duct ligation is the treatment of choice for high output or recurrent chylothorax with a 96 % success rate. Surgical pleurodesis is effective in some cases and may be an option for marginal patients.

Cytokine-secreting herpes viral mutants effectively treat tumor in a murine metastatic colorectal liver model by oncolytic and T-cell-dependent mechanisms.

In this model of hepatic micrometastases, the antitumor efficacy and role of the T-cell and natural killer (NK) cell populations were studied for oncolytic herpes simplex virus type-1 (HSV-1) viral mutants containing the granulocyte-monocyte colony stimulating factor (GM-CSF (NV1034)) or interluken-12 (IL-12 (NV1042)) cytokine genes. These were compared to saline and control virus (NV1023) in vitro and in vivo. HSV-1 mutants were assessed for cytotoxicity, replication and cytokine expression in CT-26 cells. A syngeneic micrometastatic liver model was then established in naive and immune cell-depleted animals to assess the antitumor efficacy of these viruses. In vitro cytotoxicity and viral replication were similar for each virus, resulting in greater than 80 and 98% cytotoxicity at multiplicity of infection of 1 and 10, respectively. Peak viral titers were 25- to 50-fold higher than initial titer and were not significantly different between viruses. In vivo, all three viruses reduced metastases relative to control, but cytokine-secreting viruses did so with greater efficacy compared to NV1023. This effect was abrogated by T-cell depletion, but not NK-cell depletion. Single-agent therapy with oncolytic viral agents containing GM-CSF or IL-12 is effective in a murine model of liver metastases and likely involves direct viral oncolysis and actions of specific immune effector cells.

Fluorescent cholangiography in a mouse model: an innovative method for improved laparoscopic identification of the biliary anatomy.

BACKGROUND: Real-time imaging of the biliary anatomy may facilitate safe and timely completion of laparoscopic cholecystectomy. This study sought to determine whether the unique autofluorescent properties of bile could facilitate intraoperative identification of the biliary anatomy in mice using fluorescent cholangiography. METHODS: Fluorimetry was performed on samples of mouse bile to determine excitation and emission spectra. For seven mice, chevron laparotomy was performed, followed by liver retraction to expose the porta hepatis. Using stereomicroscopy, photographs were taken in brightfield and fluorescent modes without a change in depth or focus. Six surgical residents evaluated the pictures and identified the gallbladder, cystic duct, common bile duct, and whether the cystic duct joined the right hepatic duct or the common bile duct. RESULTS: Fluorimetry demonstrated autofluorescence of bile at an excitation wavelength of 475 nm. Intense emission was observed at 480 nm. At these settings, fluorescent stereomicroscopy easily identified the gallbladder and biliary tree in mice. This technique decreased diagnostic errors of the biliary anatomy 11-fold (2% vs 22%; p < 0.01), as compared with brightfield visualization. Fluorescent stereomicroscopy also was used to diagnose bile leak, obstruction, and complex anatomy. Using a prototype 5-mm laparoscope equipped with fluorescent filters, the results were reproduced. CONCLUSIONS: Fluorescent cholangiography based solely on the autofluorescence of bile may facilitate real-time identification of the biliary anatomy during laparoscopic procedures, without the need for extraneous dye administration or the use of radiography. This technique has the potential to decrease the rate of iatrogenic biliary tract injuries during laparoscopic cholecystectomy.

Virally-directed fluorescent imaging (VFI) can facilitate endoscopic staging.

BACKGROUND: Replication-competent, tumor specific herpes simplex virus NV1066 expresses green fluorescent protein (GFP) in infected cancer cells. We sought to determine the feasibility of GFP-guided imaging technology in the intraoperative detection of small tumor nodules. METHODS: Human cancer cell lines were infected with NV1066 at multiplicities of infection of 0.01, 0.1 and 1. Cancer cell specific infectivity, vector spread and GFP signal intensity were measured by flow cytometry and time-lapse digital imaging (in vitro); and by use of a stereomicroscope and endoscope equipped with a fluorescent filter (in vivo). RESULTS: NV1066 infected all cancer cell lines and expressed GFP at all MOIs. GFP signal was significantly higher than the autofluorescence of normal cells. One single dose of NV1066 spread within and across body cavities and selectively infected tumor nodules sparing normal tissue. Tumor nodules undetectable by conventional thoracoscopy and laparoscopy were identified by GFP fluorescence. CONCLUSION: Virally-directed fluorescent imaging (VFI) is a real-time novel molecular imaging technology that has the potential to enhance the intraoperative detection of endoluminal or endocavitary tumor nodules.

Minimally invasive localization of oncolytic herpes simplex viral therapy of metastatic pleural cancer.

Herpes simplex virus-1 (HSV-1) oncolytic therapy and gene therapy are promising treatment modalities against cancer. NV1066, one such HSV-1 virus, carries a marker gene for enhanced green fluorescent protein (EGFP). The purpose of this study was to determine whether NV1066 is cytotoxic to lung cancer and whether EGFP is a detectable marker of viral infection in vitro and in vivo. We further investigated whether EGFP expression in infected cells can be used to localize the virus and to identify small metastatic tumor foci (<1 mm) in vivo by means of minimally invasive endoscopic systems equipped with fluorescent filters. In A549 human lung cancer cells, in vitro viral replication was determined by plaque assay, cell kill by LDH release assay, and EGFP expression by flow cytometry. In vivo, A549 cells were injected into the pleural cavity of athymic mice. Mice were treated with intrapleural injection of NV1066 or saline and examined for EGFP expression in tumor deposits using a stereomicroscope or a fluorescent thoracoscopic system. NV1066 replicated in, expressed EGFP in infected cells and killed tumor cells in vitro. In vivo, treatment with intrapleural NV1066 decreased pleural disease burden, as measured by chest wall nodule counts and organ weights. EGFP was easily visualized in tumor deposits, including microscopic foci, by fluorescent thoracoscopy. NV1066 has significant oncolytic activity against a human NSCLC cell line and is effective in limiting the progression of metastatic disease in an in vivo orthotopic model. By incorporating fluorescent filters into endoscopic systems, a minimally invasive means for diagnosing small metastatic pleural deposits and localization of viral therapy for thoracic malignancies may be developed using the EGFP marker gene inserted in oncolytic herpes simplex viruses.

Role of surgery in Rhodococcus equi pulmonary infections.

Rhodococcus equi (R. equi) is a soil-dwelling bacterium that is increasingly associated with pulmonary infections in immunocompromised patients. While antibiotic therapy remains the cornerstone of treatment, surgery combined with antibiotics has an important role in select cases. We report two cases of pulmonary R. equi in immunocompromised patients who were treated with antibiotics, followed by surgical resection of the infected tissues, and then long-term antibiotics. Both patients had excellent outcomes. We advocate surgical resection of grossly infected pulmonary tissue as an adjunct to antimicrobial therapy for treatment of this uncommon, but potentially lethal pathogen.

Denture esophageal impaction refractory to endoscopic removal in a psychiatric patient.

Impaction of dental prostheses is frequently encountered in psychiatric patients. These patients may present an especially challenging problem because the diagnosis may be delayed, resulting in increased morbidity and mortality. Delay in diagnosis in such patients has been attributed to their inability to give a reliable clinical history. In addition, radiolucent dentures cannot be easily detected by radiographic examination. The purpose of this report is to describe a psychiatric patient with an impacted radiopaque dental prosthesis that was refractory to endoscopic intervention. An esophagotomy was needed to successfully remove the foreign body.

Biomechanical and clinical performance of a new synthetic monofilament absorbable suture.

The clinical and mechanical performance of a new, monofilament, synthetic absorbable suture (Biosyn) was evaluated and compared to that of a braided synthetic absorbable suture (Vicryl). The monofilament synthetic absorbable suture was significantly stronger than the braided synthetic absorbable suture over the 4 weeks of implantation. In addition, the monofilament suture potentiated less bacterial infection than did the braided suture. The handling characteristics of the monofilament suture were superior to the braided suture because the monofilament suture required fewer throws to achieve knot security, encountered lower drag forces in fascia and colon, and had a greater double-wrapped first-throw knot security. Evaluated independently in clinical settings, the monofilament sutures were found to have excellent strength, first-throw hold, knot security, passage through tissue, knot repositioning, and ease of handling.