Epigenetic Mechanisms and Therapeutic Targets in Chemoresistant High-Grade Serous Ovarian Cancer.

High-grade serous ovarian cancer (HGSOC) is the most common ovarian cancer subtype, and the overall survival rate has not improved in the last three decades. Currently, most patients develop recurrent disease within 3 years and succumb to the disease within 5 years. This is an important area of research, as the major obstacle to the treatment of HGSOC is the development of resistance to platinum chemotherapy. The cause of chemoresistance is still largely unknown and may be due to epigenetics modifications that are driving HGSOC metastasis and treatment resistance. The identification of epigenetic changes in chemoresistant HGSOC enables the development of epigenetic modulating drugs that may be used to improve outcomes. Several epigenetic modulating drugs have displayed promise as drug targets for HGSOC, such as demethylating agents azacitidine and decitabine. Others, such as histone deacetylase inhibitors and miRNA-targeting therapies, demonstrated promising preclinical results but resulted in off-target side effects in clinical trials. This article reviews the epigenetic modifications identified in chemoresistant HGSOC and clinical trials utilizing epigenetic therapies in HGSOC.

Four-limb compartment syndrome associated with the systemic capillary leak syndrome.

Systemic capillary leak syndrome, or the Clarkson syndrome, is an extremely rare condition in which increased capillary permeability results in a massive shift of fluid into the extravascular space. This is followed rapidly by hypotensive shock, haemoconcentration, and, potentially, substantial oedema of the limbs resulting in an acute compartment syndrome. It is important for orthopaedic surgeons to be aware of this syndrome as our medical colleagues, who initially care for these patients, are less familiar with the diagnosis and the need for emergency management of the associated compartment syndrome should it develop. There have been fewer than 100 cases of this entity reported. This case report is the first to describe the subsequent development of a compartment syndrome in all four limbs. Clinical vigilance and continuous monitoring of intracompartmental pressure is necessary in these patients in order to help reduce limb-threatening complications.

Audit of performance of size 1.5 ProSeal laryngeal mask airways in infants less than six months undergoing inguinal herniotomy.

Many anaesthetists have found the size 1.5 classic Laryngeal Mask Airway unsuitable for use in children under 10 kg, whereas recent studies evaluating the ProSeal Laryngeal Mask Airway (PLMA) show high success rates, even during laparoscopic surgery. Our routine practice has been to use tracheal intubation for inguinal herniotomy in children weighing less than 10 kg. Following the introduction of the PLMA to our hospital, we decided to audit our use of the PLMA 1.5 in this group of patients. We included 20 consecutive infants, aged less than six months and weighing 5 to 10 kg. We recorded patient, anaesthetic and insertion details, device performance data and complications. No aspect of anaesthetic practice was changed by involvement in this audit. The PLMA was inserted successfully at the first attempt in 85% (17/20) of infants. Overall successful insertion occurred in 90% (18/20) and satisfactory airway maintenance was provided for the duration of anaesthesia in 90% (18/20). The mean leak pressure was 24 cmH2O (range 15 to 30 cmH2O). We found the 1.5 PLMA provided a satisfactory airway in 90% of infants. This report adds to the evidence that the PLMA 1.5 can provide a satisfactory alternative to intubation in selected infants.

Evaluation of four manikins as simulators for teaching airway management procedures specified in the Difficult Airway Society guidelines, and other advanced airway skills.

Ten volunteers evaluated the performance of four currently available manikins: Airway Management Trainer, Airway Trainer, Airsim and Bill 1 as simulators for the 16 procedures described in the Difficult Airway Society Guidelines (DAS techniques) and eight other advanced airway techniques (non-DAS techniques), by scoring and ranking each manikin and procedure. Manikin performance was unequal (p < 0.0001 for both SCORE and RANK data for both DAS and non-DAS techniques). Post hoc analysis ranked the manikins for DAS techniques as: 1st Laerdal, 2nd Trucorp, 3rd equal VBM and Ambu. For non-DAS techniques, the ranking was: 1st equal Laerdal and Trucorp, 3rd equal VBM and Ambu. The power to discriminate for individual procedures was considerably lower but for 15 of 16 DAS techniques and 6 of 8 non-DAS techniques, manikin performance differed significantly. Post hoc tests showed significant performance differences between individual manikins for 10 DAS procedures, with the Laerdal manikin performing best.

Evaluation of four airway training manikins as simulators for inserting the LMA Classic*.

Airway manikins have traditionally been used for teaching mask ventilation and tracheal intubation. There is an increasing need to use manikins for training in procedures such as insertion of the laryngeal mask airway. We have assessed four new airway training manikins (latest versions of the Airway Trainer (Laerdal, Norway), Airway Management Trainer (Ambu, UK), 'Bill 1' (VBM, Germany) and Airsim (Trucorp, Ireland)) as simulators for insertion of the LMA Classic laryngeal mask airway. Twenty volunteer anaesthetists inserted a size-4 laryngeal mask airway five times into each of the four manikins, in random order. Each insertion was assessed using objective and subjective tests. Subjective assessment varied widely but overall assessment indicated that the Airway Management Trainer was the poorest simulator for insertion of the laryngeal mask airway. The 'Bill 1' and Airsim manikins performed best as simulators for insertion of the laryngeal mask airway, although realistic ventilation with 'Bill 1' was not possible.

Partial liquid ventilation and nitric oxide in experimental acute lung injury.

OBJECTIVE: To investigate the effects of inhaled nitric oxide (iNO) and partial liquid ventilation (PLV) on oxygenation and pulmonary haemodynamics in acute lung injury (ALI), and to assess their effects on lung function, systemic haemodynamics and lung injury. METHODS: Using saline lung lavage, ALI was induced in 18 piglets. A control group was ventilated with conventional mechanical ventilation (CMV) for 2 h. An iNO-first group received iNO for the first hour and then iNO with PLV. A PLV-first group received PLV for the first hour and then PLV with iNO. Variables were measured at baseline, 5 min postlavage, and at 1 h and 2 h postlavage. RESULTS: During the first hour, both treatment groups showed improvement in oxygenation index (OI). At 2 h, the dif-ferences in OI were statistically significant (P = 0.037), with a mean +/- SD of 23.8 +/- 20.7 in the control group, 4.4 +/- 0.9 in the PLV-first group and 6.5 +/- 3.1 in the iNO-first group. The OI was similar in both treatment groups (P = 0.178). At 2 h, the pulmonary artery pressure (PAP) was significantly different (P = 0.04) between groups, with a mean +/- SD PAP of 36.3 +/- 7.2 mmHg in the control group, 27.4 +/- 4.0 mmHg in the PLV-first group and 30.0 +/- 4.1 mmHg in the iNO-first group. The PAP was similar in both treatment groups (P = 0.319). CONCLUSION: In ALI, oxygenation and pulmonary hypertension are improved with PLV and iNO given together, regardless of the order in which they are commenced.

Laparotomy for necrotizing enterocolitis: intensive care nursery compared with operating theatre.

OBJECTIVE: To determine whether neonates requiring laparotomy for necrotizing enterocolitis (NEC) are more stable perioperatively and have less disruption of physiological parameters if surgery is performed in the neonatal intensive care unit (NICU) compared with the operating theatre (OR). METHODOLOGY: A retrospective case review was performed on 233 neonates referred for further surgical management of severe NEC in the period January 1989 to December 1997. Mortality and morbidity were compared by calculating the score for neonatal acute physiology (SNAP) and its attendant risk of mortality score. Thirty-six separate physiological variables were also compared pre- and postoperatively and the mean postoperative change was calculated. RESULTS: For neonates weighing less than 1500 g, mortality was linked to illness severity, as measured by SNAP, rather than operative location. Specific adverse events associated with secondary transfer to the OR included hypothermia, deterioration in oxygenation parameters, ventilation parameters and platelet count. The liberal use of blood products, albumin and bicarbonate in perioperative resuscitation may have obscured other effects. CONCLUSIONS: The use of the neonatal intensive care nursery for surgery on neonates weighing less than 1500 g with severe NEC can be justified and such use should be encouraged. In contrast, secondary transport of neonates weighing less than 1500 g to the OR for laparotomy is associated with significant deterioration in a number of physiological parameters, which may impact on morbidity.

Breast feeding practices and severe hyperbilirubinaemia.

This study establishes the association between early onset severe hyperbilirubinaemia (serum bilirubin (SBR) level greater than or equal to 272 mumol/L) with no assigned cause and breast feeding. The rates of breast feeding at hospital discharge increased from 46.4 to 75.4% in non-insured (public) women and 58.6 to 89.2% in insured (private) women between 1975 and 1987, and were accompanied by an increase in severe hyperbilirubinaemia from 1.6 to 3.1% in public and 0.9 to 3.6% in private babies. The case control study involved 125 term breast feeding infants born between 1 July 1985 and 1 July 1986 with severe hyperbilirubinaemia (SBR level 272 mumol/L) with no assigned cause who were compared with 125 matched controls who had peak SBR levels less than or equal to 272 mumol/L. Severe hyperbilirubinaemia was associated with primiparous and non-Caucasian mothers, non-smoking and oxytocin usage. Univariate analysis of feeding practice variables revealed that less frequent breast feeds, greater weight loss and less frequent stools over the first 3 days related to severe hyperbilirubinaemia (P less than 0.05). Multivariate analysis of the eight significant univariate factors revealed that maternal non-smoking, less frequent breast feeding, less frequent stooling and excessive infant weight loss were the best predictors of severe hyperbilirubinaemia. With the wide promotion of breast feeding, the contribution of individual feeding practices to severe hyperbilirubinaemia demands ongoing analysis and review.