Recent Publications by CFE Educators

Radiation therapy occupies an important role in the treatment of gynecologic malignancies. Unfortunately, traditional approaches result in the irradiation of large volumes of normal tissues exposing patients to many toxicities and precluding dose escalation in select patients. A novel approach to the planning and delivery of radiation therapy, known as intensity-modulated radiation therapy (IMRT), has been introduced. Unlike conventional approaches, IMRT conforms the prescription dose to the shape of the target in three dimensions, thus sparing the surrounding normal tissues. Multiple studies have demonstrated the clear superiority of IMRT planning in these patients in terms of normal tissue sparing. Promising clinical results have also been published, suggesting that IMRT reduces the incidence of acute and chronic toxicity in these women. Ongoing studies are focusing on tumor control and patient outcome. Although further work is needed, these results suggest that IMRT may represent a major advancement in the planning and delivery of radiation therapy in patients with gynecologic malignancies.

Endomorphin-2 (EM2) is a tetrapeptide with remarkable affinity and selectivity for the mu-opioid receptor. In the present study, we used double-fluorescence and electron microscopic immunocytochemistry to identify subsets of EM2-expressing neurons in dorsal root ganglia and spinal cord dorsal horn of adult rats. Within the lumbar dorsal root ganglia, we found EM2 immunoreactivity mainly in small-to-medium size neurons, most of which co-expressed the neuropeptide substance P (SP). In adult rat L4 dorsal root ganglia, 23.9% of neuronal profiles contained EM2 immunoreactivity and ranged in size from 15 to 36 microM in diameter (mean 24.3 +/- 4.3 microM). Double-labelling experiments with cytochemical markers of dorsal root ganglia neurons showed that approximately 95% of EM2-immunoreactive cell bodies also label with SP antisera, 83% co-express vanilloid receptor subtype 1/capsaicin receptor, and 17% label with isolectin B4, a marker of non-peptide nociceptors. Importantly, EM2 immunostaining persisted in mice with a deletion of the preprotachykinin-A gene that encodes SP. In the lumbar spinal cord dorsal horn, EM2 expression was concentrated in presumptive primary afferent terminals in laminae I and outer II. At the ultrastructural level, electron microscopic double-labelling showed co-localization of EM2 and SP in dense core vesicles of lumbar superficial dorsal horn synaptic terminals. Finally, 2 weeks after sciatic nerve axotomy we observed a greater than 50% reduction in EM2 immunoreactivity in the superficial dorsal horn. We suggest that the very strong anatomical relationship between primary afferent nociceptors that express SP and EM2 underlies an EM2 regulation of SP release via mu-opioid autoreceptors.

The vanilloid receptor-like 1 protein (VRL-1, also called TRPV2) is a member of the TRPV family of proteins and is a homolog of the capsaicin/vanilloid receptor (VR1, or TRPV1). Although VRL-1 does not bind capsaicin, like VR1 it is activated by noxious heat (>52 degrees C). Unlike VR1, however, VRL-1 is primarily expressed by medium- and large-diameter primary afferents, which suggests that nociceptive processing is but one of the functions to which VRL-1 contributes. To provide information on the diverse spinal circuits that are engaged by these VRL-1-expressing primary afferents, we completed a detailed immunocytochemical map of VRL-1 in rat spinal cord, including light and electron microscopic analysis, and generated a more comprehensive neurochemical characterization of VRL-1-expressing primary afferents. Consistent with previous reports, we found that VRL-1 and VR1 are expressed in different dorsal root ganglion (DRG) cell bodies. Almost all VRL-1-expressing cells labeled for N52 (a marker of myelinated afferents), consistent with VRL-1 expression in Adelta and Abeta fibers. EM analysis of the DRG and dorsal roots confirmed this and revealed two categories of neurons based on the intensity of immunolabeling. The densest VRL-1 immunoreactivity in the spinal cord was found in lamina I, inner lamina II, and laminae III/IV. This is consistent with the expression of VRL-1 by myelinated nociceptors that target laminae I and IIi and in nonnociceptive Abeta fibers that target laminae III/IV. Dorsal rhizotomy reduced, but did not eliminate, the immunostaining in all dorsal horn laminae, which indicates that VRL-1 expression derives from both DRG cells and from neurons intrinsic to the brain or spinal cord. Spinal hemisection reduced immunostaining of the ipsilateral dorsal columns in segments rostral to the lesion and in the dorsal column nuclei, presumably from the loss of ascending Abeta afferents, but there was no change caudal to the lesion. Thus, supraspinal sources of dorsal horn VRL-1 immunoreactivity are likely not significant. Although we never observed VRL-1 immunostaining in cell bodies in the superficial dorsal horn, there was extensive labeling of motoneurons and ventral root efferents-in particular, in an extremely densely labeled population at the lumbosacral junction. Finally, many ependymal cells surrounding the central canal were intensely labeled. These results emphasize that VRL-1, in contrast to VR1, is present in a diverse population of neurons and undoubtedly contributes to numerous functions in addition to nociceptive processing.

BACKGROUND

Frontotemporal dementia (FTD) is a clinically heterogeneous condition that can be associated with clinical manifestations of an extrapyramidal disorder or motor neuron disease. A range of histologic patterns has been described in patients with FTD. The most common familial form of this condition is caused by mutations in the microtubule-associated protein tau gene (MAP tau) and is associated with neuronal or glial tau inclusions.

OBJECTIVES

To determine the clinical, anatomic, and pathological features of San Francisco family A and to map the mutation responsible for disease in this family.

DESIGN

A systematic clinical, neuropsychologic, neuroimaging, and chromosome segregation analysis of San Francisco family A was performed. A pathological and biochemical assessment of a family member was made.

SETTING

Family study.

PATIENTS

San Francisco family A, with FTD, variable extrapyramidal symptoms, and prominent motor neuron disease. Afflicted family members do not have a MAP tau coding or splice regulatory sequence mutation, and the MAP tau is genetically excluded.

MAIN OUTCOME MEASURES

Comparison of clinical, neuropsychologic, neuroimaging, and linkage findings of San Francisco family A with other familial forms of FTD and amyotrophic lateral sclerosis (ALS).

RESULTS

The most probable location for the mutation responsible for this condition is on chromosome arm 17q, distal to the MAP tau. All previously identified susceptibility loci for FTD and ALS are excluded. Autopsy findings from an afflicted family member show distinctive tau and alpha-synuclein inclusions. Another unique feature is that the insoluble tau protein consists predominantly of the 4R/0N isoform.

CONCLUSION

The condition affecting members of San Francisco family A is clinically, pathologically, and genetically distinct from previous familial forms of FTD and ALS.

As the number of cancer survivors in the United States continues to grow, clinicians must be aware of the possible therapy-related second primary malignancies to which their patients are susceptible. No guidelines have been established for the routine screening of cancer survivors for thoracic malignancies, such as lung cancer, esophageal cancer, and pleural mesothelioma. In general, clinicians should remain cognizant of the fact that previous radiation for a variety of malignancies may have increased their patient's risk for developing a therapy-induced second primary tumor within the thorax. Potential signs and symptoms of thoracic malignancies should be approached with heightened vigilance in any patient who has a history of radiation exposure, regardless of how remote.

BACKGROUND

Numerous studies have tested for associations between common variants of the angiotensin-converting enzyme gene (ACE) and late-onset Alzheimer disease (AD), but results have been inconclusive.

METHODS

Relevant studies were systematically identified, and data were abstracted according to predefined criteria.

RESULTS

The odds ratio (OR) for AD in individuals with the I allele of the ACE D/I polymorphism compared with those with the DD genotype was 1.27 (95% CI, 1.10 to 1.47; p 0.001). Heterogeneity between studies was significant (p 0.001) but not in strata defined by race and age (p > or = 0.10). The risk of AD associated with the I allele appeared to be higher among Asians (OR 2.44; 95% CI, 1.68 to 3.53) when compared with the risk among Caucasians (OR 1.18; 95% CI, 1.02 to 1.37) (p for comparison 0.001), and in younger cases (mean age 65 to 74 years) (OR 1.54; 95% CI, 1.23 to 1.93) when compared with the risk in older cases (OR 1.13; 95% CI, 0.95 to 1.35) (p for comparison = 0.03).

CONCLUSIONS

The I allele of the ACE D/I polymorphism is associated with an increased risk of late-onset AD. Further study of the pathogenetic characteristics of this allele and independent confirmation of the association in larger studies are warranted.

BACKGROUND

X-linked dominant hypophosphatemic rickets (XLHR) is a hereditary metabolic bone syndrome that is only beginning to be understood and is rarely associated with progression to irreversible tertiary hyperparathyroidism. We report our surgical experience with 6 patients with XLHR who underwent parathyroidectomy for associated autonomous parathyroid hyperfunction.

HYPOTHESIS

Parathyroidectomy can successfully treat tertiary hyperparathyroidism in the setting of XLHR, although an understanding of expected operative findings and postoperative complications is essential.

DESIGN

The study group comprised 6 patients with XLHR identified from our endocrine surgery database. Presentation, surgical procedure, parathyroid pathologic findings, and subsequent outcome are outlined.

RESULTS

There were 4 women and 2 men. All were exposed to long-term vitamin D and phosphate supplementation therapy. All had persistently elevated preoperative levels of parathyroid hormone and serum calcium. The patients were treated as follows: 3 had total parathyroidectomy, 2 had 3 parathyroid glands identified and resected, and 1 had 2 abnormal parathyroid glands resected with 2 normal-appearing parathyroid glands left in situ. One patient subsequently required completion parathyroidectomy for recurrent disease. Pathologic examination results revealed hyperplasia of all resected parathyroid glands in 4 of 6 patients. One patient had a single adenoma with 3-gland hyperplasia, and 1 patient had a double adenoma. The principal complication of this procedure was profound symptomatic hypocalcemia requiring intravenous calcium infusion. Hungry bone syndrome was also observed in most subjects. Long-term, all patients achieved normocalcemia.

CONCLUSION

Tertiary hyperparathyroidism is a rare but recognized complication of XLHR. Parathyroidectomy effectively treats this complication caused by autonomous parathyroid hyperfunction, but profound postoperative hypocalcemia necessitates careful management.