Treatment patterns and long-term survival outcomes for patients with stage III non-small cell lung cancer: A retrospective study.

AIM: Lung cancer is the leading cause of cancer-related deaths in Australia with poor long-term survival outcomes. Stage III non-small cell lung cancer (NSCLC) is a highly heterogenous group with diverse tumor characteristics and multiple, possible treatment options. We present retrospective data on patient characteristics, treatment patterns, and long-term outcomes in stage III NSCLC patients treated at a single cancer center in New South Wales, Australia. METHODS: Stage III NSCLC patients were identified from the 'Nepean Cancer Research Biobank'. Patient demographics, cancer-related information, and long-term follow-up data were collected and analyzed. RESULTS: A total of 88 patients were eligible for analysis with 61% of them diagnosed as stage IIIA, 35% IIIB, and 4% IIIC. Induction chemotherapy was administered in 20% of the patients. Overall, 48% of the study population underwent surgery, and 38% underwent concurrent chemoradiotherapy (CCRT). Both median progression-free survival and overall survival (OS) were superior in stage IIIA patients in comparison to stage IIIB (and IIIC) patients (22 vs. 11 months, p = .018; and 58 vs. 19 months, p = .048, respectively). Patients who were younger (<65 years old), good Eastern Cooperative Oncology Group performance status (ECOG PS <2), and females had better prognosis on univariate analysis. There was a nonstatistically significant trend toward better median OS with CCRT in comparison to surgery (58 vs. 37 months, p = .87). CONCLUSIONS: Long-term outcomes remain poor, and hence better treatment strategies are urgently needed in stage III NSCLC. Equally, more robust, prospective studies would help delineate the optimal treatment modality in these patients.

Reintervention and Survival After Limited Lung Resection for Lung Cancer Treatment in Australia.

BACKGROUND: To investigate the risk and predictors of reintervention (surgery or radiotherapy) after limited resection for lung cancer. METHODS: A population-based, all-inclusive study using linked data from the New South Wales Admitted Patient Data Collection and Death Register included all patients undergoing limited resection for lung cancer between July 1, 2002, and March 31, 2014. Univariate and adjusted competing risk analyses were used to estimate the effect of potential factors for risk of reintervention within 6 months and 24 months of the initial surgery. RESULTS: The overall 5-year survival for lung cancer patients undergoing limited lung resection was 52% (49% to 54%); for patients aged 70 years or more, the survival rate was 44% (40% to 47%). Reintervention occurred in 6.2% by 6 months and 11.3% by 24 months after the surgery. Younger age, surgery in private hospitals, and fewer comorbidities were independently associated with increased risk of reintervention. Patients who had the surgery performed in high surgical volume hospitals had 49% lower risk of reintervention within the first 6 months (95% confidence interval: 0.30 to 0.85). The effect of hospital surgical volume was attenuated by 24 months (hazard ratio 0.87, 95% confidence interval: 0.60 to 1.28). Patients undergoing reintervention within 6 months or 24 months had a twofold (1.52 to 2.57) and 2.3-fold (1.89 to 2.83) increased risk of death, respectively. CONCLUSIONS: The reintervention rate within 6 or 24 months of initial limited lung cancer resection was modest, but there was considerable variation among hospitals. Reintervention was not a benign event and was associated with lower survival in an Australian population.

Microphysiologic Human Tissue Constructs Reproduce Autologous Age-Specific BCG and HBV Primary Immunization in vitro.

Current vaccine development disregards human immune ontogeny, relying on animal models to select vaccine candidates targeting human infants, who are at greatest risk of infection worldwide, and receive the largest number of vaccines. To help accelerate and de-risk development of early-life effective immunization, we engineered a human age-specific microphysiologic vascular-interstitial interphase, suitable for pre-clinical modeling of distinct age-targeted immunity in vitro. Our Tissue Constructs (TCs) enable autonomous extravasation of monocytes that undergo rapid self-directed differentiation into migratory Dendritic Cells (DCs) in response to adjuvants and licensed vaccines such as Bacille Calmette-Guérin (BCG) or Hepatitis B virus Vaccine (HBV). TCs contain a confluent human endothelium grown atop a tri-dimensional human extracellular matrix substrate, employ human age-specific monocytes and autologous non heat-treated plasma, and avoid the use of xenogenic materials and exogenous cytokines. Vaccine-pulsed TCs autonomously generated DCs that induced single-antigen recall responses from autologous naïve and memory CD4+ T lymphocytes, matching study participant immune-status, including BCG responses paralleling donor PPD status, BCG-induced adenosine deaminase (ADA) activity paralleling infant cohorts in vivo, and multi-dose HBV antigen-specific responses as demonstrated by lymphoproliferation and TCR sequencing. Overall, our microphysiologic culture method reproduced age- and antigen-specific recall responses to BCG and HBV immunization, closely resembling those observed after a birth immunization of human cohorts in vivo, offering for the first time a new approach to early pre-clinical selection of effective age-targeted vaccine candidates.

Tracheobronchial stents in palliative care: a case series and literature review.

OBJECTIVE: To evaluate the outcomes of tracheobronchial stenting in patients with malignant central airway obstruction and assist practitioners in palliative settings in understanding the indications, contraindications and management of tracheobronchial stents. METHODS: This retrospective study involved a consecutive case series of palliative patients with central airway obstruction secondary to inoperable cancers who underwent tracheobronchial stenting at a single institution. The European Cooperative Oncology Group (ECOG) scale was used to evaluate patient functional status before and after tracheobronchial stenting. RESULTS: Twenty-three patients underwent tracheobronchial stenting for malignant central airway obstruction. The majority of patients presented with symptoms of worsening dyspnoea (21 of 23; 91%). Postoperatively, there was a significant improvement in mean ECOG performance status from 2.88±0.34 to 1.58±0.50 (p<0.01). There was no intraoperative mortality resulting from tracheobronchial stenting. Five patients (21.74%) re-presented to hospital due to worsening symptoms and required emergency bronchoscopy. Two patients had stent migration, requiring stent replacement. One patient restenosed from tumour granulation, requiring microdebrider to debulk the mass. Two patients had stent failure secondary to external tumour compression, leading to death. CONCLUSION: Tracheobronchial stenting is a safe and effective procedure that offers rapid palliation of symptoms and improvement in patient functional status.

Consensus minimum data set for lung cancer multidisciplinary teams: Results of a Delphi process.

BACKGROUND AND OBJECTIVE: While multidisciplinary team (MDT) care in lung cancer is widely practiced, there are few guidelines for MDT on best data collection strategies. MDT meetings need ready access to information for the provision of optimal treatment recommendations (the primary purpose of the meeting), audit of team performance and benchmarking. This study aimed to develop a practical data set designed for these goals through a recognized consensus process with health professionals who participate in formal MDT settings. METHODS: A modified Delphi process with three iterations (two surveys and one consensus conference) was carried out involving over 100 Australian lung cancer MDT health professionals. RESULTS: In total, 122 lung cancer MDT health professionals responded to the Round 1 survey from over 350 invitees. Of the 122, 98 were available for invitation to Round 2. Of 98, 52 (53%) invitees responded to the Round 2 survey. After two rounds, 51 data elements across 8 domains (patient demographics, risk factors, biopsy data, staging, timeliness, treatment, follow-up and patient selection) achieved consensus, defined as 80% agreement. For Round 3, 33 MDT lead clinicians were invited to participate in a consensus conference. Of 33, 14 (42%) invitees distilled the 47 data elements into 23 elements across 8 domains to address the study objectives. CONCLUSION: A practical data set for lung cancer MDT to use for optimal treatment recommendations and to evaluate team performance was developed through recognized consensus methodology. Access to streamlined, relevant and feasible data collection strategies may improve MDT decision-making, audit of team performance and facilitate benchmarking.

Measuring and Modeling Highly Accurate 15 N Chemical Shift Tensors in a Peptide.

NMR studies measuring chemical shift tensors are increasingly being employed to assign structure in difficult-to-crystallize solids. For small organic molecules, such studies usually focus on 13 C sites, but proteins and peptides are more commonly described using 15 N amide sites. An important and often neglected consideration when measuring shift tensors is the evaluation of their accuracy against benchmark standards, where available. Here we measure 15 N tensors in the dipeptide glycylglycine at natural abundance using the slow-spinning FIREMAT method with SPINAL-64 decoupling. The accuracy of these 15 N tensors is evaluated by comparing to benchmark single crystal NMR 15 N measurements and found to be statistically indistinguishable. These FIREMAT experimental results are further used to evaluate the accuracy of theoretical predictions of tensors from four different density functional theory (DFT) methods that include lattice effects. The best theoretical approach provides a root mean square (rms) difference of ±3.9 ppm and is obtained from a fragment-based method and the PBE0 density functional.

Patients' and doctors' preferences for adjuvant chemotherapy in resected non-small-cell lung cancer: What makes it worthwhile?

BACKGROUND: Adjuvant chemotherapy (ACT) in non-small-cell lung cancer (NSCLC) improves overall survival, but the benefits must be weighed against its harms. We sought to determine the survival benefits that patients and their doctors judged sufficient to make ACT in NSCLC worthwhile. METHODS: 122 patients completed a self-administered questionnaire at baseline and 6 months (before & after ACT, if they had it); 82 doctors completed the questionnaire once only. The time trade-off method was used to determine the minimum survival benefits judged sufficient in four hypothetical scenarios. Baseline survival times were 3 years & 5 years and baseline survival rates (at 5 years) were 50% & 65%. RESULTS: At baseline, the median benefits judged sufficient by patients were an extra 9 months (Interquartile range (IQR) 1-12 months) beyond 3 years & 5 years and an extra 5% (IQR 0.1-10%) beyond 50% & 65%. At 6 months (n=91), patients' preferences had the same median benefit (9 months & 5%) but varied more (IQRs 0-18 months & 0-15%) than at baseline. Factors associated with judging smaller benefits sufficient were deciding to have ACT (P=0.01, 0.02) and better well-being (P=0.01, 0.006) during ACT. Doctors' preferences, compared with patients' preferences, had similar median benefits (9 months & 5%) but varied less (IQR 6-12 months versus 1-12 months, P<0.001; 5%-10% versus 0.1-10%, P<0.001). CONCLUSION: Most patients and doctors judged moderate survival benefits sufficient to make ACT in NSCLC worthwhile, but the preferences of doctors varied less than those of patients. Doctors should endeavour to elicit patients' preferences during discussions about ACT in NSCLC.

Fracture and aspiration of a tracheostomy tube.

A 70-year-old woman presented with a fracture and aspiration of her polyvinyl chloride tracheostomy tube. Her chest X-ray showed that a foreign body was lodged in the right main bronchus. She was otherwise asymptomatic. The foreign body was removed under general anaesthesia using a flexible bronchoscope. The patient developed pneumonia after the procedure and was admitted to the intensive care unit. She was discharged home 5 days after the event with no permanent complications.

Optimized surface markers for the prospective isolation of high-quality hiPSCs using flow cytometry selection.

hiPSC derivation and selection remains inefficient; with selection of high quality clones dependent on extensive characterization which is not amenable to high-throughput (HTP) approaches. We recently described the use of a cocktail of small molecules to enhance hiPSC survival and stability in single cell culture and the use of flow cytometry cell sorting in the HTP-derivation of hiPSCs. Here we report an enhanced protocol for the isolation of bona fide hiPSCs in FACS-based selection using an optimized combination of cell surface markers including CD30. Depletion of CD30(+) cells from reprogramming cultures almost completely abolished the NANOG and OCT4 positive sub-population, suggesting it is a pivotal marker of pluripotent cells. Combining CD30 to SSEA4 and TRA-1-81 in FACS greatly enhanced specificity and efficiency of hiPSC selection and derivation. The current method allows for the efficient and automated, prospective isolation of high-quality hiPSC from the reprogramming cell milieu.

New directions in cellular therapy of cancer: a summary of the summit on cellular therapy for cancer.

A summit on cellular therapy for cancer discussed and presented advances related to the use of adoptive cellular therapy for melanoma and other cancers. The summit revealed that this field is advancing rapidly. Conventional cellular therapies, such as tumor infiltrating lymphocytes (TIL), are becoming more effective and more available. Gene therapy is becoming an important tool in adoptive cell therapy. Lymphocytes are being engineered to express high affinity T cell receptors (TCRs), chimeric antibody-T cell receptors (CARs) and cytokines. T cell subsets with more naïve and stem cell-like characteristics have been shown in pre-clinical models to be more effective than unselected populations and it is now possible to reprogram T cells and to produce T cells with stem cell characteristics. In the future, combinations of adoptive transfer of T cells and specific vaccination against the cognate antigen can be envisaged to further enhance the effectiveness of these therapies.

Recurrent posterior circulatory emboli from a mildly stenosed bicuspid aortic valve.

Bicuspid aortic valve (BAV) is a common condition but is only rarely associated with embolic complications. We describe a 42-year-old man with recurrent posterior circulatory ischemic strokes that resulted in ataxia and cognitive impairment. Transesophageal echocardiography demonstrated a BAV with mild stenosis, moderate calcification, and a dilated ascending aorta. The degree of calcification and the valve phenotype might be important factors implicating the BAV as a rare cause of ischemic stroke.

Stabilization of RNA oligomers through reverse micelle encapsulation.

The cellular milieu is rich in diversity of both simple and complex molecules and is also quite crowded. By contrast, typical sample concentrations employed for in vitro investigation of biophysics and structural biology make use of purified macromolecules in simple buffer systems at concentrations that range from micromolar to millimolar. Although this formulation has proven to be compatible with a wide range of biological and structural studies, it is quite different from the relatively crowded conditions typically found within cells. The importance of these crowding effects for proteins has been recognized for some time, but the equivalent analysis is underexplored in nucleic acids. Encapsulation with surfactant-based reverse micelles has emerged as an effective biophysical tool, allowing study of the influence of ionic strength, pH, hydration, and crowding on biologically active macromolecules over a wide range of conditions. We have encapsulated an oligonucleotide model of TAR RNA from HIV and the 5' stem loop oligonucleotide of the U4 snRNA. Observation of imino (1)H resonances is an established method for evaluating the stability of nucleic acid oligonucleotides, implying the presence of stacked, hydrogen bonded base pairs. Inspection of (1)H NMR spectra of the RNA molecules reveals that the intensity of several of the imino resonances increases upon encapsulation. Additional resonances not observed in spectra of the oligonucleotides free in solution support the suggestion that the molecules have gained stability. These results indicate that RNA oligonucleotides may acquire significant stability in the presence of cellular levels of crowding.

An engineered human antibody fab fragment specific for Pseudomonas aeruginosa PcrV antigen has potent antibacterial activity.

Pseudomonas aeruginosa is an opportunistic pathogen that can cause acute lung injury and mortality through the delivery of exotoxins by the type III secretion system (TTSS). PcrV is an important structural protein of the TTSS. An engineered human antibody Fab fragment that binds to the P. aeruginosa PcrV protein with high affinity has been identified and has potent in vitro neutralization activity against the TTSS. The instillation of a single dose of Fab into the lungs of mice provided protection against lethal pulmonary challenge of P. aeruginosa and led to a substantial reduction of viable bacterial counts in the lungs. These results demonstrate that blocking of the TTSS by a Fab lacking antibody Fc-mediated effector functions can be sufficient for the effective clearance of pulmonary P. aeruginosa infection.

Significant clinical and radiological resolution of a spinal cord syrinx following the release of a tethered cord in a patient with an anatomically normal conus medullaris. Case report.

The authors describe a case of progressive neurological deficit caused by syringomyelia in a 7-year-old boy with a normally positioned conus medullaris. This deficit responded favorably to surgical untethering of the filum terminale, with subsequent clinical and radiological improvement. The authors discuss the implications of their findings in the context of the current understanding of the pathophysiology of tethered cord syndrome, particularly in relation to the ongoing debate in the neurosurgical literature.

Primary malignant melanoma of the cerebellopontine angle: a diagnostic dilemma: case report.

OBJECTIVE: To present a rare case of a primary malignant melanoma of the central nervous system presenting as a cerebellopontine angle (CPA) tumor and to delineate aspects of the clinical presentation and magnetic resonance imaging scan characteristics that may suggest this unusual condition. CLINICAL PRESENTATION: The clinical presentation consisted of a short duration of right-sided sensorineural hearing loss, facial weakness, and ataxia in a previously healthy man. Brain magnetic resonance imaging scans showed a right-sided CPA tumor exhibiting shortening of T1 and T2 relaxation times, but overall neuroradiological features were not consistent with any commonly occurring CPA tumors. INTERVENTION: Gross total excision of the lesion was accomplished via a right suboccipital craniectomy. Histological examination revealed a malignant melanoma. A detailed search excluded extracranial primary melanoma. CONCLUSION: Correlation of clinical and imaging findings offer the most important clues in the diagnosis of such unusual primary malignant tumors of the CPA. A history of rapid onset of audiovestibular symptoms, presence of facial palsy, and shortening of T1 and T2 relaxation times on magnetic resonance imaging scans should arouse the clinician's suspicions.