Recommendations for the use of next-generation sequencing in patients with metastatic cancer in the Asia-Pacific region: a report from the APODDC working group.

INTRODUCTION: Next-generation sequencing (NGS) diagnostics have shown clinical utility in predicting survival benefits in patients with certain cancer types who are undergoing targeted drug therapies. Currently, there are no guidelines or recommendations for the use of NGS in patients with metastatic cancer from an Asian perspective. In this article, we present the Asia-Pacific Oncology Drug Development Consortium (APODDC) recommendations for the clinical use of NGS in metastatic cancers. METHODS: The APODDC set up a group of experts in the field of clinical cancer genomics to (i) understand the current NGS landscape for metastatic cancers in the Asia-Pacific (APAC) region; (ii) discuss key challenges in the adoption of NGS testing in clinical practice; and (iii) adapt/modify the European Society for Medical Oncology guidelines for local use. Nine cancer types [breast cancer (BC), gastric cancer (GC), nasopharyngeal cancer (NPC), ovarian cancer (OC), prostate cancer, lung cancer, and colorectal cancer (CRC) as well as cholangiocarcinoma and hepatocellular carcinoma (HCC)] were identified, and the applicability of NGS was evaluated in daily practice and/or clinical research. Asian ethnicity, accessibility of NGS testing, reimbursement, and socioeconomic and local practice characteristics were taken into consideration. RESULTS: The APODDC recommends NGS testing in metastatic non-small-cell lung cancer (NSCLC). Routine NGS testing is not recommended in metastatic BC, GC, and NPC as well as cholangiocarcinoma and HCC. The group suggested that patients with epithelial OC may be offered germline and/or somatic genetic testing for BReast CAncer gene 1 (BRCA1), BRCA2, and other OC susceptibility genes. Access to poly (ADP-ribose) polymerase inhibitors is required for NGS to be of clinical utility in prostate cancer. Allele-specific PCR or a small-panel multiplex-gene NGS was suggested to identify key alterations in CRC. CONCLUSION: This document offers practical guidance on the clinical utility of NGS in specific cancer indications from an Asian perspective.

The expanding role of extracorporeal membrane oxygenation retrieval services in Australia.

Herein we detail the cases of three patients transferred on veno-arterial extracorporeal membrane oxygenation (VA ECMO) from a tertiary referral hospital to an ECMO centre. We highlight the benefits of such a transfer and offer this as a model of care for unwell patients likely to require a prolonged period of ECMO support.

Genotype-matched treatment for patients with advanced type I epithelial ovarian cancer (EOC).

BACKGROUND: Genomic alterations that activate the MAPK signaling pathway frequently occur in Type I Epithelial Ovarian Cancers (EOCs). We evaluated therapeutic response outcomes in patients with type I EOC treated with genotype-matched therapy on clinical trials enrolled in a prospective molecular profiling program. MATERIAL AND METHODS: Formalin fixed paraffin embedded tumor tissues were prospectively screened for genomic alterations using MALDI-ToF mass-spectrometry platform or targeted sequencing using the Illumina MiSeq TruSeq Amplicon Cancer Panel. Treatment outcomes on genotype-matched trials were retrospectively reviewed using RECIST version 1.1 and Gynecological Cancer Intergroup CA125 related-response criteria RESULTS: 55 patients with type I EOC underwent molecular profiling, 41 (75%) low grade serous (LGS), 9 (16%) clear cell (CC), and 5 (9%) mucinous (MC) histologies. Thirty-five patients (64%) were found to have ≥1 somatic mutations: 23 KRAS, 6 NRAS, 5 PIK3CA, 2 PTEN, 1 BRAF, 1 AKT, 1 TP53, and 1 CTNNB1. Fifteen patients were subsequently enrolled in genotype-matched phase I or II trials, including 14 patients with KRAS/NRAS mutations treated with MEK inhibitor targeted combinations. Among 14 RECIST evaluable patients, there were 7 partial responses (PR), 7 stable disease (SD) and 1 disease progression (PD). CA125 responses were observed in 10/10 evaluable KRAS/NRAS mutant patients treated with MEK inhibitor combinations CONCLUSIONS: Genotyping and targeted sequencing of Type I EOCs frequently identifies actionable mutations. Matched treatment with MEK-based combination therapy in KRAS and/or NRAS mutant type I EOC patients is an active therapeutic strategy.

Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup: recurrent disease.

This manuscript reports the consensus statements regarding recurrent ovarian cancer (ROC), reached at the fifth Ovarian Cancer Consensus Conference (OCCC), which was held in Tokyo, Japan, in November 2015. Three important questions were identified: (i) What are the subgroups for clinical trials in ROC? The historical definition of using platinum-free interval (PFI) to categorise patients as having platinum-sensitive/resistant disease was replaced by therapy-free interval (TFI). TFI can be broken down into TFIp (PFI), TFInp (non-PFI) and TFIb (biological agent-free interval). Additional criteria to consider include histology, BRCA mutation status, number/type of previous therapies, outcome of prior surgery and patient reported symptoms. (ii) What are the control arms for clinical trials in ROC? When platinum is considered the best option, the control arm should be a platinum-based therapy with or without an anti-angiogenic agent or a poly (ADP-ribose) polymerase (PARP) inhibitor. If platinum is not considered the best option, the control arm could include a non-platinum drug, either as single agent or in combination. (iii) What are the endpoints for clinical trials in ROC? Overall survival (OS) is the preferred endpoint for patient cohorts with an expected median OS < or = 12 months. Progression-free survival (PFS) is an alternative, and it is the preferred endpoint when the expected median OS is > 12 months. However, PFS alone should not be the only endpoint and must be supported by additional endpoints including pre-defined patient reported outcomes (PROs), time to second subsequent therapy (TSST), or time until definitive deterioration of quality of life (TUDD).

Prevalence of Recommendations Made Within Dental Research Articles Using Uncontrolled Intervention or Observational Study Designs.

BACKGROUND: Evidence to inform clinical practice is reliant on research carried out using appropriate study design. The objectives of this work were to (i) identify the prevalence of articles reporting on human studies using uncontrolled intervention or observational research designs published in peer-reviewed dental journals and (ii) determine the nature of recommendations made by these articles. METHODS: Six peer-reviewed dental journals were selected. Issues published in January to June 2013 were examined and the types of articles published categorized. Following pre-defined inclusion/exclusion criteria, human studies classified as using uncontrolled intervention or observational research designs were subject to detailed review by two independent investigators, to examine if they presented clinical, policy or research recommendations and if these recommendations were supported by the data presented. RESULTS: 52.9% (n = 156) of studies published during the time period met the inclusion criteria. Studies with uncontrolled intervention or observational research designs comprised a larger proportion of the primary research studies published in the journals with lower impact factors (73.3%; n = 107) compared to the high impact journals (38.9%; n = 49). Analysis showed that 60.9% (n = 95) of the included studies made recommendations for clinical practice/dental policy. In 28.2% (n = 44) of studies, the clinical/policy recommendations made were judged to not be fully supported by the data presented. CONCLUSIONS: Many studies published in the current dental literature, which are not considered to produce strong evidence, make recommendations for clinical practice or policy. There were some cases when the recommendations were not fully supported by the data presented.

Introduction of an interdisciplinary heart team-based transcatheter aortic valve implantation programme: short and mid-term outcomes.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) has been developed to treat symptomatic aortic stenosis in patients deemed too high risk for open-heart surgery. To address this complex population, an interdisciplinary heart team approach was proposed. AIM: Present the short- and mid-term outcomes of the first 100 patients in the Royal Prince Alfred Hospital multidisciplinary TAVI programme. METHODS: Single-centre registry. Baseline and procedural data were prospectively recorded. Outcomes were recorded according to Valve Academic Research Consortium - version 2 guidelines. RESULTS: All patients underwent a comprehensive interdisciplinary pre-procedural evaluation. Sixty-eight transfemoral and 32 transapical implantations were performed. Mean age was 82 (±8.9) years old with an average logistic EuroSCORE of 33. Although 13 procedures had major complications, there was no intraprocedural mortality. During the first month, 9% of patients were re-admitted due to heart failure and 13% had a permanent pacemaker implanted. A 3% 30-day and 8% follow-up (mean 17 months) mortalities were recorded. While no significant differences in the rate of complications were found between the first and second half of the experience, all cases of mortality within 30 days (n = 3) occurred in the initial half. Sustained haemodynamic results were obtained with TAVI (immediate mean aortic valve gradient reduction from 47 to 9 mmHg; 1-year echocardiographic gradient 9.9 mmHg, with no moderate or severe aortic regurgitation). CONCLUSION: Excellent results can be achieved with TAVI in very high-risk patients at an Australian institution. A comprehensive evaluation based on a heart team can overcome most of the difficulties imposed by this challenging population.

Anaortic, total-arterial, off-pump coronary artery bypass surgery: why bother?

Coronary artery bypass grafting (CABG) remains the standard of care for multi-vessel coronary disease. However, the increased rate of peri-operative stroke reported after surgery compared to percutaneous coronary intervention (PCI) remains of concern. Anaortic, total-arterial, off-pump coronary artery bypass (OPCAB) grafting is a technique that offers the main advantages of surgical revascularisation with a rate of stroke that is equivalent to that of PCI. Some recent trials comparing conventional on-pump CABG with OPCAB have questioned the efficacy of the off-pump technique - these are most often performed with manipulation of the ascending aorta. We review the potential benefits of the anaortic, total-arterial OPCAB technique to explain why it is being employed by an increasing number of surgeons.

International retrieval of adults on extracorporeal membrane oxygenation support.

A retrieval service was established in New South Wales to provide mobile extracorporeal membrane oxygenation support to patients with severe, acute cardiac or respiratory failure. This service has also retrieved four adult patients from Nouméa, New Caledonia to Sydney on extracorporeal membrane oxygenation support, which are the first international retrievals of this type from Australia. We discuss our experience with these patients, three of whom survived to hospital discharge. However, one patient referred from New Caledonia died before extracorporeal membrane oxygenation could be established.

Combining cariporide with glyceryl trinitrate optimizes cardiac preservation during porcine heart transplantation.

Sodium-hydrogen exchange inhibitors, such as cariporide, are potent cardioprotective agents, however, safety concerns have been raised about intravenously (i.v.) administered cariporide in humans. The aim of this study was to develop a preservation strategy that maintained cariporide's cardioprotective efficacy during heart transplantation while minimizing recipient exposure. We utilized a porcine model of orthotopic heart transplantation that incorporated donor brain death and 14 h static heart storage. Five groups were studied: control (CON), hearts stored in Celsior; CAR1, hearts stored in Celsior with donors and recipients receiving cariporide (2 mg/kg i.v.) prior to explantation and reperfusion, respectively; CAR2, hearts stored in Celsior supplemented with cariporide (10 mumol/L); GTN, hearts stored in Celsior supplemented with glyceryl trinitrate (GTN) (100 mg/L); and COMB, hearts stored in Celsior supplemented with cariporide (10 mumol/L) plus GTN (100 mg/L). A total of 5/5 CAR1 and 5/6 COMB recipients were weaned from cardiopulmonary bypass compared with 1/5 CON, 1/5 CAR2 and 0/5 GTN animals (p = 0.001). Hearts from the CAR1 and COMB groups demonstrated similar cardiac function and troponin release after transplantation. Supplementation of Celsior with cariporide plus GTN provided superior donor heart preservation to supplementation with either agent alone and equivalent preservation to that observed with systemic administration of cariporide to the donor and recipient.

The effects of hormone resuscitation on cardiac function and hemodynamics in a porcine brain-dead organ donor model.

We compared the effects of hormone resuscitation (HR) with a norepinephrine-based protocol on cardiac function, hemodynamics and need for vasopressor support after brain death in a porcine model. Following brain death induction, animals were treated with norepinephrine and fluids for 3 h. In the following 3 h, they continued on norepinephrine and fluids (control) or received additional HR (triiodothyronine, methylprednisolone, vasopressin, insulin). Data were collected pre-brain death, 3 and 6 h post-brain death. At 6 h, median norepinephrine use was higher in controls (0.563 vs. 0 microg/kg/min; p < 0.005), with 6/8 HR animals weaned off norepinephrine compared with 0/9 controls. Mean arterial pressure was higher in HR animals at 6 h (74 +/- 17 vs. 54 +/- 14 mmHg; p < 0.05). Cardiac contractility was also significantly higher in HR animals at 6 h (stroke work index 1.777 vs. 1.494). After collection of 6 h data, all animals were placed on the same low dose of norepinephrine. At 6.25 h, HR animals had higher stroke work (3540 +/- 1083 vs. 1536 +/- 702 mL.mmHg; p < 0.005), stroke volume (37.2 +/- 8.2 vs. 21.5 +/- 9.8 mL; p < 0.01) and cardiac output (5.8 +/- 1.4 vs. 3.2 +/- 1.2 L/min; p < 0.005). HR in a porcine model of brain death reduces norepinephrine requirements, and improves hemodynamics and cardiac function. These results support the use of HR in the management of the brain-dead donor.

Reconstruction of the trachea with a tubed radial forearm free flap.

BACKGROUND: We present the case of a patient with adenoid cystic carcinoma of the trachea who had 60 mm of the trachea excised and reconstructed with a stented radial forearm free flap. The patient was well in the immediate postoperative period with good function of the neotrachea. Problems developing after the reconstruction included proximal stricture, sputum retention, and recurrent pneumonia. RESULT: The patient died of malignant hypercalcemia 16 months after the reconstruction. To our knowledge this is the first reported case of a total tracheal resection and reconstruction with a combination of free tissue transfer and internal stenting. CONCLUSION: We conclude that tracheal reconstruction has the potential to provide a reliable airway in patients not able to be reconstructed with a primary anastomosis.

Optimization of left ventricular function with carvedilol before high-risk cardiac surgery.

Patients with severe left ventricular dysfunction and symptomatic heart failure caused by ischemic or valvular heart disease face a high morbidity and mortality risk from cardiac surgery. We present data showing that excellent surgical outcome can be achieved after pre-treatment of such patients with carvedilol.

A brain dead donor model of porcine orthotopic cardiac transplantation for assessment of cardiac allograft preservation.

BACKGROUND: We aimed to develop a large animal model of orthotopic cardiac transplantation, incorporating donor brain death, to assess new methods of preservation of the donor heart. METHODS: Brain death was achieved in the donor pig by inflation of a 20 cc subdural balloon 1 h prior to harvest. The donor heart was stored for 6 h with conventional hypothermic ischaemic preservation. It was then transplanted orthotopically into the recipient pig using the Lower and Shumway technique. One hour after reperfusion, the transplanted heart was weaned from cardiopulmonary bypass with dobutamine support. Dobutamine support was continued for up to 4 h, if required. After 6 h of physiological and biochemical evaluation, the recipient was euthanased and the heart excised for histological assessment. RESULTS: All pigs experienced the classical haemodynamic changes associated with brain death. This resulted in the release of Troponin I, consistent with myocardial injury. The donor operation was successfully completed in 11 out of 13 pigs. Six out of 11 transplanted hearts were successfully weaned from cardiopulmonary bypass, but required ongoing dobutamine support. CONCLUSIONS: This porcine model of orthotopic cardiac transplantation is a relevant and practical large animal model for the assessment of new methods of preservation of the donor heart.

Combined heart and single-lung transplantation in complex congenital heart disease.

We present a patient with a history of tricuspid and pulmonary atresia who underwent a classic Glenn shunt and a Potts shunt during childhood, resulting in different right and left pulmonary physiology. Because of progression of cardiopulmonary disease and the fact that the right lung was "protected," the patient underwent combined heart-left single-lung transplantation. The postoperative course was uneventful. Potential early and late advantages of this approach include simplifying of the operative procedure and mitigating the potential effects of obliterative bronchiolitis.

Recurrent pyogenic cholangitis or "oriental cholangiohepatitis' in occidentals: case reports of four patients.

The first description of recurrent pyogenic cholangitis occurring in four occidentals is presented. While recurrent pyogenic cholangitis is a common syndrome of uncertain aetiology among orientals (also known as oriental cholangiohepatitis), it has not previously been described in occidentals. Four such patients are described. They presented with recurrent attacks of ascending cholangitis and associated hepatolithiasis, biliary stricturing and dilation. Focal hepatic involvement was treated by segmental liver resection and recurrent disease by interventional endoscopy or radiology.

Aging of human segmental oligosynaptic reflexes for control of leg movement.

A heteronymous group I oligosynaptic reflex from the common peroneal nerve to vastus medialis muscle was compared with a group I homonymous monosynaptic reflex to soleus, using electrical stimulation of peripheral nerve trunks in two groups of healthy men, mean ages 22 and 65 years. The oligosynaptic reflex was still elicitable with age, its magnitude decreasing similarly to the monosynaptic reflex. A further group of older subjects, mean age 75 years, showed similar results. Clearly, the oligosynaptic reflex is not lost with healthy aging. The motor interneuronal pool may at least partially avoid the age-related cell loss of motoneuronal pools, with consequent maintenance of segmental participation for movements such as gait. The slowing of conduction velocities, for these proprioceptive reflex arcs, may reduce the effectiveness of autoregulation of the gait.

An optimized quality control procedure for hematology analyzers with the use of retained patient specimens.

The authors propose guidelines for the use of retained patient specimens for the quality control of multichannel hematology analyzers. They demonstrate that control limits for patient specimen replicates may be derived from the long-term standard deviations (s) of commercial whole blood controls. They then use computer stimulation of the Coulter multichannel hematology instrument to determine power functions of various procedures using retained specimens. These power functions show that the use of three patient specimens and +/- 2 s limits are optimal for the detection of systematic error. They recommend that three different, previously analyzed normal range specimens be periodically analyzed, e.g., at eight-hour intervals. The differences between the current and original measurements should then be calculated and compared with their +/- 2 s limits. If at least two of the three differences for any directly measured parameter exceed the +/- 2 s limits, there will be a high probability of significant analytic error. Because the power functions of the derived red blood cell parameters, hematocrit, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration demonstrate relatively low error detection capabilities, the authors recommend that these parameters not be monitored with the retained patient specimen procedure.