Overall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase III trial.

BACKGROUND: IMpower010 (NCT02486718) demonstrated significantly improved disease-free survival (DFS) with adjuvant atezolizumab versus best supportive care (BSC) following platinum-based chemotherapy in the programmed death-ligand 1 (PD-L1)-positive and all stage II-IIIA non-small-cell lung cancer (NSCLC) populations, at the DFS interim analysis. Results of the first interim analysis of overall survival (OS) are reported here. PATIENT AND METHODS: The design, participants, and primary-endpoint DFS outcomes have been reported for this phase III, open-label, 1 : 1 randomised study of atezolizumab (1200 mg q3w; 16 cycles) versus BSC after adjuvant platinum-based chemotherapy (1-4 cycles) in adults with completely resected stage IB (≥4 cm)-IIIA NSCLC (per the Union Internationale Contre le Cancer and American Joint Committee on Cancer staging system, 7th edition). Key secondary endpoints included OS in the stage IB-IIIA intent-to-treat (ITT) population and safety in randomised treated patients. The first pre-specified interim analysis of OS was conducted after 251 deaths in the ITT population. Exploratory analyses included OS by baseline PD-L1 expression level (SP263 assay). RESULTS: At a median of 45.3 months' follow-up on 18 April 2022, 127 of 507 patients (25%) in the atezolizumab arm and 124 of 498 (24.9%) in the BSC arm had died. The median OS in the ITT population was not estimable; the stratified hazard ratio (HR) was 0.995 [95% confidence interval (CI) 0.78-1.28]. The stratified OS HRs (95% CI) were 0.95 (0.74-1.24) in the stage II-IIIA (n = 882), 0.71 (0.49-1.03) in the stage II-IIIA PD-L1 tumour cell (TC) ≥1% (n = 476), and 0.43 (95% CI 0.24-0.78) in the stage II-IIIA PD-L1 TC ≥50% (n = 229) populations. Atezolizumab-related adverse event incidences remained unchanged since the previous analysis [grade 3/4 in 53 (10.7%) and grade 5 in 4 (0.8%) of 495 patients, respectively]. CONCLUSIONS: Although OS remains immature for the ITT population, these data indicate a positive trend favouring atezolizumab in PD-L1 subgroup analyses, primarily driven by the PD-L1 TC ≥50% stage II-IIIA subgroup. No new safety signals were observed after 13 months' additional follow-up. Together, these findings support the positive benefit-risk profile of adjuvant atezolizumab in this setting.

[Antibiotic consumption and bacterial sensitivity in a teaching hospital: A 5-year study]. / Profil de consommation et de sensibilité aux antibiotiques utilisés dans un centre hospitalier universitaire : étude rétrospective sur cinq ans.

INTRODUCTION: To reduce risks of antibiotic resistance, governmental and learned societies decreed the optimal use of antibiotics. The relation between antibiotic consumption and bacterial resistance increase has been clearly demonstrated over the last several years. Antibiotic consumption data and bacterial sensitivity data are regularly published, but very few publications have searched for a correlation between these two variables. This study focused on antibiotic use and consumption as well as bacterial sensitivity to these antibiotics. OBJECTIVES: The main objective was to describe the changes in antibiotic consumption and bacterial sensitivity in a mother-child teaching hospital. The secondary objectives were to explore whether antibiotic use and bacterial sensitivity were correlated and to comment on the usefulness of these data for clinicians. METHODS: This was a 5-year retrospective, descriptive, cross-sectional study. All samples from usually sterile biologic liquids of hospitalized pediatric patients were included in the study. The samples from outpatient clinics were excluded. All types of bacteria identified in more than 30 isolates were included in the study. The antibiotics usually used to treat these bacteria were included. To assess antibiotic consumption, we calculated the number of days of therapy per 1000 patient-days for hospitalized pediatric patients and we calculated the Pearson correlation coefficient between antibiotic consumption and sensitivity rates to these antibiotics. Two scenarios were explored: one with correlation by year and one with the next year for bacterial sensitivity. RESULTS: During the study period (2010-2011 to 2014-2015), overall antibiotics consumption remained relatively stable. Concerning bacterial sensitivity, we noted important changes (sensitivity rates increased for 12 antibiotic-bacteria pairs, remained stable for five, and decreased for 15). We found three significant correlations for the first scenario: Pseudomonas aeruginos-ceftazidime (P=0.01), P. aeruginosa-ciprofloxacin and fluoroquinolone consumption (P=0.02), Enterococcus sp-ampicillin and penicillin consumption (P=0.04). For the second scenario, we found only two significant correlations: coagulase-negative Staphylococcus-oxacilline and penicillin consumption (P=0.02), P. aeruginosa/piperacillin (P=0.04). CONCLUSION: This exploratory study allowed us to describe antibiotic consumption and bacterial sensitivity progression. To our knowledge, this is the first study exploring the correlation between antibiotic consumption and the bacterial sensitivity rate in pediatrics in Canada. It remains very difficult to show this correlation between these two variables because of the multiple sources of bacterial resistance. These data are particularly useful for the antimicrobial stewardship programs and for clinicians.

Descending necrotizing mediastinitis: An analysis of the effects of serial surgical debridement on patient mortality.

OBJECTIVES: Descending necrotizing mediastinitis is a polymicrobial infection originating in the oropharynx with previously reported mortality rates of 25% to 40%. This investigation reviews the effects of serial surgical drainage and debridement on the survival of patients with descending necrotizing mediastinitis. METHODS: A retrospective review of patients from 1980 through 1998 with a diagnosis of descending necrotizing mediastinitis was performed. Their records were abstracted for personal demographics, hospital course, morbidity, and mortality. Also abstracted were all reports of patients with descending necrotizing mediastinitis published in English between 1970 and 1999. RESULTS: We treated 10 patients in whom descending necrotizing mediastinitis was identified. The mean age of the patients was 38 years. They underwent a mean of 6 +/- 4 computed tomographic imaging studies, 4 +/- 1 transcervical drainage procedures, and 2 +/- 1 transthoracic drainage procedures. Three patients required abdominal exploration and 4 underwent tracheostomy. No deaths occurred. In contrast, 96 patients with descending necrotizing mediastinitis were identified from the literature with a mean age of 38 years. They underwent a mean of 2 +/- 1 computed tomographic imaging studies, 2 +/- 1 transcervical drainage procedures, and 0.7 + 0.3 transthoracic drainage procedures. Sixteen (17%) patients required abdominal exploration and 34 (35%) underwent tracheostomy. Twenty-eight (29%) patients from the literature cohort died during their treatment. CONCLUSION: Descending necrotizing mediastinitis remains a life-threatening infection. On the basis of experience accrued in treating these patients, an algorithm incorporating computed tomographic imaging for diagnosis and surveillance and serial transcervical and transthoracic operative drainage is outlined in the hope of reducing the excessive mortality of descending necrotizing mediastinitis.

Pancreatoduodenal necrosis after endoscopic injection of cyanoacrylate to treat a bleeding duodenal ulcer: a case report.

N-butyl 2-cyanoacrylate monomer was injected at endoscopy in an attempt to control arterial bleeding from a duodenal ulcer crater. Segmental infarction of the duodenum and pancreatic head followed and necessitated pancreatoduodenectomy. Butyl 2-cyanoacrylate monomers have been used with angiography as embolization agents and with endoscopy to control variceal bleeding. To our knowledge, there are no reports of its use by endoscopic injection to stop arterial bleeding. Its potential for embolism in nonselective endoscopic injections may minimize the clinical application of butyl 2-cyanoacrylate monomers in the treatment of arterial gastrointestinal bleeding.

Influence of phasic afferent information on phrenic neural output during hypercapnia.

We measured the moving time average (MTA) of the phrenic neurogram before and after removal of phasic afferent information from the lungs, chest wall, and oscillations in blood gases by using constant-flow ventilation (CFV). Anesthetized dogs were studied at various levels of steady-state and progressive hypercapnia during spontaneous breathing and during CFV. When steady-state and progressive hypercapnia were compared, the frequency and height of the MTA phrenic neurogram were independent of the rate of induction of hypercapnia during each mode of ventilation. During spontaneous ventilation, the response to hypercapnia comprised mainly an increase in frequency with only a slight increase in the amplitude of the MTA phrenic waveform. During muscular paralysis and CFV, the responses were similar to those observed after vagotomy with mainly an increase in the amplitude and only a small increase in frequency. For both spontaneous breathing and CFV, increases in frequency were achieved mainly by a shortening in expiratory time with the inspiratory time remaining relatively constant. Our data support the concept of a centrally patterned respiratory generator, whose inherent pattern is modified by phasic feedback from peripheral receptors mainly of vagal origin.

Tracheobronchial resection and reconstruction.

OBJECTIVE: To assess the indications and results of airway resection and how frequently airway reconstructive options changed proposed therapy. DESIGN: A retrospective survey of patients undergoing major airway resection. SETTING: University of Washington-affiliated hospitals, Seattle, May 1992 through December 1996. PATIENTS: Fifty consecutive patients with resectable benign and malignant tracheal or main bronchial disease undergoing tracheobronchial resections. INTERVENTIONS: Patients underwent major airway resection as follows: tracheal or laryngotracheal resection, 23 patients; carinal resection, 6; and bronchial sleeve resection with or without pulmonary resection, 21. Indications for surgery were non-small cell lung cancer in 19 patients, primary airway tumor in 12, thyroid carcinoma in 1, and tracheal or bronchial stenosis in 18. MAIN OUTCOME MEASURES: Change in prereferral planned therapy from palliative to definitive or to pulmonary-sparing procedure, morbidity and mortality, relief of symptoms, and survival. RESULTS: Mortality was 0%, and morbidity, 32% (15/50). Airway reconstruction changed the proposed therapy in 42 patients (84%). Functional results were good to excellent in 17 (94%) of 18 patients with benign disease. Patients with malignant disease had a 1-year survival of 93% (27/29) and a 2-year survival of 67% (12/18). CONCLUSIONS: Airway resection and reconstruction provide reliable relief of benign and malignant tracheobronchial disease with minimal morbidity and mortality. Airway reconstruction frequently changed prereferral planned therapy and provided definitive and parenchymal-sparing procedures to patients with complex airway lesions.

Ambulatory mediastinoscopy and anterior mediastinotomy.

Ambulatory facilities are being used more and more for various diagnostic and therapeutic procedures. We report 158 consecutive mediastinoscopies and anterior mediastinotomies performed in an ambulatory setting from July 1981 to February 1990. There were 120 patients with a malignancy: 114 bronchogenic carcinomas, 4 lymphomas, 1 teratocarcinoma, and 1 carcinoma of the stomach. Thirty-eight patients had a benign condition, including sarcoidosis in 27 and miscellaneous diagnosis in 11. Twenty-two patients (14%) were admitted the same day: 9 for elective operation in view of bed availability, 8 for medical observation, and 5 for overnight admission for nonmedical reasons. Six nonfatal complications were encountered: hemoptysis (2), atrial fibrillation (1), pneumonia (1), mediastinal self-contained bleed (1), and tear of a pulmonary artery (1). There was no operative mortality. Overall, ambulatory mediastinoscopy and anterior mediastinotomy permitted a diagnosis in 47 patients (20%) and confirmed unresectable malignant disease in 29 patients, thus sparing unnecessary admission to a surgical ward in 76 (48%) of the 158 patients. Mediastinoscopy and anterior mediastinotomy can be safely performed in an ambulatory setting and do alleviate the need for hospitalization in a substantial number of patients.

Incarcerated parahiatal hernia with gastric necrosis.

A parahiatal diaphragmatic hernia developed five years after transthoracic Heller myotomy. Failure to recognize this complication resulted in strangulation and necrosis of the gastric fundus. To our knowledge, this is the first reported case of a postoperative parahiatal hernia that did not follow the use of a diaphragmatic counterincision. Prompt recognition of this complication will prevent unnecessary morbidity and mortality.

Carcinoid crisis after biopsy of a bronchial carcinoid.

Pulmonary carcinoids are rarely associated with carcinoid syndromes and even less commonly with carcinoid crisis. Somatostatin analogues can control carcinoid syndrome or crisis with tumors of gastrointestinal origin. We report the successful use of a somatostatin analogue in preventing carcinoid crisis at the time of resection of an "active" bronchial carcinoid tumor.

Postpneumonectomy chylothorax.

Chylothorax complicating pulmonary resections is exceptional and management of this complication remains controversial. We report a case of chylothorax after a right pneumonectomy and radical subcarinal nodal dissection. Successful nonoperative management consisted of controlled tube drainage, fasting, and total parenteral nutritional support for a period of 2 weeks. A review of the literature reveals 27 other cases of this complication after intrapleural pneumonectomy: 12 were treated by conservative measures alone and 15 required surgical intervention. Factors that will determine the management and the ultimate success of conservative management include (1) a relative delay in initial occurrence, (2) a decrease in or complete cessation of leakage while receiving total parenteral nutrition, and (3) favorable lymphangiographic findings.

Combined microneurosurgical and thoracoscopic removal of neurogenic dumbbell tumors.

The resection of posterior mediastinal dumbbell tumors has until now required laminectomy and some form of open access to the thoracic cavity. Over a 1-year period, a novel surgical approach combining posterior microneurosurgical and anterior video-assisted thoracoscopy techniques was used in 4 patients. In 3 patients, the tumor was removed successfully with minimal postoperative discomfort and rapid recovery. In the fourth patient, limited thoracotomy became necessary to control bleeding. This new approach, which combines modern-day neurosurgical and general thoracic surgical techniques, appears safe and could become the preferred method for removing most benign posterior mediastinal dumbbell tumors.

Percutaneous placement of tracheal T tube.

Tracheal T tubes provide effective palliation of unresectable benign and malignant tracheal obstruction, but placement may be difficult when previous operation, radiation, or tumor limits surgical exposure of the cervical trachea. Percutaneous placement using commercially available percutaneous tracheostomy kits may provide an alternative approach in these cases.

Colobronchial fistula due to Crohn's disease.

Enteropulmonary fistulas may present as recurrent localized pneumonia. A case of one such fistula originating from the colon in a patient with Crohn's disease is discussed.

Bronchial-atrial fistula after lung transplant resulting in fatal air embolism.

We describe a rare case of fatal air embolism in a patient in whom a left atrial-bronchial fistula developed 1 month after single lung transplant. The cause was a combination of mediastinal infection and bronchial necrosis.

Bronchial revascularization in double-lung transplantation: a series of 8 patients. Bordeaux Lung and Heart-Lung Transplant Group.

Donor airway ischemia is the main cause for defective tracheal or bronchial healing after double-lung transplantation. Anatomical studies and bronchial arteriograms have shown that the right intercostal bronchial artery is constant (95% of instances) and provides an important blood supply to the distal trachea, the carina, and the right bronchial tree as well as to the left side through a subcarinal and periadventitial anastomostic network. To maintain this important bilateral bronchial circulation, it is of capital importance not to mobilize the arteries individually and to avoid large dissections around the carina. Both bronchi can thus be revascularized by indirect aortic reimplantation using a bypass graft to a single aortic patch that includes the origin of the right intercostal bronchial artery. Furthermore, the origin of other vessels (a common trunk and left arteries) can be found within a short distance of the right intercostal bronchial artery and possibly be contained within the same aortic patch. From a series of 56 lung transplantations, 8 patients underwent restoration of the bronchial vascularization using a recipient saphenous vein graft between the donor bronchial arteries and the anterior aspect of the recipient's ascending aorta. A lower tracheal anastomosis was performed. Bronchial arterial blood supply was evaluated both by endoscopy and by arteriography at about the 15th postoperative day. The bronchial circulation was visualized at this time in five of seven arteriographies, and this was associated with excellent tracheal healing in all 8 patients.

Endoscopic upper thoracic sympathectomy.

Thoracoscopic sympathectomy provides a superb surgical option for the many patients with incapacitating essential hyperhidrosis. Whether one thoracoscopic approach to sympathectomy is ever likely to prevail is doubtful, as the results of the various reported techniques seem to be quite similar. There are definite advantages to the single-port approaches, which are faster and usually do not require repositioning of the patient to do both sides. In the rare instances where dense apical adhesions are encountered or when significant bleeding is encountered from one of the intercostal vessels, the two- or three-port approaches definitely provide better control (see commentary in article by Kohno and Takamoto). Surgeon preference probably dictates which approach is used at the different centers. Compensatory sweating remains a frequent and sometimes serious complication of the procedure, particularly in individuals living in hot climates. An understanding of its mechanisms needs improvement, with the hope of preventing its occurrence in the future. In the meantime, patients have to be informed of its frequency, and operations could probably be tailored to the patients' needs and their local climate.

Ex-vivo fine needle aspiration. A new method of xenografting non-small cell carcinoma of the lung.

Ex-vivo needle aspiration (xvFNA) has been rarely used to obtain viable tumor cells. It has been occasionally employed for short-term cultures. Xenografting of lung carcinoma in athymic nude mice provides a good animal model for the study of this neoplasm. Successful engraftment using conventional methods has been disappointing) low (d 40%). Enzymatic digestion of the tumor fragments to obtain cell suspension lowers viability. We postulated that xvFNA might provide readily available tumor cell suspensions for xenografting lung carcinoma and that it would provide a higher success rate of engraftment than the conventional techniques. We aseptically performed xnFNA in 35 cases of freshly resected non-small cell carcinoma of the lung. These included 15 adenocarcinomas, 17 squamous carcinomas and 3 undifferentiated non-small cell carcinoma (UNSCC). Tumor cell suspensions were injected subcutaneously in athymic nude mice. Tumor necrosis in the aspirates ranged from 20-90% (median 60%). Gross evidence of engraftment was seen in 30 of 35 cases (85.7%) 1-19 weeks postimplantation (median 2 weeks). This was seen in UNSCC (3/3), squamous carcinomas (13/17) and adenocarcinomas (14/15). Xenograft sizes ranged from 5-34 mm (median 19 mm). They showed similar morphology to the primary tumors. Ex-vivo FNA used for harvesting lung carcinoma cells and their xenografting is an effective method for obtaining viable material for studying this neoplasm.

The effect of high dose vitamin A on the morphology and proliferative activity of xenograft lung and head and neck cancer.

In vitro studies have suggested that vitamin A lowers invasive potential of squamous cell carcinoma. Epidemiological data have also indicated that high dose vitamin A may improve survival in patients with previously resected lung carcinoma. To our knowledge, no studies have attempted to test the in vivo effect of vitamin A on the morphology and growth rate of lung and head and neck cancer. Freshly resected tumor cell suspensions were obtained by ex vivo fine needle aspiration and injected subcutaneously in duplicate in athymic male nude mice. Two to six weeks post-engraftment tests and controls were separated for each xenograft. Mice with test xenografts were given water soluble vitamin A (Aquasol ATM, Astra pharmaceutical, Westborough, MA, U.S.A) at a dose of 10,000 U/Kg/day intraperitoneally for 6 to 10 weeks (median 8 weeks). One to two hours prior to sacrifice bromodexouridine (BrdU) was injected intraperitoneally to assess the S-phase fraction in both test and control xenografts. Blood vitamin A levels in test and control animals were measured after sacrifice using high performance liquid chromatography (HPLC). Sections of test and control xenografts were routinely stained to assess morphologic differentiation and mitotic counts. Unstained sections of xenografts were immunostained by the antibody to BrdU to test for BrdU labeling index (BLI) reflecting S-phase fraction (SPF) and also by the MIB-1 antibody to assess proliferative activity. Eighteen tumors were studied. These included 9 squamous cell carcinomas of the lung, 5 squamous cell carcinomas of the head and neck, and 4 adenocarcinomas of the lung. Blood levels of vitamin A in test animals were 7 to 23 times those of the control animals (median 13 times). Neovascularization of the xenografts was seen in all cases. The morphology and mitotic activity of the test and control xenografts showed no significant difference. SPF and proliferative activity measured by BrdU and MIB-1 immunolabelling respectively showed no significant difference between test and control xenografts. Our study suggests that there is no significant in vivo effect of high dose vitamin A on the morphology and growth rate of xenografted non small cell carcinoma of the lung or squamous cell carcinoma of the head and neck.