Robotic Heller myotomy: a safe operation with higher postoperative quality-of-life indices.

INTRODUCTION: Achalasia is a primary motility disorder of the esophagus that is treated most effectively with operative myotomy. Excellent outcomes with laparoscopic myotomy and fundoplication are well known. Heller myotomy utilizing a computer-enhanced (robotic) laparoscopic platform allows for a more precise dissection by utilizing the superior optics of a 3-dimensional camera and greater degrees of freedom provided by robotic instrumentation. How this affects outcome and quality of life is unknown. METHODS: We assessed patients' health perceptions using a standardized, validated, health-related, disease-specific quality-of-life metric. Sixty-one consecutive patients undergoing laparoscopic or robotic myotomy over a 6-year period were evaluated prospectively. All operations were performed using intraoperative manometric and endoscopic guidance and all except 5 patients had a fundoplication. The effects of the operation on health-related quality of life were evaluated with the Short Form (SF-36) Health Status Questionnaire and a disease-specific gastroesophageal reflux disease activity (GERD) activity index (GRACI) preoperatively and postoperatively. All patients completed the questionnaire at both time points. Patient scores were compared using 2-way repeated measures analyses of variance followed by the Tukey test. Operative time, estimated blood loss, duration of stay, intraoperative complication, and postoperative complications were analyzed. RESULTS: Thirty-seven patients had laparoscopic and 24 patients had robotic Heller myotomy. There was an increase in SF-36 overall evaluation of health postoperatively compared with preoperatively in both groups (P < .05). The robotic myotomy patients had better SF-36 Role Functioning (emotional) and General Health Perceptions (P < .05) compared with the laparoscopic group. The GRACI showed an equivalent improvement in severity of symptoms in both groups (P < .05). Operative time was 287 +/- 9 minutes for laparoscopic cases and 355 +/- 23 minutes for robotic cases. Estimated blood loss and duration of stay were not different between groups. There were 3 operative esophageal perforations (8%) during laparoscopic myotomy and all were repaired immediately. There were no perforations or operative complications in the robotic group. Neither group had any additional complications. CONCLUSIONS: Minimally invasive operative myotomy improves functional status and overall evaluation of health in patients with achalasia. Robotic myotomy had no intraoperative esophageal perforations compared with an 8% intraoperative rate during laparoscopic myotomy. Heller myotomy with partial fundoplication using a robotic platform appears to be a more precise and safer operation than laparoscopic myotomy with improved quality-of-life indices postoperatively compared with laparoscopic myotomy with fewer complications; this suggests that, in skilled hands, the robotic platform may be safer, with improved quality-of-life outcomes.

Loss of the retinoblastoma tumor suppressor: differential action on transcriptional programs related to cell cycle control and immune function.

Functional inactivation of the retinoblastoma tumor suppressor gene product (RB) is a common event in human cancers. Classically, RB functions to constrain cellular proliferation, and loss of RB is proposed to facilitate the hyperplastic proliferation associated with tumorigenesis. To understand the repertoire of regulatory processes governed by RB, two models of RB loss were utilized to perform microarray analysis. In murine embryonic fibroblasts harboring germline loss of RB, there was a striking deregulation of gene expression, wherein distinct biological pathways were altered. Specifically, genes involved in cell cycle control and classically associated with E2F-dependent gene regulation were upregulated via RB loss. In contrast, a program of gene expression associated with immune function and response to pathogens was significantly downregulated with the loss of RB. To determine the specific influence of RB loss during a defined period and without the possibility of developmental compensation as occurs in embryonic fibroblasts, a second system was employed wherein Rb was acutely knocked out in adult fibroblasts. This model confirmed the distinct regulation of cell cycle and immune modulatory genes through RB loss. Analyses of cis-elements supported the hypothesis that the majority of those genes upregulated with RB loss are regulated via the E2F family of transcription factors. In contrast, those genes whose expression was reduced with the loss of RB harbored different promoter elements. Consistent with these analyses, we found that disruption of E2F-binding function of RB was associated with the upregulation of gene expression. In contrast, cells harboring an RB mutant protein (RB-750F) that retains E2F-binding activity, but is specifically deficient in the association with LXCXE-containing proteins, failed to upregulate these same target genes. However, downregulation of genes involved in immune function was readily observed with disruption of the LXCXE-binding function of RB. Thus, these studies demonstrate that RB plays a significant role in both the positive and negative regulations of transcriptional programs and indicate that loss of RB has distinct biological effects related to both cell cycle control and immune function.

Malignant transformation of oral lichen planus.

AIMS: To investigate the malignant potential of oral lichen planus (OLP), a common mucocutaneous disease of unknown aetiology. The malignant potential of OLP is still controversial, with studies reporting malignant transformation rates of between 0 and 5.6%. We also aimed to identify factors that might be associated with malignant transformation. METHODS: We retrospectively reviewed the records of 832 patients with histologically confirmed OLP treated at the Dental Hospital, Newcastle upon Tyne during the period 1983-1996. RESULTS: Of these 832 patients, a total of seven (0.8%) developed intra-oral squamous cell carcinoma (SCC), including three cases of carcinoma in situ. It was noted that OLP patients with SCC are more likely to be women, relatively young and have a low tobacco and alcohol intake. However, they had a good long-term prognosis. CONCLUSIONS: We conclude that the risk of malignant transformation in OLP is real but not high. Clinicians should have a higher index of suspicion of the possibility of malignancy developing in OLP, because such patients are different from typical patients who develop oral malignancy. Follow-up for at least 6 years is recommended.

Regulation of exit from quiescence by p27 and cyclin D1-CDK4.

The synthesis of cyclin D1 and its assembly with cyclin-dependent kinase 4 (CDK4) to form an active complex is a rate-limiting step in progression through the G1 phase of the cell cycle. Using an activated allele of mitogen-activated protein kinase kinase 1 (MEK1), we show that this kinase plays a significant role in positively regulating the expression of cyclin D1. This was found both in quiescent serum-starved cells and in cells expressing dominant-negative Ras. Despite the observation that cyclin D1 is a target of MEK1, in cycling cells, activated MEK1, but not cyclin D1, is capable of overcoming a G1 arrest induced by Ras inactivation. Either wild-type or catalytically inactive CDK4 cooperates with cyclin D1 in reversing the G1 arrest induced by inhibition of Ras activity. In quiescent NIH 3T3 cells expressing either ectopic cyclin D1 or activated MEK1, cyclin D1 is able to efficiently associate with CDK4; however, the complex is inactive. A significant percentage of the cyclin D1-CDK4 complexes are associated with p27 in serum-starved activated MEK1 or cyclin D1 cell lines. Reduction of p27 levels by expression of antisense p27 allows for S-phase entry from quiescence in NIH 3T3 cells expressing ectopic cyclin D1, but not in parental cells.

Enforced CDK4 expression in a hematopoietic cell line confers resistance to the G1 arrest induced by ionizing radiation.

In hematopoietic cells, gamma-irradiation causes a p53-dependent transient G1 phase cell cycle arrest. Various extracellular growth inhibitory signals elicit G1 arrest by targeting CDK4. Here we show that in a myeloid cell line, 32D cl 3, enforced expression of CDK4, but not cyclins D2 nor D3, overrides the gamma-irradiation-induced G1 arrest. CDK4 does not confer resistance to the radiation-induced G2 block observed in parental cells. Ectopic expression of CDK4 overcomes the ionizing radiation-induced inhibition of CDK4 and CDK2 kinase activity. The levels of CDK4 protein do not change after exposure to ionizing radiation in either parental cells or those overexpressing CDK4. Ionizing radiation induces the expression of both p53 and p21, and in cells constitutively synthesizing exogenous CDK4, the return of p53 protein levels to baseline is prolonged. Increased levels of p21 are found associated with CDK4, and not CDK2, in the lines overexpressing CDK4, compared to the parental line, after exposure to ionizing radiation. Enforced expression of CDK4 may therefore overcome a gamma-irradiation-induced G1 arrest through the titration of the CDK inhibitor p21 allowing both CDK4 and CDK2 to remain active.

Cemento-ossifying fibroma of the mandible.

Cemento-ossifying fibromas are normally slow-growing, benign lesions. A cemento-ossifying fibroma occurring in a 25 year old female is presented with clinical features of a rapidly enlarging tumour within a period of less than three years. Radiolucent areas with a short history of rapid enlargement should be subjected to pathological investigation prior to definitive surgery so that the appropriate treatment may be undertaken.

MRI T staging of squamous cell carcinoma of the oral cavity: radiological-pathological correlation.

Fifty patients with primary or suspected recurrent squamous cell carcinoma of the oral cavity were examined pre-operatively with magnetic resonance imaging (MRI) to determine the tumour stage. Pathological correlation was available in all cases. Twenty-five of 35 patients with primary disease were correctly staged (MR Tstage 0-4). In another four patients there was good size correlation between MR and pathology, but two cases had false positive MR interpretation of bone invasion. MRI has proved accurate at excluding the presence of bone invasion (negative predictive value 97%), but a positive scan may not discriminate between tumour and other dental pathology (positive predictive value 67%). Assessment of local extent was otherwise good with invasion of muscles of the floor of the mouth and muscles of mastication always predicted correctly. Salivary gland abnormality was frequent, and MRI correctly distinguished between obstructive sialectasis and direct invasion. The results of MR staging in patients with recurrent disease were less accurate. Where diagnostic scans can be obtained MRI can provide useful information for the surgeon or radiotherapist regarding the local extent of tumour, and may assist in treatment planning. Assessment of cervical lymphadenopathy can be performed as part of same procedure.

The role of MRI scanning in the diagnosis of cervical lymphadenopathy.

In a blind, prospective trial, 42 patients undergoing 51 cervical lymph node dissections for head and neck malignancies were investigated by a preoperative MRI scan. Histological examination of the dissection specimens recorded the distribution, size, percentage of neoplastic involvement and any extra-capsular spread of the sampled nodes. The MRI correctly diagnosed all 17 positive nodes (sensitivity 100%). However it could not differentiate between enlarged reactive and malignant nodes, so there was a significant false positive rate (specificity 53%). Routine use of MRI scans will allow an unnecessary neck dissection to be avoided in a patient with a clinically negative neck who also has a negative MRI scan.

In vivo effects of Candida albicans products on rat oral epithelium.

Candida albicans has been associated with epithelial hyperplasia in some diseases of oral mucosa and skin but its etiologic role in these lesions is poorly understood. To test its ability to induce epithelial proliferation, the invasive hyphal form was cultured for 5 h and 23 h in chemically defined medium and yeast-free culture supernatants were injected below the buccal epithelium of young adult Sprague Dawley rats. The mitotic activity was assessed using the metaphase arrest technique 11 h and 31 h after supernatant injection. There was a significant increase in epithelial mitotic activity 31 h after injection with 5 h culture supernatants compared to control media indicating that the supernatants have an effect on epithelial cells, possibly by direct action on them.

Preparation of nitroso-13N-labeled nitrosoureas.

A method is described for the preparation of 13N-labeled N-nitrosoureas, specifically 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. The 13N is generated as ammonia by the 12C(d,n)13N reaction on methane gas. The product is selectively trapped and subsequently oxidized to nitrous acid which reacts with the parent urea in solution to form the 13N-labeled nitrosourea.

Preparation of [18-F]haloperidol.

A procedure is described that permits the preparation of [18F]haloperidol in 140 min at specific activities ranging from 4-5 muCi mg-1. A key step in the synthetic route involves the incorporation of 18F into the molecule through a Schiemann-type reaction, which involves the pyrolysis of the diazonium tetrafluoroborate salt of 4-[4-(p-chlorophenyl)-4-hydroxypiperidino]-4'-aminobutyrophenone.