Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma.

PURPOSE: Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are associated with sensitivity of lung adenocarcinomas to the EGFR tyrosine kinase inhibitors, gefitinib and erlotinib. Acquired drug resistance is frequently associated with a secondary somatic mutation that leads to the substitution of methionine for threonine at position 790 (T790M). We aimed to identify additional second-site alterations associated with acquired resistance. EXPERIMENTAL DESIGN: Tumor samples were obtained from 48 patients with acquired resistance. Tumor cell DNA was analyzed for EGFR kinase domain mutations. Molecular analyses were then done to characterize the biological properties of a novel mutant EGFR allele. RESULTS: A previously unreported mutation in exon 21 of EGFR, which leads to substitution of alanine for threonine at position 854 (T854A), was identified in one patient with a drug-sensitive EGFR L858R-mutant lung adenocarcinoma after long-term treatment with tyrosine kinase inhibitors. The T854A mutation was not detected in a pretreatment tumor sample. The crystal structure analyses of EGFR suggest that the T854 side chain is within contact distance of gefitinib and erlotinib. Surrogate kinase assays show that the EGFR T854A mutation abrogates the inhibition of tyrosine phosphorylation by erlotinib. Such resistance seems to be overcome by a new irreversible dual EGFR/HER2 inhibitor, BIBW 2992. CONCLUSIONS: The T854A mutation is the second reported second-site acquired resistance mutation that is within contact distance of gefitinib and erlotinib. These data suggest that acquired resistance to ATP-mimetic EGFR kinase inhibitors may often be associated with amino acid substitutions that alter drug contact residues in the EGFR ATP-binding pocket.

Stump appendicitis: a comprehensive review of literature.

Appendectomy for appendicitis is one of the most common procedures performed in the United States. Residual tissue left after an initial appendectomy risks the development of stump appendicitis. A comprehensive review of the English-language literature revealed 36 reported cases of stump appendicitis. Typically, patients present with signs and symptoms similar to acute appendicitis; however, due to prior surgery, the diagnosis is difficult and the rate of appendiceal stump perforation is extremely high. Herein, we present a case of a 32-year-old female presenting with right lower quadrant pain, nausea, and fever 5 months after laparoscopic appendectomy. Upon surgery, an appendiceal stump was discovered.

Subdiaphragmatic bronchogenic cysts: a comprehensive review of the literature.

Bronchogenic cysts are foregut-derived developmental anomalies most commonly encountered in the mediastinum and rarely in the abdomen or retroperitoneally. A comprehensive review of the English-language literature of subdiaphragmatic bronchogenic cysts (sBCs) revealed only 48 reported cases of sBC. Although most cases are incidentally discovered, preoperative differential diagnosis often includes tumors with malignant potential and necessitates surgical resection to obtain a definitive diagnosis. Herein, we describe a case of a 46-year-old female presenting with intermittent left flank pain, upon which computed tomography demonstrated a retroperitoneal mass. Upon resection, histopathology revealed the mass to be a thin-walled cystic mass lined by ciliated columnar cells and cartilage, consistent with a subdiaphragmatic bronchogenic cyst. A comprehensive literature review of sBC was also performed.

Esophageal reconstruction with alternative conduits.

Alternative conduits for esophageal replacement become necessary when the stomach is unavailable for use. Common options for conduit creation include the jejunum and the colon. Prior abdominal operations, inflammatory bowel disease, or other mesenteric or abdominal disorders may limit use of either organ and a thorough history is essential when planning for alternative reconstruction. Most often the jejunum is free of intrinsic disease and provides a long segment for esophageal replacement. Limitations on the length of conduit that can be constructed with the jejunum have largely been overcome. A colonic conduit can also provide adequate length to reach the neck.

Salvage esophagectomy after failed definitive chemoradiation for esophageal adenocarcinoma.

BACKGROUND: Outcomes of salvage esophagectomy after definitive chemoradiation (CRT) for squamous cell carcinoma are well defined. Previous reports of salvage esophagectomy in patients with recurrent adenocarcinoma after definitive CRT are limited by small numbers and high morbidity and mortality rates. METHODS: We reviewed our experience of 65 patients with esophageal adenocarcinoma treated from 1997 to 2010 who underwent salvage esophagectomy after failed definitive CRT. We then compared this group to 65 matched patients of 521 total patients with esophageal adenocarcinoma who received preoperative CRT followed by planned esophagectomy. Propensity matching and multivariable analysis were performed. RESULTS: Median time to surgery from completion of therapy for the salvage group was 216 days. Major postoperative events (major pulmonary event, conduit loss, leak, readmission to intensive care unit) occurred in 35% (23 of 65) of salvage patients and 31% (20 of 65) of the planned resection matched group. Anastomotic leak occurred in 18.5% (12 of 65) and 11.3 (59 of 521) of salvage and planned groups, respectively. Thirty-day mortality was 3.1% (2 of 65) after salvage resection and 4.6% (3 of 65) after planned resection. There was no difference in 3-year overall or median survival between the two groups of patients (32 months, 48% salvage, versus 40 months, 57% planned resection). Multivariable analysis did not identify salvage strategy or time from completion of therapy to resection as a predictor of major event or death. CONCLUSIONS: Postoperative morbidity, mortality, and overall survival of patients after salvage esophagectomy are comparable to matched patients after planned resection. These results suggest that patients with esophageal adenocarcinoma who fail definitive CRT and recur locoregionally should be considered for salvage esophagectomy at experienced esophageal centers.

Prognostic and therapeutic implications of EGFR and KRAS mutations in resected lung adenocarcinoma.

BACKGROUND: Somatic mutations in EGFR (exons 19 and 21) and KRAS (exon 2) are found in lung adenocarcinomas and have potential prognostic value in patients with advanced disease. These mutations also have therapeutic significance, as they predict for sensitivity and resistance, respectively, to EGFR tyrosine kinase inhibitor therapy. Whether EGFR and KRAS mutations also have an impact on survival in patients who undergo lung resection for curative intent in the absence of targeted therapy has not been established. METHODS: We analyzed the clinical characteristics and outcomes data for 296 patients who underwent resection at our institution for stage I-III lung adenocarcinoma. Tumors were assessed for both EGFR and KRAS mutations by established methods. RESULTS: EGFR and KRAS mutations were found in tumors from 40 (14%) and 50 (17%) patients, respectively. Patients with EGFR mutant tumors were more likely to be never smokers (48%), present with stage I disease (88%), and had a 90% (95% confidence interval [CI] 70-97%) 3-year overall survival, whereas patients with KRAS mutant tumors were more likely to be former/current smokers (92%), present with locally advanced disease (40%), and had a 66% (95% CI 48-79%) 3-year overall survival. CONCLUSIONS: EGFR and KRAS mutations define distinct molecular subsets of resected lung adenocarcinoma. Because EGFR and KRAS mutations also predict whether tumors are sensitive or resistant, respectively, to EGFR tyrosine kinase inhibitors, they can readily be used in clinical trials to help guide the administration of specific types of adjuvant therapy.

Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma.

Genetic lesions affecting a number of kinases and other elements within the epidermal growth factor receptor (EGFR) signaling pathway have been implicated in the pathogenesis of human non-small-cell lung cancer (NSCLC). We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other potential somatic mutations in genes of this pathway that could contribute to lung tumorigenesis. We have identified in 2 of 207 primary lung tumors a somatic activating mutation in exon 2 of MEK1 (i.e., mitogen-activated protein kinase kinase 1 or MAP2K1) that substitutes asparagine for lysine at amino acid 57 (K57N) in the nonkinase portion of the kinase. Neither of these two tumors harbored known mutations in other genes encoding components of the EGFR signaling pathway (i.e., EGFR, HER2, KRAS, PIK3CA, and BRAF). Expression of mutant, but not wild-type, MEK1 leads to constitutive activity of extracellular signal-regulated kinase (ERK)-1/2 in human 293T cells and to growth factor-independent proliferation of murine Ba/F3 cells. A selective MEK inhibitor, AZD6244, inhibits mutant-induced ERK activity in 293T cells and growth of mutant-bearing Ba/F3 cells. We also screened 85 NSCLC cell lines for MEK1 exon 2 mutations; one line (NCI-H1437) harbors a Q56P substitution, a known transformation-competent allele of MEK1 originally identified in rat fibroblasts, and is sensitive to treatment with AZD6244. MEK1 mutants have not previously been reported in lung cancer and may provide a target for effective therapy in a small subset of patients with lung adenocarcinoma.

Mutational analysis of EGFR and related signaling pathway genes in lung adenocarcinomas identifies a novel somatic kinase domain mutation in FGFR4.

BACKGROUND: Fifty percent of lung adenocarcinomas harbor somatic mutations in six genes that encode proteins in the EGFR signaling pathway, i.e., EGFR, HER2/ERBB2, HER4/ERBB4, PIK3CA, BRAF, and KRAS. We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other potential somatic mutations in genes of this signaling pathway that could contribute to lung tumorigenesis. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed genomic DNA from a total of 261 resected, clinically annotated non-small cell lung cancer (NSCLC) specimens. The coding sequences of 39 genes were screened for somatic mutations via high-throughput dideoxynucleotide sequencing of PCR-amplified gene products. Mutations were considered to be somatic only if they were found in an independent tumor-derived PCR product but not in matched normal tissue. Sequencing of 9MB of tumor sequence identified 239 putative genetic variants. We further examined 22 variants found in RAS family genes and 135 variants localized to exons encoding the kinase domain of respective proteins. We identified a total of 37 non-synonymous somatic mutations; 36 were found collectively in EGFR, KRAS, BRAF, and PIK3CA. One somatic mutation was a previously unreported mutation in the kinase domain (exon 16) of FGFR4 (Glu681Lys), identified in 1 of 158 tumors. The FGFR4 mutation is analogous to a reported tumor-specific somatic mutation in ERBB2 and is located in the same exon as a previously reported kinase domain mutation in FGFR4 (Pro712Thr) in a lung adenocarcinoma cell line. CONCLUSIONS/SIGNIFICANCE: This study is one of the first comprehensive mutational analyses of major genes in a specific signaling pathway in a sizeable cohort of lung adenocarcinomas. Our results suggest the majority of gain-of-function mutations within kinase genes in the EGFR signaling pathway have already been identified. Our findings also implicate FGFR4 in the pathogenesis of a subset of lung adenocarcinomas.

Severe hypophosphatemia associated with gallstone pancreatitis: a case report and review of the literature.

Severe hypophosphatemia (<1.0 mg/dl) is a rarely reported complication of acute pancreatitis; when it does occur, it is typically attributed to alcohol abuse rather than the pancreatitis itself (1-5). In the literature, pancreatitis is not cited as a cause of hypophosphatemia (5, 6-16). Both pancreatitis and hypophosphatemia have widespread ramifications on human physiology, affecting hematologic, neural, hepatic, endocrine, respiratory, and renal systems. Given the possible synergistic consequences of pancreatitis and low serum phosphate, we emphasize the importance of recognizing hypophosphatemia as a complication of pancreatic inflammation.Herein, we report a case of acute pancreatitis unrelated to alcohol abuse associated with severe hypophosphatemia and review the pathophysiology.

Primary squamous cell carcinoma of the colon associated with hypercalcemia and hyperleukocytosis. Report of a case.

BACKGROUND/AIMS: Squamous cell carcinoma of the colon is a rare entity. We report a case of a patient who presented with a perforated squamous cell carcinoma of the sigmoid colon. RESULTS: A 45-year-old female presented with a 2-month history of worsening abdominal pain, bloody diarrhea, and vomiting. She underwent an exploratory laparotomy and was found to have keratinizing squamous cell carcinoma of the sigmoid colon that had perforated forming multiple abscess cavities. The postoperative course was complicated by hypercalcemia and persistent hyperleukocytosis, ultimately resulting in the patient's death. CONCLUSIONS: We present the second reported case of squamous cell carcinoma of the colon associated with hypercalcemia and the first reported case of associated hyperleukocytosis.