Cherie P. Erkmen

Bexarotene Plus Erlotinib Suppress Lung Carcinogenesis Independent of KRAS Mutations in Two Clinical Trials and Transgenic Models

The rexinoid bexarotene represses cyclin D1 by causing its proteasomal degradation. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib represses cyclin D1 via different mechanisms. We conducted a preclinical study and 2 clinical/translational trials (a window-of-opportunity and phase II) of bexarotene plus erlotinib. The combination repressed growth and cyclin D1 expression in cyclin-E- and KRAS/p53-driven transgenic lung cancer cells. The window-of-opportunity trial in early-stage non–small-cell lung cancer (NSCLC) patients (10 evaluable), including cases with KRAS mutations, repressed cyclin D1 (in tumor biopsies and buccal swabs) and induced necrosis and inflammatory responses. The phase II trial in heavily pretreated, advanced NSCLC patients (40 evaluable; a median of two prior relapses per patient (range, 0–5); 21% with prior EGFR-inhibitor therapy) produced three major clinical responses in patients with prolonged progression-free survival (583-, 665-, and 1,460-plus days). Median overall survival was 22 weeks. Hypertriglyceridemia was associated with an increased median overall survival (P = 0.001). Early PET (positron emission tomographic) response did not reliably predict clinical response. The combination was generally well tolerated, with toxicities similar to those of the single agents. In conclusion, bexarotene plus erlotinib was active in KRAS-driven lung cancer cells, was biologically active in early-stage mutant KRAS NSCLC, and was clinically active in advanced, chemotherapy-refractory mutant KRAS tumors in this study and previous trials. Additional lung cancer therapy or prevention trials with this oral regimen are warranted. Cancer Prev Res; 4(6); 818–28. ©2011 AACR.

Comparing Histone Deacetylase Inhibitor Responses in Genetically Engineered Mouse Lung Cancer Models and a Window of Opportunity Trial in Patients with Lung Cancer

Histone deacetylase inhibitor (HDACi; vorinostat) responses were studied in murine and human lung cancer cell lines and genetically engineered mouse lung cancer models. Findings were compared with a window of opportunity trial in aerodigestive tract cancers. In human (HOP62, H522, and H23) and murine transgenic (ED-1, ED-2, LKR-13, and 393P, driven, respectively, by cyclin E, degradation-resistant cyclin E, KRAS, or KRAS/p53) lung cancer cell lines, vorinostat reduced growth, cyclin D1, and cyclin E levels, but induced p27, histone acetylation, and apoptosis. Other biomarkers also changed. Findings from transgenic murine lung cancer models were integrated with those from a window of opportunity trial that measured vorinostat pharmacodynamic responses in pre- versus posttreatment tumor biopsies. Vorinostat repressed cyclin D1 and cyclin E expression in murine transgenic lung cancers and significantly reduced lung cancers in syngeneic mice. Vorinostat also reduced cyclin D1 and cyclin E expression, but increased p27 levels in post- versus pretreatment human lung cancer biopsies. Notably, necrotic and inflammatory responses appeared in posttreatment biopsies. These depended on intratumoral HDACi levels. Therefore, HDACi treatments of murine genetically engineered lung cancer models exert similar responses (growth inhibition and changes in gene expression) as observed in lung cancer cell lines. Moreover, enhanced pharmacodynamic responses occurred in the window of opportunity trial, providing additional markers of response that can be evaluated in subsequent HDACi trials. Thus, combining murine and human HDACi trials is a strategy to translate preclinical HDACi treatment outcomes into the clinic. This study uncovered clinically tractable mechanisms to engage in future HDACi trials. Mol Cancer Ther; 12(8); 1545–55. ©2013 AACR.

Noninvasive Positive Pressure Ventilation Following Esophagectomy: Safety Demonstrated in a Pig Model

BACKGROUND Respiratory complications occur in 20% to 65% of patients who have undergone esophagectomy. While noninvasive positive pressure ventilation (NPPV) is associated with fewer complications than endotracheal intubation (ET), it is relatively contraindicated after esophagectomy due to potential injury to the anastomosis. We created ex vivo and in vivo pig models to determine the pressure tolerance of an esophagectomy anastomosis and compare it to esophageal pressure during NPPV. METHODS We created a stapled side-to-side, functional end-to-end esophagogastric anastomosis. With continuous intraluminal pressure monitoring, we progressively insufflated the anastomosis with a syringe until we detected an anastomotic leak, and recorded the maximum pressure before leakage. We performed this experiment in 10 esophageal specimens and 10 live pigs. We then applied a laryngeal mask airway (LMA) to five live pigs and measured the pressure in the proximal esophagus with increasing ventilatory pressures. RESULTS The perforation was always at the anastomosis. The ex vivo and in vivo anastomoses tolerated a mean of 101 ± 44 cm H2O and 84 ± 38 cm H2O before leak, respectively. There was no significant difference between the pressure thresholds of ex vivo and in vivo anastomoses (P = .51). When 20, 30, and 40 cm H2O of positive pressure via LMA were delivered, the esophagus sensed 5 ± 4 cm H2O (25%), 11 ± 11 cm H2O (37%), and 15 ± 9 cm H2O (38%), respectively. CONCLUSIONS Our pig model suggests that an esophagectomy anastomosis can tolerate a considerably higher pressure than is transmitted to the esophagus during NPPV. NPPV may be a safe alternative to ET after esophagectomy.

Thymoma-associated paraneoplastic encephalitis (TAPE): Diagnosis and treatment of a potentially fatal condition

Up to 50% of patients with thymoma have paraneoplastic neurologic syndromes, the most common being myasthenia gravis. There are rare case reports of thymoma-associated paraneoplastic limbic or extralimbic encephalitis that can lead to progressive neurologic decline and death without treatment. We report a case of a malignant thymoma presenting as paraneoplastic encephalitis and review the clinical characteristics, treatments used, and outcome of 28 patients with this disorder published according to a PubMed and MEDLINE search (1950–2010).

Use of Cervicothoracic Anatomy as a Guide for Directed Drainage of Descending Necrotizing Mediastinitis

Descending necrotizing mediastinitis is a potentially lethal infection originating from the oropharynx. Adequate abscess drainage is crucial to successful treatment. We present novel management of descending necrotizing mediastinitis using a series of anterior mediastinal incisions adjoined by Penrose drains. The success of this treatment was dependent on radiographic documentation of infection confined to the anterior cervicothoracic plane.

Case report: Successful treatment of recurrent chordoma and bilateral pulmonary metastases following an 11-year disease-free period.

INTRODUCTION Chordomas are rare but aggressive tumors due to local recurrence and distant metastases. They originate commonly in the sphenooccipital and sacrococcygeal regions, and metastasize to the lungs, bone, skin, liver, and lymph nodes. They occur more frequently in men and people over the age of 40. PRESENTATION OF CASE A 28 year-old female presented with sacrococcygeal chordoma for which she received wide local excision and adjuvant radiation therapy. She enjoyed an unusual disease-free survival for 11 years until a routine surveillance scan of the pelvis identified local recurrence. Further work up revealed bilateral pulmonary metastases. She underwent local excision of the recurrent tumor and video-assisted thoracoscopic (VATS) wedge resection of pulmonary metastases. She also received adjuvant radiation therapy to the recurrent resection bed. Two years later, she remains free of disease and symptoms. DISCUSSION Chordomas are commonly insensitive to chemotherapy and radiation, making surgery the most successful therapeutic modality. However, there are few guidelines on the surveillance and treatment of recurrent chordoma. We report success with aggressive surgical resection of recurrence and metastasis as well as adjuvant radiation therapy. CONCLUSION The prolonged survival of our patient underscores the importance of (1) aggressive surgical resection of chordoma, whether primary, recurrent, or metastatic, with adjuvant radiation therapy, (2) minimization of surgical seeding of tumor, and (3) diligent cancer surveillance.

Endoscopy after esophagectomy: Safety demonstrated in a porcine model

Background: Endoscopy is useful in assessing conduit ischemia and anastomotic leaks after esophagectomy but poses a theoretical threat of anastomotic disruption. We used a porcine model to evaluate the safety of endoscopy after esophagectomy. Methods: We performed esophagectomies in 10 live pigs and performed endoscopy with progressive air insufflation and continuous intraluminal pressure monitoring. We stopped insufflation when the intraluminal pressure reached a plateau. We assessed the integrity of the conduit and anastomosis via endoscopy. We also performed pulse oximetry of the stomach and Doppler velocimetry of the right gastroepiploic artery on 5 live pigs to study the effects of endoscopic gastric insufflation. Results: With gentle air insufflation, there was no measurable increase in intraluminal pressure, disruption of the conduit or anastomosis, or significant gastric distension. With progressive insufflation, the intraluminal pressure reached a plateau at a maximum of 8.7 ± 2.1 cm H2O (95% confidence interval, 7.2‐10.2). At this plateau, air leaked retrograde via the mouth, which prevented further gastric distension. There were no significant changes in oxyhemoglobin saturation along various regions in the stomach even with maximal insufflation sustained for 10 minutes. There was a momentary reduction in gastroepiploic flow from 12.0 ± 1.0 [95% confidence interval, 10.8‐13.2] mL/min/100 g to 9.6 ± 1.5 [95% confidence interval, 7.8‐11.4] mL/min/100 g immediately after maximal insufflation, but flow recovered to 11 ± 1.3 [9.6, 12.8] mL/min/100 g after 10 minutes of sustained insufflation. Conclusions: Endoscopy after esophagectomy with gentle or maximal air insufflation results in safe endoluminal pressures and minimal disturbance of blood flow and oxygenation.

Clinical pathway for esophagectomy improves perioperative nutrition.

BACKGROUND Clinical pathways reduce hospitalization and costs in colorectal and pancreatic cancer. We describe creating an esophagectomy pathway and analyze its implementation and effects. METHODS We documented the process of developing an esophagectomy clinical pathway. We performed a retrospective review of prospectively collected data on 12 patients before pathway implementation and 12 patients after. RESULTS Pathway Implementation: more patients were presented at tumor board (9 pathway vs. 2 pre-pathway; p=0.012) and chose their postoperative care facility before surgery (8 vs. 0; p=0.0013) OUTCOMES: There were no changes in mortality (0 vs. 0), major complications (5 vs. 5), hospitalization (median 9.5 vs. 12 days; p=0.82), and total charges (

Role of Thoracic Surgeons in Lung Cancer Screening: Opportune Time for Involvement

98,395 vs.

An Enhanced Shared Decision Making Model to Address Willingness and Ability to Undergo Lung Cancer Screening and Follow-Up Treatment in Minority Underserved Populations

96,946; p=0.96). Pathway patients lost significantly less weight preoperatively (2.3% vs. 7.6%; p=0.01) and perioperatively (6.3% vs. 12%; p=0.02). CONCLUSIONS This is the first study to report the process of designing and implementing an esophagectomy pathway. While there was no significant decrease in mortality, complications, hospitalization, or charges, our pathway significantly decreased pre- and perioperative weight loss, which we attribute to coordinated patient education and care.