Test performance of PET-CT for mediastinal lymph node staging of pulmonary carcinoid tumours.

Positron emission tomography-CT (PET-CT) is one of the initial mediastinal staging modality for non-small cell lung cancer; however, the clinical utility in carcinoid tumours is uncertain. We sought to determine the test performance of PET-CT for mediastinal lymph node staging of pulmonary carcinoid tumours. We collated data from seven institutions, performing a retrospective search on pathological databases for a consecutive series of patients who underwent thoracic surgery (with lymph nodal dissection) for carcinoid tumours with preoperative PET-CT staging. PET-CT results were compared with the reference standard of pathologic results obtained from lymph node dissection and test performance reported using sensitivity and specificity. From November 1999 to January 2013, 247 patients from seven institutions underwent surgery for carcinoid tumours with a corresponding preoperative PET-CT scan. The mean age of the patients was 61 (SD 15, range 73) and 84 were male patients (34%). The pathologic subtype was typical carcinoid in 217 patients (88%) and atypical carcinoid in 30 patients (12%). Results from lymph node dissection were obtained in 207 patients. The calculated sensitivity and specificity of PET-CT to identify mediastinal lymph node disease was 33% (95% CI 4% to 78%) and 94% (95% CI 89% to 97%), respectively. Our results indicate that PET-CT has a poor sensitivity but good specificity to detect the presence of mediastinal lymph node metastases in pulmonary carcinoid tumours. Mediastinal lymph node metastases cannot be ruled out with negative PET-CT uptake, and if the absence of mediastinal lymph node disease is a prerequisite for directing management, tissue sampling should be undertaken.

Is a thoracotomy rather than thoracoscopic resection associated with improved survival after pulmonary metastasectomy?

A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was 'in patients undergoing pulmonary metastasectomy, does a thoracotomy (rather than a thoracoscopic approach) affect survival?' Altogether >153 papers were found using the reported search, of which seven represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. No papers were greater than level-three evidence. Length of stay and length of chest drainage were found to be significantly shorter in the minimally invasive groups in one study, although this result is undermined by significant differences between the two cohorts. One paper demonstrated that, although there was a significantly closer resection margin in thoracoscopic resections, this had no effect on survival or recurrence rates. A prognostic analysis found no correlation between surgical approach and survival across a number of primary pathologies. However, by analysing the results by primary pathology, the sample groups were small. Despite no difference being found in outcome, more complications were seen with open resections in one study, and although there was a trend towards improved disease survival following resection of single resections by video-assisted thoracoscopic surgery (VATS), this did not reach significance. We conclude that there have been few high-quality studies to date, and further studies would be beneficial. From the published data, VATS metastasectomy has been associated with shorter hospital stays, chest drainage times and perioperative complications. We did not find evidence for a survival difference with either approach, and the lack of high-quality data makes it impossible to recommend any particular surgical approach in terms of long-term survival.

A survey of U.K. units and a suggested protocol for free flap reconstruction of the lower limb: follow-up and management in the first postoperative week.

A survey was performed of U.K. lower-limb reconstruction services and the protocol for management of free flaps to the lower limb in the first postoperative week. The postoperative period is of vital importance in these patients due to the complex nature of microsurgical tissue transfer. A range of answers were received in response to the questions regarding protocols, with no overall consensus on the postoperative plan for these patients. Patients are being managed differently in different units across the United Kingdom. A protocol that has been used successfully by the senior author is described, and we encourage others without a protocol to adopt this one.

Notch signaling reveals developmental plasticity of Pax4(+) pancreatic endocrine progenitors and shunts them to a duct fate.

Relatively little is known about the developmental signals that specify the types and numbers of pancreatic cells. Previous studies suggested that Notch signaling in the pancreas inhibits differentiation and promotes the maintenance of progenitor cells, but it remains unclear whether Notch also controls cell fate choices as it does in other tissues. To study the impact of Notch in progenitors of the beta cell lineage, we generated mice that express Cre-recombinase under control of the Pax4 promoter. Lineage analysis of Pax4(+) cells demonstrates they are specified endocrine progenitors that contribute equally to four islet cell fates, contrary to expectations raised by the dispensable role of Pax4 in the specification of the alpha and PP subtypes. In addition, we show that activation of Notch in Pax4(+) progenitors inhibits their differentiation into alpha and beta endocrine cells and shunts them instead toward a duct fate. These observations reveal an unappreciated degree of developmental plasticity among early endocrine progenitors and raise the possibility that a bipotent duct-endocrine progenitor exists during development. Furthermore, the redirection of Pax4(+) cells from alpha and beta endocrine fates toward a duct cell type suggests a positive role for Notch signaling in duct specification and is consistent with the more widely defined role for Notch in cell fate determination.

Pten constrains centroacinar cell expansion and malignant transformation in the pancreas.

To determine the role of the phosphatidylinositol 3-kinase (PI3-K) pathway in pancreas development, we generated a pancreas-specific knockout of Pten, a negative regulator of PI3-K signaling. Knockout mice display progressive replacement of the acinar pancreas with highly proliferative ductal structures that contain abundant mucins and express Pdx1 and Hes1, two markers of pancreatic progenitor cells. Moreover, a fraction of these mice develop ductal malignancy. We provide evidence that ductal metaplasia results from the expansion of centroacinar cells rather than transdifferentiation of acinar cells. These results indicate that Pten actively maintains the balance between different cell types in the adult pancreas and that misregulation of the PI3-K pathway in centroacinar cells may contribute to the initiation of pancreatic carcinoma in vivo.

Comparison of the generic neuronal differentiation and neuron subtype specification functions of mammalian achaete-scute and atonal homologs in cultured neural progenitor cells.

In the vertebrate peripheral nervous system, the proneural genes neurogenin 1 and neurogenin 2 (Ngn1 and Ngn2), and Mash1 are required for sensory and autonomic neurogenesis, respectively. In cultures of neural tube-derived, primitive PNS progenitors NGNs promote expression of sensory markers and MASH1 that of autonomic markers. These effects do not simply reflect enhanced neuronal differentiation, suggesting that both bHLH factors also specify neuronal identity like their Drosophila counterparts. At high concentrations of BMP2 or in neural crest stem cells (NCSCs), however, NGNs like MASH1 promote only autonomic marker expression. These data suggest that that the identity specification function of NGNs is more sensitive to context than is that of MASH1. In NCSCs, MASH1 is more sensitive to Notch-mediated inhibition of neurogenesis and cell cycle arrest, than are the NGNs. Thus, the two proneural genes differ in other functional properties besides the neuron subtype identities they can promote. These properties may explain cellular differences between MASH1- and NGN-dependent lineages in the timing of neuronal differentiation and cell cycle exit.