Charles Perkins

Prognostic Accuracy of Computed Tomography Findings for Patients With Laryngeal Cancer Undergoing Laryngectomy

PURPOSE The indications for upfront laryngectomy in the management of laryngeal cancer are a functionless larynx and extralaryngeal extension. Practically, clinicians rely on imaging to predict which patients will have T4 disease. Our goal was to review the accuracy of preoperative computed tomography (CT) scanning in determining the necessity for initial laryngectomy for advanced laryngeal cancer. PATIENTS AND METHODS In total, 107 consecutive untreated laryngectomy specimens with high-quality, preoperative CT imaging interpreted by our neuroradiologists were reviewed. Radiographic findings, including sclerosis, invasion, penetration, extralaryngeal spread, and subglottic extension were correlated with pathologic findings. CT images were not reinterpreted, since our purpose was to assess the original interpretations. RESULTS CT imaging reported 23 cases of thyroid cartilage penetration and 27 cases of extralaryngeal spread. Pathology reported 12 cases of thyroid cartilage invasion, 29 cases of penetration, and 45 cases of extralaryngeal disease. CT imaging identified 17 (59%) of 29 cases of pathologically documented thyroid cartilage penetration and 22 (49%) of 45 cases of pathologically documented extralaryngeal spread. Pathologically proven extralaryngeal spread without thyroid cartilage penetration occurred in 18 (40%) of 45 cases. The positive predictive values for thyroid cartilage penetration and extralaryngeal spread were 74% and 81%. Sclerosis was of limited value in predicting thyroid cartilage invasion or penetration. Cricoid or arytenoid destruction predicted for thyroid cartilage penetration at rates of 57% and 63%. CONCLUSION CT imaging has clear limitations when deciding whether there is thyroid cartilage penetration or extralaryngeal spread of advanced laryngeal cancer. Extralaryngeal spread without thyroid cartilage penetration was more common than expected. Alternate methods of pretreatment assessment are needed.

Functional consequence of substitutions at residue 171 in human galactose-1-phosphate uridylyltransferase.

Impairment of the human enzyme galactose-1-phosphate uridylyltransferase (hGALT) results in the potentially lethal disorder classic galactosemia. Although a variety of naturally occurring mutations have been identified in patient alleles, few have been well characterized. We have explored the functional significance of a common patient mutation, F171S, using a strategy of conservative substitution at the defined residue followed by expression of the wild-type and, alternatively, substituted proteins in a null-background strain of yeast. As expected from patient studies, the F171S-hGALT protein demonstrated <0.1% wild-type levels of activity, although two of three conservatively substituted moieties, F171L- and F171Y-hGALT, demonstrated ∼10% and ∼4% activity, respectively. The third protein, F171W, demonstrated severely reduced abundance, precluding further study. Detailed kinetic analyses of purified wild-type, F171L- and F171Y-hGALT enzymes, coupled with homology modeling of these proteins, enabled us to suggest that the effects of these substitutions resulted largely from altering the position of a catalytically important residue, Gln-188, and secondarily, by altering the subunit interface and perturbing hexose binding to the uridylylated enzyme. These results not only provide insight into the functional impact of a single common patient allele and offer a paradigm for similar studies of other clinically or biochemically important residues, but they further help to elucidate activity of the wild-type human GALT enzyme.

'Loop' domain deletional mutant of Bcl-xL is as effective as p29Bcl-xL in inhibiting radiation-induced cytosolic accumulation of cytochrome c (cyt c), caspase-3 activity, and apoptosis.

PURPOSE/OBJECTIVE To investigate the effect of the enforced expression of p29Bcl-xL or its loop deletional mutant, p18Bcl-xLdelta, on irradiation-induced apoptosis and cell-cycle distribution of HL-60 cells. MATERIALS & METHODS We compared the irradiation-induced molecular cascade of apoptosis in control human AML HL-60/neo versus Bcl-xL overexpressing (approximately 8-fold) (HL-60/Bcl-xL) and HL-60/Bcl-XLdelta cells that express the loop domain deletional mutant construct (delta26-83 AA) of Bcl-xL. The three cell lines were irradiated with 6MV photons to varying doses up to 20 Gy. Following this, cytosolic cyt c levels, caspase-3 activity, and the Bcl-2 family of proteins were evaluated utilizing Western blot analysis (whole cell lysate or cytosolic S-100 fraction). Apoptosis was assessed by internucleosomal DNA fragmentation, Annexin-V staining and FACS analysis, as well as by morphologic criteria. The cell-cycle effects of radiation were analyzed by flow cytometry. RESULTS Eight hours following irradiation (12 Gy) of HL-60/neo cells, a marked increase (approximately 8-fold) in the cytosolic accumulation of cyt c in the S-100 fraction was observed. This was associated with the cleavage of caspase-3, as well as the generation of its poly (ADP-ribose) polymerase (PARP) and DFF (DNA fragmentation factor)-45 cleavage activity. Twenty-four to forty-eight hours after irradiation, internucleosomal DNA fragmentation and positive Annexin-V staining (32.3+/-3.3%) was detected in HL-60/neo cells. In contrast, in both HL-60/Bcl-xL and HL-60/Bcl-xLdelta cells, a significantly lower percentage of apoptotic cells (p<0.05) were detected and internucleosomal DNA fragmentation was not induced. Following irradiation, Western analysis neither demonstrated any significant alteration in Bcl-2, p29Bcl-xL, p18Bcl-xLdelta, or Bax; nor induced CD95 (Fas receptor) or Fas ligand expression in any cell type. However, in all cell types, irradiation produced approximately a 2-fold increase in the percentage of cells in the G2/M phase of the cell cycle. CONCLUSION These results demonstrate that an intact loop domain is not necessary for the full antiapoptotic function of Bcl-xL against irradiation-induced cytosolic accumulation of cyt c, caspase activation, and apoptosis of HL-60 cells. Additionally, the cell-cycle effects of ionizing radiation in HL-60 cells are not affected by enforced expression of Bcl-xL or Bcl-xLdelta.

Single-fraction image-guided extracranial radiosurgery for recurrent and metastatic abdominal and pelvic cancers: short-term local control, metabolic response, and toxicity.

PURPOSE Extracranial radiosurgery (ECRS) is a novel treatment for inoperable recurrent or metastatic abdominopelvic cancers. However, local control, metabolic response, and acute toxicity remain undefined. We therefore analyzed these endpoints in patients treated with single-fraction image-guided ECRS at Emory University. METHODS 20 patients with recurrent or metastatic inoperable abdominal or pelvic cancers (23 sites) were treated with single-fraction ECRS using a Varian linear accelerator between 08/2006 and 02/2008. Patients with pancreas, biliary and liver cancer were part of an IRB-approved ongoing dose-escalation trial. 14 patients had received prior abdominal or pelvic external beam radiation. In 13 patients pre-treatment PET/CT was used to delineate the target volume. Image-guidance was provided by implanted fiducial markers and on-board imaging in 13 patients, and with cone-beam CT in 1 patient. 8 Patients were treated with respiratory gating. The median single-fraction dose delivered was 18 Gy. Each patient was assessed at 1 week, 1 month, and 3 months after radiosurgery for toxicity, and at approximately 1 month and 3 months with PET/CT for metabolic tumor response. Partial response was defined as a reduction in size of > 10% on CT and a decrease in maximum SUV of > 15% on PET. Complete response was defined as complete resolution on CT, and a reduction of SUV to background levels on PET. RESULTS The median follow-up was 6.3 months (range 1.5-12.2 months). The overall response rate (the sum of complete responses and partial responses) by treated site was noted in 36% (1 month), 47% (3 months) and 48% (final). A complete response was achieved in 13% (3 sites). At last follow-up, local control (sum of response rate and stable disease) was 74%. The metabolic response rate by pet only(sum of partial and complete responders) was 85% on final analysis. 23% of pet avid sites achieved a complete response. Two pet avid treated sites (13%) did show evidence of progression at 3 months, but subsequent CT/FDG-PET scans showed a decrease in maximum SUV; no patients suffered progressive disease based on metabolic imaging at last follow-up. Grade 1-2 upper GI acute toxicity (nausea, vomiting, gastritis, and pain) was noted in 47% and 55% of patients at 1 week and 1 month, respectively. Correspondingly, acute lower GI toxicity (diarrhea, pain) was lower at 12% and 6%. Overall grade 1-2 GI toxicity was seen in 59% of patients at 1 week (pain and nausea being the most common) and 61% of patients at 1 month post stereotactic body radiotherapy (SBRT) (nausea being the most common). CONCLUSIONS Single-fraction image-guided ECRS for recurrent or metastatic abdominopelvic cancers is safe and effective in the short term. 3-month local control was very good , and was predicted by an early metabolic response as seen on PET/CT. Acute side effects were mild, with no patient experiencing grade 3 or greater toxicity. Dose escalation and long-term studies are warranted for this treatment approach.

Major Salivary Gland Tumors

Malignancies of the parotid, submandibular, and sublingual glands account for approximately 4% of all head and neck cancers. A total of 80% of malignant major salivary gland tumors occur in the parotid gland. In adults, roughly a quarter of parotid tumors and one half of submandibular tumors are malignant.