Revisiting the role of positron-emission tomography/computed tomography in determining the need for planned neck dissection following chemoradiation for advanced head and neck cancer.

OBJECTIVES/HYPOTHESIS: Planned neck dissection following chemoradiation (CR) has been advocated in patients with head and neck squamous cell cancer (HNSCC) with advanced nodal disease and a clinical complete response to CR because of the potential for residual occult nodal disease. The utility of positron-emission tomography/computed tomography (PET-CT) in identifying occult nodal disease in this scenario is controversial. METHODS: The medical records of all patients treated with CR for advanced HNSCC with N2 or N3 disease from December 2003 to June 2007 were reviewed. Patients with a complete clinical response were included if PET-CT performed 8 to 11 weeks after CR showed no distant disease and they underwent planned neck dissection. RESULTS: Thirty-two patients met study criteria. PET-CT was positive for residual nodal disease in 20 patients (63%). Pathology revealed carcinoma in 10 patients (31%): six of 20 patients with positive PET-CT scans (30%) and four of 12 patients with negative PET-CT scans (33%). The sensitivity and specificity of PET-CT was 60% and 36%. Regional recurrence developed in two patients (6%) who were not successfully salvaged. CONCLUSIONS: PET-CT performed 8 to 11 weeks after CR does not reliably predict the need for planned post-treatment neck dissection in patients with a complete clinical response following CR. Regional recurrence rates are comparable to those reported for patients observed with PET-CT, suggesting no advantage for planned neck dissection, and salvage rates were poor. These data suggest that delaying the timing of PET-CT, with surgery reserved for positive findings, is a reasonable alternative to planned neck dissection to avoid unnecessary surgery.

Vascular "pseudo invasion" in laparoscopic hysterectomy specimens: a diagnostic pitfall.

Total laparoscopic hysterectomy has been shown to be an equally effective and safe technique when compared with conventional abdominal surgery for endometrial carcinoma. The procedure, as performed at our institution, involves the use of a uterine balloon manipulator (RUMI manipulator and Koh Colpotomizer system) for optimal surgical control. The fallopian tubes are cauterized to prevent transtubal spread of the tumor. The balloon manipulator thus creates a positive closed pressure system within the uterine cavity. After observing extensive displacement of tumor into small and large blood vessels in 1 case of grade 1, stage 1b endometrial carcinoma, we reviewed slides from 37 hysterectomy specimens (7 for endometrial carcinoma or atypical hyperplasia and 30 for benign conditions) performed laparoscopically between August 2004 and March 2006 at Emory University and Crawford Long Hospitals. We reviewed all slides for the presence or absence of endometrial tumor/tissue in vascular spaces. Patients with endometrial carcinoma/atypical complex hyperplasia included 6 FIGO grade I endometrioid carcinomas (3 stages 1A; 3 stages 1B) and 1 patient with atypical complex hyperplasia. Tumor within blood vessels was noted in 5 of 7 (71%) cases. In 3 cases, including the case of atypical complex hyperplasia, the number of vessels containing tumor were too numerous to count small and large caliber blood vessels. In the remainder, 1 case had 2 small vessels involved and in the other 7 small vessels showed tumor within vascular lumina. Benign endometrial glands and stromal tissue were noted within vascular spaces in 4 of 30 (13%) hysterectomy specimens removed for benign conditions. We describe a hitherto unreported artifact of vascular pseudo invasion in hysterectomy specimens obtained using the technique of total laparoscopic abdominal hysterectomy. We postulate that the creation of a closed pressure system generated as part of the operative technique is likely responsible for this phenomenon. Pathologists need to be aware of this artifact to avoid misinterpretation of vascular invasion in these cases with its associated therapeutic and prognostic implications.

Utility of positron emission tomography-computed tomography in identification of residual nodal disease after chemoradiation for advanced head and neck cancer.

OBJECTIVES: Planned neck dissection after chemoradiation (CR) is often advocated in patients with head and neck squamous cell cancer (HNSCC) with advanced nodal disease who demonstrate a clinical complete response to CR because identification of residual occult nodal disease is difficult. We sought to investigate the utility of positron emission tomography-computed tomography (PET-CT) in identifying patients with occult nodal disease after CR. STUDY DESIGN: Nonrandomized retrospective cohort analysis. MATERIALS AND METHODS: The medical records of all patients treated with primary CR for advanced HNSCC with N2 or N3 disease from December 2003 to June 2005 were reviewed. Patients with a clinical complete response were eligible for inclusion if PET-CT performed at 8 to 10 weeks after CR showed no evidence of distant disease and they were treated with a planned neck dissection. RESULTS: Seventeen patients met study criteria. PET-CT was positive for residual nodal disease in 11 (64.7%) patients, with a standardized uptake value (SUV) range of 1.7 to 3.8. Pathologic examination revealed residual viable carcinoma in five (29.4%) patients, with tumor size ranging from 2.0 to 9.5 mm. Carcinoma was present in 2 of 11 (18.2%) patients with positive PET-CT scans and 3 of 6 (50%) patients with negative PET-CT scans. The sensitivity and specificity of PET-CT in predicting occult nodal disease was 40% and 25%, respectively. There was no correlation between PET-CT findings and histologic findings (P = .26) or between SUV and size of viable tumor (P = .67). CONCLUSIONS: A significant proportion of HNSCC patients with advanced neck disease harbor residual occult metastases after CR. PET-CT is not sufficiently specific or sensitive to reliably predict the need for posttreatment neck dissection.

Down-regulation of BCRP/ABCG2 in colorectal and cervical cancer.

Expression of Breast Cancer Resistance Protein (BCRP/ABCG2) in tumor cells is associated with resistance to multiple chemotherapeutic agents. BCRP also protects against phototoxicity by mediating the efflux of protoporphyrins from cells. However, chemotherapy and photodynamic therapy are effective treatment options for cancer. Furthermore, protoporphyrins are essential, in the form of heme, for the synthesis of nitric oxide, over-production of which is associated with cancer. This raises the question as to whether the expression of this transporter is altered in cancer. To address this question, we investigated the expression of BCRP in colorectal cancer and cervical cancer. Paired normal and cancer tissues from colectomy specimens were used for the analysis of BCRP mRNA by RT-PCR and Northern blot. BCRP was analyzed by immunohistochemistry/immunofluorescence. Similar studies were also done with specimens of normal cervix and cancer cervix. A commercial dot blot was probed to quantify the expression of BCRP in paired normal and cancer cDNA samples from 154 patients with tumors in 19 different tissues. BCRP mRNA was present in normal colorectal tissue and showed a 6-fold decrease in cancer. BCRP was abundant in the normal colon and showed a decrease in colon cancer. The down-regulation of BCRP mRNA and protein was also evident in cervical cancer. There was also a decrease in BCRP mRNA in cancer in 12 of the 19 different tissues collected from 154 patients. These data show that cancer-associated down-regulation of BCRP is likely to be a common phenomenon in several tissues. Decreased expression of BCRP may have a role in tumorigenesis by allowing accumulation of genotoxins and over-production of nitric oxide.

Up-regulation of the amino acid transporter ATB(0,+) (SLC6A14) in carcinoma of the cervix.

OBJECTIVE: ATB(0,+) is an energy-coupled transporter for arginine and amino acid-based prodrugs. The objective of the study was to examine the expression of this transporter in cervical cancer. METHODS: Specimens of normal ectocervical mucosa and cervical squamous cell carcinoma were used for determination of ATB(0,+) mRNA levels by RT-PCR. A commercial dot blot of paired normal cervix and cervical cancer cDNA was also used to quantify ATB(0,+) mRNA. ATB(0,+) mRNA and protein in tissue sections were analyzed by in situ hybridization and immunohistochemistry/immunofluorescence. RESULTS: ATB(0,+) mRNA increased 5.6-fold (P < 0.0004) in cervical cancer compared to normal cervix. This was associated with a parallel increase in ATB(0,+) protein. CONCLUSIONS: Expression of ATB(0,+) is minimal in normal cervix and is up-regulated in cervical cancer. The up-regulation of this highly concentrative transporter for arginine and prodrugs in cervical cancer has significant clinical and therapeutic relevance.

Diabetic ketoacidosis increases extracellular levels of the major inducible 70-kDa heat shock protein.

OBJECTIVES: Diabetic ketoacidosis (DKA) represents a metabolic stress whose treatment induces a systemic proinflammatory cytokine profile and accentuates life-threatening acute complications. The present study determined whether serum levels of the major inducible 70-kDa heat shock protein (Hsp72), a modulator of cytokine expression, were influenced by DKA and its treatment. DESIGN AND METHODS: Serum levels of Hsp72 and glucose were measured in five adolescents with type 1 diabetes mellitus (T1DM) prior to, during and following correction of severe DKA. Samples from nine relatively euglycemic T1DM patients served as controls. RESULTS: DKA pre-treatment samples showed significant elevation in Hsp72 (40.8 +/- 6.9 ng/ml) relative to euglycemic T1DM controls (33.6 +/- 3.2 ng/ml) (P < 0.05). Treatment resulted in a decline in Hsp72 to control levels within 24 h, with Hsp72 and glucose levels being tightly correlated (r = 0.9258). CONCLUSION: Extracellular Hsp72 is increased by DKA, paralleling changes in serum glucose levels.

Upregulation of the amino acid transporter ATB0,+ (SLC6A14) in colorectal cancer and metastasis in humans.

ATB(0,+) (SLC6A14) is a Na(+)/Cl(-)-coupled arginine transporter expressed at low levels in normal colon. Arginine is an essential amino acid for tumor cells. Arginine is also the substrate for nitric oxide synthases (NOSs). Since arginine and arginine-derived nitric oxide (NO) play a critical role in cancer, we examined the expression of ATB(0,+) in colorectal cancer. Paired normal and cancer tissues from colectomy specimens of 10 patients with colorectal cancer and from the liver tissue of one patient with hepatic metastasis from a colonic primary were used for the analysis of the levels of ATB(0,+) mRNA, inducible NOS (iNOS) mRNA and the corresponding proteins. Tissues samples from the colon, liver, and lymph nodes of an additional patient with metastatic colon cancer were analyzed for ATB(0,+) protein alone. We also examined the levels of nitrotyrosylated proteins. The ATB(0,+) mRNA increased 22.9+/-3.0-fold in colorectal cancer compared to normal tissue and the increase was evident in each of the 10 cases examined. iNOS mRNA increased 5.2+/-1.1-fold in cancer specimens. The changes in mRNA levels were associated with an increase in ATB(0,+), iNOS, and nitrotyrosylated proteins. The increased expression of ATB(0,+) and iNOS was also demonstrated in liver and lymph node specimens with metastases from colonic primaries. This study strongly suggests that the upregulation of ATB(0,+) may have a pathogenic role in colorectal cancer. Since ATB(0,+) is a versatile transporter not only for arginine but also for several drugs including NOS inhibitors, these findings have significant clinical and therapeutic relevance.

The new mycobacterial species--emerging or newly distinguished pathogens.

Diseases due to nontuberculous mycobacteria are increasing in frequency, especially in patients with compromised immunity. A number of "new" mycobacterial species have been described in the last decade, largely as the result of the use of new tools to identify previously unrecognized mycobacteria found in the environment and in clinical specimens. This article reviews many of these potentially pathogenic organisms, summarizing what is known regarding their phenotypic and genotypic characterization, antimicrobial susceptibility, and clinical significance.