Notalgia paresthetica associated with cervical spinal stenosis and cervicothoracic disk disease at C4 through C7.

Notalgia paresthetica (NP) is a common refractory, sensory, neuropathic syndrome with the hallmark symptom of localized pruritus of the unilateral infrascapular back. It generally is a chronic noncurable condition with periodic remissions and exacerbations. While the dermatologic syndrome may be multifactorial in etiology, a possible association with underlying cervical spine disease should be evaluated for proper treatment. Collaborative multispecialty evaluation by dermatology, radiology, orthopedic surgery, and neurology may be indicated for primary management of this condition. First-line therapy for NP with associated cervical disease may include nondermatologic noninvasive treatments such as spinal manipulation, physical therapy, massage, cervical traction, cervical muscle strengthening, and oral nonsteroidal anti-inflammatory drugs and muscle relaxants. Notalgia paresthetica may in fact be a cutaneous sign of an underlying degenerative cervical spine disease. We report a case of a patient with cervical spinal stenosis that corresponded directly with the clinical findings of NP.

Macrophage colony stimulating factor: not just for macrophages anymore! A gateway into complex biologies.

Macrophage colony stimulating factor (M-CSF, also called colony stimulating factor-1) has traditionally been viewed as a growth/differentiation factor for monocytes, macrophages, and some female-specific tumors. As a result of alternative mRNA splicing and post-translational processing, several forms of M-CSF protein are produced: a secreted glycoprotein, a longer secreted form containing proteoglycan, and a short membrane-bound isoform. These different forms of M-CSF all initiate cell signaling in cells bearing the M-CSF receptor, called c-fms. Here we review the biology of M-CSF, which has important roles in bone physiology, the intestinal tract, cancer metastases to the bone, macrophage-mediated tumor cell killing and tumor immunity. Although this review concentrates mostly on the membrane form of human M-CSF (mM-CSF), the biology of the soluble forms and the M-CSF receptor will also be discussed for comparative purposes. The mechanisms of the biological effects of the membrane-bound M-CSF reveal that this cytokine is unexpectedly involved in many complex molecular events. Recent experiments suggest that a tumor vaccine based on membrane-bound M-CSF-transduced tumor cells, combined with anti-angiogenic therapy, should be evaluated further for use in clinical trials.

Confluent and reticulate papillomatosis.

A 24-year-old man had an asymptomatic rash on his chest and arms for one year. On his chest, there were brown confluent plaques in a reticulate pattern. A scraping for fungus was negative. A biopsy showed papillomatosis, orthokeratosis, and melanin pigment at the basal layer of the epidermis. The patient was started on a six-week course of minocycline twice/day. Six weeks later, the patient was completely clear of the rash. Confluent and reticulate papillomatosis is an uncommon dermatosis that tends to occur on the chest. The pathogenesis is unknown. Minocycline has been reported to work well in the treatment of this dermatosis.

Unraveling the paradoxes of HIV-associated psoriasis: a review of T-cell subsets and cytokine profiles.

HIV-associated psoriasis appears paradoxical, being a T-cell mediated disease in the face of decreasing T-cell counts. Furthermore, psoriasis is generally mediated by type-1 cytokines, whereas in HIV, type-2 cytokines tend to predominate. How can one have psoriasis in the essentially Th2 environment of HIV? The details and pertinent research regarding T cell subsets and cytokine profiles in psoriasis, HIV, and HIV-associated psoriasis were reviewed. It appears that both in the presence and absence of HIV infection, psoriasis is largely mediated by memory CD8 T cells, and that IFN-gamma secreted by these cells and others is of key importance. Studying psoriasis in a model such as HIV in which certain elements of the immune system are stripped away or altered may help us better understand the pathogenic mechanisms and potential treatment targets for psoriasis vulgaris.

Antiangiogenic drugs synergize with a membrane macrophage colony-stimulating factor-based tumor vaccine to therapeutically treat rats with an established malignant intracranial glioma.

Combining a T9/9L glioma vaccine, expressing the membrane form of M-CSF, with a systemic antiangiogenic drug-based therapy theoretically targeted toward growth factor receptors within the tumor's vasculature successfully treated >90% of the rats bearing 7-day-old intracranial T9/9L gliomas. The antiangiogenic drugs included (Z)-3-[4-(dimethylamino)benzylidenyl]indolin-2-one (a platelet-derived growth factor receptor beta and a fibroblast growth factor receptor 1 kinase inhibitor) and oxindole (a vascular endothelial growth factor receptor 2 kinase inhibitor). A total of 20-40% of the animals treated with the antiangiogenic drugs alone survived, while all nontreated controls and tumor vaccine-treated rats died within 40 days. In vitro, these drugs inhibited endothelial cells from proliferating in response to the angiogenic factors produced by T9/9L glioma cells and prevented endothelial cell tubulogenesis. FITC-labeled tomato lectin staining demonstrated fewer and constricted blood vessels within the intracranial tumor after drug therapy. Magnetic resonance imaging demonstrated that the intracranial T9 glioma grew much slower in the presence of these antiangiogenic drugs. These drugs did not affect in vitro glioma cell growth nor T cell mitogenesis. Histological analysis revealed that the tumor destruction occurred at the margins of the tumor, where there was a heavy lymphocytic infiltrate. Real-time PCR showed more IL-2-specific mRNA was present within the gliomas in the vaccinated rats treated with the drugs. Animals that rejected the established T9/9L glioma by the combination therapy proved immune against an intracranial rechallenge by T9/9L glioma, but showed no resistance to an unrelated MADB106 breast cancer.

Photodynamic therapy with aminolevulinic acid topical solution and visible blue light in the treatment of multiple actinic keratoses of the face and scalp: investigator-blinded, phase 3, multicenter trials.

OBJECTIVE: To determine the safety and efficacy of photodynamic therapy (PDT) using 20% wt/vol aminolevulinic acid hydrochloride (hereinafter "ALA") and visible blue light for the treatment of multiple actinic keratoses of the face and scalp. DESIGN: Randomized, placebo-controlled, uneven parallel-group study. INTERVENTIONS: Patients (N = 243) were randomized to receive vehicle or ALA followed within 14 to 18 hours by PDT. Follow-up visits occurred 24 hours and 1, 4, 8, and 12 weeks following PDT. Target lesions remaining at week 8 were re-treated. MAIN OUTCOME MEASURE: Clinical response based on lesion clearing by week 8. RESULTS: Most patients in both groups had 4 to 7 lesions. Complete response rates for patients with 75% or more of the treated lesions clearing at weeks 8 and 12 were 77% (128/166) and 89% (133/149), respectively, for the drug group and 18% (10/55) and 13% (7/52), respectively, for the vehicle group (P<.001, Cochran-Mantel-Haenszel general association test). The 95% confidence interval for the difference in response rates at week 8 was 46.9% to 71.0% and at week 12, 65.3% to 86.3%. The week 12 response rate includes 30% of patients who received a second treatment. Most patients experienced erythema and edema at the treated sites, which resolved or improved within 1 to 4 weeks after therapy, and stinging or burning during light treatment, which decreased or resolved by 24 hours after light treatment. CONCLUSION: Findings indicate that topical ALA PDT is an effective and safe treatment for multiple actinic keratoses of the face and scalp.

Intra-arterial administration of TNF-alpha followed by arterial ablation is an effective therapy for a regionally confined TNF-resistant rat mammary adenocarcinoma.

Tumor necrosis factor-alpha (TNF-alpha) is an immunomodulatory cytokine that has exhibited anti-tumor activity in a variety of experimental systems. However, the toxicities associated with systemic administration of TNF-alpha have limited its clinical utility and have led to the investigation of targeted delivery techniques with the ability to present the TNF-alpha dose directly to the vascular bed of the tumor. The intra-arterial (IA) administration of TNF-alpha to patients with liver metastases represents one such approach, and recent work suggests that subsequent ablation of the tumor's arterial supply via embolization may enhance the efficacy of intra-arterial treatments (hepatic chemoembolization). The present study was undertaken to test the hypothesis that IA administration of TNF-alpha is superior to the intravenous (IV) route for inhibition of tumor growth in a regionally confined rat mammary adenocarcinoma model that provides for ablation of the arterial supply to the tumor following cytokine therapy. Rats bearing hind limb mammary adenocarcinomas received single IA or IV infusions of 8 x 10(5), 1 x 10(6), and 1.5 x 10(6) units of TNF-alpha via the common femoral artery (CFA) followed 1 h later by ligation of the artery. Control animals received either no treatment or IA infusion of 2% normal rat serum (NRS) followed by ipsilateral CFA ligation. Tumor size was measured every other day after treatment. Tumor growth inhibition occurred in the first 5 to 10 days after treatment. IV administration of TNF-alpha did not result in visual tumor necrosis or significant reduction in the rate of tumor growth. IA administration of TNF-alpha resulted in statistically significant diminution of tumor size as compared to untreated controls and animals receiving IA 2% normal rat serum (NRS; P<0.05 at days 6, 8 and 10), regardless of the dose employed. The maximum growth inhibition with IA TNF-alpha was a 91% reduction in tumor volume that was achieved with a dose of 1 x 10(6) U TNF-alpha. These results demonstrate improved anti-tumor activity with the IA administration of TNF-alpha over the IV route in a regionally confined mammary adenocarcinoma. IA administration of biologic response modifiers like TNF-alpha may therefore be a useful approach for the hepatic chemoembolization of breast adenocarcinomas metastatic to the liver.

Living T9 glioma cells expressing membrane macrophage colony-stimulating factor produce immediate tumor destruction by polymorphonuclear leukocytes and macrophages via a "paraptosis"-induced pathway that promotes systemic immunity against intracranial T9 gliomas.

Cloned T9-C2 glioma cells transfected with membrane macrophage colony-stimulating factor (mM-CSF) never formed subcutaneous tumors when implanted into Fischer rats, whereas control T9 cells did. The T9-C2 cells were completely killed within 1 day through a mechanism that resembled paraptosis. Vacuolization of the T9-C2 cell's mitochondria and endoplasmic reticulum started within 4 hours after implantation. By 24 hours, the dead tumor cells were swollen and terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL)-positive. Bcl2-transduced T9-C2 cells failed to form tumors in rats. Both T9 and T9-C2 cells produced cytokine-induced neutrophil chemoattractant that recruited the granulocytes into the tumor injection sites, where they interacted with the tumor cells. Freshly isolated macrophages killed the T9-C2 cells in vitro by a mechanism independent of phagocytosis. Nude athymic rats treated with antiasialo GM1 antibody formed T9-C2 tumors, whereas rats treated with a natural killer cell (NK)-specific antibody failed to form tumors. When treated with antipolymorphonuclear leukocyte (anti-PMN) and antimacrophage antibodies, 80% of nude rats formed tumors, whereas only 40% of the rats developed a tumor when a single antibody was used. This suggests that both PMNs and macrophages are involved in the killing of T9-C2 tumor cells. Immunocompetent rats that rejected the living T9-C2 cells were immune to the intracranial rechallenge with T9 cells. No vaccinating effect occurred if the T9-C2 cells were freeze-thawed, x-irradiated, or treated with mitomycin-C prior to injection. Optimal tumor immunization using mM-CSF-transduced T9 cells requires viable tumor cells. In this study optimal tumor immunization occurred when a strong inflammatory response at the injection of the tumor cells was induced.

T9 glioma cells expressing membrane-macrophage colony stimulating factor produce CD4+ T cell-associated protective immunity against T9 intracranial gliomas and systemic immunity against different syngeneic gliomas.

Cloned T9 glioma cells (T9-C2) expressing the membrane form of macrophage colony stimulating factor (mM-CSF) inoculated subcutaneously into rats do not grow and glioma-specific immunity is stimulated. Immunotherapy experiments showed that intracranial T9 tumors present for one to four days could be successfully eradicated by peripheral vaccination with T9-C2 cells. CD4+ and CD8+ T splenocytes from immunized rats, when restimulated in vitro with T9 cells, produced interleukin-2 and -4. Protective immunity against intracranial T9 gliomas could only be adoptively transferred into naive rats by the CD4+ splenocytes obtained from T9-C2 immunized rats. Rats immunized by the T9-C2 tumor cells also resisted two different syngeneic gliomas (RT2 and F98) but allowed a syngeneic NUTU-19 ovarian cancer to grow. Such cross-protective immunity against unrelated gliomas suggests that mM-CSF transfected tumor cells have immunotherapeutic potential for use as an allogeneic tumor vaccine.