The PanSurg-PREDICT Study: Endocrine Surgery During the COVID-19 Pandemic.

BACKGROUND: In the midst of the COVID-19 pandemic, patients have continued to present with endocrine (surgical) pathology in an environment depleted of resources. This study investigated how the pandemic affected endocrine surgery practice. METHODS: PanSurg-PREDICT is an international, multicentre, prospective, observational cohort study of emergency and elective surgical patients in secondary/tertiary care during the pandemic. PREDICT-Endocrine collected endocrine-specific data alongside demographics, COVID-19 and outcome data from 11-3-2020 to 13-9-2020. RESULTS: A total of 380 endocrine surgery patients (19 centres, 12 countries) were analysed (224 thyroidectomies, 116 parathyroidectomies, 40 adrenalectomies). Ninety-seven percent were elective, and 63% needed surgery within 4 weeks. Eight percent were initially deferred but had surgery during the pandemic; less than 1% percent was deferred for more than 6 months. Decision-making was affected by capacity, COVID-19 status or the pandemic in 17%, 5% and 7% of cases. Indication was cancer/worrying lesion in 61% of thyroidectomies and 73% of adrenalectomies and calcium 2.80 mmol/l or greater in 50% of parathyroidectomies. COVID-19 status was unknown at presentation in 92% and remained unknown before surgery in 30%. Two-thirds were asked to self-isolate before surgery. There was one COVID-19-related ICU admission and no mortalities. Consultant-delivered care occurred in a majority (anaesthetist 96%, primary surgeon 76%). Post-operative vocal cord check was reported in only 14% of neck endocrine operations. Both of these observations are likely to reflect modification of practice due to the pandemic. CONCLUSION: The COVID-19 pandemic has affected endocrine surgical decision-making, case mix and personnel delivering care. Significant variation was seen in COVID-19 risk mitigation measures. COVID-19-related complications were uncommon. This analysis demonstrates the safety of endocrine surgery during this pandemic.

Surgery in reference centers improves survival of sarcoma patients: a nationwide study.

BACKGROUND: NETSARC (netsarc.org) is a network of 26 sarcoma reference centers with specialized multidisciplinary tumor boards (MDTB) aiming to improve the outcome of sarcoma patients. Since 2010, presentation to an MDTB and expert pathological review are mandatory for sarcoma patients nationwide. In the present work, the impact of surgery in a reference center on the survival of sarcoma patients investigated using this national NETSARC registry. PATIENTS AND METHODS: Patients' characteristics and follow-up are prospectively collected and data monitored. Descriptive, uni- and multivariate analysis of prognostic factors were conducted in the entire series (N = 35 784) and in the subgroup of incident patient population (N = 29 497). RESULTS: Among the 35 784 patients, 155 different histological subtypes were reported. 4310 (11.6%) patients were metastatic at diagnosis. Previous cancer, previous radiotherapy, neurofibromatosis type 1 (NF1), and Li-Fraumeni syndrome were reported in 12.5%, 3.6%, 0.7%, and 0.1% of patients respectively. Among the 29 497 incident patients, 25 851 (87.6%) patients had surgical removal of the sarcoma, including 9949 (33.7%) operated in a NETSARC center. Location, grade, age, size, depth, histotypes, gender, NF1, and surgery outside a NETSARC center all correlated to overall survival (OS), local relapse free survival (LRFS), and event-free survival (EFS) in the incident patient population. NF1 history was one of the strongest adverse prognostic factors for LRFS, EFS, and OS. Presentation to an MDTB was associated with an improved LRFS and EFS, but was an adverse prognostic factor for OS if surgery was not carried out in a reference center. In multivariate analysis, surgery in a NETSARC center was positively correlated with LRFS, EFS, and OS [P < 0.001 for all, with a hazard ratio of 0.681 (95% CI 0.618-0.749) for OS]. CONCLUSION: This nationwide registry of sarcoma patients shows that surgical treatment in a reference center reduces the risk of relapse and death.

Could machine learning improve the prediction of pelvic nodal status of prostate cancer patients? Preliminary results of a pilot study.

We tested and compared performances of Roach formula, Partin tables and of three Machine Learning (ML) based algorithms based on decision trees in identifying N+ prostate cancer (PC). 1,555 cN0 and 50 cN+ PC were analyzed. Results were also verified on an independent population of 204 operated cN0 patients, with a known pN status (187 pN0, 17 pN1 patients). ML performed better, also when tested on the surgical population, with accuracy, specificity, and sensitivity ranging between 48-86%, 35-91%, and 17-79%, respectively. ML potentially allows better prediction of the nodal status of PC, potentially allowing a better tailoring of pelvic irradiation.

Video-assisted thoracoscopic surgery for ectopic mediastinal parathyroid adenoma.

Background: Primary hyperparathyroidism (PHPT), caused by an ectopic mediastinal parathyroid adenoma, is uncommon. In the past, when the adenoma was not accessible from the neck, median sternotomy was advocated for safe and successful parathyroidectomy. Video-assisted thoracoscopic surgical (VATS) parathyroidectomy represents a modern alternative approach to this problem. Methods: Information on patients undergoing VATS was obtained from a specific database, including clinical presentation, biochemistry, preoperative imaging, surgical approach and patient outcomes. A comprehensive literature review was undertaken to draw comparisons with other publications. Results: Over a 2-year period, nine patients underwent VATS parathyroidectomy for sporadic PHPT. Five patients had persistent PHPT following previous unsuccessful parathyroidectomy via cervicotomy, and four had had no previous parathyroid surgery. The median duration of surgery was 90 (range 60-160) min. Eight patients were cured biochemically, with no major complications. One patient required conversion to a median sternotomy for removal of a thymoma that had resulted in false-positive preoperative imaging. Conclusion: With appropriate preoperative imaging, multidisciplinary input and expertise, VATS parathyroidectomy is an effective, safe and well tolerated approach to ectopic mediastinal parathyroid adenoma.

Antecedentes: El hiperparatiroidismo primario (primary hyperparathyroidism, pHPT) causado por un adenoma paratiroideo ectópico mediastínico es infrecuente. Hace años, cuando un adenoma no era accesible por vía cervical se propugnaba una esternotomía media para efectuar una paratiroidectomía segura y con éxito. La paratiroidectomía por cirugía toracoscópica asistida por video (video­assisted thoracoscopic surgical, VATS) es una alternativa moderna para el abordaje de esta patología. Métodos: La información de los pacientes tratados con VATS se obtuvo de una base de datos específica, incluyendo presentación clínica, bioquímica, radiología preoperatoria, abordaje quirúrgico y resultados de los pacientes. Se efectuó una revisión extensa de la literatura para efectuar comparaciones con otras publicaciones. Resultados: Durante un periodo de 2 años, 9 pacientes fueron tratados mediante paratiroidectomía por VATS debido a un pHPT esporádico, de los cuales 5 presentaban pHPT persistente después del fracaso de una paratiroidectomía por cervicotomía, mientras que los 4 restantes no habían sido operados previamente de cirugía paratiroidea. El tiempo medio operatorio fue de 101 minutos (rango 60­160). Ocho pacientes se curaron bioquímicamente, sin ninguna complicación mayor. Un paciente precisó conversión a una esternotomía media para extirpar un timoma que había sido un falso positivo en la radiología preoperatoria. Conclusión: La paratiroidectomía por VATS es una intervención efectiva, segura y bien tolerada para la extirpación de un adenoma ectópico mediastínico, siempre y cuando se disponga de radiología preoperatoria adecuada, equipo multidisciplinar y experiencia.

[Late outcome of 89 patients with soft-tissue sarcomas treated by surgery and three different radiotherapy schedules]. / Résultats à long terme d'une série de 89 patients suivis pour un sarcome des tissus mous traités par chirurgie conservatrice et trois modalités d'irradiation postopératoire.

PURPOSE: To evaluate the outcome of patients treated for soft tissue sarcoma using three different post-operative radiotherapy schedules. METHODS AND MATERIALS: Between 1990 and 2003, 89 patients (median age 50.8 years) presenting with soft tissue sarcoma (located to the limbs for 66 of them) underwent post-conservative-surgery radiotherapy. Pathology was liposarcoma in 35 cases and 54 others tumors. Tumors grades (FNCLCC classification) were 1, 2, 3 or unknown in 29, 32, 19 and 9 cases, respectively. Surgery was considered as complete in 68 patients. Irradiation was normofractionated (NF) in 62 cases, hyperfractionated (BF) in 19 cases and hypofractionated (HF) in 8 cases. For all the patients, median delivered dose was 61 Gy [34-76 Gy]. RESULTS: Median follow-up of alive patients was 73,8 months [3-184]. Five-year local control (LC) and overall survival (OS) rates were 85.5 and 71.2% respectively. According to multifactorial analysis, favourable prognostic factors were for local control, complete surgery (P=0.0075) and for overall survival, complete surgery (P=0.0267), grade 1 tumor (P=0.012) and absence of distant recurrence (P=0.0488). There was no statistical evidence of difference for the five-year LC and OS rates between the patients who received NF, BF or HF. There were few complications and there were comparable in the three groups. CONCLUSIONS: This retrospective serie showed similar results for all the schedules. There is no evidence to recommend bifractionation. Hypofractionation should be used only in selected patients with poor performans status.

Development of humanized mice for the study of hepatitis C virus infection.

The development of a small animal model for hepatitis C virus (HCV) infection is a critical issue for the development of novel anti-HCV drugs. To this aim, we have tried many different approaches for generating mice carrying humanized liver. Main efforts were focused on the transplantation of human hepatocytes into immunocompromised mice (SCID-/-, Bg-/-) carrying a genetic lethal liver disease (Alb-uPA). Survival of homozygotic animals should largely depend on early transplantation with healthy hepatocytes. In parallel to establishing a colony of Alb-uPA/SCID/Bg mice, we developed a microsurgical procedure for intrasplenic xenotransplantation of healthy hepatocytes in 1-week-old mice. So far, we generated several chimeras by xenotransplanting human hepatocytes in Alb-uPA+/+/SCID-/-/Bg-/- mice at 1 week after birth. In a first step, identification of successfully engrafted animals is possible by quantification of human serum albumin and human alpha 1 antitrypsin in mouse sera. Additional preliminary histomorphological analysis of liver sections from chimeric animals was also carried out. One of the mice was transiently infected with HCV, reaching viremia levels of approximately 10(5) genomes/mL. However, the efficiency of this system to generate chimeric mice is still very limited. We are currently exploring the use of more robust models of hepatic disease. Moreover, we have been also exploring novel strategies for the generation of chimeric mice by xenotransplanting human adult stem cells, instead of human hepatocytes, at preimmune stages of development.

A comparison of the effects of daunomycin and adriamycin on various DNA polymerases.

The effects of the anthracycline antiboties, daunomycin and adriamycin, on the DNA-directed activities of DNA polymerases from murine sarcoma virus, rat liver (high-molecular-weight species), Escherichia coli, and Micrococcus luteus were determined. Under all conditions tested, these compounds had greater inhibitory effect against the viral polymerase than against cellular polymerase. The inhibition of murine sarcoma virus DNA polymerase by daunomycin was competitive with respect to DNA. For viral DNA polymerase it was concluded that the inhibition was predominatly caused by the interaction of duanomycin with the primer-template DNA. Also, an appreciable reversal of the daunomycin-induced inhibition of this polymerase by an increase in Mg-2+ concentration is consistent with the conclusion derived by competition experiments. In contrast, the inhibition of both rat liver and M. luteus DNA polymerases was essentially noncompetitive with DNA. Also, bacterial enzymes wer e less sensitive to inhibition by these drugs than the virion polymerase. The strong and preferential inhibiton of viral DNA polymerase is discussed in relation to a differential sensitivity of normal as compared to tumor cells observed in some cell lines.

Relationship between activity and amino sugar stereochemistry of daunorubicin and adriamycin derivatives.

The effects of 4'-epi-daunorubicin, 4'-epi-adriamycin, and the corresponding beta anomers on the in vitro activity of Escherichia coli DNA polymerase I and RNA polymerase were determined and compared with the effects of the parent compounds. The observed effects parallel the cytotoxic activities, assayed by inhibition of mouse embryo fibroblast proliferation, and the inhibitory activities on DNA synthesis in cultured cells. The data indicate that the inverted configuration at position 1 of the amino sugar results in a markedly reduced biological activity. This conclusion is also substantiated by the data obtained with the beta anomer of adriamycin. A preliminary investigation on the binding properties of these derivatives suggests that the inverted configuration at C-1' produces a significant decrease in the binding to DNA. In contrast, epimerization at position 4' did not produce any significant change in activity. The relationship between biological and biochemical activity and DNA binding properties of the tested compounds are discussed with particularly reference to antitumor activity.

Relationship between effects on nucleic acid synthesis in cell cultures and cytotoxicity of 4-demethoxy derivatives of daunorubicin and adriamycin.

Four new derivatives of daunorubicin and two new derivatives of Adriamycin characterized by the absence of the methoxyl groups at the C-4 position have been studied in cell cultures in vitro to establish structure-activity relationships. 4-Demethoxydaunorubicin was 27 to 100 times more active than was daunorubicin when inhibiting the cloning efficiency of exponential-phase HeLa cells and, like daunorubicin, was slightly active on early plateau-phase cells. DNA synthesis in mouse embryo fibroblasts stimulated by fetal calf serum was inhibited equally by the two compounds, although 4-Demethoxydaunorubicin was slightly more active than was daunorubicin when inhibiting RNA synthesis. The beta anomer of 4-demethoxydaunorubicin showed a reduced activity on HeLa cells compared to its alpha anomer, but it was equally active on DNA synthesis. The stereoisomers of 4-demethoxydaunorubicin bearing the inverted configuration in positions 7 and 9 were devoid of significant cytotoxic activity and were only slightly active on DNA synthesis at the doses tested. 4-demethoxyadriamycin and 4-demethoxy-4'-epi-adriamycin were 65 to 500 times more active than was Adriamycin on HeLa cell cloning efficiency and about 10 times more active on DNA synthesis in mouse embryo fibroblasts. Cell uptake in mouse embryo fibroblasts was also investigated for all the new derivatives tested.

Villonodular synovitis of the ankle. Analysis of the risk of recurrence.

INTRODUCTION: Villonodular synovitis (VNS) is a rare disease with an incidence of 1.8 per 1,000,000 inhabitants. VNS of the ankle has seldom been described and evaluated given its extreme rarity (2.5% of VNS cases). It presents an 11% recurrence rate. We report a continuous retrospective series with the main objective of clinically and radiologically evaluating these ankles searching for any risk factors of recurrence. At revision the study's main endpoint was the existence of local recurrence (radiological and clinical) and the secondary endpoint was the existence of tibiotalar osteoarthritis. The working hypothesis was that recurrence could be subclinical, warranting systematic imaging studies during follow-up. MATERIAL AND METHODS: The study was retrospective, conducted on seven patients (six males) whose mean age was 42 years treated over a period of 9 years (two diffuse forms and five localized forms). The initial treatment consisted in synovectomy via the conventional approach. Four patients also received adjuvant isotopic synoviorthesis treatment. The revision was clinical (MMTS, AOFAS, and OMAS scores) and radiological (standard and MRI) to evaluate the joint after-effects and search for recurrence. RESULTS: Six patients were seen at a mean 6.5 years of follow-up. One case of early recurrence (4 years) was noted, with a major clinical manifestation because it was associated with joint destruction requiring arthrodesis, and one case of late asymptomatic recurrence (9 years), diagnosed radiologically on the follow-up MRI. The functional results remained good at follow-up (MMTS 77%, AOFAS 71, OMAS 71). Five of the six patients returned to their daily activities. At revision, no sign of osteoarthritis was observed. No risk factor for recurrence was demonstrated. DISCUSSION/CONCLUSION: The hypothesis was confirmed with the existence of asymptomatic recurrence at revision, underscoring the value of systematic MRI at follow-up. Other than major joint destruction, the prognosis remains good even in case of recurrence. The literature emphasizes the existence of an initial diffuse form and partial surgical resection as risk factors of recurrence. None of the reports in the literature has proven that adjuvant treatment, whose modalities do not meet with consensus, reduces this risk. LEVEL OF EVIDENCE: Retrospective series, level IV.

Blockade of endogenous neurotrophic factors prevents the androgenic rescue of rat spinal motoneurons.

Target-derived neurotrophic factors are assumed to regulate motoneuron cell death during development but remain unspecified. Motoneuron cell death in the spinal nucleus of the bulbocavernosus (SNB) of rats extends postnatally and is controlled by androgens. We exploited these features of the SNB system to identify endogenously produced trophic factors regulating motoneuron survival. Newborn female rat pups were treated with the androgen, testosterone propionate, or the oil vehicle alone. In addition, females received trophic factor antagonists delivered either into the perineum (the site of SNB target muscles) or systemically. Fusion molecules that bind and sequester the neurotrophins (trkA-IgG, trkB-IgG, and trkC-IgG) were used to block activation of neurotrophin receptors, and AADH-CNTF was used to antagonize signaling through the ciliary neurotrophic factor receptor-alpha (CNTFRalpha). An acute blockade of trkB, trkC, or CNTFRalpha prevented the androgenic sparing of SNB motoneurons when antagonists were delivered to the perineum. Trophic factor antagonists did not significantly reduce SNB motoneuron number when higher doses were injected systemically. These findings demonstrate a requirement for specific, endogenously produced trophic factors in the androgenic rescue of SNB motoneurons and further suggest that trophic factor interactions at the perineum play a crucial role in masculinization of this neural system.

The interaction of daunorubicin and doxorubicin with DNA and chromatin.

Isotherms that describe the binding of anthracycline antibiotics (including daunorubicin and doxorubicin (adriamycin)) to calf thymus DNA and chromatin have been obtained by means of fluorescence measurements. As expected for charged ligands, the association constants for the interaction of all drugs examined with DNA were found to be dependent on the ionic strength. However, in the case of the daunorubicin-DNA interaction, a marked decrease in the number of binding sites was also observed when the ionic strength was increased. It is suggested that the effect of salt concentration on the number of potential binding sites of daunorubicin molecules to DNA may be the result of some salt-induced alterations in the DNA conformation. This interpretation is also supported by binding data obtained with calf thymus chromatin; Whereas at low salt concentration the binding parameters for the doxorubicin-chromatin interaction are similar to those expected by neutralization of the phosphate groups by histones, modifications of the DNA structure in chromatin are invoked to account for the reduction and heterogeneity of daunorubicin binding sites. The side chain at C-9 could play an important role in determining the strength and specificity of the anthracycline-DNA interaction.

The interaction of adriamycin and its beta anomer with DNA.

The results of thermal denaturation, fluorescence, calorimetric and viscosimetric studies on the interaction of adriamycin and its beta anomer with DNA are reported. Whereas all equilibrium, hydrodynamic and thermodynamic measurements are consistent with the proposed intercalative binding model for the adriamycin-DNA complex, the binding mechanism for the reaction of the beta anomer with DNA remains uncertaian. All DNA binding properties of this stereoisomer are substantially different from those of the parent compound. The results suggest that the amino sugar residue of the natural antibiotic may interact stero-specifically with the DNA helix, thus dictating the orientation of the tetracvclic chromophore within the intercalation site. The alteration in the DNA binding capacity and the changes in interactions with DNA following in inversion of configuration at C-1', parallel a lack of biological activity observed for the beta anomer.

[Bilateral periventricular nodular heterotopia in a couple mother-infant]. / Etereotropia nodulare periventricolare biventricolare in una coppia madre-neonato.

Bilateral periventricular nodular heterotopia in a couple mother-infant. Bilateral periventricular nodular heterotopia (BPNH) is a malformation of neuronal migration, recently recognized X-linked. We report a case of BPNH associated with mega-cisterna magna diagnosed by ultrasound imaging at 27 weeks' gestation and confirmed by MR at 11 days of life. Similar findings in the mother's MR underlines the recurrency of this malformation in the same family.

Critical analysis of olecranon fracture management by pre-contoured locking plates.

BACKGROUND: Fractures of the proximal ulna are rare and usually managed surgically. Strong fixation of the harware is essential to obtain good outcomes. We report our experience with pre-contoured locking plate fixation of complex olecranon fractures and present a critical appraisal of the outcomes. HYPOTHESIS: Pre-contoured locking plates provide good outcomes, but their clinical tolerance may be limited in some instances. MATERIALS AND METHODS: From September 2009 to December 2011, 28 patients were managed using a pre-contoured locking compression plate (LCP(®)). Among them, 6 were excluded because of missing data, which left 22 patients (11 males and 11 females) with a mean age of 55.7 years, including 12 who were employed. The fracture was on the dominant side in 11 patients. According to the Mayo Clinic classification, 15 fractures were type II and 7 type III. In addition to the ulnar fracture, a radial head fracture was present in 9 patients and a coronoid process fracture in 5 patients. Functional recovery was assessed using the Broberg-Morrey score and Mayo Elbow Performance Score (MEPS). Radiographs were obtained to evaluate the quality of fracture reduction and fracture healing, as well as to look for ossifications and osteoarthritis. RESULTS: Mean follow-up was 20 months. Flexion was 131°, extension loss was 9.5°, pronation was 79°, and supination was 80.5°. The mean Broberg-Morrey score was 96.7 and the mean MEPS score 96.6. Fracture healing occurred in all patients, within a mean of 10.6 weeks. Evidence of early osteoarthritis was found in 6 patients, ossifications in 3 patients, and synostosis in 1 patient. An infection was successfully treated with lavage and antibiotic therapy in 1 patient. The fixation hardware was removed in 6 patients. No prognostic factors were identified. DISCUSSION-CONCLUSION: Our hypothesis was confirmed. The outcomes are encouraging and comparable to those reported in the literature. The critical issue is the limited clinical tolerance of the plate with a high rate of posterior impingement requiring plate removal (27%). Rigorous technique is essential during plate implantation. LEVEL OF EVIDENCE: Level IV, retrospective study.

A phase II study of 5-fluorouracil and high-dose folinic acid in combination with cyclophosphamide and mitoxantrone for advanced breast cancer.

38 patients with advanced breast adenocarcinoma were treated in a phase II study with 5-fluorouracil and high-dose folinic acid combined with cyclophosphamide and mitoxantrone. 6 patients had received prior chemotherapy for advanced disease, all with an anthracycline-containing regimen. Treatment was generally well tolerated. The most common side-effect was myelosuppression, with 1 toxic death due to leukopenia-related sepsis. 1 patient developed severe congestive heart failure 12 months from the end of therapy. 36 patients were evaluable for response. The overall response rate was 55%. Median duration of response was 8 months and median survival time was 16 months. This regimen warrants further investigations.

Ten-year results of treatment of ductal carcinoma in situ (DCIS) of the breast with conservative surgery and radiotherapy.

The optimal treatment of ductal carcinoma in situ (DCIS) of the breast has not yet been established. The effectiveness of adjuvant postoperative radiotherapy after conservative surgery is debated. Few data are available in Italy on the combined treatment. A collaborative multi-institutional study on this issue in 10 radiation oncology departments of the north-east of Italy was conducted. One hundred and thirty nine women with DCIS of the breast were treated between 1980 and 1990. Age ranged between 28 and 88 years (median 50 years). Surgical procedures were: quadrantectomy in 108, lumpectomy in 22 and wide excision in 9 cases. The axilla was surgically staged in 97 cases: all the patients were node-negative. Radiation therapy was delivered with 60Co units (78%) or 6 MV linear accelerators (22%) for a median total dose to the entire breast of 50 Gy (mean 49.48 Gy; range 45-60 Gy). The tumour bed was boosted in 109 cases (78%) at a dose of 4-30 Gy (median 10 Gy) for a minimum tumour dose of 58 Gy. Median follow-up was 81 months. Thirteen local recurrences were recorded, 7 intraductal and 6 invasive. All recurrent patients had a salvage mastectomy and are alive and free of disease. Actuarial overall, cause-specific and recurrence-free survival at 10 years are of 93%, 100% and 86%, respectively. The results of this retrospective multicentric study substantiate the favourable data reported in the literature and confirm the efficacy of the breast-conserving treatment of DCIS employing conservative surgery and adjuvant radiation therapy.

In vivo localization and characterization of functional ciliary neurotrophic factor receptors which utilize JAK-STAT signaling.

The ciliary neurotrophic factor receptor is critically involved in embryonic motor neuron development. Postnatally, it may contribute to neuronal maintenance and regeneration. In addition, pharmacological stimulation of the receptor may slow the progression of several neurodegenerative disorders. The widespread nervous system expression of ciliary neurotrophic factor receptor components and the effects of low ciliary neurotrophic factor concentrations on a wide variety of cells in culture combine to suggest that functional ciliary neurotrophic factor receptors are expressed by many classes of neurons in vivo. However, the in vivo signaling properties and distribution of functional ciliary neurotrophic factor receptors have not been directly determined. We developed a novel in vivo assay of functional ciliary neurotrophic factor receptors which revealed that, in the adult nervous system, cranial and spinal motor neurons are very sensitive to ciliary neurotrophic factor and display a rapid, robust increase in phospho-STAT3 in their dendrites, cell bodies and nuclei, which is specifically blocked by the ciliary neurotrophic factor receptor antagonist, AADH-CNTF. In distinct contrast, several other classes of ciliary neurotrophic factor receptor expressing neurons fail to increase phospho-STAT3 levels following ciliary neurotrophic factor treatment, even when ciliary neurotrophic factor is applied at high concentrations. Leukemia inhibitory factor and epidermal growth factor elicit the same cell-type-dependent pattern of phospho-STAT3 increases. Responsive and non-responsive neurons express comparable levels of STAT3.Therefore, in vivo ciliary neurotrophic factor receptor-initiated STAT3 signal transduction is regulated in a very cell-type-dependent manner. The present data suggest that at least some of this regulation occurs at the STAT3 tyrosine phosphorylation step. These unexpected results also suggest that other forms of receptor-initiated STAT3 signal transduction may be similarly regulated.