BRAF mutation testing for patients diagnosed with stage III or stage IV melanoma: practical guidance for the Australian setting.

Targeted therapy (BRAF inhibitor plus MEK inhibitor) is now among the possible treatment options for patients with BRAF mutation-positive stage III or stage IV melanoma. This makes prompt BRAF mutation testing an important step in the management of patients diagnosed with stage III or IV melanoma; one that can help better ensure that the optimal choice of systemic treatment is initiated with minimal delay. This article offers guidance about when and how BRAF mutation testing should be conducted when patients are diagnosed with melanoma in Australia. Notably, it recommends that pathologists reflexively order BRAF mutation testing whenever a patient is found to have American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage III or IV melanoma (i.e., any metastatic spread beyond the primary tumour) and that patient's BRAF mutation status is hitherto unknown, even if BRAF mutation testing has not been specifically requested by the treating clinician (in Australia, Medicare-subsidised BRAFV600 mutation testing does not need to be requested by the treating clinician). When performed in centres with appropriate expertise and experience, immunohistochemistry (IHC) using the anti-BRAF V600E monoclonal antibody (VE1) can be a highly sensitive and specific means of detecting BRAFV600E mutations, and may be used as a rapid and relatively inexpensive initial screening test. However, VE1 immunostaining can be technically challenging and difficult to interpret, particularly in heavily pigmented tumours; melanomas with weak, moderate or focal BRAFV600E immunostaining should be regarded as equivocal. It must also be remembered that other activating BRAFV600 mutations (including BRAFV600K), which account for ∼10-20% of BRAFV600 mutations, are not detected with currently available IHC antibodies. For these reasons, if available and practicable, we recommend that DNA-based BRAF mutation testing always be performed, regardless of whether IHC-based testing is also conducted. Advice about tissue/specimen selection for BRAF mutation testing of patients diagnosed with stage III or IV melanoma is also offered in this article; and potential pitfalls when interpreting BRAF mutation tests are highlighted.

Cytoreductive surgery and heated intraperitoneal chemotherapy for peritoneal carcinomatosis secondary to mucinous adenocarcinoma of the appendix.

Cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is a radical but effective treatment option for select peritoneal malignancies. We sought to determine our early experience with this method for peritoneal carcinomatosis secondary to mucinous adenocarcinomas of appendiceal origin. As such, we performed a retrospective clinical study of 30 consecutive patients undergoing CRS with planned HIPEC at the Princess Alexandra Hospital, between June 2009 to December 2012, with mucinous adenocarcinomas of the appendix. CRS was performed in 30 patients, 13 received HIPEC intraoperatively and 17 received early postoperative intra-peritoneal chemotherapy (EPIC) in addition. Mean age was 52.3 years and median hospital stay was 26 days (range 12-190 days). Peritoneal cancer index scores were 0-10 in 6.7% of patients, 11-20 in 20% of patients and >20 in 73.3% of patients. Complete cytoreduction was achieved overall in 21 patients. In total, 106 complications were observed in 28 patients. Ten were grade 3-A, five were grade 3-B and one grade-5 secondary to a fatal PE on day 97. In patients who received HIPEC, there was no difference in disease-free survival (P = 0.098) or overall survival (P = 0.645) between those who received EPIC versus those who did not. This study demonstrates that satisfactory outcomes with regards to morbidity and survival can be achieved with CRS and HIPEC, at a single-centre institution with growing expertise in the technique. Our results are comparable with outcomes previously described in the international literature.

Acute atrial stretch results in conduction slowing and complex signals at the pulmonary vein to left atrial junction: insights into the mechanism of pulmonary vein arrhythmogenesis.

BACKGROUND: The pulmonary vein-left atrial (PV-LA) junction is key in pathogenesis of AF, and acute stretch is an important stimulus to AF. We aimed to characterize the response of the junction to acute stretch, hypothesizing that stretch would result in electrophysiological changes predisposing to re-entry. METHODS AND RESULTS: Fifteen participants undergoing cardiac surgery underwent evaluation of the right superior PV-LA junction using an epicardial mapping plaque. In 10, this was performed before and after atrial stretch imposed by rapid volume expansion, and in 5, it was performed with an intervening observation period. Activation was characterized by conduction slowing and electrogram fractionation transversely across the PV-LA junction, with lines of block also demonstrated perpendicular to the junction. Conduction was decremental (plaque activation time 135.8 ± 46.8 ms with programmed extra stimuli at 10 ms above effective refractory period versus 66.1 ± 22.9 ms with pacing at 400 ms; P<0.001) and percentage fractionation was greater with programmed extra stimuli at 10 ms above (33.5%± 15.3% versus 20.7%± 14.0%, P=0.001). Right atrial pressure increased by 2.5 ± 1.8 mm Hg (P=0.002) with volume expansion. Stretch resulted in conduction slowing across the PV-LA junction (increase in activation time 10.9 ± 14.6 ms in acute stretch group versus -0.1 ± 4.5 ms in control group; P=0.002). Conduction slowing was more marked with programmed extra stimuli at 10 ms above effective refractory period than with stable pacing (13.4 ± 16.5 ms versus 1.7 ± 5.4 ms; P=0.003). Stretch resulted in a significant increase in fractionated electrograms (7.9%± 7.0% versus -0.4 ± 3.3; P=0.004). CONCLUSIONS: Acute stretch results in conduction slowing across the PV-LA junction, with a greater degree of signal complexity. This substrate may be important in AF initiation and maintenance by promoting re-entry.