Phase II study of gemcitabine, oxaliplatin in combination with panitumumab in KRAS wild-type unresectable or metastatic biliary tract and gallbladder cancer.

BACKGROUND: Current data suggest that platinum-based combination therapy is the standard first-line treatment for biliary tract cancer. EGFR inhibition has proven beneficial across a number of gastrointestinal malignancies; and has shown specific advantages among KRAS wild-type genetic subtypes of colon cancer. We report the combination of panitumumab with gemcitabine (GEM) and oxaliplatin (OX) as first-line therapy for KRAS wild-type biliary tract cancer. METHODS: Patients with histologically confirmed, previously untreated, unresectable or metastatic KRAS wild-type biliary tract or gallbladder adenocarcinoma with ECOG performance status 0-2 were treated with panitumumab 6 mg kg(-1), GEM 1000 mg m(-2) (10 mg m(-2) min(-1)) and OX 85 mg m(-2) on days 1 and 15 of each 28-day cycle. The primary objective was to determine the objective response rate by RECIST criteria v.1.1. Secondary objectives were to evaluate toxicity, progression-free survival (PFS), and overall survival. RESULTS: Thirty-one patients received at least one cycle of treatment across three institutions, 28 had measurable disease. Response rate was 45% and disease control rate was 90%. Median PFS was 10.6 months (95% CI 5-24 months) and median overall survival 20.3 months (95% CI 9-25 months). The most common grade 3/4 adverse events were anaemia 26%, leukopenia 23%, fatigue 23%, neuropathy 16% and rash 10%. CONCLUSIONS: The combination of gemcitabine, oxaliplatin and panitumumab in KRAS wild type metastatic biliary tract cancer showed encouraging efficacy, additional efforts of genetic stratification and targeted therapy is warranted in biliary tract cancer.

Phase I/II study of neoadjuvant bevacizumab, erlotinib and 5-fluorouracil with concurrent external beam radiation therapy in locally advanced rectal cancer.

BACKGROUND: To determine the maximal tolerated dose of erlotinib when added to 5-fluorouracil (5-FU) chemoradiation and bevacizumab and safety and efficacy of this combination in patients with locally advanced rectal cancer. PATIENTS AND METHODS: Patients with Magnetic resonance imaging (MRI) or ultrasound defined T3 or T4 adenocarcinoma of the rectum and without evidence of metastatic disease were enrolled. Patients received infusional 5-FU 225 mg/M2/day continuously, along with bevacizumab 5 mg/kg days 14, 1, 15 and 29. Standard radiotherapy was administered to 50.4 Gy in 28 fractions. Erlotinib started at a dose of 50 mg orally daily and advanced by 50 mg increments in the subsequent cohort. Open total mesorectal excision was carried out 6-9 weeks following the completion of chemoradiation. RESULTS: Thirty-two patients received one of three dose levels of erlotinib. Erlotinib dose level of 100 mg was determined to be the maximally tolerated dose. Thirty-one patients underwent resection of the primary tumor, one refused resection. Twenty-seven patients completed study therapy, all of whom underwent resection. At least one grade 3-4 toxicity occurred in 46.9% of patients. Grade 3-4 diarrhea occurred in 18.8%. The pathologic complete response (pCR) for all patients completing study therapy was 33%. With a median follow-up of 2.9 years, there are no documented local recurrences. Disease-free survival at 3 years is 75.5% (confidence interval: 55.1-87.6%). CONCLUSIONS: Erlotinib added to infusional 5-FU, bevacizumab and radiation in patients with locally advanced rectal cancer is relatively well tolerated and associated with an encouraging pCR.

Associative learning in premature hydranencephalic and normal twins.

A hydranencephalic infant lacking cerebral hemispheres and a normal twin were tested for associative learning. After repeated trials in which two stimuli were temporally paired, test trials were given in which the second stimulus was omitted. Cardiac orienting responses to stimulus omission indicated that learning had taken place in both infants.

The Impact of Pathologic Complete Response in Patients with Neoadjuvantly Treated Locally Advanced Rectal Cancer-a Large Single-Center Experience.

Small cohort studies demonstrated better oncologic outcomes for patients with pathologic complete response (PathCR) after neoadjuvant treatment for locally advanced rectal cancer. This study reviews long-term outcomes of a large cohort of clinically stage II/III rectal cancer patients who received neoadjuvant chemoradiation and surgery. This is a retrospective analysis of a single-center cohort, including all clinical stage II/III rectal cancer patients who received neoadjuvant chemoradiation and surgery between 2004 and 2014 (n = 271). Cox regressions were done to assess the influence of PathCR on recurrence-free survival (RFS) and overall survival (OS), adjusting for postoperative chemotherapy, clinical AJCC staging, comorbidity, and age where appropriate. PathCR patients had significantly lower distant recurrence rates (4 vs. 15.8%; P = 0.028) and lower disease-specific mortality rates (0 vs. 8.1%; P = 0.052), compared to patients with residual disease. PathCR was associated with longer RFS (HR, 5.6 [95% CI 1.3-23.1] P = 0.018) and longer OS (HR, 3.4 [1.31-10.0] P = 0.014) compared to having pathological residual disease. This large single-center study shows that patients with PathCR have significant longer RFS and OS than patients with residual disease on pathology after neoadjuvant chemoradiation.

Acute eosinophilic pneumonia. A summary of 15 cases and review of the literature.

Idiopathic acute eosinophilic pneumonia (AEP) is an acute febrile illness that may be mistaken for an infectious pneumonia. Patients are often young and otherwise healthy. Clues to considering this disorder in a differential diagnosis include the acuity and severity of the clinical presentation and an initial chest X-ray with diffuse infiltrates, often interstitial, and the presence of Kerley B lines and/or evidence of pleural fluid. The diagnosis can be made through examination of bronchoalveolar lavage fluid in most cases, with careful exclusion of other similar eosinophilic lung disease. Although it can lead to life-threatening respiratory failure, AEP is easily treatable with corticosteroids. This disease has not been reported to recur in any patients to this point.

Sandwich ELISA formats designed to detect 17 kDa IL-1 beta significantly underestimate 35 kDa IL-1 beta.

The IL-1 beta precursor (proIL-1 beta) represents a significant component of total IL-1 beta production in certain cell types such as keratinocytes, fibroblasts and alveolar macrophages. It has been presumed that immunodetection systems for the mature 17 kDa IL-1 beta can be used interchangeably for the 35 kDa intracellular proIL-1 beta. However, during attempts to purify alveolar macrophage proIL-1 beta, we found that conventional enzyme-linked immunoassays (ELISAs) (using antibodies directed against the 17 kDa mature IL-1 beta) underestimated the amounts of 35 kDa proIL-1 beta by at least ten-fold compared to detection by Western blot techniques. This difference was due to the fact that ELISAs, with an antigen capture format (i.e., that use more than one epitope), can more readily see these distinct epitopes on mature or partially processed IL-1 beta than on the proIL-1 beta molecule. This problem does not occur with the Western blot technique, either because only one antibody is needed and hence there is no stearic blockade of a second epitope or because it denatures 35 kDa proIL-1 beta during the immobilization step, presumably better exposing epitopes as expressed on mature 17 kDa IL-1 beta. The problem with the ELISA can be partially corrected by proteolytic removal of the aminoterminus of 35 kDa proIL-1 beta with neutrophil elastase. More accurate determinations of proIL-1 beta by ELISA can be made by using 35 kDa proIL-1 beta as the reference standard (when the 35 kDa proIL-1 beta is free of molecular weight IL-1 beta). These data suggest that there are conformational differences between the carboxyterminus of 35 kDa proIL-1 beta and mature 17 kDa IL-1 beta which may affect immunodetection when using antibodies directed against mature 17 kDa IL-1 beta.

Coccidioidal meningitis complicated by cerebral arteritis and infarction.

A case of coccidioidal meningitis with cerebral arteritis in a nonendemic area is reported. Interesting clinical features were the difficulties in clinical diagnosis, hydrocephalus, and neurological deficits. An autopsy revealed chronic basal meningitis, cerebral arteritis, cerebral infarcts, hydrocephalus, and an old solitary pulmonary granuloma all due to Coccidioides immitis. The rare occurrence of cerebral arteritis due to C. immitis and clinicopathological correlations are discussed.

The use of expandable metal stents to facilitate extubation in patients with large airway obstruction.

OBJECTIVE: To determine the clinical utility of placing airway stents to facilitate weaning in ventilator-dependent patients with large airway obstruction. METHODS: A chart review of mechanically ventilated patients who received expandable metal airway stents to attempt a facilitation of weaning. RESULTS: Eight patients, 3 women and 5 men, ranging in age from 37 to 82 years, had respiratory failure associated with large airway obstruction and underwent flexible bronchofluoroscopic placement of 12 expandable metal stents (7 Wallstents [Schneider; Minneapolis, MN], 2 Palmaz [Johnson & Johnson; Warren, NJ], and 3 Ultraflex [Microinvasive; Natick, MA]). Six had respiratory failure that was secondary to malignant airway disease, and two had benign airway disease. Seven patients with tracheal or mainstem bronchial obstruction were weaned from the ventilator within 0 to 11 days of stent placement after having previously required mechanical ventilation from 2 to 52 days. There were no associated complications. Following prolonged attempts at weaning, one patient with lobar bronchus obstruction died after mechanical ventilation was withdrawn. CONCLUSIONS: Expandable metal airway stents may be safely deployed in mechanically ventilated patients and can facilitate weaning from the mechanical ventilator. Mechanically ventilated patients with tracheal and mainstem bronchus obstruction are the best candidates for deployment of expandable airway stents to facilitate weaning.

HIV-associated bronchiolitis obliterans organizing pneumonia.

A man with serologic evidence of HIV infection and a depressed T-helper:suppressor ratio developed fever, pulmonary infiltrates, and respiratory failure. Bronchoalveolar lavage and transbronchial biopsy failed to reveal an infectious cause; however, an open lung biopsy demonstrated classic bronchiolitis obliterans organizing pneumonia. The patient responded completely to corticosteroids. To the best of our knowledge, this represents a previously undescribed and readily treatable cause of respiratory failure in patients with HIV infections.

Churg-Strauss syndrome associated with zafirlukast.

The leukotriene receptor antagonist zafirlukast (Accolate; Zeneca Pharmaceuticals; Wilmington, Del) recently was approved for use as maintenance therapy for persistent asthma. This new product has been well received due to convenient dosing and relatively few side effects. Based on initial success with this product, it is likely that similar compounds will be available for use in the near future. In this report, a case is described of a 47-year-old white man with moderate persistent asthma in whom Churg-Strauss syndrome developed while he was receiving zafirlukast therapy. Acute respiratory insufficiency, arthralgia, and prominent rash developed which required hospitalization. The patient's symptoms rapidly reversed following discontinuation of zafirlukast therapy and administration of systemic corticosteroids. Although the incidence of Churg-Strauss syndrome associated with zafirlukast therapy is rare, this case report illustrates steps that may be taken to diagnose quickly and treat this life-threatening condition should it occur.

Postoperative respiratory failure due to acute eosinophilic pneumonia.

A non-smoking 63-year-old man developed respiratory failure following surgical repair of a thoracoabdominal aortic aneurysm. He had severe hypoxemia and an elevated minute ventilation requiring prolonged mechanical support. Initial postoperative chest radiographs revealed new, transient, migratory infiltrates, and the patient received broad-spectrum antibiotic therapy. Chest radiographs subsequently demonstrated persistent, diffuse infiltrates, and bronchoalveolar lavage (BAL) analysis demonstrated significant eosinophilia (30%) with no evidence of infection. A diagnosis of acute eosinophilic pneumonia was made, and treatment with intravenous methylprednisolone resulted in rapid clinical improvement, and extubation. Acute eosinophilic pneumonia is not a previously recognized cause of postoperative respiratory failure and prolonged mechanical ventilation. It should be suspected in postoperative patients with unexplained diffuse lung infiltrates and acute respiratory failure.

Measurement of outcomes in adults receiving pharmaceutical care in a comprehensive asthma outpatient clinic.

We hypothesized that a pharmacist-provided comprehensive education program in conjunction with care provided by a pulmonologist would lead to improved economic, clinical, and humanistic outcomes in adults with asthma, compared with similar patients receiving care from a pulmonologist alone. The experimental group reported receiving more information about asthma self-management (p=0.001), were more likely to monitor peak flow readings (p=0.004), and had increased satisfaction with care, and perceived higher quality of care. Both groups had less lost productivity, fewer emergency department visits, fewer hospitalizations, and fewer physician visits, as well as improvement in symptoms scores within 45 days. Both groups improved in all functional status domains except the mental component score of the SF-12. Our results show a positive impact on outcomes in adults with asthma who received pharmaceutical care.

Bedside tracheostomy in the intensive care unit: a prospective randomized trial comparing open surgical tracheostomy with endoscopically guided percutaneous dilational tracheotomy.

OBJECTIVES: Objectives of the study were 1) to analyze the complication incidence and resource utilization of two methods of bedside tracheostomy and 2) to define selection criteria for bedside tracheostomy. STUDY DESIGN: Prospective randomized trial in the setting of a tertiary care center at a university hospital. METHODS: One hundred sixty-four consecutive intubated patients selected for elective tracheostomy were enrolled. One hundred patients met selection criteria for bedside tracheostomy and were randomly assigned to either open surgical tracheostomy (50) or endoscopically guided percutaneous dilational tracheotomy(50). The remaining 64 patients received open surgical tracheostomies in the operating room. Main outcome measures were 1) perioperative and postoperative complication incidence and 2) resource utilization. RESULTS: Patients meeting our selection criteria for bedside tracheostomy had a significantly reduced perioperative complication rate compared with those who failed to meet these criteria, and subsequently underwent tracheostomy placement in the operating room (5% vs. 20%, P less than or equal to.01). No statistically significant difference was found in the perioperative complication incidence between the two methods of bedside tracheostomy. However, percutaneous tracheostomy placement at the bedside resulted in a significant increase in postoperative complication incidence (16% vs. 2%, P <.05) and incurred an additional patient charge of $436 per bedside procedure. CONCLUSIONS: This investigation prospectively confirms the safety of bedside tracheostomy placement in properly selected patients. Complication incidence and resource utilization are defined for two methods of bedside tracheostomy. The results of this study confirm that open surgical tracheostomy represents the standard of care in bedside tracheostomy placement by providing a more secure airway at a markedly reduced patient charge. These findings will aid in the development of protocols and pathways for surgical airway management in critically ill patients to maximize cost-effective, high-quality care.

Taxol enhances but does not induce interleukin-1 beta and tumor necrosis factor-alpha production.

Taxol is a potent, microtubule-stabilizing, antineoplastic drug that induces interleukin-1-beta (IL-1-beta) and tumor necrosis factor-alpha (TNF-alpha) release by thioglycolate-elicited mouse peritoneal macrophages. Because taxol use and subsequent cytokine release in human subjects could be associated with toxicity, the present study was performed to determine how taxol affects cytokine production from fresh human mononuclear cells. Cells were incubated overnight with varying doses of bacterial endotoxin, either with or without taxol, 10 mumol/L. Taxol alone did not induce IL-1-beta or TNF-alpha release by mononuclear cells. However, at all doses of endotoxin from 1 pg/ml to 1 microgram/ml, the addition of taxol resulted in a 50% to 100% increase in IL-1-beta release (p < 0.001) and a 25% to 50% increase in TNF-alpha release (p < 0.01). In contrast, taxol caused a reduction in intracellular pro-IL-1-beta levels. Kinetic studies demonstrated that taxol enhanced IL-1-beta release by mononuclear cells at all time points tested from 4.5 hours to 18 hours after stimulation. Taxol alone did not stimulate IL-1-beta or TNF-alpha mRNA transcription. A similar enhancement of IL-1-beta release was noted in endotoxin-stimulated alveolar macrophages. In summary, these results show that under endotoxin-free conditions, the microtubule-stabilizing agent taxol does not induce IL-1-beta or TNF-alpha production by human mononuclear cells or alveolar macrophages but does enhance production of both of these cytokines in conjunction with a second stimulus.

Colchicine has opposite effects on interleukin-1 beta and tumor necrosis factor-alpha production.

To study the role of microtubules in cytokine production, the effect of the microtubule depolymerizing agent colchicine on lipopolysaccharide endotoxin (LPS)-induced interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) release by blood monocytes and alveolar macrophages were examined. Immunofluorescence microscopy demonstrated that LPS resulted in the appearance of microtubule-containing cytoplasmic appendages and that colchicine, which resulted in microtubule disruption in monocytes, blocked appendage formation. Colchicine resulted in approximately 50% increase in LPS-induced IL-1 beta release and a 50% decrease in LPS-induced TNF-alpha release by human monocytes at all doses of LPS tested. Although colchicine resulted in a statistically significant increase in LPS-stimulated human alveolar macrophage IL-1 beta release, the increase was not as great as that observed with monocytes. Northern blot analysis suggested that the colchicine effect occurs pretranslationally because colchicine caused an increase in LPS-stimulated IL-1 beta mRNA levels and a decrease in TNF-alpha mRNA levels. These results suggest that microtubules contribute to the regulation of endotoxin-stimulated mononuclear phagocyte cytokine production and that this regulation differs significantly between IL-1 beta and TNF-alpha.