Metabolomic and BH3 profiling of esophageal cancers: novel assessment methods for precision therapy.

BACKGROUND: Esophageal cancers accounted for nearly 16,000 deaths in 2016. The number of patients with esophageal cancers increases every year. Neoadjuvant chemoradiotherapy (nCRT) prior to esophagectomy is a standard treatment for esophageal cancers. The patients who have no residual tumor (pathological complete response (pCR)) at surgery are the most likely to experience long term survival. Accurately determining which patients will have a pCR will improve prognostic information for patients and families, confirm lack of response to nCRT, or avoid surgery if no residual tumor is present. Imaging, endoscopy, and liquid biomarkers have all failed to detect pCR without performing an esophagectomy. METHODS: In this study, we are enrolling patients with esophageal adenocarcinoma and squamous cell carcinoma. Patients will undergo standard evaluation including CT scans, laboratory tests, endoscopy with biopsies, and evaluation by a thoracic surgeon. Tissue biopsy is required for enrollment that will be sent for BH3 profiling and metabolomics. Patients will be treated with standard nCRT followed by surgery. Patients with metastatic disease are not eligible. Surgery at the National Cancer Institute will be minimally-invasive robotic surgery. Patients will remain on study indefinitely with regular clinic visits and imaging tests. DISCUSSION: The mitochondria are critically involved in the intrinsic pathway apoptosis. Bcl-2 homology domain 3 (BH3) profiling is a technique to measure a cell's susceptibility to apoptosis. BH3 profiling measures the relative interactions of proteins that induce or block apoptosis. The collective balance of these proteins determines whether a cell is near the threshold to undergo apoptosis. If the cell is near this threshold, then the tumor may be more likely to die when treated with nCRT. The mitochondria secrete metabolites that may be detectable as biomarkers. Metabolomics is a global assessment of all metabolite changes that has been performed for detection, monitoring, prognosis, and treatment response in cancers. Stratification of patients based on whether pCR occurs or not may elucidate metabolomic signatures that may be associated with response. We are asking whether BH3 profiling or a metabolomic signature will correlate with tumor death after nCRT for esophageal cancer. TRIAL REGISTRATION: NCT03223662 ; Clinicaltrials.gov. July 21, 2017.

Randomized phase II trial of a first-in-human cancer cell lysate vaccine in patients with thoracic malignancies.

BACKGROUND: Although most malignancies express cancer-testis antigens (CTA), immune responses to these proteins are limited in thoracic oncology patients. This trial was undertaken to examine if a cancer cell lysate vaccine could induce immunity to CTA, and to ascertain if metronomic cyclophosphamide and celecoxib enhances vaccine-induced immune responses. METHODS: Eleven patients with primary thoracic malignancies and 10 patients with extrathoracic neoplasms metastatic to the chest rendered NED by conventional therapies were randomized to receive H1299 lung cancer cell lysates (10 mg protein/vaccine) with Iscomatrix™ adjuvant via deep intradermal injection q 4 weeks ×6 with or without daily oral metronomic cyclophosphamide/celecoxib. The primary endpoint was serologic response to purified CTA assessed 1 month after the 6th vaccination. Secondary endpoints included assessment of the effects of cyclophosphamide and celecoxib on frequency and magnitude of vaccine-induced immune responses to CTA. Exploratory endpoints included evaluation of the effects of the vaccine regimens on peripheral immune subsets. Standard of care imaging studies were obtained at baseline and 1 month after the 3rd and 6th vaccinations. RESULTS: All patients exhibited local and systemic inflammatory responses lasting 72-96 hours following vaccinations. There were no dose limiting treatment related toxicities. Fourteen patients (67%) completed all six vaccinations. Eight of 14 patients (57%) exhibited serologic responses to NY-ESO-1. One patient developed antibodies to GAGE7; several patients exhibited reactivity to XAGE and MAGE-C2. Vaccine therapy decreased the percent of Tregs (P=0.0068), PD-1 expression on Tregs (P=0.0027), PD-L1 expression on CD14+ monocytes (P=0.0089), PD-L1 expression on classical monocytes (P=0.016), and PD-L1 expression on intermediate monocytes (P=0.0031). Cyclophosphamide/celecoxib did not appear to increase immune responses or enhance vaccine-induced alterations in peripheral immune subsets. CONCLUSIONS: H1299 lysate vaccines with Iscomatrix™ induce immune responses to CTA and modulate peripheral immune subsets in a manner that may enhance antitumor immunity in patients with thoracic malignancies.

Reversal of sympathetic interruption by removal of clips.

BACKGROUND: Sympathetic interruption offers excellent control of hyperhidrosis and facial blushing (FB), but some patients have side effects prompting a wish to reverse the procedure. Reversal when the chain has been cut is challenging, whereas reversal when the chain has been clipped is straightforward. The peripheral nerves regenerate; however, little is known about the regeneration of the sympathetic chain after clip removal. We reviewed our results with reversal of sympathetic interruption through removal of clips. METHODS: An institutional review board-approved retrospective review of patients treated for hyperhidrosis and FB from November 2004 to March 2014 was performed. We analyzed those patients undergoing sympathetic interruption with clips (N = 82). RESULTS: Eight patients (10%) requested and underwent reversal of the procedure between 12 days and 5.8 years (median = 73.5 days) after the initial procedure. Compensatory sweating was the most frequent complaint (n = 6), and excessive palmar dryness was second (n = 3), the latter occurring in patients without primary palmar hyperhidrosis. The interval between clip removal and follow-up ranged from 2 days to 4.5 years (median = 141 days). Five of 8 patients thus far have had their symptoms reversed through removal of clips (Table 1). CONCLUSIONS: The percentage of patients requesting reversal of sympathectomy is significant and appears to most commonly result from compensatory sweating (CS); however, excessive palmar dryness also occurs in those without primary palmar hyperhidrosis. It appears that the best results with reversal are obtained when the clips are removed early after placement. We counsel our patients that ideally clips should be removed within 2 weeks for reversal.

Minimally invasive transhiatal esophagectomy after thoracotomy.

Patients with end-stage achalasia may not be candidates for a transhiatal minimally invasive esophageal resection because of anatomic challenges and adhesions from previous interventions, namely, thoracotomy. Given the tactile feedback provided through a GelPort laparoscopic system (Applied Medical, Rancho Margarita, CA) we proposed that a minimally invasive transhiatal esophagectomy would be feasible in this patient cohort. The procedure was successful in 4 patients; seven complications occurred in 3 of the patients. At follow-up all patients demonstrated that they were meeting their nutritional needs with an oral diet.