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.

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.

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.

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.

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.

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.

Acute eosinophilic pneumonia: radiologic and clinical features.

PURPOSE: To determine the radiographic and computed tomographic (CT) characteristics of acute eosinophilic pneumonia. MATERIALS AND METHODS: Twelve consecutive patients with acute eosinophilic pneumonia were included in the study. The diagnosis was based on clinical symptoms and results of bronchoalveolar lavage. Plain chest radiographs were obtained in all patients; CT scans were obtained in three patients. Two thoracic radiologists reviewed the radiographs and CT scans. RESULTS: Ten patients had bilateral areas of air-space opacity on images obtained at presentation; in seven of these patients, interstitial areas of opacity were also present. Two patients had bilateral interstitial areas of opacity and no areas of air-space opacity. Interlobular septal thickening and ground-glass attenuation were present on CT scans in two patients; patchy bilateral consolidation was present on CT scans in one patient. Pleural effusion was present on radiographs in seven patients (58%) and was bilateral in five. Pleural effusion was present at some point during the course of disease in all patients. In all patients, air-space disease markedly improved within 3 days of initiation of treatment with corticosteroids. CONCLUSION: Acute eosinophilic pneumonia should be considered as a possible diagnosis when a previously healthy person presents with acute respiratory failure of unknown origin.

Changes in mononuclear phagocyte microtubules after endotoxin stimulation. I. Changes in microtubule stability.

Microtubules are in a dynamic equilibrium of polymerization and depolymerization. In monocytes and macrophages, microtubules bind endotoxin and partly regulate inflammatory events such as cytokine production. To characterize the morphologic differences between alveolar macrophage and blood monocyte microtubules after LPS stimulation, cells were examined by immunofluorescent microscopy and laser confocal microscopy. Fresh monocytes contained an average of 26 microtubules per cell which significantly increased to 31 microtubules per cell following a 30-min exposure to LPS (P < 0.001). Using a nocodazole-based assay of microtubule dynamic instability, the half-life of fresh unstimulated human monocyte microtubules was approximately 18 s and extended to 26 s following a 30-min exposure to LPS. In vitro maturation of monocytes for 18 h increased microtubule stability but not number. Compared to monocytes, alveolar macrophage microtubules were longer, more numerous, and much more stable. These results suggest that alveolar macrophage microtubules are more numerous and stable than blood monocyte microtubules and that LPS causes an increase in monocyte microtubule number and stability.

Changes in mononuclear phagocyte microtubules after endotoxin stimulation. II. Changes in microtubule composition.

Microtubules are integral components of the cytoskeleton of human cells and are composed of alpha- and beta-tubulin as well as a variable number of microtubule-associated proteins. In monocytes and macrophages, microtubules bind endotoxin and partly regulate endotoxin-induced inflammatory events such as cytokine production. Endotoxin causes a rapid alteration in monocyte microtubule stability. To characterize the effect of endotoxin on mononuclear phagocyte microtubule composition, Western blots and flow cytometry were performed on human monocytes and the monocyte/macrophage-like cell line THP-1. Compared to unstimulated monocytes, monocytes stimulated with endotoxin for 18 h had increased quantities of alpha-, beta-, and tyrosinated alpha-tubulin as well as microtubule-associated protein-2. PMA-differentiated THP-1 cells had increased levels of alpha-tubulin, beta-tubulin, microtubule-associated protein-5, microtubule-associated protein-2, and tau after endotoxin stimulation. These results indicate that endotoxin can alter mononuclear phagocyte microtubules by causing an increase in certain microtubule component proteins.

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.

Detection of IL-5 and IL-1 receptor antagonist in bronchoalveolar lavage fluid in acute eosinophilic pneumonia.

BACKGROUND: Acute eosinophilic pneumonia is an idiopathic cause of respiratory failure, characterized by very high numbers of alveolar eosinophils without significant blood eosinophilia. OBJECTIVE: The purpose of this study was to determine which cytokines are associated with acute eosinophilic pneumonia. METHODS: Soluble IL-1 type II receptor and the cytokines IL-1 beta, IL-1ra, IL-3, IL-5, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor-alpha were measured in serum and in bronchoalveolar lavage fluid from two patients with acute eosinophilic pneumonia during both acute and convalescent phases. RESULTS: Compared with patients with adult respiratory distress syndrome, the patients with acute eosinophilic pneumonia had high bronchoalveolar lavage fluid levels of IL-5, IL-1ra, and soluble type II IL-1 receptor but not IL-1 beta, tumor necrosis factor-alpha, IL-3, or granulocyte-macrophage colony-stimulating factor. Bronchoalveolar lavage fluid levels of IL-5 and IL-1ra fell after resolution of symptoms. In the serum of patients with acute eosinophilic pneumonia, IL-5 was not detectable, and IL-1ra was initially high but fell after corticosteroid treatment. CONCLUSION: Acute eosinophilic pneumonia is characterized by locally high levels of IL-5, IL-1ra, and soluble type II IL-1 receptor in the alveolar space.

Taxol and colchicine increase LPS-induced pro-IL-1 beta production, but do not increase IL-1 beta secretion. A role for microtubules in the regulation of IL-1 beta production.

IL-1 beta is a proinflammatory cytokine secreted chiefly by monocytes and macrophages. Currently, much of its mechanism of processing and secretion is poorly understood, but there is increasing evidence that the microtubule system may be involved. For example, it is known that taxol and colchicine, two drugs that affect microtubule structure and function, increase LPS-induced IL-1 beta release. However, it is not known whether these drugs affect the synthesis of the 31-kDa precursor (pro-IL-1 beta) or the processing and release of mature IL-1 beta. To test this, an assay was used that allowed for the temporal separation of IL-1 beta synthesis and release. The addition of taxol or colchicine to the secretory phase of the assay resulted in no significant change in IL-1 beta release. However, when these drugs were added to the stimulus for IL-1 beta production, there was a significant increase in both IL-1 beta release and total IL-1 beta production, as measured by ELISA. These findings indicate that taxol and colchicine increase LPS-induced IL-1 beta release by an increase in the production of the precursor molecule. Thus, it is unlikely that microtubules are involved in the IL-1 beta secretory machinery in any significant manner, but they do play a role in the regulation of pro-IL-1 beta production.

Immunosuppressive properties of surfactant and plasma on alveolar macrophages.

Alveolar macrophages have been shown to be major producers of the potent proinflammatory cytokines interleukin-1 beta and tumor necrosis factor-alpha, and of the antiinflammatory cytokine interleukin-1 receptor antagonist. During the adult respiratory distress syndrome the normally surfactant-coated alveolus becomes flooded with plasma proteins, altering the milieu of alveolar cells such as alveolar macrophages. To understand alveolar macrophage function during the adult respiratory distress syndrome, the individual and combined effects of surfactant and plasma on alveolar macrophage cytokine production was examined. A synthetic surfactant (Exosurf) and a bovine-derived surfactant (Survanta) both inhibited production of interleukin-1 beta, pro-interleukin-1 beta, tumor necrosis factor-alpha, and interleukin-1 receptor antagonist in a dose-dependent manner. This inhibition was noted when both endotoxin and heat-killed Staphylococcus aureus were used as stimuli. Autologous plasma also inhibited interleukin-1 beta and tumor necrosis factor-alpha release in a dose-dependent manner, but, unlike surfactant, plasma did not inhibit interleukin-1 receptor antagonist release. Similarly, the combination of plasma and surfactant inhibited interleukin-1 beta and tumor necrosis factor-alpha release but not interleukin-1 receptor antagonist release. In support of these data, interleukin-1 receptor antagonist was detectable in five of six bronchoalveolar lavage fluid samples from patients with adult respiratory distress syndrome at a mean concentration of 465 pg/ml; on the other hand, interleukin-1 beta was not detectable in any of these samples. These results indicate that the relative production of interleukin-1 beta, tumor necrosis factor-alpha, and interleukin-1 receptor antagonist can be altered depending on the local concentration of both surfactant and plasma.

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.

Macrophage and monocyte IL-1 beta regulation differs at multiple sites. Messenger RNA expression, translation, and post-translational processing.

Maturation of blood monocytes into macrophages is accompanied by a number of functional changes including decreased IL-1 beta release in response to LPS. This limitation has previously been ascribed to transcriptional regulation. However, in seeming conflict with the observed depression in IL-1 beta mRNA levels, recent work demonstrates increased intracellular IL-1 beta in macrophages. Therefore, the present study sought to explain these differences by comparing IL-1 beta production from autologous alveolar macrophage and blood monocyte pairs at multiple regulatory sites, including endotoxin responsiveness, mRNA expression, protein translation, and post-translational processing. Macrophages did not differ from monocytes in endotoxin sensitivity, but when analyzed by both ELISA and Western blot, were confirmed to have limitations in IL-1 beta release. Gene expression studies demonstrated that at 4 h, macrophage IL-1 beta steady state mRNA levels were 3-fold lower than the monocyte's. However, total IL-1 beta protein production, as measured by [35S]methionine labeling with immunoprecipitation, demonstrated three- to sixfold higher amounts in macrophages at comparable time points. The enhanced protein production in the face of relatively low mRNA levels suggests that macrophages translate IL-1 beta mRNA more efficiently. Furthermore, characterization of IL-1 beta release into supernatants revealed that whereas monocyte release occurred early, represented 5 to 20% of the intracellular amounts, and contained largely processed IL-1 beta, macrophage release was delayed, represented 1 to 5% of the intracellular amounts, and contained primarily unprocessed IL-1 beta. Taken together, these data demonstrate that the limitations in alveolar macrophage IL-1 beta release occur due to slower export and conversion of 35- to 17-kDa protein and are not due to differences in sensitivity to endotoxin or to transcriptional control mechanisms.